Guideline: Management and treatment of MDR-TB

Contents:
1. Introduction
2. Drug resistance
2.1 Definitions of drug resistance
2.2 Treatment outcomes
2.3 Causes of DR-TB
2.4 Interventions to prevent drug-resistant TB
2.5 Diagnosing MDR-TB
2.6 Diagnosing XDR-TB
2.7 Drug-resistant TB case finding in HIV-infected patients
2.8 Case finding for drug-resistant TB
3. Treatment strategies for MDR-TB and XDR-TB
3.1 Regimen of DR-TB treatment
3.2 Regimen for isoniazid-resistant tuberculosis
3.3 MDR-TB regimen
3.3.1 Choice of a MDR-TB regimen
3.3.1.1 Shorter MDR-TB regimen
3.3.1.2 Longer MDR-TB regimens
3.3.2 Duration of longer MDR-TB treatment regimens
3.3.3 Procedure following missed treatment
3.4 XDR-TB regimen
3.5 Surgical interventions in patients with MDR-TB
3.6 TB of the central nervous system treatment
3.7 Adjuvant therapies in drug-resistant TB treatment
3.8 Palliative care
4. Treatment of drug-resistant TB in special conditions and situations
4.1 Pregnancy
4.2 Breastfeeding
4.3 Contraception
4.4 Children
4.5 Diabetes mellitus
4.6 Renal insufficiency
4.7 Drug-resistant TB and HIV co-treatment
5 Monitoring and evaluation of patients treated in MDR-TB regimen
5.1 Pretreatment screening and evaluation
5.2 Monitoring progress of treatment
5.3 Examinations at baseline and during treatment
5.4 Monitoring and management of adverse events
5.5 Safety reporting
5.6 Data management and project monitoring
6 Patient consent
7 Inpatient and ambulatory treatment
7.1 Organization of the Health System in Albania
7.1.1 Primary health care
7.1.2 Secondary health care
7.1.3 Tertiary health care
7.2 Tuberculosis control in Albania
7.2.1 Lung dispensaries
7.2.2 Family doctors
7.3 Models of MDR-TB care (hospitalization/ambulatory)
8 Notes about new TB drugs
8.1 Duration of bedaquiline and delamanid
8.2 Drug-drug interactions
8.3 Overlapping toxicities
9 Literature
Annex 1 Target groups for DST
Annex 2 General considerations of anti-tuberculosis medicines
Annex 3 Summary of known cross-resistance between anti-TB drugs
Annex 4 Adjustment of anti-TB drugs in renal insufficiency
Annex 5 Activities for monitoring treatment response
Annex 6 Baseline and routine monitoring for patients on MDR-TB regimens
Annex 7 Adverse effects, suspected agent(s) and management strategiesa
Annex 8 Commonly used ancillary medications
Annex 9 Potential overlapping and additive toxicities of ART and anti-TB treatment
Annex 10 Baseline and routine monitoring for patients on MDR-TB regimens
Annex 11. Adverse events of clinical significance or special interest for aDSM
Annex12 Clinical and laboratory testing schedule for active tuberculosis drug-safety monitoring and
management (aDSM)

Figure 1 Detection of MDR-TB for suspected of MDR-TB including MDR-TB contacts, failure and
relapses of retraitment and retraitment after after defaulters and HIV suspected for TB
Figure 2 Algorithm for interpretation of results from molecular methods
Table 1 Definitions of treatment outcomes for drug-resistant patients
Table 2 Grouping of medicines recommended for use in longer MDR-TB regimens
Table 3 Dosing of medicines for adults
Table 4 Dosing for children and adults < 30 kg (30)
Table 5 Contraindications for new and repurposed drugs
Table 6 Possible drug-drug interactions with the new TB drugs
Table 7 Possible drug-drug interactions between antiretrovirals and the new TB drugs
Table 8 Non-TB drugs that have potential overlapping toxicities with the new TB drugs
Table 9 Treatment of extrapulmonary TB with new and repurposed drugs
Table 10 New TB Drugs in special populations
Annex 11. Adverse events of clinical significance or special interest for aDSM
Abbreviations
ADR ........................................................................................Adverse drug reaction
aDSM .............................................Active drug-safety monitoring and management
AE………………………………………………………………….. Adverse Events
AFB…………………………………………………Acid-Fast Bacilli (Bacilli Koch)
AIDS..............................................................Acquired Immunodeficiency Syndrome
AIDS..............................................................Acquired Immunodeficiency Syndrome
ALT ......................................................................................Alanine aminotransferase
ART........................................................................................... Antiretroviral therapy
AST ...................................................................................Aspartate aminotransferase
CNS .........................................................................................Central nervous system
CPT ........................................................................Cotrimoxazole preventive therapy
CYP3A4 ..................................................................................Cytochrome P450 3A4
DOT...................................................................................Directly Observed Therapy
DOTS ...............................................................Core approach underpinning the Stop
DOTS.............................................Directly Observed Therapy Short Course Strategy
DRS .................................................................................Drug resistance surveillance
DR-TB................................................................................................... Resistance TB
DST........................................................................................Drug Sensibility Testing
ECDC……………………… European Centre for Disease Prevention and Control
FDC............................................................................... Fixed dose drug combination
FQ ......................................................................................................Fluoroquinolone
FT4 ........................................................................................................Free thyroxine
GDF ............................................................................................Global Drug Facility
GFR .....................................................................................Glomerular filtration rate
HII…………………………………………………...…… Health Insurance Institute
HIV.............................................................Human immunodeficiency virus infection
Hr-TB........................................................................................ Isoniazid-resistant TB
IPH…………………………………………………………Institute of Public Health
LPA……………………………………………………………….. Line-Probe Assay
M/XDR-TB ....................................................Multi- or extensively drug-resistant TB
MDR………………………………………………………… Multi-Drug Resistance
MDR-TB..............................................................................Multi-Drug Resistance TB
MoH..................................................................................................Ministry of Health
NRLTB…………………………… National Reference Laboratory for Tuberculosis
NRTI ...........................................................Nucleoside reverse transcriptase inhibitor
NTM...............................................................................Nontuberculous Mycobacteria 
NTP.............................................................National Tuberculosis Control Programme
PHC.....................................................................Prevention and Control of HIV/AIDS
PLHIV............................................................................People Living with HIV/AIDS
PMDT.................................... Programmatic management of drug-resistant TB
RR-TB.................................................................................. Rifampicin Resistance TB
SAE......................................................................................... Serious Adverse Events
SGOT ...............................................Serum glutamic-oxaloacetic transaminase
SGPT................................................................. Serum glutamic-pyruvic transaminase
TB ………………………………………………………………………..Tuberculosis
TSH.................................................................................Thyroid Stimulating Hormone
WHO……………………………………………………....World Health Organization
XDR-TB................................................................................. Extensive drug resistance
γGT ........................................................................Gamma glutamyl transferase
Abbreviations of anti-tuberculosis drugs
H....................................................................................Isoniazid
R....................................................................................Rifampicin
S....................................................................................Streptomycin
Lfx.................................................................................Levofloxacin
Mfx................................................................................Moxifloxacin
Bdq................................................................................Bedaquiline
Lzd.................................................................................Linezolid
Cfz.................................................................................Clofazimine
Cs...................................................................................Cycloserine
Trd.................................................................................Terizidone
E.....................................................................................Ethambutol
Dlm................................................................................Delamanid
Z.....................................................................................Pyrazinamide
Ipm-Cln..........................................................................Imipenem-cilastin
Mpm...............................................................................Meropenem
Am .................................................................................Amikacin
S......................................................................................Streptomycin
Pto...................................................................................Prothioamide
Eto...................................................................................Ethionamide
PAS.................................................................................p-aminosalicylic acid

1. Introduction

The World Health Organization (WHO) and the European Centre for Disease Prevention and
Control (ECDC) consider Albania as a country having a sufficiently good National TB Control
Programme and which has been successful in the fight against TB. The stabilized epidemiologic
situation in Albania is reflected in a low bacterial resistance and especially the multi-drug
resistance (MDR): < 2% at national level. There are good treatment results, with approximately
90% successful treatments. (1)

In Albania (2016) the MDR/RR-TB estimates incidence is 0.42 (0.05-0.78) per 100 000 population,
among notified pulmonary TB cases – 7 (1-14). Estimated % of TB cases with MDR/RR-TB among
new cases - 2.3% (0.64–5.8), and previously treated cases - 6.7% (0.17–32). Percentage of notified
tested for rifampicin resistance: new cases – 9%, previously treated cases - 20%, total number 40
(Includes patients diagnosed before 2016 and patients who were not laboratory-confirmed). One
MDR/RR-TB patient started on treatment. (2)

The two reasons why multidrug resistance continues to emerge and spread are mismanagement
of TB treatment and person-to-person transmission. Inappropriate or incorrect use of
antimicrobial drugs, or use of ineffective formulations of drugs (such as use of single drugs, poor
quality medicines or bad storage conditions), and premature treatment interruption can cause
drug resistance, which can then be transmitted, especially in crowded settings such as prisons
and hospitals.

Antimicrobial resistance has become a topical health and security concern for countries worldwide
[3]. Global efforts to end tuberculosis will continue to face a major challenge with the widespread
dissemination of TB resistant strains (4, 5, 6).
While most of the susceptible TB patients who can expect a relapse-free treatment with a 6-month
course of first-line medication (7), patients with multidrug-resistant TB (MDR-TB), require
treatment regimens which are longer, less effective and less accessible than first-line regimens, as
well more costly, toxic and complicated to deliver (8), presenting challenge to health service
providers to ensure patient adherence and cure rates.

The World Health Organization (WHO) estimates that 3.9% of previously untreated and 21% of
previously treated TB cases occurring worldwide in 2015 had MDR/RR-TB (9). Only 20% of these
cases have access to adequate testing and treatment. (9) Treatment outcomes are poorer than those
achieved in drug-susceptible TB, with treatment success rates of 52% globally. (9)
Each year about 580 000 (range 520 000–640 000) new MDR/RR-TB cases emerge among new and
retreated TB patients, and cause about 250 000 (range 160 000–340 000) deaths. Globally, 51% of
MDR-TB patients have strains with additional resistance to fluoroquinolones or second-line
injectable agents, critical agents of any second-line MDR-TB treatment regimen, while 9.5% are
resistant to both of these classes of medicines - extensively drug-resistant TB (XDR-TB) (9).
Resistance to tuberculosis drugs is obstacle to effective TB care and prevention globally. Multidrug-
resistant TB (MDR-TB) is multifactorial and fuelled by improper treatment of patients, poor
management of supply and quality of drugs, and airborne transmission of bacteria in public places.
Case management becomes difficult. (10)

The programmatic management of drug-resistant TB requires good practices in many aspects of

care, including using approved diagnostics to confirm drug resistance, using quality assured
medicines, complying with WHO’s recommended doses, supporting patients to improve adherence
to treatment, and monitoring patients’ response and adverse events. Regular microscopy and culture
of sputum or other specimens remains important to ensure that treatment failure is detected early.
(11)

The introduction of new diagnostic and treatment tools for the management of drug-resistant
TB is making a significant contribution to enable earlier diagnosis of multidrug-resistant TB
(MDR-TB), and more effective treatment in cases were therapeutic options are very limited.
(10)

The identification and effective treatment of all individuals with active TB is the cornerstone of TB
prevention, control, and eventual elimination. MDR-TB treatment is more complex and expensive.
Regimens are not only less effective than treatment regimens for drug-susceptible TB, but are also
more toxic (leading to grave potential side effects) and of longer duration. Many patients find it
difficult to adhere to treatment that causes such severe physical side effects. Drug resistance is most
likely to occur when patients do not complete a full course of treatment, or when an incorrect
regimen is prescribed or miscalculated the length of therapy. It may also occur when drugs are of
poor quality or not consistently available. (12)

For MDR-TB patients, psychosocial support is important because, besides the stressful role of some
of the factors favoring the disease, it also affects the quality of life because of the long-term impact
of the disease and the adverse drug reactions produced by its treatment. Social support contribute to
improving the quality of life, to enable the patient to access health care and adherence to treatment.
Ahead of enrolment on MDR-TB treatment, all patients should receive appropriate counselling to
enable informed and participatory decision-making. Patient information material needs to reflect the
new changes so that patients are appropriately informed about their treatment options. Furthermore,
active TB drug safety monitoring and management (aDSM) is essential for all patients enrolled on
MDR-TB treatment. (10, 20)
It is imperative to stress that the DOTS strategy remain the cornerstone of TB control and the most
effective tool for preventing the onset and dissemination of drug resistance. Without the essential
elements of TB control fully in place, management of MDR-TB will undoubtedly fail in the long
term, as one cannot control it if the tap is not turned off. (13)

Management of MDR-TB imposes a tremendous challenge to National TB Programmes. In the

programmatic management of TB it is a priority to prevent the generation and amplification of drug
resistance. (14) If drug-resistant TB (DR-TB, referring to any drug resistance) is present or develops
during treatment, it is essential to apply an appropriate DR-TB regimen. (15)

The prevention of initial MDR-TB and appropriate management of existing cases is key to the
effective control of the spread of TB. High-quality care and control practices with high rates of case
detection and cure, DST for all patients and the provision of appropriate treatment for all DR-TB
patients are crucial for TB control. (17)

In 2014, the World Health Organization (WHO) and European Respiratory Society published a
framework for the elimination of tuberculosis (TB) in low incidence countries, describing the
priority actions to achieve this goal. These include: investment on new tools for early diagnosis,
access to universal drug susceptibility testing (DST), contact investigation and continuous
surveillance. (17, 18)

The 2016 guidelines emphasize the importance of 1) the optimal combination of medicines and
approach towards regimen design for TB patients (both adults and children) with RR-TB, MDR-
TB, XDR-TB and isoniazid-resistant TB, as well as for patients with Mycobacterium bovis disease;
2) the effectiveness and safety of standardised regimens lasting up to 12 months for the treatment of
patients with MDR-TB (“shorter regimens”) when compared with longer conventional treatment; 3)
the effect of time to start of treatment on drug-resistant TB patient outcomes; and 4) the effect of
surgical interventions on treatment outcomes for patients with drug-resistant TB. (19)
WHO, August 2018, has communicated the key changes to treatment of multidrug- and rifampicin-
resistant tuberculosis (MDR/RR-TB), and the immediate steps to be taken to ensure that MDR/RR-
TB patients receive treatment in accordance with the latest evidence on effectiveness and safety.
(20) 

The Guideline “ Management and treatment of MDR-TB” is a contribution concerning

to define all the steps and requirement, roles and responsibilities regarding Management and
treatment of MDR-TB; MDR-TB regimens in Management and treatment of MDR-TB; assistance
in protocols of treatment for all MDR-TB patients, and offer all possibilities on treatment and
management for all MDR-TB patients in Albania. This guideline is part of the guidelines series of
Management and treatment of TB and LTBI; Management and treatment of TB in children; TB and
MDR-TB infection control guidelines and screening policy for health workforce; Drug management
guidelines; and Operational Protocol on Patient -Centred Services for TB within PHC.
These guidedlines serves to the medical staff of the center that manages and treats MDR/RR-TB
patients and for antitubercular network committed to the prophylaxis, diagnosis and treatment of
these patients.

2 Drug resistance

2.1 Definitions of drug resistance

The confirmation of drug resistance depends on a laboratory diagnosis.
Classification based on drug resistance:
• Mono-resistance: resistance to one first-line anti-TB drug only.
• Poly-resistance: resistance to more than one first-line anti-TB drug, other than both
isoniazid and rifampicin.
• Multidrug resistance (MDR): resistance to at least both isoniazid and rifampicin.
• Extensive drug resistance (XDR): resistance to any fluoroquinolone, and at least one of
three second-line injectable drugs (capreomycin, kanamycin and amikacin), in addition to
multidrug resistance.
• Rifampicin resistance (RR): resistance to rifampicin detected using phenotypic or
genotypic methods, with or without resistance to other anti-TB drugs. It includes any
resistance to rifampicin, in the form of mono-resistance, poly-resistance, MDR or XDR.

These categories are not all mutually exclusive. When enumerating rifampicin-resistant TB (RR-
TB), for instance, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB)
are also included. (10, 13, 21)

Types of Drug-Resistant Cases:

There are two principal pathways leading to the development of active drug-resistant TB:
(1) acquired (secondary) drug resistance and (2) primary drug resistance.

1- Acquired (secondary) or Drug resistance in a previously treated TB case: Presence of a

resistant strain in a TB patient who has previously received at least one month of TB therapy. These
cases are likely to have been initially infected with a drug-susceptible M. tuberculosis strain, but
during the course of anti-tuberculosis treatment, drug resistance emerged. Without genotyping of
original and subsequent isolates, it is impossible to discern whether previously treated patients have
always been infected with drug-resistant strains, were reinfected with a new drug-resistant strain
(primary resistance), or whether their strains evolved on treatment (secondary resistance). Hence the
current terminology: drug resistance in new vs. previously treated cases. (21)
Acquired drug resistance is the result of inadequate, incomplete or poor treatment quality that
allows the selection of mutant resistant strains. If drug-susceptible TB is treated with a regimen
exclusively based on a single effective TB medicine, there is a risk that bacteria with drug-resistant
mutations will be selected and multiply further during the course of treatment, eventually becoming
the dominant strain. If a person infected with a strain, initially resistant to a specific medicine is
treated with that medicine plus a new additional medicine, then there is a risk of developing
resistance to the additional medicine. Step-wise additions of drugs may eventually lead to more
severe patterns of drug resistance and eventually to untreatable forms of TB.

Simultaneous natural mutations in Mycobacterium tuberculosis resulting in resistance to more

than one TB medicine are very rare. Therefore, appropriate treatment with a combination of
several quality-assured TB medicines dramatically diminishes the risk of selection of resistant
strains. This is the rationale for using a combination of quality-assured medicines when treating
TB, while ensuring good adherence. Poor treatment outcomes, including acquired drug-resistant
TB, can be caused by inappropriate treatment; inadequate drug quality and supply; and patient
factors hampering adherence and treatment responses. (10)
Clinically significant drug resistance usually emerges after 1 to 2 months of administration of an
inadequate drug regimen. (21)

2 - Primary drug resistance or new and previously treated Drug resistance in a new TB case:
Presence of a resistant strain of M. tuberculosis in a patient newly diagnosed with TB who has not
previously been treated with TB drugs (or therapy of less than one month duration). (21)
Primary or initial drug resistance means that a person has been infected with a drug-resistant TB
strain. Transmission of drug-resistant TB occurs exactly in the same way as transmission of drug
susceptible TB. High prevalence of drug-resistant TB in the community increases the risk of drug-
resistant TB exposure in the community. Undiagnosed, untreated, or poorly treated drug-resistant
TB contributes to sustained high drug-resistant TB prevalence, as well as high proportions of
infectious drug-resistant TB cases among the community. (10)

2.2 Treatment outcomes

The treatment outcome definitions for patients treated for RR-/MDR-TB using combination second-
line drug treatment are (10):

Table 1 Definitions of treatment outcomes for drug-resistant patients. (22)

Treatment outcome definition
Cured Treatment completed as recommended by the
national policy without evidence of failure and
three or more consecutive cultures
taken at least 30 days apart are negative after
the intensive phase.a
Treatment completed Treatment completed as recommended by the
national policy without evidence of failure but
no record that three or more consecutive
cultures taken at least 30 days apart are
negative after the intensive phase.a
Treatment failed Treatment terminated or need for permanent
regimen change of at least two anti-TB drugs
because of:
• Lack of conversionb by the end of the
intensive phasea; or
• Bacteriological reversionb in the continuation
phase after conversionb to negative; or
• Evidence of additional acquired resistance to
fluoroquinolones or second-line injectable
drugs; or
• Adverse drug reactions.
Died A patient who dies for any reason during the
course of treatment.
Lost to follow-up A patient whose treatment was interrupted for
two consecutive months or more.
Not evaluated A patient for whom no treatment outcome is
assigned. (This includes cases “transferred
out” to another treatment unit and whose
treatment outcome is unknown).
Treatment success The sum of Cured and Treatment completed.
a
For Treatment failed, lack of conversion by the end of the intensive phase implies that the patient
does not convert within the maximum duration of the intensive phase applied by the programme. If
no maximum duration is defined, an 8-month cut-off is proposed. For regimens without a clear
distinction between intensive and continuation phases, a cut-off eight months after the start of
treatment is suggested to determine when the criteria for Cured, Treatment completed and
Treatment failed start to apply.
b
The terms ‘conversion’ and ‘reversion’ of culture as used here are defined as follows:
-Conversion (to negative): Culture is considered to have converted to negative when two
consecutive cultures, taken at least 30 days apart, are found to be negative. In such a case, the
specimen collection date of the first negative Culture is used as the date of conversion.
-Reversion (to positive): Culture is considered to have reverted to positive when, after an initial
conversion, two consecutive cultures, taken at least 30 days apart, are found to be positive. For the
purpose of defining Treatment failure, reversion is considered only when it occurs in the
continuation phase.

"Recurrent TB" is defined as having either (1) or (2) after cure or completion of treatment:
1. Two consecutive positive cultures, or
2. One positive culture with clinical signs and symptoms or radiographic deterioration (an isolated
positive smear or culture without clinical or radiographic deterioration after treatment completion
provides insufficient evidence to define recurrent TB).

If genotyping is available, recurrent TB may be further classified as relapse, reinfection, or

undetermined as defined below:
- Relapse: isolates of the recurrent episode share the same genotype pattern with isolates of the first
episode of MDR-TB.
- Reinfection: isolates of the recurrent episode and isolates of the first episode of MDR-TB have
different genotype patterns.
-Undetermined: there is insufficient information to determine whether the recurrent episode is due
to relapse or reinfection.

2.3 Causes of DR-TB

Although its causes are microbial, clinical and programmatic, DR-TB is essentially a man-made
phenomenon. From a microbiological perspective, resistance is caused by a genetic mutation that
makes a drug ineffective against the mutant bacilli. From a clinical and programmatic perspective, it
is an inadequate or poorly administered treatment regimen that allows a drug-resistant strain to
become the dominant strain in a patient infected with TB. (13)

Drug-resistant TB can occur when the drugs used to treat TB are misused or mismanaged.
Examples of misuse or mismanagement include:

 People do not complete a full course of TB treatment

 Health care providers prescribe the wrong treatment (the wrong dose or length of time)
 Drugs for proper treatment are not available
 Drugs are of poor quality

Drug-resistant TB is more common in people who:

 Do not take their TB drugs regularly

 Do not take all of their TB drugs
 Develop TB disease again, after being treated for TB disease in the past
 Come from areas of the world where drug-resistant TB is common
 Have spent time with someone known to have drug-resistant TB disease

Risk Factors in Persons with a History of TB

Suspicion for drug-resistant TB should be high if the patient has 1 or more of the following
characteristics on current or prior treatment (10):
• Large bacillary load with extensive (bilateral or cavitary) disease
• Lack of conversion of cultures to negative during therapy
• Lack of improvement or only partial improvement in TB symptoms
• Worsening of TB symptoms or radiograph findings
• Nonadherence or intermittent or erratic ingestion of prescribed anti-TB regimen
• Lack of directly observed therapy (DOT) or poorly supervised therapy
• History of an inappropriate treatment regimen, including:
• Administration of single-drug therapy
• Too few effective drugs
• Inadequate drug doses

Risk Factors in Persons without Prior TB History

Clinical suspicion of drug resistance should occur when a patient with TB symptoms and signs has
a history of 1 or more of the following (10):

• Exposure to a person with documented drug-resistant TB.

• Residence in or travel to a region with high rates of drug-resistant TB.
• Residence or work in an institution or setting in which drug-resistant TB is documented.
• Treatment of pulmonary problems with a prolonged course of multiple medicines or an
injectable agent for more than a few weeks in a foreign country; i.e., the patient may not realize
that he/she was treated for TB.
• Treatment of a pulmonary problem with a fluoroquinolone.
• Previous treatment for latent TB infection (LTBI) when signs of TB disease were not
recognized.

If a patient is suspected of harboring drug-resistant M. tuberculosis based on treatment failure, a

history of previous therapy, or epidemiologic information, consider using an empirically expanded
regimen, particularly if the patient is seriously ill and/or has extensive disease (increased risk of
relapse and failure).

2.4 Interventions to prevent drug-resistant TB

There are five principal ways to prevent drug-resistant TB (10):

1. Early detection and high quality treatment of drug-susceptible TB.
2. Early detection and high quality treatment of drug-resistant TB.
3. Effective implementation of infection control measures.
4. Strengthening and regulation of health systems.
5. Addressing underlying risk factors and social determinants.

2.5 Diagnosing MDR-TB

Drug resistance can be detected using special laboratory tests which test the bacteria for
sensitivity to the drugs or detect resistance patterns. These tests can be molecular in type (such as
Xpert MTB/RIF) or else culture-based. Molecular techniques can provide results within hours
and have been successfully implemented even in low resource settings.

MDR-TB should be suspected in patients who fail to respond both to first-line and retreatment
regimens despite good documented compliance, as well as those persons who are in close contact
with a MDR-TB patient. The diagnosis of MDR-TB relies on DST. (15, 19)
Bacteriological examinations in patients with drug-resistant TB include sputum smear
microscopy, culture and DST as well as molecular techniques such as Xpert MTB/RIF and
line-probe assay (LPA). (10)

For a patient to be considered bacteriologically confirmed at the start of second-line treatment,

the following criteria must be met:
1. At least one pre-treatment specimen was positive on sputum smear microscopy, Xpert
MTB/RIF or culture.
2. The collection date of the sample on which the laboratory examination was performed was
less than 30 days before or seven days after the initiation of second-line treatment. (10)

Rapid drug susceptibility testing (DST) of isoniazid and rifampicin or of rifampicin alone is
recommended over conventional testing or no testing at the time of diagnosis of TB, subject to
available resources. (10, 23)

Fig 1 Detection of MDR-TB for suspected of MDR-TB including MDR-TB contacts, failure and
relapses of retraitment and retraitment after after defaulters and HIV suspected for TB (33)

When a molecular method detects rifampicin resistance, the decision on further steps depends on
the patient’s risk of having drug-resistant TB:
• In patients originating from a group at high risk of MDR-TB, a WHO-recommended regimen for
MDR-TB, and another sputum sample (taken immediately, prior to treatment onset) should be sent
for phenotypic or another genotypic DST to isoniazid. The sample should be subjected to
phenotypic DST against fluoroquinolones and second-line injectable agents.
• In patients originating from a group at low risk of MDR-TB, this result may be considered
unexpected and further follow-up is required. When the result of a second test shows rifampicin
susceptibility (an unsurprising result in an individual at low risk of MDR-TB), first-line regimen
should be prescribed.
When the result of a second test is in accordance with the initial finding of rifampicin resistance,
regimen for MDR-TB with the addition of isoniazid should be started without any further delay. An
additional sample should be taken for phenotypic or genotypic DST to confirm resistance to
rifampicin and also test for susceptibility to isoniazid, fluoroquinolones and second-line injectable
agents.

Molecular methods are not suitable for monitoring of treatment response. Results can stay
positive for M. tuberculosis by detection of DNA in dead organisms after viable bacteria have
been eliminated, resulting in false-positive results. Therefore, culture remains the preferred
method for monitoring patient response to drug-resistant TB therapy.

Figure 2 Algorithm for interpretation of results from molecular methods (10)

2.6 Diagnosing XDR-TB

All patients diagnosed with MDR-TB should preferably be tested for XDR-TB.
The two strongest risk factors for XDR-TB are:
1. Failure of an MDR-TB treatment regimen, which contains second-line drugs including an
injectable agent and a fluoroquinolone; and
2. close contact with an individual with documented XDR-TB or with an individual for
whom treatment with a regimen including second-line drugs is failing or has failed.
XDR-TB is diagnosed through conventional phenotypic DST. (10, 13)

2.7 Drug-resistant TB case finding in HIV-infected patients

The diagnosis of TB in HIV-infected people is more complex and may be confused with
other pulmonary or systemic infections. PLHIV are more likely than HIV-negative persons
to have smear-negative TB or extrapulmonary TB.
WHO recommends Xpert MTB/RIF as a primary diagnostic test in the following individuals: (i) all
adults and children living with HIV who have signs or symptoms of TB, (ii) those seriously ill and
suspected of having TB regardless of HIV status, and (iii) those with unknown HIV status
presenting with strong clinical evidence of HIV infection in HIV-prevalent settings.
Because unrecognized drug-resistant TB is associated with very high mortality in HIV-infected
patients, all patients diagnosed with HIV-associated TB should receive a rapid molecular
test, including Xpert MTB/RIF or line probe assay, for the detection of potential drug resistance.
HIV-infected patients with MDR-TB or rifampicin resistance should be tested for second-line
anti-TB drug resistance. (10, 13)

2.8 Case finding for drug-resistant TB

Case finding for drug-resistant TB refers to the process of (13):
• identifying individuals who may have drug-resistant TB;
• evaluating them appropriately;
• diagnosing drug-resistant TB; and
• recording and reporting any drug-resistant TB diagnosed according to standardized criteria

3.Treatment strategies for MDR-TB and XDR-TB

3.1 Regimen of DR-TB treatment

The composition of a regimen should be tailored to result in:
1) early bactericidal effect (immediate and substantial reduction of metabolically highly active
bacilli) to arrest transmissibility, to reduce the risk of selecting resistant mutants, and thus prevent
treatment failure, and
2) sterilizing effect (elimination of bacilli with low metabolic activity) to reduce the risk of relapse
after successful treatment completion. (24, 25)

The definition of an "effective TB medicine" includes both laboratory DST results and the
patient's TB treatment history, including the TB contact history. In short, clinical judgement is
often necessary to decide whether a specific drug counts as an effective TB medicine.

An anti-TB drug is considered likely to be effective if (26):

1. The drug has not been used in a regimen that failed to cure the individual patient.
2. DST performed on the patient’s strain indicates that it is susceptible to the drug.
3. No known resistance to drugs with high cross-resistance. For example, resistance to
kanamycin is highly associated with amikacin resistance.
4. No known close contacts with resistance to the drug.
5. Drug resistance surveys demonstrate that resistance to the drug is rare in patients with
similar TB history. This is particularly important for drugs for which DST is not routinely
performed.
The hierarchy of the building steps is based on evidence of effectiveness of the drug against
TB, potential adverse effects, and the likely background resistance in MDR-TB strains.

3.2 Regimen for isoniazid-resistant tuberculosis

In patients with rifampicin-susceptible, isoniazid-resistant TB, 6 months of combination

treatment with rifampicin, ethambutol, pyrazinamide and levofloxacin, with or without
isoniazid, is recommended.
In patients with confirmed rifampicin-susceptible and isoniazid-resistant tuberculosis, it is not
recommended to add streptomycin or other injectable agents to the treatment regimen.

This recommendation aims to increase cure rates in patients with isoniazid-resistant TB

(HR-TB), in whom a 2HRZE/4HR regimen is more likely to fail than in isoniazid-susceptible
TB patients. Levofloxacin is only to be used after rifampicin-resistance has been excluded with
rapid molecular testing.

Ideally, Hr-TB treatment is only started after isoniazid resistance and susceptibility to
fluoroquinolone have been reliably confirmed. Extending the duration of treatment beyond 6
months may be necessary when Hr-TB is detected in the course of a first-line TB treatment or in
patients with extensive disease. The addition of isoniazid would add benefit to this regimen,
especially in cases of FDC -drug may be more convenient for the patient and the health service.
(11, 27)
Empirical treatment of Hr-TB is not generally advised. In cases where Hr-TB diagnosis is strongly
presumed (e.g. close contacts of Hr-TB cases with active TB but without laboratory confirmation of
Hr-TB), (H)REZ-Lfx may be introduced pending laboratory confirmation of isoniazid resistance, so
long as rifampicin resistance has been reliably excluded. Should DST results eventually indicate
susceptibility to isoniazid, levofloxacin is stopped and the patient completes a 2HRZE/4HR
regimen.

For patients, in whom Hr-TB is detected after the start of treatment with the 2HRZE/4HR regimen,
the (H)REZ component drugs are continued (or pyrazinamide and ethambutol are re-introduced)
and levofloxacin added once rifampicin resistance has been excluded.

The (H)REZ-Lfx regimen is given for as long as it is necessary for the patient to receive
levofloxacin for six months. Thus, in cases where the diagnosis of Hr-TB is made after first-line TB
treatment has already been initiated, the patient may receive more than six months of (H)REZ by
the end of treatment.

When the confirmation of isoniazid resistance arrives late into treatment with a 2HRZE/4HR
regimen (e.g. 5 months after start during the continuation phase), the clinician would need to
decide, based on an assessment of patient condition and laboratory tests, whether a 6 months course
of (H)REZ-Lfx needs to be started at that point or not.

The addition of levofloxacin to (H)REZ is recommended in all patients with Hr-TB, with exception
of the following (27):

(i) in cases where resistance to rifampicin cannot be excluded;

(ii) known or suspected resistance to levofloxacin;

(iii) known intolerance to fluoroquinolones;

(iv) pregnancy or during breastfeeding (not an absolute contraindication).

Warning: known or suspected risk for prolonged QTc interval

In Hr-TB cases in whom a fluoroquinolone cannot be used, the patient may still be treated with
6(H)REZ. The 6(H)REZ regimen has been shown to be more effective at treating Hr-TB than a
2HRZE/4HR regimen

If rifampicin resistance is detected, the patient needs to be started on a recommended MDR-TB

treatment regimen.

When additional resistance (e.g. to both fluoroquinolones and pyrazinamide) is suspected or

confirmed, treatment regimens may have to be designed individually with other second-line TB
medicines.

Treatment prolongation beyond 6 months: may be considered for patients with extensive cavitary
disease or in patients slow to convert to negative smear/culture. In the latter, acquisition of
additional resistance to rifampicin must be ruled-out, as well as resistance to fluoroquinolones and
pyrazinamide if possible. Such patients require careful monitoring and follow-up.

Certain Hr-TB patients have documented additional resistance, but in many it may be undetected. In
most forms of polydrug resistance, such as to Hr+E or Hr+S or Hr+S+E or Hr+Z, treatment can
proceed with 6(H)REZ-Lfx. In cases with Hr+Lfx resistance, treatment with 6(H)REZ is proposed.
However when there is resistance to three key agents, such as H+Z+Lfx, the 6(H)REZ-Lfx may not
contain enough agents to ensure relapse-free cure and to avert the acquisition of resistance to the
remaining medicines of the regimen. In such circumstances, medicines such as linezolid,
ethionamide and cycloserine may have to be considered in order to compose a regimen with
sufficient effective agents. It is also not clear if prolonging the duration of these individualized
regimens has a bearing on the likelihood of cure. Bedaquiline and delamanid have been developed
for use in MDR-TB and extensively drug-resistant TB (XDR-TB) and evaluated for this patient
group. They are therefore not recommended for use in other forms of drug resistant TB like Hr-TB
and in rifampicin-susceptible polydrug resistant TB. (28)
Most of the isoniazid-resistant tuberculosis are treated with levofloxacin. Moxifloxacin, that is
generally reserved for MDR-TB regimens, can replace levofloxacin in Hr-TB regimens.

3.3 MDR-TB regimen

Patients with multidrug or rifampicin-resistant TB (MDR/RR-TB) require second-line

treatment regimens.
MDR/RR-TB patients may be treated using a 9–11 month MDR-TB treatment regimen
(the shorter regimen) unless they have resistance to second-line anti-TB agents or
meet other exclusion criteria. In these cases, a longer (individualized) regimen with at least
five effective anti-TB agents in the intensive phase and four agents in the continuation phase is
recommended for 20 months or more. Partial resection surgery has a role in treating MDR-
TB. (11)

Rifampicin-resistant TB (RR-TB) refers to TB strains that are considered eligible for

treatment with MDR-TB regimens. Rifampicin-resistant TB strains may be susceptible
to isoniazid, or resistant to isoniazid (i.e. MDR-TB), or resistant to other medicines from the
first-line group (poly-resistant) or from the second-line medicine group (e.g. XDR-TB).
A second-line TB medicine is used to treat drug-resistant TB.
Any patient (child or adult) with RR-TB in whom isoniazid resistance is absent or unknown
may be treated with a recommended MDR-TB regimen, either a shorter MDR-TB regimen,
or if this cannot be used, a longer MDR-TB regimen to which isoniazid is added.

TB patients with strains found to be rifampicin resistant when tested with Xpert MTB/RIF, line
probe assay (LPA) or conventional diagnostics need to start MDR-TB treatment regimen
irrespective of whether isoniazid resistance is undetermined or confirmed. (19)
Most adults and children with pulmonary forms of MDR/RR-TB who do not have additional
resistance to fluoroquinolones and injectable agents may be effectively cured with a shorter MDR-
TB regimen. (19)

Choosing the treatment regimen for RR-/MDR-TB

• Confirmed resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen
(except isoniazid resistance)?
• Exposure to >1 second-line medicines in the shorter MDR-TB regimen for >1 month?
• Intolerance to >1 medicines in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug
interactions)?
• Pregnancy?
• Extrapulmonary disease?
• At least one medicine in the shorter MDR-TB regimen not available?
↓ ↓
NO YES

↓ If: failing regimen, drug intolerance, ↓

Shorter MDR-TB return after interruption >2 months, Longer MDR-TB
 regimen emergence of any exclusion criterion regimens
------------------------------------------→

Intensive phase Intensive phase

Duration: 4–6 months Duration: ≤ 8 months
Composition: 4 second-line anti-TB agents Composition: ≥ 5 effective anti-TB agents

Continuation phase
Duration: 5 months Duration: ≥ 12 months
Composition: 2 second-line anti-TB agents Composition: ≥ 4 effective anti-TB agents

3.3.1 Choice of a MDR-TB regimen

- Treatment options for MDR-TB are increasingly becoming more individualised as a result of
innovations in diagnostics and growing scientific understanding of the molecular basis for drug
resistance and the pharmacokinetics and pharmacodynamics of TB medicines. Three signals are
clear from the current scientific evidence assessment (20):
• The feasibility of effective and fully oral treatment regimens for most patients;
• The need to ensure that drug resistance is excluded (at least to the fluoroquinolones and
injectables) before starting patients on treatment, especially for the shorter MDR-TB regimen;
• The need for close monitoring of patient safety and treatment response and a low threshold for
switching non-responding patients or those experiencing drug intolerance to alternative
medicines and/or new regimens based on the regrouping of agents in Table 2.

3.3.1.1 Shorter MDR-TB regimen

A shorter MDR-TB treatment regimen is recommended in patients with

- rifampicin-resistant TB or MDR-TB,
- who have not been previously treated with second-line drugs, and
- in whom resistance to fluoroquinolones and second-line injectable agents has been excluded or is
considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead of the
longer regimens. (29)
In patients with MDR/RR-TB who were not previously treated with second-line drugs and in
whom resistance to fluoroquinolones and second-line injectable agents was excluded or is
considered highly unlikely, a shorter MDR-TB regimen of 9–12 months may be used instead
of the longer regimens.
• Recommendation applies to adults, children, PLHIV
• Ideally, patients are tested for resistance to fluoroquinolones and second-line injectable drugs; not
recommended in case of 2nd line drug resistance, extrapulmonary disease and pregnancy

The shorter MDR-TB regimen is the treatment option of first choice for MDR/RR-TB patients,
subject to eligibility. The regimen may be used in children and in patients on antiretroviral agents,
but it is not indicated if strains have (or are highly likely to have) resistance to medicines in the
regimen (except isoniazid). All efforts should be made to exclude resistance to fluoroquinolones
and to injectable agents in the regimen before starting treatment, preferably by using in vitro testing
with molecular or phenotypic methods. It is not indicated in pregnancy (the aminoglycosides and
thiamides may be replaced with other medicines in a longer regimen) nor in patients with
extrapulmonary forms of disease. (19)
Shorter MDR-TB regimen refers to a course of treatment for MDR/RR-TB lasting 9 to 12
months, which is largely standardized.
Recommended structure is as follows:
4-6 Am (Km) -Mfx-Pto(Eto)-Cfz-Z-Hhigh-dose-E
5 Mfx-Cfz-Z-E

Shorter MDR-TB regimens showed an overall comparable likelihood of treatment success with
longer regimens, with a lower risk of treatment interruption. However, shorter regimens were
associated with higher risk of treatment failure and relapse compared to longer regimens, especially
when resistance to key medicines in the shorter regimen was present or when longer regimens
included one or more of the Group A medicines listed in Table 2. (20)
Decisions to start newly diagnosed patients on the standardized shorter MDR-TB regimen should be
made according to patient preference and clinical judgement, for patients who do not have any of
the following conditions (20):
- Resistance or suspected ineffectiveness to a medicine in the shorter MDR-TB regimen (except
isoniazid resistance);
- Exposure to one or more 2nd line medicines in the regimen for >1 month (unless susceptibility
these 2nd line medicines is confirmed);
- Intolerance to any medicine in the shorter MDR-TB regimen or risk of toxicity (e.g. drug-drug
interactions);
- Pregnancy;
- Disseminated, meningeal or central nervous system TB; or any extrapulmonary disease in HIV
patients.

Shorter MDR-TB regimens can be modified from the standardized form recommended*:
- bedaquiline or linezolid replacing the injectable agent or
- levofloxacin replacing moxifloxacin.

*The health care providers considering the use of modified shorter regimens should note that evidence is currently
lacking on the effect of replacing any of the agents with alternatives in the shorter regimen (e.g replacing the injectable
with bedaquiline or other oral agents; replacing moxifloxacin with levofloxacin).

The health care providers should consider (20):

- in the interim, inform patients on treatment about the relative benefits and harms of
continuing their current regimens, most notably the injectables and ethionamide-
protionamide;
- intensify clinical, safety and microbiological monitoring in order to rapidly switch patients
to new longer MDR-TB regimens upon the first signs of non-response or drug intolerance.
- using the standardized shorter MDR-TB regimen with good results and with adequate
capacity for monitoring drug safety;
 Pregnancy was an exclusion criterion for the shorter MDR-TB treatment regimen.
Two of the core components of the shorter MDR-TB regimens – the injectable agent and
ethionamide (or prothionamide) – are usually contraindicated in pregnancy. Withholding
these medicines from the shorter MDR-TB treatment regimen could seriously compromise
its effectiveness. Thus for pregnant women, it is recommended that a longer individualized
regimen be used which can allow the inclusion of four or more effective second-line TB
medicines with no known teratogenic properties. (29)

People living with HIV need to be given the same consideration for treatment with the shorter
MDR-TB treatment regimen as people who are HIV seronegative. (29)

3.3.1.2 Longer MDR-TB regimens

Longer MDR-TB regimens usually last 18-20 months and may be standardized or
individualized.
These regimens are usually designed to include at least five medicines considered to be
effective.

TB medicines recommended for use in longer MDR-TB regimens is presented in Table 2 (20).
Medicines are grouped into three categories and ranked based on the latest evidence about the
balance of effectiveness to safety:
- Group A: Medicines to be prioritised: levofloxacin/moxifloxacin, bedaquiline and linezolid
- Group B: Medicines to be added next: clofazimine, cycloserine/terizidone
- Group C: Medicines to be included to complete the regimens and when agents from Groups A
and B cannot be used: ethambutol, delamanid, pyrazinamide, imipenem-cilastatin, meropenem,
amikacin (streptomycin), ethionamide/prothionamide, p-aminosalicylic acid;

Notes: Medicines no longer recommended are kanamycin and capreomycin, given increased risk of treatment failure
and relapse associated with their use in longer MDR-TB regimens. Use of amikacin did not show a similar association,
although the same safety concerns as for the other injectables apply. Amoxicillin-clavulanic acid is only to be used to
accompany the carbapenems.

Table 2 also indicates the overall approach to designing longer MDR-TB regimens for adults and
children based on the revised grouping. The regimen is designed by adding medicines sequentially
going down the three groups.

Apart from the ranking by balance of effectiveness and harms, choice is also determined by:
- a preference for oral over injectable agents;
- the results of drug-susceptibility testing (DST);
- history of previous use of the medicine in a patient;
- drug tolerability; and potential drug-drug interactions.

Table 2 Grouping of medicines recommended for use in longer MDR-TB regimens (20)
Group Medicine Abbreviation
Group A: Levofloxacin or Lfx
Include all three medicines Moxifloxacin Mfx
(unless they cannot be used) Bedaquiline Bdq
Linezolid Lzd
Group B: Clofazimine Cfz
Add both medicinës Cycloserine or Cs
(unless they cannot be used) Terizidone Trd
Group C: Ethambutol E
Add to complete the regimen Delamanid Dlm
and when medicines from Pyrazinamide Z
Group A and B cannot be Imipenem-cilastin or Ipm-Cln
used Meropenem Mpm
Amikacin Am
(or Streptomycin) (S)
Ethionamide or Eto
Prothioamide Pto
p-aminosalicylic acid PAS

Notes (20):
1. Evidence on the safety and effectiveness of Bdq beyond 6 months was insufficient for review;
extended Bdq use in individual patients will need to follow ‘off-label’ use best practices.
2. Optimal duration of use of Lzd is not established. Use for at least 6 months was shown to be
highly effective, although toxicity may limit its use.

3. The position of Dlm will be re-assessed. Evidence on the safety and effectiveness of Dlm beyond
6 months was insufficient for review; extended use of Dlm in individual patients will need to follow
‘off-label’ use best practices.
4. Evidence on concurrent use of Bdq and Dlm was insufficient for review.
5. Z is only counted as an effective agent when DST results confirm susceptibility.
6. Amoxicillin-Clavulanic acid is administered with every dose of Imp-Cln or Mpm but is not
counted as a separate agent and should not be used as a separate agent.
7. Am and S are only to be considered if DST results confirm susceptibility and high-quality
audiology monitoring for hearing loss can be ensured. S is to be considered only if Am cannot be
used and if DST results confirm susceptibility (S resistance is not detectable with 2nd line
molecular line probe assays and phenotypic DST is required).

3.3.2 Duration of longer MDR-TB treatment regimens

In the treatment of patients with MDR-TB, an intensive phase of eight months is suggested for most
patients; the duration may be modified according to the patient’s response to therapy.
In the treatment of patients newly diagnosed with MDR-TB (i.e. not previously treated for MDR-
TB), a total treatment duration of 20 months is suggested for most; the duration may be modified
according to the patient’s response to therapy. (29)

3.3.3 Procedure following missed treatment

Great care should be taken to ensure that patients continue to take all their treatment for the duration
prescribed. Ahead of enrolment on MDR-TB treatment, all patients should receive appropriate
counselling to enable informed and participatory decision-making. Social support to enable
adherence to treatment is very important to ensure a patient-centred approach to the delivery of
care.
Identification of potential causes of nonadherence should be sought and resolved.
Any missed days should be made up by extending the regimen by the number of days missed but
not exceed 10% of the planned study regimen duration. Treatment interruption for two consecutive
months or more will be classified as "lost to follow-up". (30)
Prevention of treatment interruption is an important factor to increase the likelihood of treatment
success. To ensure patient adherence, the patient's visit to health care facilities should be facilitated
or by home visits of health care staff or by using digital technologies for daily communication. The
full participation of the patient is helped by a good relationship with a key worker and by an
understanding of the illness. Patient and family education is needed in order to reduce stigma.
Every effort should be made to retrieve patients who default from treatment. The skills of social
workers and community health care workers should be used to assist with default retrieval.

3.4 XDR-TB regimen

MDR-TB patients with strains resistant to fluoroquinolones or the second-line injectable drugs
(kanamycin, amikacin, capreomycin) represent a particular concern. Regimens containing more
drugs were associated with the highest odds of success for MDR-TB patients who had additional
resistance to fluoroquinolones and/or second-line injectable agents. In patients with RR-TB and
MDR-TB, if there is confirmed or well-founded belief of resistance to medications from
fluoroquinolones or second-line injectable agents, the medicines in the regimen that belong to these
classes are substituted. Success in XDR-TB patients was highest if at least six drugs were used in
the intensive phase and four in the continuation phase. A different meta-analysis provides empiric
evidence that the use of later-generation fluoroquinolones significantly improved treatment
outcomes in patients with XDR-TB, even though DST demonstrated resistance to a representative
fluoroquinolone. (10)
Following schemes would be considered acceptable (20):
 Mfx-Bdq-Lzd-Cfz-Cs(Trd)- Eto (Pto)
 Mfx-Bdq-Lzd-Cfz-Cs-PAS
 Mfx-Bdq-Lzd-Cfz-Z-Ipm Cln
 Bdq-Lzd-Cfz- Eto (Pto)-Cs-Z
 Mfx-Bdq-Lzd- Cs(Trd)-E-PAS
 Mfx-Lzd- Cs(Trd)-Dlm-E-Z
 Mfx-Bdq-Lzd-Z-Cs(Trd)-PAS
 Bdq-Lzd-Z-Cs(Trd)-E-PAS
(General considerations of anti-tuberculosis medicines are summarized in Annex 2)

Table 3 Dosing of medicines for adults (30)

Drug Weight group
30-50 kg More than 50 kg
Bedaquiline (100 mg tablets) 400 mg once daily for 2 weeks, then 200 mg 3 times per
week afterwards
Delamanid (50 mg tablets) 100 mg twice daily (200 mg total daily dose)
Linezolid (600 mg tablets) 600 mg once daily*
Levofloxacin (250 mg or 500 mg tablets) 750 mg 1000 mg
Moxifloxacin (400 mg tablets) 600 mg 800 mg
Clofazimine (100 mg gel capsules) 100 mg 100 mg
Ethambutol (400 mg tablets) 800 mg 1200 mg
Pyrazinamide (500 mg tablets) 1500 mg 2000 mg
Isoniazid, high dose (300 mg tablets) 400 mg 600 mg
Prothionamide (250 mg tablets) 500 mg 750 mg
Cicloserine 500 mg 750 mg
Imipenem-cilastin or Meropenem 1000 mg IV every 12 hours
Amx/Clv 875/125 tablets Dosing as adjunctive therapy with a carbapenem:
Dose based on the clavulanic acid component, 125 mg 60
minutes orally before the IV infusion of the carbapenem.
p-aminosalicylic acid 8gr 12 gr
Amikacin (1000 mg vials) 15 mg per kilogram body weight (maximum 1 g)**
* Linezolid dose is commonly reduced to 600 mg three times a week or 300 mg daily
in patients with linezolid-induced peripheral neuropathy.
** Kanamycin dose may be reduced to 10 mg/kg (max dose 750 mg) or decreased in
frequency to three times a week in adults over 59 years of age.

Table 4 Dosing for children and adults < 30 kg (30)

Drugs Dosing
Bedaquiline > 12 years and > 33 kg: 400 mg daily for 14 days followed by
200 mg three times a week (same as adult dose)
< 12 years or < 33 kg: correct dose is unknown, but 6 mg/kg for 2
weeks, then 3 mg/kg afterwards may be tried
Delamanid > 35 kg: 100 mg twice daily (same as adult dose)
20-34 kg: 50 mg twice daily
< 20 kg: correct dose is unknown, but 3-4 mg/kg may be tried
Linezolid >= 12 years: 10 mg/kg once daily
< 12 years: 10 mg/kg twice daily
Clofazimine 2-3 mg/kg daily or every other day for a maximum daily dose of
100 mg (gel caps cannot be split)

3.5 Surgical interventions in patients with MDR-TB

In patients with RR-TB or MDR-TB patients, elective partial lung resection (lobectomy or wedge
resection) may be used alongside a recommended MDR-TB regimen. Prognosis appeared to be
better when partial lung resection was performed after culture conversion. (29)
There are and other possible surgical interventions in TB (e.g. emergency operations or
extrathoracic procedures). Patients undergoing more radical pneumonectomy were not observed to
have better outcomes than those who did not undergo surgery. The benefits of surgery are likely to
depend on the patient subgroups. The effect is expected to be moderate in the average patient
considered appropriate for surgery. Despite the perioperative complications it was considered that
there is an overall net benefit from surgery. Surgery is only to be considered after careful selection
of candidates. It is not indicated in patients with extensive bilateral disease. The case series which
showed surgery to be effective may have a selection bias, as very sick patients with co-morbidities,
older patients, and those with extensive disease are often excluded from surgery.
Resection surgery should be timed such that the patient has the best possible chance of cure with the
least morbidity. Thus, the timing of surgery may be earlier in the course of the disease when the
patient's risk of morbidity and mortality are lower, for example, when the disease is still localized to
one lung or one lung lobe. In other words, surgery should not be considered a last resort. Generally,
at least two months of therapy should be given prior to resection surgery to decrease the bacterial
infection in the surrounding lung tissue. Even with successful resection, the intensive phase and
total treatment duration should be guided by the recommendations.
General indications for resection surgery include patients that remain smear-positive, with
resistance to a large number of drugs; and localized pulmonary disease.

3.6 TB of the central nervous system treatment

Data on the CNS penetration of second-line antituberculous agents is limited. This is an important
management consideration as poor penetration and the lack of an effective immune response in the
CNS can affect response. Some drugs used in management of MDR CNS TB penetrate the blood-
brain barrier and these include quinolones, pyrazinamide, linezolid, cycloserine, and ethionamide.
Although Pyrazinamide has good CNS penetration, although caution should be exercised, as a large
percentage of MDR-TB strains may be resistant. This property makes them important in treatment
regimens, and they should be used in consultation with the specific susceptibility profile.
Ethambutol, penetrates the blood-brain barrier in the presence of inflammation, but not otherwise
due to its high molecular weight. Amikacin was chosen over capreomycin as it has better
cerebrospinal fluid penetration. (7) The use of isoniazid in the management of isoniazid resistant
disease is controversial. The WHO recommends use of high dose isoniazid in MDR CNS TB unless
there is high level isoniazid resistance. Its benefits include a highly bactericidal action and good
penetration to the CNS, which allow high peak concentrations in the CSF, often exceeding
minimum inhibitory concentrations. (33)
PAS do not penetrate the CNS well and should not be counted on as effective drug to treat MDR-
TB meningitis. Kanamycin, amikacin and streptomycin only penetrate the cerebrospinal fluid in the
presence of meningeal inflammation. There are little data on the CNS penetration of capreomycin,
clofazimine, bedaquiline or delamanid. (7)

3.7 Adjuvant therapies in drug-resistant TB treatment

Corticosteroids
In drug-resistant TB patients, the adjuvant use of corticosteroids has been shown not to increase
mortality when the patient is on an effective regimen. Corticosteroids can be beneficial in
conditions like severe central nervous system or pericardial involvement. That may also help in
respiratory insufficiency and miliary TB. Prednisone is commonly used with a tapering of dosage
over several weeks. (29)
Corticosteroids may also alleviate symptoms in patients with an exacerbation of obstructive
pulmonary disease. When a more immediate response is needed, injectable corticosteroids are
often initially used. Corticosteroids can weaken the body’s response to fight TB and therefore
should only be used if clearly indicated and if the patient is on an adequate effective regimen. If
corticosteroids are used in an inadequate regimen, this could accelerate the deterioration of the
patient. (29)

3.8 Palliative care

Suspension of treatment should only be considered after all other options for treatment have been
explored as this is a delicate situation and difficult for family members and caretakers, but it is
especially difficult for the patient as treatment is often viewed as his/her only hope. Psychosocial
support must be rendered to the patient and family. If the DR-TB clinical management team is
confident that all medications have been taken and that there is no possibility of adding other drugs
or surgery, the treatment should be considered a failure and suspension of therapy recommended or
provision of palliative care. (35)
Conditions under which treatment may be suspended include (35):
• The patient’s quality of life is poor, particularly when medications used in DR-TB treatment have
considerable side effects, and continuing them while the treatment is failing may cause additional
suffering.
• Continuing treatment that is failing can amplify resistance in the patient’s strain, resulting in
resistance to all available anti-tuberculosis drugs. This ‘super-resistant strain’ can be transmitted to
others.
MDR-TB treatment consists of a treatment cycle; if no response is seen, reassessment of the
regimen and treatment plan as well as formulation of a new plan of action are necessary.
Suspension of drug therapy is recommended in cases where the medical personnel involved are
confident that all the prescribed drugs have been ingested and there is no possibility of adding other
drugs or carrying out surgery. (10) If persisted smear sputum/culture positive after 4 months of
intensive treatment and 3 to 5 months of continuation (36) or in the past eight to 10 months of
treatment (10), a decision on palliative care should be taken. The situation should be explained to
the patient and family. Have to be convinced that it is not embedded. It should be instructed in
relation to the basics of infection control. MDR patients with late stadies of AIDS have very poor
prognosis. They have poor tolerance to treatment, in these cases it may be more appropriate for a
simptomatic medication and infection control.

Consideration in suspending anti-TB therapy and changing it to palliative/end-of-life care is when

the drugs used in MDR-TB treatment have significant adverse effects, and continuing them while
the treatment is failing may cause additional unnecessary suffering; continuing a treatment that is
failing can amplify resistance in the patient’s strain, but should not be withheld for fear of drug
resistance amplification alone. (10) The approach to suspending therapy should start with
discussions among the clinical team. Once the clinical team decides that treatment should be
suspended, a clear plan should be prepared for approaching the patient and the family. It is not
recommended to suspend therapy before the patient understands and accepts the reasons to do so,
and agrees with the supportive care offered. (10)

4 Treatment of drug-resistant TB in special conditions and situations

4.1 Pregnancy

All female patients of childbearing age should be tested for pregnancy upon initial evaluation.
Pregnancy is not a contraindication for treatment of active drug-resistant TB, but poses great risk to
the lives of both the mother and fetus. In MDR-TB patients who are pregnant, the main objective
is to design a regimen that is effective and likely to cure the mother. The highest risk to both
mother and fetus is from inadequately treated MDR-TB. While drugs with identified
teratogenic risks may be not primary choices, the potential teratogenic impact of these drugs
should be considered in perspective of the risks to the mother/baby/family/community of
not treating the mother with an appropriate regimen. (26)
Pregnant patients should be carefully evaluated, taking into consideration the gestational age and
severity of drug-resistant TB. The risks and benefits of treatment should be carefully considered,
with the primary goal of smear conversion to protect the health of the mother and child, both before
and after birth. The following are some general principles to consider when treating pregnant
women:
• Benefits and risks of treatment. Most pregnant patients should be started on treatment as
soon as the diagnosis is made. However, since the majority of teratogenic effects occur in the first
trimester, treatment may be delayed until the second trimester when the patient is very
stable with minimum disease. Delaying treatment carries a risk as TB can advance quickly
in a pregnant patient. A decision to start treatment in the first trimester or to postpone
until after the first trimester should be agreed to by at least the patient and the doctor,
after analysis of the risks and benefits. The decision is based primarily on clinical judgment
established on the basis of signs/symptoms and severity/aggressiveness of the disease.
• Avoid injectable agents. Aminoglycosides can be particularly toxic to the developing fetal
ear.
• Avoid ethionamide. Ethionamide can increase the risk of nausea and vomiting associated
with pregnancy, and teratogenic effects have been observed in animal studies.
• Consider termination of pregnancy if the mother’s life is compromised. (29)

4.2 Breastfeeding
In lactating mothers on treatment, most anti-TB drugs will be found in the breast milk in
concentrations that would equal only a small fraction of the therapeutic dose used in an infant.
However, any effects on infants of such exposure during the full course of drug-resistant TB
treatment have not been established. Therefore, it is preferable to provide infant formula options as
an alternative to breastfeeding. Clinicians and parents may agree to breastfeeding when the formula
is not a feasible option. A woman who is breastfeeding and has active drug-resistant TB should
receive a full course of anti-TB treatment. Timely and properly applied chemotherapy is the best
way to prevent transmission of tubercle bacilli to the baby.
The mother and her baby should not be completely separated. However, if the mother is sputum
smear positive, the care of the infant should be left to family members until she becomes sputum
smear negative, if this is feasible. When the mother and infant are together, this common time
should be spent in well-ventilated areas or outdoors. The mother should use a surgical mask until
she becomes sputum smear negative. (29)

4.3 Contraception
Birth control is strongly recommended for all non-pregnant sexually active women receiving
therapy for drug-resistant TB because of the potential consequences for both the mother and
fetus resulting from drug-resistant TB treatment during pregnancy.
There is no contraindication to the use of oral contraceptives with non-rifamycin containing
regimens. Patients who vomit directly after taking an oral contraceptive can be at risk of
decreased absorption of the drug and therefore of decreased efficacy. These patients should
be advised to take their contraceptives apart from times when they may experience vomiting
caused by the anti-TB treatment medications. Patients who vomit at any time directly after, or
within the first two hours after taking the contraceptive tablet, should use a barrier method of
contraception until a full month of the contraceptive tablets being tolerated.
For patients with mono- and poly-resistant TB but who are susceptible to rifampicin, the use of
rifampicin interacts with the contraceptive drugs resulting in decreased efficacy of protection
against pregnancy. Condoms are a reasonable solution. (29)

4.4 Children
DR-TB in children is usually transmitted from close contact with adult pulmonary DR-TB source
cases, although some older children with cavitary pulmonary disease may acquire DR-TB through
poor treatment management. As in adults, the diagnosis of DR-TB is by M. tuberculosis culture and
DST, but children with TB often have a negative culture because of the paucibacillary nature of
primary TB. Therefore, in children, DR-TB should also be suspected if 1) there is known contact
with an adult DR-TB source case; 2) there is known contact with an adult source case with
unknown DST who is a treatment failure, has recurrent TB or who has died; or 3) a child does not
respond or gets worse on adherent fi rst-line antituberculosis treatment. If MDR-TB is strongly
suspected in a child, but is not confirmed by culture and DST, appropriate empirical MDR-TB
treatment should not be withheld on the basis of an absent culture or DST result. However, every
effort should be made to obtain specimens for culture and DST in these children to confirm the
diagnosis. (15)
The treatment of culture negative children with clinical evidence of active TB disease and a contact
with a documented case of drug-resistant TB should be guided by the results of DST and the history
of the contact’s exposure to anti-TB drugs. The risks and benefits of each drug should be carefully
considered while designing a regimen. Frank discussions with family members is critical, especially
at the outset of therapy. Although fluoroquinolones have been shown to retard cartilage
development, the benefit of fluoroquinolones in treating drug-resistant TB in children have shown
to outweigh any risk.
In children, microbiological monitoring of the response to treatment is often difficult (for
the same reasons it is difficult to obtain a microbiological diagnosis). This makes it difficult to
diagnose treatment failure in children. Persistent abnormalities on chest radiographs do not
necessarily signify a lack of improvement. In children, weight loss or, more commonly, failure to
gain weight adequately in the presence of proper nutritional intake, is of particular concern and
often one of the first (or only) signs of treatment failure. This is another key reason to monitor
weight carefully in children. (29)
The basic principles of management of adult and childhood DR-TB are similar, but because
children often have paucibacillary disease, some aspects of management may differ. The important
principles specifically related to children are (15):
1 A child contact of an adult DR-TB source case should receive treatment according to the adult’s
DST result if no M. tuberculosis isolate is obtained from the child.
2 At least three (children with early primary disease only) or preferably four or more drugs to which
the child’s or adult source case’s isolate is susceptible or naïve should be administered. 3 Growth
and development need to be monitored and drug dosages should be adjusted for weight gain.
4 The patient/parent/care giver should receive counselling about adverse effects, treatment duration
and importance of adherence to treatment at every visit.
5 Early primary (hilar adenopathy or contained primary pulmonary [Ghon] focus) MDR-TB in
children could probably be treated for 12–15 months only.
6 Microbiological monitoring in children is important, but follow-up cultures are often difficult to
obtain and are more often negative. Clinical and chest radiographic monitoring during follow-up is
helpful.
Although children treated with the same drugs experience fewer adverse effects than adults, they
also need to be monitored carefully, as it is more difficult to assess adverse effects in children than
in adults. (15)
Poor adherence to treatment by the source case, often the mother or care giver, raises doubts as to
whether the child will be taken for treatment. (15)

4.5 Diabetes mellitus

Diabetic patients with MDR-TB are at risk for poor treatment outcomes. In addition, the presence of
diabetes mellitus may potentiate the adverse effects of anti-TB drugs, especially renal dysfunction
and peripheral neuropathy. Diabetes must be managed closely throughout the treatment of drug-
resistant TB. The health care provider should be in close communication with the physician who
manages the patient’s diabetes. Oral hypoglycaemic agents are not contraindicated during the
treatment of drug-resistant TB but may require the patient to increase the dosage as the use of
ethionamide or prothionamide may make it more difficult to control insulin levels. However, none
of the anti-TB drugs are contraindicated. Creatinine and potassium levels should be monitored more
frequently, often weekly for the first month and then at least monthly thereafter in view of the renal
effects of aminoglycosides. (29)

4.6 Renal insufficiency

Renal insufficiency caused by longstanding TB infection itself or previous use of aminoglycosides
is not uncommon. Great care should be taken in the administration of second-line drugs in
patients with renal insufficiency, and the dose and/or the interval between dosing should be
adjusted. The dosing is based on the patient’s creatinine clearance, which is an estimate of the
glomerular filtration rate or renal function. (29) (See Annex 4)

4.7 Drug-resistant TB and HIV co-treatment

The composition of the treatment regimen for MDR-TB does not differ for people living with HIV.
Antiretroviral therapy is recommended for all patients with HIV and drug-resistant TB requiring
second-line anti-tuberculosis drugs, irrespective of CD4 cell-count, as early as possible (within the
first eight weeks) following initiation of anti-tuberculosis treatment. (29)
ART in HIV-infected patients with TB improves survival for both drug-resistant and
susceptible disease. Cohorts of patients treated for MDR- and XDR-TB without the
benefit of ART have experienced mortality greater rates. Undue delay in the start of ART could
result in significant risk of HIV-related death among patients with advanced disease. (29)

Antiretroviral therapy is recommended for all patients with HIV and drugresistant-
TB requiring second-line anti-TB drugs, irrespective of CD4 cell-count, as
early as possible (within the first 8 weeks) following initiation of anti-TB treatment.

TB treatment should be initiated first, followed by ART as soon as possible within the first 8 weeks
of treatment. HIV-positive TB patients with profound immunosuppression (e.g. CD4 cell counts
less than 50 cells/mm3) should receive ART within the first 2 weeks of initiating TB treatment. (11,
29, 37)

Bedaquiline be used with caution in people living with HIV. Very limited data are available on
drug–drug interactions with antiretroviral medicines. Therefore, people living with HIV who will be
receiving bedaquiline as part of MDR-TB treatment should have their antiretroviral therapy (ART)
regimens designed in close consultation with HIV clinicians and ART specialists. (31, 38)
Provide co-trimoxazole to all patients with HIV according to WHO recommendations.
Co-trimoxazole is not known to interact significantly with any of the second-line anti-TB
drugs. There are, however, overlapping toxicities between ART, second-line anti-TB drugs,
and co-trimoxazole, so co-infected drug-resistant TB patients should be monitored closely
(see Annex 9).
The complexity of antiretroviral regimens and second-line TB treatment, each with its own
toxicity profiles and some of which may be potentiated by concomitant therapy, demands
rigorous clinical monitoring. Annex 10 describes the monitoring requirements while on drug-
resistant TB therapy and indicates where any extra monitoring is required for patients co-infected
with HIV and/or on ART. (10)

Given that the regimens together are particularly difficult to take, the stigma of both diseases
can result in serious discrimination, and the risk of mortality is very high, patients with
HIVassociated drug-resistant TB may require special socioeconomic, nutritional and psychosocial
support to successfully complete treatment.
Adverse effects are more common in HIV patients. The multiple medicines involved in
drugresistant TB with recognized high toxicity risks, often combined with ART, results in a high
incidence of adverse effects. Some toxicities are common to both anti-TB treatment and
ART, which may result in added rates of adverse events. Monitoring needs to be more intense for
both response to therapy and adverse effects.
There are several known interactions between drugs used to treat HIV and TB (10):
• Rifamycin derivatives. While rifamycin derivatives are not used in MDR-TB treatment,
they are used in the treatment of rifampicin-sensitive poly- and mono-resistant TB.
Guidance on use of rifamycin derivative-based regimens and ART (including with protease
inhibitor-based regimens) is available elsewhere.
• Bedaquiline. This drug is metabolized by the CYP3A4 and has multiple drug interactions
with protease inhibitors and non-nucleoside reverse-transcriptase inhibitors (NNRTI).
• Delamanid. CYP3A4 is the metabolizer of delamanid. Many drugs can either induce or
inhibit the CYP3A4 system, resulting in drug–drug interactions.
• Quinolones and didanosine. Buffered didanosine contains an aluminium/magnesiumbased
antacid and if given jointly with fluoroquinolones may result in decreased
fluoroquinolone absorption; it should be avoided, but if it is necessary it should be
given six hours before or two hours after fluoroquinolone administration.
• Ethionamide/prothionamide. Based on limited existing information of the metabolism
of thiamides (ethionamide and prothionamide), this drug class may have interactions with
antiretroviral drugs. Ethionamide/prothionamide are metabolized by the CYP450 system,
though it is not known which of the CYP enzymes are responsible. Whether doses of
ethionamide/prothionamide and/or certain antiretroviral drugs should be modified during
the concomitant treatment of drug-resistant TB and HIV is completely unknown.
• Clarithromycin. Clarithromycin is a substrate and inhibitor of CYP3A and has multiple
drug interactions with protease inhibitors and NNRTIs. If possible avoid the use of
clarithromycin in patients co-infected with drug-resistant TB and HIV because of both
its weak efficacy against Mycobacterium tuberculosis, multiple drug interactions, and added
adverse events.

In general, HIV patients have a higher rate of adverse drug reactions to both TB and non-TB
medications, and the risk of adverse drug reaction increases with the degree of immunosuppression.
Identifying the source of adverse effects in patients receiving concomitant therapy for drug-resistant
TB and HIV is difficult.
Many of the medications used to treat drug-resistant TB and HIV have overlapping, or in some
cases additive, toxicities. Often it may not be possible to link side-effects to a single drug, as the
risk of resistance for ART precludes the typical medical challenge of stopping all medications and
starting them one by one.
When possible, avoid the use of agents with shared side-effect profiles. Often, however, the
benefit of using drugs that have overlying toxicities outweighs the risk. Therefore, if two
drugs with overlapping toxicities are determined to be essential in a patient’s regimen, it is
recommended with increased monitoring of adverse effects rather than disallowing a certain
combination.
See Annex 9 for more inforantion about potential overlapping and additive toxicities of ART and
anti-TB treatment.

Immune reconstitution inflammatory syndrome (IRIS)

IRIS has emerged as an important complication of ART. IRIS is relatively common in mild
to moderate forms in patients with TB started on ART (seen in up to one third of patients in
some studies; however, it is relatively rare in its severe forms. This syndrome can present
as a paradoxical worsening of the patient’s clinical status, often due to a previously subclinical and
unrecognized opportunistic infection. These reactions may present as fever,
enlarging lymph nodes, worsening pulmonary infiltrates, respiratory distress, or exacerbation of
inflammatory changes at other sites. It generally presents within three months of the initiation of
ART and is more common with a low CD4 cell count (<50 cells/mm3).(10)

It is important to note that IRIS is a diagnosis of exclusion. Patients with advanced AIDS may show
clinical deterioration for a number of other reasons. New opportunistic infections or previously
subclinical infections may be unmasked following immune reconstitution and cause clinical
worsening. IRIS can also be confused with TB treatment failure, and co-infected patients may be
demonstrating progression of TB disease due to drug resistance.
The management of IRIS is complex and depends on the clinical status of the patient and the
site and extent of involvement. Various treatment modalities have been employed, including
nonsteroidal anti-inflammatory drugs (NSAIDs) in mild disease and corticosteroids in
moderate to severe disease. Most patients can be treated without interruption of ART.(10)
5 Monitoring and evaluation of patients treated in MDR-TB regimen

Patients who receive MDR-TB treatment regimen need to be monitored during treatment and after
completion of treatment. This could be conducted in terms for patient response and treatment
outcomes. (see Annex 10)

5.1 Pretreatment screening and evaluation

The required initial pretreatment clinical investigation includes a thorough medical history and
physical examination. The initial evaluation serves to establish a baseline and may identify patients
who are at increased risk for adverse effects or poor outcomes. The monitoring of treatment and the
management of adverse effects may have to be more intensive in patients with pre-existing
conditions or conditions identified at the initial evaluation (diabetes mellitus, renal insufficiency,
acute or chronic liver disease, thyroid disease, mental illness, drug or alcohol dependence, HIV
infection, pregnancy, lactation and others). (13)

5.2 Monitoring progress of treatment

Patients should be monitored closely for signs of treatment failure. Clinically, the most important
way to monitor response to treatment is through regular history-taking and physical examination.
The classic symptoms of TB – cough, sputum production, fever and weight loss – generally
improve within the first few months of treatment and should be monitored frequently by the
medical team. The recurrence of TB symptoms after sputum conversion, for example, may be the
first sign of treatment failure. For children, height and weight should be measured regularly to
ensure that they are growing normally. A normal growth rate should resume after a few months of
successful treatment. (13)

The use of sputum-smear microscopy and culture rather than sputum-smear microscopy alone is
recommended for the monitoring of patients with MDR-TB during treatment. (29) The most
important objective evidence of improvement is conversion of the sputum smear and culture to
negative. While sputum smear is still useful clinically because of its much shorter turnaround time,
sputum culture is much more sensitive and is necessary to monitor the progress of treatment.
Sputum examinations are also dependent on the quality of the sputum produced, so care should be
taken to obtain adequate specimens. (13)

Persistently positive sputums and cultures for AFB should be assessed for NTM, as overgrowth
with NTM in lung damage secondary to TB is not uncommon. In such cases, although DR-TB may
be adequately treated, treatment may need to be directed towards the NTM as well. (13)
Sputum conversion is slower in DR-TB than in drug-susceptible TB. Paucibacillary culture results
should not be automatically regarded as negative when treating DR-TB. Acquired drug resistance
and treatment failure often begin with the growth of one or two colonies on a sputum culture.
Culture conversion should not be considered to be equivalent to cure. A certain proportion of
patients may initially convert and later revert to positive sputum culture.
Sputum smears and cultures should be monitored closely throughout treatment. The tests be
performed monthly before smear and culture conversion, with conversion defined as two
consecutive negative smears and cultures taken 30 days apart. After conversion, the minimum
period recommended for bacteriological monitoring is monthly for smears and quarterly for
cultures. (13)

For patients who remain smear- and culture-positive during treatment or who are suspects for
treatment failure, DST can be repeated. It is usually not necessary to repeat DST within less than
three months of completion of treatment.
The chest radiograph may be unchanged or show only slight improvement, especially in re-
treatment patients with chronic pulmonary lesions. Chest radiographs should be taken at least every
six months, when a surgical intervention is being considered, or whenever the patient’s clinical
situation has worsened. (13)

5.3 Examinations at baseline and during treatment

- Sputum smear, culture, and DST should be done at baseline; sputum smear and culture should
then be done monthly until completion of treatment. They should also be repeated at six and 12
months after completing treatment.
- Body weight and height should be measured at baseline to determine body mass index, which is a
predictor of outcome; weight should then be assessed monthly.
- Screening for diabetes is ideally done for all patients by measuring hemoglobin A1c. A fasting
blood glucose is an acceptable alternative if it is not possible to measure hemoglobin A1c.
- Screening for HIV, hepatitis B, and hepatitis C is important. Both are common co-morbidities
among MDR-TB patients.
- HIV-positive patients should have a CD4 count and viral load before starting treatment, and
regularly thereafter according to guidelines.
- Serum creatinine should be measured to screen for acute kidney injury or chronic renal disease. It
should be repeated monthly in patients receiving an injectable.
- Full blood count should be performed for all patients at the beginning of treatment, as anemia is
common in MDR-TB patients and is a predictor of poor outcome.
- Visual acuity and Ishihara testing should be performed at the start of treatment and monthly
thereafter for patients receiving linezolid.
- Audiometry, should be performed at baseline and monthly thereafter in patients receiving an
injectable drug.
- Electrocardiogram (ECG) should be obtained at the start of treatment and regularly thereafter in
patients who are receiving QT-prolonging drugs.
- Thyroid stimulating hormone (TSH) should be measured at baseline and every three months
thereafter in patients receiving ethionamide or prothionamide.
- All female patients of child-bearing age should be evaluated for pregnancy at the start of treatment
and as appropriate during treatment.
- A chest x-ray should be performed at baseline and as needed during treatment. (30)

5.4 Monitoring and management of adverse events

Second-line drugs have many more adverse effects than the first-line antituberculosis drugs. Close
monitoring of patients is necessary to ensure that the adverse effects of second-line drugs are
recognized quickly. The ability to monitor patients for adverse effects daily is one of the major
advantages of DOT.(13)
Patients should be screened monthly by the doctor of the dispensary in the diagnosis and
management of adverse events (AE). An AE is an unexpected medical problem that happens during
treatment with a drug or other therapy. AEs may be mild, moderate, or severe, and may be caused
by something other than the drug or therapy being given. (32)

Proper management of adverse effects begins with patient education. Before starting treatment, the
patient should be instructed in detail about the potential adverse effects that could be produced by
the prescribed drug regimen, and if and when to notify a health-care provider. (13)

Management of AEs should take patient safety and treatment requirements into consideration. One
or more drugs may need to be suspended or the dose reduced. Replacement of offending drugs
should take the clinical condition and bacteriological status of the patient into account and a
decision made after careful case review. (32)

5.5 Safety reporting

All serious adverse events (SAEs) should be reported immediately to the relevant national
pharmacovigilance authority according to national guidelines (e.g. 72 hours). An SAE is any
untoward medical occurrence that at any dose:
-Results in death.
-Requires inpatient hospitalization or prolongation of existing hospitalization.
-Results in persistent or significant disability/incapacity.
-Is life-threatening.
-Is a congenital anomaly or a birth defect.

The appropriate and timely management of all AEs and ADRs is an integral component of
aDSM and patient care. Close coordination of aDSM activities with main pharmacovigilance
structures at the countrylevel is essential to avoid overlap and duplication. The overall objectives of
aDSM are to reduce risks from drug-related harms in patients on second line
treatment for drug-resistant TB and to generate standardized aDSM data to inform future
policy updates on the use of such medicines. (39)
Patients targeted for aDSM should undergo active and systematic clinical and laboratory
assessment during treatment to detect drug toxicity and AEs. All AEs detected should be managed
in a timely manner in order to deliver the best possible patient care.
The responsibility for the coordination of aDSM is from the committee of the NTP, integrated
within routine PMDT programme monitoring. (39)
The package of aDSM contains clinical and laboratory test records at baseline (treatment
initiation) and during regular reviews (e.g. monthly intervals), integrated into an
expanded version of the programmatic MDR-TB (second-line TB) Treatment Card. The treatment
initiation form should be completed before the start of treatment (to document any abnormality that
could later be confused with a drug-related SAE) and the review form should be completed at
scheduled encounters with the patient. In addition, information on SAEs occurring in-between visits
should also be captured using the same forms. aDSM is not aimed at replacing or duplicating efforts
of national pharmacovigilance units but to complement current capacities and address barriers to
undertake active pharmacovigilance within the context of TB care. In addition to drug-safety
monitoring, aDSM also incorporates a component that promotes the clinical management of all
ADRs and AEs regardless of their seriousness. SAEs may require a drastic intervention, such as
termination of the drug suspected of having caused the event. (39)

Key recommendations (30):

- Implement standard monitoring for all patients DR-TB treatment
- Monitor both smear and culture monthly to evaluate treatment response.
- Increase monitoring for HIV coinfected patients and for those on ART.
- Health-care workers in DR-TB control programmes should be familiar with the
management of common adverse effects of MDR-TB therapy.
- Ancillary drugs for the management of adverse effects should be available to the patient.

5.6 Data management and project monitoring

Patient data should be recorded on standard NTP treatment cards and documents.

6 Patient consent
Patients should receive information of the treatment at the beginning of treatment whether he/she
receives new or not new TB drugs. Whole process of the treatment shoud be described at the
beginning (shorter, individualized, with Bedaquiline or Delamanid etc). Inform patients that they
may talk to anyone they feel comfortable talking with about the drug and that they can take time to
reflect on whether they want to receive it or not. Assure the patient that if they do not understand
some of the words or concepts, that you will take time to explain them as you go along and that they
can ask questions now or later. Explain the treatment scheme, the reason for the application, how
the treatment will be taken, the side effects, and monitoring tests. It is important to state clearly that
receiving the drug (eg bedaquiline) is voluntary. (10)
After providing the patient education material to the patient, consent in patients starting new TB
drugs must be obtained. The consent process will ensure the patient is:
-Aware of the novel nature of the new TB drug;
- Appreciates the reason why the drug is being proposed to be included in their treatment regimen;
- Recognizes the possible benefits and potential harms, including the uncertainty that surrounds
outcomes.
For patients considered minor or incapacitated by national law, consent from the legal
representative is additionally required. (26)
(See Annex 13)

7 Inpatient and ambulatory treatment

7.1 Organization of the Health System in Albania

The diagnostic and treatment healthcare is organized in three levels:
 primary health care
 secondary hospital care
 tertiary hospital care

7.1.1 Primary health care is represented by primary health care centres. Health care centres
provide all services of primary health care: public health services and promotion, which are
supported and supervised by IPH as well as the diagnosis, treatment, recovery and other health care
services.

7.1.2 Secondary health care is represented by district and regional hospitals.

7.1.3 Tertiary health care is represented by University Hospital Centre, which is the national
centre of referral and diagnosis.

7.2 Tuberculosis control in Albania

At ambulatory care, Tuberculosis control is provided by lung disease dispensaries, which are
generally extensions of former dispensaries against tuberculosis. Their staff consist of one or
several pulmonologists, some nurses, a radiology technician, a bacteriological laboratory technician,
in case there are such laboratories.

TB control in Albania is organized vertically, i.e. it is a closed system within the pulmonology
speciality. Efforts are being made to integrate it in primary care or to involve the family doctor in
TB control, and particularly in providing treatment during the continuation phase.
Tirana University Hospital “Shefqet Ndroqi”, is the leading institution in the fight against
tuberculosis. National Reference Laboratory for Tuberculosis (NRLTB) and NTP are integrated
structures of this hospital. It is the only hospital in Tirana with rooms dedicated for TB treatment,
for the organization of the isolation area, able to accommodate MDR TB patients (2-3 patients per
year with an average staying in the isolation area of 6 months). Are in construction two negative
pressure rooms for MDR patients.
The following diagram reflects the general organization of TB in Albania:

Ministry of Health
(National Committee for TB Control)

UHT “Shefqet Ndroqi” Department of

National TB Programme NTP Pulmonary Diseases

Dispensaries

The suspected or diagnosed MDR-TB cases shall refer for evaluation and treatment formulation
regimen in the University Hospital SH. Ndroqi. MDR-TB cases are hospitalized for treatment
during the intensive phase.
Children with TB are treated in the University Hospital “Nënë Tereza” and cases of meningitis or
other forms of extrapulmonary TB are treated by specialty, in the same hospital.

7.2.1 Lung dispensaries

Medical staff working in dispensaries is trained for the implementation of DOTS. Generally, there
is a good commitment of dispensaries staff in DOTS implementation, but medication under
supervision remains a problem. Lung dispensaries are subordinate to hospital directorates, but
recently there have been some districts which passed under subordination of the primary care.

7.2.2 Family doctors

They have been considered as an important part for tuberculosis control, even though until today
they have not been included in concrete terms or by law in its control, despite that in the obligations
of the family doctor in the contract with the Health Insurance Institute (HII) several tasks are
mentioned. Generally, family doctors are aware of their role in TB control in the future and are ready to
collaborate for its diagnosis and treatment. The family doctor must be involved in TB control, both during
the diagnosis and also during the treatment and prophylaxis. Family doctors, having well-defined terms of
reference, will be responsible for treatment during the continuation phase; they will assist in close contact
control and in the chemoprophylaxis. The patient centred model would be an option to be further evaluated
based on progress of health sector reform.

7.3 Models of MDR-TB care (hospitalization/ambulatory)

WHO guidelines The World Health Organization treatment guidelines for drug-resistant
tuberculosis 2016 contain no specific recommendations on isolation and hospital infection control.
The guideline states “Culture positive extensively drug-resistant TB (XDR-TB) patients should be
in respiratory isolation at all times”, which implies that even patients who are AFB-microscopy
negative and PCR-negative but culture positive should be kept in isolation but not necessarily in a
negative pressure room in hospital. This applies only to XDR patients, and isolation may be in the
patient’s own home provided he/she is kept in their own rooms and all contacts use N95 respirators
when in contact with the patient. The WHO policy package for infection control includes
managerial activities, administrative controls and environmental controls. Managerial activities
include implementation of infection control coordination bodies at hospital level and different
activities including heath facilities construction and renovation. The administrative controls are
aimed at regulating the flow of staff, visitors and patients through triage, separation of infectious
cases and minimisation of the time spent at the health facility, while maximising prevention of
transmission and minimising risks. The environmental measures aim at enhancing ventilation
(natural or mechanical) and investing in facility improvement, while applying strict personal
protection measures including respirators for health staff (and visitors) and surgical masks for
patients. The combination of different infection control strategies, including diagnosis of HIV
infection and treatment with antiretroviral therapy, are able to avert a significant proportion of
infections and, consequently, future cases. (40) Furthermore, treatment of XDR-TB is often
ineffective in rapidly interrupting transmission making it infectious longer than theoretically
necessary. (40)
MDR-TB cases are hospitalized for treatment during the intensive phase or until they convert to
smear negative/culture negative status. The hospital-based model of care is being enforced in all
MDR-TB patients, that is, compulsory isolation while sputum smear/culture remains positive.
Compulsory isolation should be considered only and exclusively when all measures, and not only
the measures easy to implement, to ensure adherence to treatment have been systematically
exhausted. (10) Hospitalization was common and remains a critical care component for patients
who were older, had comorbidities, or required complex management due to XDR-TB. (41) The
detection of SAEs lead to hospitalization, or prolongation of hospitalization.

Patients must be hospitalized at the initiation of MDR-TB treatment for a period of time to ensure
that patients can tolerate the regimen. MDR-TB cases are hospitalized for treatment during the
intensive phase (with an average staying of 6 months). It may also be advisable for specific groups
and for very ill people, for instance when adverse events occur during treatment. (30)
Hospitalization was common and remains a critical care component for patients who were older,
had comorbidities, or required complex management due to XDR-TB. (41) The detection of SAEs
lead to hospitalization, or prolongation of hospitalization. (10) Under the conditions of our country
it is necessary to keep pulmonary TB cases, particularly sputum smear-positive ones, hospitalized
until their conversion to sputum negative.
Home-based care should be offered to patients and families who want to keep the patient at home,
whenever appropriate infection control practices can be followed. (10) Patients being in good social-
economic conditions may be treated more early under ambulatory care. In both cases, the healthcare
staff shall give the drugs to the patient every day, and the patient should take them in their presence.
After hospital discharge DOT can be implemented in cooperation with primary health care service,
at the closes health care centre.
Directly Observed Therapy (DOT) should be administered throughout the whole treatment course
and the shorter regimen should be administered seven days per week during intensive phase and at
least five days per week during continuation phase. Ambulatory DOT services could be either
"facility-based" in which patients visit a health care facility daily for treatment, or "community-
based" in which a nurse (from dispanceries or primary health care) visits the patients daily for drug
administration (or vice versa) and accompanies the patient to follow-up visits and liaises with the
clinical staff. Enablers and incentives (such as travel expenditure or food) during the whole
treatment course are helpful and should be consistently provided whenever possible. (30) as part of
patients centred model were pay per performance incentives would be anm option.
During transition period until full health sector reform would take place with implementation of
patient centred model treatment supporters system with provision of providers and patient’s
incentives and enablers should be developed.

During the treatment follow up stage, the patients shall take the medication from the nearest healthcare
unit. During the treatment follow up stage, the patient shall be under the control of the family doctor
and patronage nurse in cooperation with the dispensary staff. The dispensaries staff in cities and
villages and the staff of the nearest healthcare centre shall follow the treatment at the follow up stage.
This collaboration will bring about advantages in TB control. This shall establish better relations
between the medical staff in the districts and TB patients and their family members, thus
influencing on better control of close contacts of TB patients.

Patients failing to appear for the treatment or leaving the treatment shall be contacted immediately and
undergo the treatment. If such a thing is not achieved, the dispensary and district epidemiologist should
be notified accordingly.

TB cases shall undergo personalized treatment. Cases that do not have social support and are at risk
of not receiving treatment on daily basis shall be managed according to a specia l program. TB
patients shall be provided with social and economic support during the treatment stage, in the form
of basic food packages and transport incentives.

Medical staff working in dispensaries in cooperation with primary health care service have the
following responsibilities:
- Strictly administer DOT on a daily basis.
- Ensure that the patient attends all scheduled follow-up visits and examinations.
- Monitor adverse events closely and address adverse events in a timely manner by informing
clinical staff.
- Update the patient treatment card on a daily basis.
- Initiate patient tracing if the patient fails to return for treatment as per schedule.
- Ensure that there is a sufficient buffer stock of drugs for patients who are currently on
treatment.

8 The informantion about new TB drugs

The endTB data also clearly shows that toxicities related to injectables and linezolid are more
common than toxicities related to either of the new TB drugs, bedaquiline or delamanid. The
effectiveness of delamanid in treatment of MDR-TB is supported by a high rate of culture
conversion within six months. Both delamanid and bedaquiline appear to be safer than commonly
used drugs such as injectables or linezolid. (31)

8.1 Duration of bedaquiline and delamanid

Bedaquiline and delamanid should be prescribed for a minimum of 24 weeks, and may be extended
until the entire length of treatment. Treatment should therefore be extended at the clinical discretion
under appropriate monitoring. Common reasons for extending bedaquiline or delamanid longer than
24 weeks include:
- Less than five effective drugs in the regimen if Bdq or Dlm is stopped.
- Late or slow response to treatment. For example, the patient is slow to sputum convert (still
strongly smear or culture positive after month 2), has slow resolution of TB symptoms, or has
extensive lung damage. (26)

Table 5 Contraindications for new and repurposed drugs (26)

Drug Relative contraindications Remarks/Precautions
All drugs Known hypersensitivity to the drug A history of anaphylaxis or severe drug
reaction like Stevens-Johnson syndrome is
an absolute contraindication.
Bdq, Dlm - Baseline ECG demonstrating a QTcF > Use with caution if QTcF > 450/470 ms in
500 ms (repeated); or male/female patients.
- History of syncopal episodes, Weekly ECG monitoring and serum
ventricular arrhythmias or severe electrolyte screening should be performed
coronary artery disease if Bdq or Dlm is being used despite a
cardiac contraindication. Dlm may prolong
the QT interval less than Bdq.
Bdq Severe hepatic failure Caution in patients with severe hepatic
impairment.
Bdq, Dlm, Severe renal failure Caution in patients with severe renal
Lzd impairment.

Ipm/Cln, Patients with central nervous system Use with caution as carbapenems have
Mpm disorders been associated with seizures.

3.5.2 Drug-drug interactions

During the formulation of the treatment regimen should be considered possible drug-drug
interactions, and in cases with HIV between antiretrovirals with the new TB drugs. Every effort
should be made to avoid the use of drugs with overlapping toxicities.
Table 6 Possible drug-drug interactions with the new TB drugs (26)
Drugs Examples/notes
Avoid use with Bdq Strong/moderate inducers of
- Efavirenz*
cytochrome P450 may decrease
- Rifamycins
blood levels of Bdq
- Phenytoin
- Carbamazepine
- Phenobarbital
Strong/moderate inhibitors of - Ritonavir-boosted PIs*
cytochrome P450 may increase - Oral azole antifungals (can be used
blood levels of Bdq up to two weeks):
o Itraconazole
o Fluconazole**
- Macrolide antibiotics other than
azithromycin**:
o Clarithromycin
o Erythromycin
Avoid use with Dlm First-line standard anti-TB therapy - First line anti-TB therapy with
(isoniazid, rifampicin, ethambutol, fixed dose combination of HREZ
pyrazinamide) appears to decrease levels of Dlm in
early studies. The mechanism is not
clear.
* All four oral azoles inhibit CYP3A4; itraconazole and posaconazole are more potent inhibitors than fluconazole or
voriconazole.
** Azithromycin does not inhibit CYP isoenzymes but does prolong the QT interval so may want to be avoided for this
reason
Table 7 Possible drug-drug interactions between antiretrovirals and the new TB drugs (26)
ARVs to avoid with Bdq
Drugs Instructions
Efavirenz (EFV) - Substitute nevirapine (NVP) or
(Using EFV with Bdq will result in integrase inhibitor instead of EFV.
low levels of Bdq) Allow a 5 day washout of EFV if
possible (substitute NVP on day 1
and then start MDR regimen 5 days
later). If patient is critically ill with
MDR-TB, no washout period is
necessary.
- When switching back to EFV after
ending treatment with Bdq, this can
be done immediately after Bdq is
stopped.

Ritonavir containing protease -If possible, use an ARV regimen

inhibitors (PIs)
(Using ritonavir with Bdq will result
in high levels of Bdq)
with no PI. One possible solution is
to substitute the PI with an integrase
inhibitors (INSTIs), e.g. dolutegravir
(DTG) or raltegravir (RAL).
- If a ritonavir-containing PI must be
used, check ECG every two weeks.

ARVs to avoid with Dlm None Dlm has very little drug-drug
interactions with ARVs and no extra
drug monitoring or regimen
adjustment is needed.

3.5.3 Overlapping toxicities

Every effort should be made to avoid the use of drugs with overlapping toxicities. However, there
may be circumstances where no other option is available and the potential benefits outweigh the
risks. For example, a fragile mental health patient with a high risk of suicide that must have
linezolid in the regimen (no other anti-TB drug options) could require a serotoninergic medication.
Psychiatric drugs are commonly used in MDR-TB patients for the treatment of cycloserine-induced
psychosis or reactive depression. The anti-psychotics in particular are well-known to prolong the
QT interval. It is the responsibility of the TB physician to understand the effects and side effects of
psychiatric drugs, and to monitor MDR-TB patients taking these drugs carefully, even if the patient
is referred to a psychiatrist.

Table 8 Non-TB drugs that have potential overlapping toxicities with the new TB drugs (26)
Drugs Examples/notes
Avoid with Bdq, Dlm Drugs that cause QT prolongation or - Oral azole antifungals (can be used
affect the heart rhythm* up to two weeks):
o Ketoconazole
o Itraconazole
o Fluconazole
- Macrolide antibiotics:
o Azithromycin
o Clarithromycin
o Erythromycin
- Antipsychotics (all have some
risk), including:
o Haloperidol
o Risperidone
- Many anti-nausea drugs, for
 example:
o Ondansetron
o Granisetron
o Domperidone
o Chlorpromazine
- Methadone
- Cardiac drugs that may affect the
heart rhythm, for example:
o Amiodarone
o Beta-blockers
o Digoxin
o Quinidine
Avoid with Lzd Medicines that increase serotonin - Serotonin re-uptake inhibitors
levels (SSRIs): fluoxetine, paroxetine
- Tricyclic antidepressants:
amitriptyline, nortriptyline
- Serotonin 5-HT1 receptor agonists
- MAO inhibitors: phenelzine,
isocarboxazid
- Other serotoninergic agents:
meperidine, bupropion, or buspirone,
quetiapine

Table 9 Treatment of extrapulmonary TB with new and repurposed drugs (26)

Drugs Recommendations
Bdq Very limited experience with Bdq in TB meningitis or TB osteomyelitis. One patient with
meningitis had undetectable levels of Bdq in CSF. Drug is protein bound and likely has
low penetration into the CSF.
Dlm Very limited experience with Dlm in TB meningitis or TB osteomyelitis. Drug is protein
bound and likely has low penetration into the CSF.
Lzd Excellent bone and soft-tissue penetration; commonly used for osteomyelitis due to gram-
positive bacteria.
Cfz Cfz has been used extensively to treat leprosy lesions in soft tissue, though it is unclear if
this means that bone and soft tissue penetration is adequate.
Ipm/Cln Both Ipm/Cln and Mpm reach measurable concentrations in CSF, but Mpm is thought to
Mpm be less neurotoxic (seizures). Both drugs have been used to treat osteomyelitis caused by
other bacteria.

Table 10 New TB Drugs in special populations (26)

Situation Recommendations
HIV - Antiretroviral therapy (ART) should be given to any HIV co-infected MDR-TB
patient without delay.
- ART can be started as soon as MDR-TB treatment is tolerated—usually within a few
days. The risk of immune reconstitution syndrome can be mitigated by designing an
appropriate MDR-TB regimen.
- Bedaquiline has important interactions with ART that will affect the choice of ART.
Chronic renal - Bedaquiline and delamanid are not renally excreted and no dose adjustment is
insufficiency required in mild/moderate renal insufficiency. There is no data on the use of either of
these drugs in patients with severe renal impairment.
- No dose adjustment of linezolid is required in patients with renal impairment;
however, the two primary metabolites of linezolid accumulate in patients with renal
impairment and the clinical significance of this is unknown.
- No dose adjustment of clofazimine is required in patients with renal impairment.
Hepatitis C - Often MDR-TB is strongly correlated with hepatitis C infection.
- Active hepatitis C is a risk factor for MDR-TB treatment failure.
- Direct-acting antivirals (DAA) are well-tolerated when given with MDR-TB
treatment.
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9 Annexes
Annex 1 Target groups for DST (10)
Risk Factors for Drug-Resistant-TB
Failure of retreatment regimens with first line anti-TB
drugs (SHREZ) a (previously known as chronic TB
cases)
Exposure to a known drug-resistant TB case
Failure of new TB regimens (HREZ)
Patients who remain sputum smear-positive at month
two or three of a first-line anti-TB drug regimen
Relapse and return after loss to follow-up, without
recent treatment failure
Exposure in institutions that have drug-resistant TB
outbreaks or a high drugresistant TB prevalence
Residence in areas with high drug-resistant TB
prevalence
History of using anti-TB drugs of poor or unknown
quality
Co-morbid conditions associated with malabsorption
or rapid-transit diarrhoea
HIV in some settings
Comments
Patients who are still sputum smear-positive at the end
of a retreatment regimen have perhaps the highest
MDR-TB rates in any group, often approaching 90%.
Most studies have shown that close contacts of MDR-
TB patients have very high rates of MDR-TB.
Patients who, while on treatment, are sputum smear-
positive at month five or later during the course of
treatment are at elevated risk for drug-resistant TB. Not
all patients in whom a regimen fails have drug-resistant
TB, and the percentage may depend on a number of
factors, including whether rifampicin was used in the
continuation phase and whether directly observed
therapy was used throughout treatment.
Patients who remain sputum smear-positive at months
two and three are at risk for drug-resistant TB.
Evidence suggests that most relapse cases and those
that return after loss to follow-up (without recent
treatment failure) do not have drug-resistant TB.
However, certain patient histories may point more
strongly to possible drug-resistant TB; for example,
erratic drug use or early relapses.
Patients who frequent homeless shelters, prisoners and
health care workers in clinics, laboratories and hospitals
can have high rates of drug-resistant TB.
Drug-resistant TB rates in many areas of the world can
be high enough to justify routine DST in all new cases.
The percentage of drug-resistant TB caused by use of
poor quality drugs is unknown but considered
significant. All drugs should comply with acceptable
international quality assurance standards.
Malabsorption may result in selective low serum drug
levels and may occur in either HIV-negative or HIV-
positive patients.
Data from the Global Project on Anti-TB Drug
Resistance Surveillance suggest an association between
HIV and MDR-TB in some parts of the world, and
 numerous drug-resistant TB outbreaks have been
documented in HIVpositive patients. Data are still
limited and specific factors involved in this association
may be country-specific. Even if HIV is not considered
to be a risk factor for drug-resistant TB in a country, it is
strongly recommended that all individuals with HIV-
associated TB have DST to rule out drug-resistant TB
and to avoid high rates of mortality due to unrecognized
drug-resistant TB in these patients.

Annex 2 General considerations of anti-tuberculosis medicines (Adapted from 10)

Levofloxacin (Lfx)
Drug class: Fluoroquinolone (FQN)
Activity against TB, Bactericidal: has strong anti-TB activity. Cross-resistance with other
mechanism of action, fluoroquinolones but may not be complete. Inhibits DNA gyrase.
and metabolism
Dose Adults: For treatment of TB disease 10–15 mg/kg once daily.
Children: 5 years and under: 15–20 mg/kg split into two doses (morning and
evening). Over 5 years: 10–15 mg/kg once daily.
Renal failure/dialysis: 750–1000 mg/dose, 3 times weekly (not daily) for
creatinine clearance <30 ml/min.
Route of administration Oral or intravenous.
Preparation Coated tablets (250 mg, 500 mg, 750 mg); solution for injection 25 mg/ml; 250
mg in 50 ml container; 500 mg in 100 ml container; 750 mg in 150 ml container.
Oral suspension is 25 mg/ml.
Storage Oral forms, undiluted solution, and pre-mixed solutions are stored at room
temperature (15–25 °C). Once diluted, the solution can be kept at room
temperature for 3 days, in the refrigerator for 2 weeks, or frozen for 6 months.
Oral absorption Excellent oral absorption.
Levofloxacin in an anion and taking with divalent cations will result in bonding
and not being absorbed: administrate two hours before or four hours after
ingestion of milk-based products, antacids, or other medications containing
divalent cations (iron, magnesium, calcium, zinc, vitamins, didanosine,
sucralfate).
CSF penetration Concentrations are 65% of that in the serum.
Special circumstances Use in pregnancy/breastfeeding: Fluoroquinolones are generally avoided during
pregnancy and breastfeeding due to possibility of arthropathy. However, there are
a few case reports of fluoroquinolones being used safely during pregnancy.
Use in renal disease: Dosage adjustment is recommended if creatinine clearance
is <50 ml/min. The drug is not cleared by haemodialysis; supplemental doses
after dialysis are not necessary.
Use in hepatic disease: Drug concentrations are not affected by hepatic disease.
Presumed to be safe in severe liver disease.
Adverse reactions Nausea and bloating. Headache, dizziness, insomnia or tremulousness.
Rare tendon rupture, arthralgias (can usually be treated symptomatically).
QTc prolongation, hypoglycaemia.
Contraindications Fluoroquinolone intolerance, prolonged QTc, pregnancy (relative
contraindication).
Monitoring Side effect monitoring, but no specific laboratory monitoring required.
Patient instructions You can take levofloxacin with food. Drink plenty of beverages. Do not take
and alerting symptoms milk-based products, antacids (especially aluminumcontaining), mineral
supplements such as iron or magnesium, or multivitamins within 2 hours of this
medication or within 4 hours after. This medicine may cause sun sensitivity; use
sunscreens. Do not undertake new strenuous activities.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Pain, swelling or tearing of a tendon (such as the back of your ankle, elbow,
 etc.), or muscle or joint pain
• Rashes, hives, bruising or blistering, trouble breathing or tightness in your chest
• Diarrhoea
• Yellow skin or eyes
• Anxiety, confusion or dizziness.

Moxifloxacin (Mfx)
Drug class: Fluoroquinolone
Activity against TB, Bactericidal: inhibits DNA gyrase; cross-resistance with other
mechanism of action, fluoroquinolones, but may be more active based on in vitro data.
and metabolism
Dose Adults: 400 mg daily (oral or IV).
Children: No established dose.
Renal failure/dialysis: No dose adjustment required.
Route of administration Oral or IV.
Preparation Tablets (400 mg); aqueous solution (400 mg/250 ml) for IV
injection.
Storage Store oral and IV products at room temperature (15–25 °C). Do not
refrigerate.
Oral absorption Good oral absorption (90% bioavailable). Moxfloxacin is an anion and taking
with divalent cations will result in bonding and not being absorbed: Administrate
2 hours before or 4 hours after ingestion of milk-based products, antacids, or
other medications containing divalent cations (iron, magnesium, calcium, zinc,
vitamins, didanosine, sucralfate).
CSF penetration Good penetration in animal model studies.
Special circumstances Use during pregnancy/breastfeeding: Fluoroquinolones are generally avoided
during pregnancy and breastfeeding due to observation of arthropathy in animal
models. However, there are a few case reports of fluoroquinolones being used
safely during pregnancy.
Use in renal disease: Excretion unchanged during renal failure; no data on effect
of dialysis.
Use in hepatic disease: Rarely associated with hepatotoxicity; use with caution.
No dose adjustment required for mild or moderate liver disease.
Adverse reactions Nausea and diarrhea.
Headache and dizziness.
Rare tendon rupture; arthralgias. Rare hepatotoxicity.
QTc prolongation, hypo/hyperglycaemia.
Contraindications Fluoroquinolone intolerance, prolonged QTc.
Monitoring Symptomatic monitoring.

Bedaquiline (Bdq)
Drug class: Diarylquinoline
Activity against TB, Bactericidal: Inhibits ATP synthesis; novel method of action; The drug has a 5.5-
mechanism of action, month half-life. CYP3A4 is the major CYP isoenzyme involved in the
and metabolism metabolism of bedaquiline. The metabolism leads to the formation of N-
monodesmethyl metabolite (M2). M2 is not thought to contribute significantly to
clinical efficacy given its lower average exposure (23–31%) in humans and lower
antimycobacterial activity (4- to 6-fold lower) compared to the parent compound.
M2 concentrations appeared to correlate with QT prolongation. Bedaquiline is
mainly eliminated in faeces. The renal clearance of unchanged drug is
insignificant.
Dose Adults: 400 mg once daily for 2 weeks, followed by 200 mg, 3 times per week for
22 weeks with food.
Children: Not yet determined.
If a dose is missed during the first 2 weeks of treatment, patients should not make
up the missed dose but should continue the usual dosing schedule. From week 3
onwards, if a 200 mg dose is missed, patients should take the missed dose as soon
as possible, and then resume the 3 times a week regimen.
Preparation and 100 mg tablets.
administration
Storage Store tablet at room temperature (15–25 °C).
Oral absorption Better absorption is obtained if taken with food.
CSF penetration No data are available regarding CNS penetration.
Special circumstances Use in pregnancy/breastfeeding: Not recommended during pregnancy or
breastfeeding due to limited data. Reproduction studies performed in rats and
rabbits have revealed no evidence of harm to the fetus.
Use in renal disease: No dosage adjustment is required in patients with mild to
moderate renal impairment (dosing not established in severe renal impairment,
use with caution).
Use in hepatic disease: No dosage adjustment is required in patients with mild to
moderate hepatic impairment. Dosing and toxicity not well established in severe
hepatic impairment, use with caution and only when the benefits outweigh the
risks.
Adverse reactions Common: Gastrointestinal distress (nausea, vomiting, abdominal pain, loss of
appetite), joint pain (arthralgia), headache. (Note: haemoptysis and chest pain
were also more frequently reported in the group receiving bedaquiline than in the
placebo treatment group).
Less common: QT prolongation, hyperuricaemia, phospholipidosis (the
accumulation of phospholipids in the body’s tissues), elevated aminotransferases.
Possibly an increased risk of pancreatitis.
Contraindications/ Do not use or discontinue bedaquiline:
Caution • Clinically significant ventricular arrhythmia.
• A QTcF interval of >500 ms (confirmed by repeat ECG).
• Severe liver disease.
• Abnormal electrolytes.
Use with caution in the following situations (with more frequent ECG monitoring
and evaluation of risk versus benefit):
• Use with other QT prolonging drugs (see drug interactions)
• A history of torsade de pointes
• A history of congenital long QT syndrome
• A history of hypothyroidism and bradyarrhythmias
• A history of uncompensated heart failure
• Serum calcium, magnesium or potassium levels below the lower limits of
normal.
Drug interactions Bedaquiline is metabolized by CYP3A4. Rifampicin (a CYP3A4 inducer)
reduces bedaquiline in blood by half. Efavirenz based on a single dose study
appears to reduce the amount of bedaquiline though inducing CYP3A4. CYP3A4
inhibitors (e.g. azole anti-fungal drugs, some macrolides, protease inhibitors, and
many others) can raise the level of bedaquiline but can be considered for use if
the benefits outweigh the risk.
Avoid use with other drugs that prolong the QT interval as additive QT
prolongation may occur (e.g. clofazimine, fluoroquinolones, delamanid, azole
anti-fungal drugs, and many others); any syncopal event (fainting) should prompt
an immediate medical evaluation and ECG.
Monitoring An ECG should be obtained before initiation of treatment, and at least 2, 4, 8, 12
and 24 weeks after starting treatment.
More frequently if heart conditions, hypothyroidism or electrolyte disturbances
are present. Liver function tests should be done monthly.
Patient instructions The patient should be informed that bedaquiline is a new anti-TB drug and there
and alerting symptoms could be unknown risks and side-effects. The following serious side-effects can
occur with bedaquiline: death, heart rhythm abnormalities, and/or hepatitis. This
medicine should be taken with food. Avoid alcohol. The patient should be
informed that in one clinical trial, more deaths were seen in people who were
treated with bedaquiline compared to people who did not receive.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Abdominal pain
• Yellowing of your skin or eyes
• Palpitations
• Chest pain
 • Fainting and near fainting events.

Linezolid (Lzd)
Drug class: Oxazolidinones
Activity against TB, Has in vitro bactericidal activity – increasing clinical experience; inhibits protein
mechanism of action, synthesis.
and metabolism
Dose Adults: 600 mg, once daily. (Reduce to 400–300 mg/day if serious
adverse effects develop).
Children: 10 mg/kg three times daily in children up to 11 years of age and 10
mg/kg (maximum dose 600 mg) twice daily in older children. Vitamin B6: All
patients should receive vitamin B6 while receiving linezolid.
Preparation Coated tablets: 400 and 600 mg; intravenous solution: 2 mg/ml: 100, 200 or 300
mg bags. Intravenous doses are administered over 30–120 minutes.
Oral powder for suspension: 100 mg/5 ml, 240 ml bottle.
Storage Store tablet at room temperature (15–25 °C). Reconstituted oral suspension may
be stored at room temperature for 21 days.
Parenteral preparation should be stored at room temperature (protect from light
and do not freeze).
Oral absorption Nearly complete oral absorption.
CSF penetration CSF concentrations are about 1/3 of those in serum in animal models, and
linezolid has been used to treat meningitis in humans.
Special circumstances Use in pregnancy/breastfeeding: Not recommended during pregnancy or
breastfeeding due to limited data.
Use in renal disease: No dose adjustment is recommended, but metabolites may
accumulate.
Use in hepatic disease: Rarely associated with increased transaminases.
Adverse reactions Myelosuppression (decreased level of platelets, decreased level of white blood
cells, and/or anaemia).
Diarrhoea and nausea.
Optic and peripheral neuropathy may be irreversible and linezolid should stopped
if these develop; weigh against the risk of permanent blindness or disabling
permanent neuropathy.
Lactic acidosis – patients who develop recurrent nausea or vomiting, unexplained
acidosis, or a low bicarbonate level while receiving linezolid should receive
immediate medical evaluation, including a lactic acid blood test.
Contraindications Hypersensitivity to oxazolidinones.
Symptoms of neuropathy (pain, numbness, tingling or weakness in the
extremities).
Drug Interactions Avoid use with patients taking serotonergic agents, such as monoamine oxidase
inhibitors (MAOIs), selective serotonin reuptake inhibitors (e.g. fluoxetine,
paroxetine), lithium, tricyclic antidepressants, etc. as it may cause serious CNS
reactions such as serotonin syndrome.
Monitoring Monitor for peripheral neuropathy and optic neuritis (visual eye tests every two
months or if symptoms develop, clinical examination for peripheral neuropathy
monthly or if symptoms develop).
Monitor a complete blood count weekly during the initial period, then monthly,
and then as needed based on symptoms; there is little clinical experience with
prolonged use.
Patient instructions This medicine may be taken with or without food. Take it with food if it irritates
and alerting symptoms the stomach. Avoid food and drinks that contain tyramine: aged cheeses, dried
meats, sauerkraut, soy sauce, tap beers and red wines. Make sure your doctor
knows if you are taking medicines for colds, congestion or depression.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Pain, numbness, tingling or weakness in the extremities
• Black, tarry stools or severe diarrhoea
• Unusual bleeding or bruising
• Unusual tiredness or weakness
• Headache, nausea or vomiting.
Clofazimine (Cfz)
Drug class: Iminophenazine
Activity against TB, In vitro activity against M. tuberculosis without much in vivo data.
mechanism of action, Generally reserved for cases with few other options. Tissue half-life estimated to
and metabolism be around 70 days.
Dose Adults: 100–200 mg daily (oral) has been used. A regimen of 200 mg daily for 2
months, followed by 100 mg daily has been used.
Children: Limited data, but doses of 1 mg/kg/day have been given.
Preparation and 50 and 100 mg capsules. Oral, not available parenterally. Improved
administration. tolerance and absorption with food.
Storage Room temperature (15–25 °C).
Oral absorption 70% absorption after an oral dose.
CSF penetration Limited data are available regarding CNS penetration.
Special circumstances Use in pregnancy/breastfeeding: Not recommended due to limited data (some
reports of normal outcomes, some reports of neonatal deaths). Avoided with
breastfeeding due to pigmentation of the infant.
Use in renal disease: No dosage adjustment required.
Use in hepatic disease: Partially metabolized by the liver; use caution and/or
adjust the dose for severe hepatic insufficiency.
Adverse reactions Common: Orange/red discoloration of skin, conjunctiva, cornea and body fluids.
Dry skin, pruritus, rash, ichthyosis, xerosis.
Gastrointestinal intolerance.
Photosensitivity.
Less common: retinopathy, severe abdominal symptoms, bleeding and bowel
obstruction; QT prolongation.
Contraindications Allergy to clofazimine.
Drug interactions Using with drugs that prolong the QT interval may cause additive QT
prolongation (e.g. bedaquiline, fluoroquinolones, delamanid, azole anti-fungal
drugs, and many others); further research is needed to understand potential
interactions with antiretrovirals.
Monitoring Symptomatic monitoring.
Patient instructions Take with food to avoid stomach upset and improve absorption.
and alerting symptoms This medicine may discolor your skin and body secretions are orange, red or
brownish-black. This should go away after stopping the medicine, but may take a
long time. Avoid the sun and use strong sunscreens.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Bloody or black stools or diarrhoea
• Yellowing of skin or eyes
• Severe nausea, vomiting, abdominal pain, cramps or burning
• Depression or thoughts of hurting oneself.

Cycloserine (Cs) [and Terizidone (Trd)]

Drug class: analog of D-alanine.
Activity against TB, Bacteriostatic: inhibits cell wall synthesis.
mechanism of action,
and metabolism
Dose Adults: 10–15 mg/kg/day usually (max. 1000 mg/day); Usually 500–750 mg/day
given in two divided doses or once a day if tolerated. Some patients may require
only alternate day 250 mg and 500 mg dosing to avoid toxicity.
Children: 10–20 mg/kg/day divided every 12 hours (daily maximum 1 g).
Pyridoxine (vitamin B6): Although supporting data are not extensive, MDR-TB
experts recommend that all patients should receive vitamin B6 while taking
cycloserine. Adults need 100 mg or more (or 50 mg per 250 mg of cycloserine)
and children should receive a dose proportionate to their weight (1–2 mg/kg/day,
with a usual range of 10–50 mg/day).
Renal failure/dialysis: 250 mg once daily or 500 mg, 3 times per week; monitor
drug concentrations to keep peak concentrations <35 mcg/ml.
Route of administration Oral; not available parenterally.
Preparation 250 mg capsule.
Storage Room temperature (15–25 °C) in airtight containers.
Oral absorption Modestly decreased by food (best to take on an empty stomach); not significantly
affected by antacids or orange juice.
CSF penetration Concentrations approach those in serum.
Special circumstances Use in pregnancy/breastfeeding: Not well studied, but no teratogenicity
documented. Use if there are not better choices.
Can be used while breastfeeding (dose the infant with vitamin B6 if
breastfed).
Use in renal disease: Cycloserine is cleared by the kidney and requires dose
adjustment for renal failure. Use with caution.
Use in hepatic disease: Not associated with hepatotoxicity.
Adverse reactions CNS toxicity, including inability to concentrate and lethargy. More
serious CNS side effects, including seizure, depression, psychosis and suicidal
ideation, usually occur at peak concentrations >35 mcg/ml, but may be seen in the
normal therapeutic range. Other side-effects include peripheral neuropathy and
skin changes.
Skin problems include lichenoid eruptions and Stevens-Johnson syndrome.
Contraindications Relative contraindications include seizure disorder, psychotic disease or alcohol
abuse.
Monitoring Peak concentrations should be obtained within the first 1–2 weeks of therapy and
monitored serially during therapy. The peak concentration should be kept below
35 mcg/ml. Baseline and monthly monitoring for depression using a tool such as
the Beck Depression Index should be done.
Patient instructions If food is taken, avoid a large fatty meal. Avoid alcohol.
and alerting symptoms You must also take a high-dose vitamin B6 supplement while on this drug.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Seizures
• Shakiness or trouble talking
• Depression or thoughts of hurting yourself
• Anxiety, confusion or loss of memory
• Personality changes, such as aggressive behavior
• Rash or hives
• Headache.

Ethambutol (Emb)
Drug class: unspecified
Activity against TB, Bacteriostatic: inhibitor of cell wall synthesis; bactericidal only at the high end of
mechanism of action, the dosing range. At doses used over long periods of time, ethambutol protects
and metabolism against further development of resistance.
Dose Adults: 15–25 mg/kg/day. Higher doses should be used only during the initial
months of therapy. For prolonged therapy, the dose should be closer to 15
mg/kg/day to avoid toxicity.
Children: 15–25 mg/kg/day; doses closer to 15 mg/kg/day should be used if the
drug is used for more than 2 months.
Renal failure/dialysis: 15–25 mg/kg/dose, 3 times weekly (not daily).
Route of administration Oral
Preparation 100 mg tablets; scored 400 mg tablets; coated 100 mg tablets; coated, scored 400
mg tablets.
Storage Room temperature (15–25 °C).
Pharmacokinetics Peak oral absorption occurs 2–4 hours after the dose. Draw a peak serum
concentration 2–3 hours after the dose; a second sample 6 hours post-dose could
be obtained if there is concern about late absorption and in order to estimate the
serum half-life.
Peak concentrations of 2–6 mcg/ml are expected with daily dosing. Intermittent
doses of 50 mg/kg can be expected to produce peaks of 4–12 mcg/ml.
Oral absorption 80% bioavailability independent of food.
CSF penetration Ethambutol penetrates meninges poorly.
Special circumstances Use in pregnancy/breastfeeding: Safe in pregnancy; can be used while
breastfeeding.
Use in renal disease: Use with caution – cleared by the kidneys; dose adjustment
 required for renal failure. Increased risk of toxicity with renal failure. If needed
for use in the regimen, consider therapeutic drug monitoring.
Use in hepatic disease: Safe in liver disease.
Adverse reactions Retrobulbar neuritis (dose-related – exacerbated during renal failure).
Contraindications Pre-existing optic neuritis; visual changes on ethambutol.
Monitoring Patients should be counselled to report any changes in vision. Baseline and
monthly visual acuity and colour discrimination monitoring should be performed
(particular attention should be given to individuals on higher doses or with renal
impairment).
Patient instructions Can be taken with food or on an empty stomach.
and alerting symptoms Instruct patients to inform their health care provider right away if any of the
following occurs:
• Any problems with your eyes: vision changes, blurring, colour blindness,
trouble seeing or eye pain
• Swelling of face
• Rash, hives or trouble breathing
• Numbness, pain or tingling in hands or feet
• Joint pain
• Fever or chills
• Nausea, vomiting, poor appetite or abdominal pain
• Headache or dizziness.

Delamanid (Dlm)
Drug class: Nitrodihydro-imidazo-oxazole.
Activity against TB, Inhibition of the synthesis of the mycobacterial cell wall components, methoxy-
mechanism of action, mycolic and keto-mycolic acid. Delamanid is a pro-drug that must be reduced by
and metabolism the deazaflavin-dependent nitroreductase to its des-nitro metabolite to be active.
The complete metabolic profile of delamanid in man has not yet been fully
elucidated. Therefore the potential for drug-drug interactions of clinical
significance to occur with delamanid and the possible consequences, including
the total effect on the QTc interval, cannot be predicted with confidence.
Plasma albumin and CYP3A regulate the formation and metabolism of DM-6705
respectively. The identified metabolites of delamanid do not show anti-
mycobacterial activity. Concentrations of the identified metabolites progressively
increase to steady state after 6 to 10 weeks.
QTc prolongation is very closely correlated with the major delamanid metabolite
DM-6705.
Delamanid disappears from plasma with a t1/2 of 30-38 hours.
Delamanid is not excreted in urine.
Dose Adults: 100 mg twice daily for 24 weeks. It is recommended to administer with
water and to be taken with, or just after a meal.
Children: Not yet determined.
Preparation and 50 mg film-coated tablets.
administration.
Storage Store tablet at room temperature and in original package.
Oral absorption Absorption is increased with a standard meal.
CSF penetration No data are available regarding CNS penetration.
Special circumstances Use in pregnancy/breastfeeding: There are very limited data from the use of
delamanid in pregnant women. Studies in animals have shown reproductive
toxicity. Available pharmacokinetic data in animals have shown excretion of
delamanid and/or its metabolites in milk.
Use in renal disease: No dosage adjustment is required in patients with mild to
moderate renal impairment Dosing not established in severe renal impairment,
use with caution and only when the benefits outweigh the risks.
Use in hepatic disease: No dosage adjustment is required in patients with mild to
moderate hepatic impairment. Dosing and toxicity not well established in severe
hepatic impairment, use with caution and only when the benefits outweigh the
risks.
Adverse reactions Common: The most frequently observed adverse drug reactions in patients treated
with delamanid (i.e. incidence > 10%) are nausea (38.3%), vomiting (33%), and
dizziness (30.2%).
 Less common: QT prolongation.
Contraindications/ Do not use or discontinue delamanid
caution • Clinically significant ventricular arrhythmia.
• A QTcF interval of > 500 ms (confirmed by repeat ECG).
• Severe liver disease.
• Serum Albumin less than 2.8.
• Abnormal electrolytes.
Use with caution in the following situations (with more frequent ECG monitoring
and evaluation of risk versus benefit):
• Use with other QT prolonging drugs.
• A history of torsade de pointes.
• A history of congenital long QT syndrome.
• A history of hypothyroidism and bradyarrhythmias.
• A history of uncompensated heart failure.
• Serum calcium, magnesium, or potassium levels below the lower limits of
normal.
Use with caution in patients sensitive to lactose.
Drug Interactions Avoid concomitant administration of strong CYP3A inducers (e.g. rifampicin,
carbamazepine). No clinically relevant reduction in delamanid exposure was
observed with weak inducers.
If co-administration of delamanid with any strong inhibitor of CYP3A
(e.g. ritonavir, ketokonazole) is necessary, consider more very frequent
monitoring of ECGs, throughout the delamanid treatment.
Delamanid does not affect plasma exposure of ARV drugs tenofovir, Kaletra
(lopinavir/ritonavir), or efavirenz. Antiretroviral drugs, tenofovir, efavirenz, and
Kaletra (lopinovir/ritonavir), do not affect delamanid exposure in a clinically
relevant manner (24% increase).
Avoid using with other drugs that prolong the QT interval as additive QT
prolongation may occur (e.g. clofazimine, fluoroquinolones, bedaquiline, azole
anti-fungal drugs, ondansetron, and several others).
Monitoring An ECG should be obtained before initiation of treatment, and at least 2, 4, 8, 12,
and 24 weeks after starting treatment with delamanid. Monitoring ECGs should
be done monthly if taking other QT prolonging drugs (i.e moxifloxacin,
clofazimine, etc).
Patient instructions The patient should be informed that delamanid is a new anti-TB drug and there
and alerting symptoms could be unknown risks and side-effects. One serious side-effect associated with
delamanid is it can change the electrical conduction of the heart, which could put
a patient at risk for arrhythmias. This medicine should be taken with food. Avoid
alcohol.
Instruct patient to inform health care provider right away if any of the following
occurs:
• Palpitations
• Chest pain
• Fainting and near fainting events

Pyrazinamide (Pza)
Drug class: synthetic derivative of Nicotinamide.
Activity against TB, Bactericidal for semi-dormant M. tuberculosis. Mechanism unclear.
mechanism of action,
and metabolism
Dose Adults: 25 mg/kg/day (max dose 2 g). Intermittent dosing at twice or thrice
weekly up to 50 mg/kg can be given.
Children: 30–40 mg/kg/dose.
Renal failure/dialysis: 25 mg/kg/dose, 3 times per week (not daily).
Route of administration Oral; not available parenterally.
Preparation 500 mg scored or unscored tablet.
Storage Store the tablets at room temperature (15–25 °C).
Oral absorption Well absorbed from the gastrointestinal tract.
CSF penetration Concentrations equivalent to serum.
Special circumstances Use during pregnancy/breastfeeding: should be used for drug-resistant TB when
the isolate is sensitive to pyrazinamide (no known teratogenicity). Can be used
 while breastfeeding.
Use in renal disease: Cleared by the kidneys; dose 3 times a week and after
dialysis.
Use in hepatic disease: Use with caution; pyrazinamide is associated with
hepatotoxicity in about 1% of patients. It can be quite severe and worsen
treatment progress.
Adverse reactions Gout (hyperuricaemia) and arthralgias. Hepatotoxicity. Rash.
Photosensitivity. Gastrointestinal upset.
Contraindications Allergy to pyrazinamide; severe gout.
Monitoring Monitor transaminases and uric acid.
Patient instructions May be taken with or without food; this medicine may cause a rash after sun
and alerting symptoms exposure, so limit sun exposure.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Skin rash, severe itching or hives
• Pain or swelling in the joints
• Yellowing of the skin or eyes or dark urine
• Nausea or vomiting
• Unusual tiredness or loss of appetite.

Imipenem (Imp)/Cilastatin (Cln)

Drug class: beta-lactam – carbapenem
Activity against TB, In vitro activity – very limited clinical experience. Given that imipenem is rapidly
mechanism of action, degraded by renal proximal tubule dipeptidases, it is used in combination with the
and metabolism dipeptidase inhibitor, cilastatin. (Conversely, meropenem a similar drug as
imipenem is stable to renal dipeptidases and requires no cilastatin). Cilastatin is
partially metabolized renally.
Dose Adults: 1000 mg IV every 12 hours. (Dosed on the imipenem component).
Should be given with clavulanate (available as amoxicillin/clavulanate) 125 mg
every 8–12 hours.
Children: Meropenem preferred. See Meropenem, drug sheet for
dosing.
Route of administration IV or IM (total recommended IM dose is not more than 1.5 gram/
day and therefore not very practical for treatment of drug-resistant
TB). No oral absorption.
Preparation Lypholized powder 1:1 ratio of imipenem and cilastatin. Vials available as 250
mg, 500 mg, 750 mg, or 1 gram and contain equal amounts of both drugs. (i.e. a
“500 mg vial” contains 500 mg of imipenem and 500 mg cilastatin).
Storage Powder should be kept at room temperature (15–25 °C); suspended product
should be kept no more than 4 hours at room temperature or no more than 24
hours refrigerated.
CSF penetration Good CSF penetration, but children with meningitis treated with imipenem had
high rates of seizures (meropenem preferred for meningitis and for children).
Special circumstances Use in pregnancy/breastfeeding: Little information is known regarding use in
pregnancy; unknown safety during breastfeeding.
Use in renal disease: Adjustment in dose based on severity of renal failure – for
example, 750 mg every 12 hours for creatinine clearance 20–40 ml/min, 500 mg
every 12 hours for creatinine clearance <20 ml/min. Dose after dialysis.
Use in hepatic disease: Elevated liver function tests have been noted in up to 6%
of patients, but no definite liver damage has been documented.
Adverse reactions Common: Diarrhoea, nausea, or vomiting.
Less common: Seizure (noted with CNS infection), palpitations,
pseudomembranous colitis.
Contraindications Carbapenem intolerance; meningitis (use meropenem rather than imipenem).
Monitoring Symptomatic monitoring.
Patient instructions Make sure your health care provider knows if you are also taking ganciclovir or
and alerting symptoms have allergy to penicillins or cephalosporins.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Fast or irregular heartbeat
 • Seizures
• Severe diarrhoea (watery or bloody)
• Skin rash, hives, or itching
• Swelling of the face, throat or lips
• Wheezing or trouble breathing.

Meropenem (Mpm)
Drug class: beta-lactam – carbapenem
Activity against TB, In vitro activity – very limited clinical experience (meropenem is stable to renal
mechanism of action, dipeptidases and requires no cilastatin).
and metabolism
Dose Adults: No oral absorption. Recent case–controlled study used 1000 mg IV every
8 hours. Must be given with clavulanate (available as amoxicillin/clavulanate),
125 mg every 8–12 hours.
Children: Not established for TB however for other bacterial infections in
children: 20 mg/kg/dose and 40 mg/kg/dose for meningitis or particularly severe
infections. Given IV every 8 hours up to 2 g per dose.
Renal failure/dialysis: Adjustment required – 750 mg every 12 hours for
creatinine clearance of 20–40 ml/min; 500 mg every 12 hours for creatinine
clearance <20 ml/min.
Route of administration IV only; No oral absorption.
Preparation Crystalline powder. Product is available in 500 mg, or 1 g vials.
Storage Powder should be kept at room temperature (15–25 °C); suspended product
should be kept no more than 4 hours at room temperature or no more than 24
hours refrigerated.
CSF penetration Adequate CSF penetration.
Special circumstances Use during pregnancy/breastfeeding: There is little information regarding use
during pregnancy; unknown safety during breastfeeding.
Use in renal disease: Dose adjustment required (see above); dose after dialysis.
Use in hepatic disease: Liver disease does not alter the pharmacodynamics of
meropenem. Adjustment in dose and interval are based on severity of renal failure
and body weight – e.g. 750 mg every 12 hours for creatinine clearance of 20–40
ml/min, 500 mg every 12 hours for creatinine clearance <20 ml/min.
Adverse reactions Diarrhoea, nausea or vomiting.
Seizure (noted with CNS infection), but rare compared to imipenem.
Rarely elevated LFTs, haematologic toxicity, hypersensitivity
Contraindications Carbapenem intolerance.
Monitoring Symptomatic monitoring.
Patient instructions Make sure your doctor knows if you are also taking valproic acid or have allergy
and alerting symptoms to penicillins or cephalosporins.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Severe diarrhoea (watery or bloody)
• Skin rash, hives or itching
• Swelling in the face, throat or lips
• Wheezing or trouble breathing.

Amikacin (Am)
Drug class: Aminoglycoside
Activity against TB, Bactericidal: Inhibits protein synthesis. Cross-resistance with kanamycin is
mechanism of action, considered complete and some data suggesting cross-resistance with capreomycin
and metabolism can occur. Primarily excreted unchanged through the kidney by glomerular
filtration.
Dose Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week (maximum dose
is generally 1 gram). 15 mg/kg/dose, 3 times per week can be used after culture
conversion is documented after initial period of daily administration.
>59 years of age: 10 mg/kg/dose (max 750 mg) 5–7 times per week or 2–3 times
per week after initial period. Alternatively, 15 mg/kg/dose 3 times per week.
Children: 15–30 mg/kg/day (max 1 gram) 5–7 days per week. 15–30 mg/kg/day
(max 1 gram) 3 days per week after initial period
daily.
Preparation and Given intravenous (IV) or intramuscular (IM). Not absorbed orally.
administration For IV solution, mix with D5W or other solutions (in at least 100 ml of fluid for
adults or 5 mg/ml for children). IM absorption can be delayed if same site is used
consistently. For IV administration, infuse over 30–60 minutes for adults; 1–2
hours for children; IM absorption is complete within 4 hours.
Storage Solution is stable at room temperature (15–25 °C); diluted solution is stable at
room temperature for at least 3 weeks or in the refrigerator for at least 60 days.
CSF penetration Variable penetration; appears to penetrate inflammed meninges better.
Special circumstances Use in pregnancy/breastfeeding: Generally avoided during pregnancy due to
congenital deafness seen with streptomycin and kanamycin. Can be used while
breastfeeding.
Use in renal disease: Use with caution. Concentrations should be monitored for
patients with impaired renal function. Interval adjustment is recommended for
renal impairment or dialysis.
12–15 mg/kg/dose after dialysis 2–3 times weekly (not daily). The drug is
variably cleared by haemodialysis.
Use in hepatic disease: Drug concentrations not affected by hepatic disease
(except a larger volume of distribution for alcoholic cirrhotic patients with
ascites). Presumed to be safe in severe liver disease; however, use with caution in
patients with severe liver disease as it may progress rapidly to hepatorenal
syndrome.
Adverse reactions Common: Local pain with intramuscular injections. Proteinuria.
Occasional: Nephrotoxicity, ototoxicity (hearing loss), vestibular toxicity
(vertigo, ataxia, dizziness). All increases with advanced age and prolonged
use. Electrolyte abnormalities, including hypokalaemia, hypocalcaemia,
and hypomagnesaemia.
Rare: Neuropathy, rash.
Contraindications Pregnancy — relative contraindication (congenital deafness).
Hypersensitivity to aminoglycosides.
Caution with renal, hepatic, vestibular or auditory impairment.
Drug interactions Co-administration of loop diuretics (furosemide) and aminoglycoside antibiotics
carries an increased risk of ototoxicity.
Monitoring Monitor renal function by documenting creatinine at least monthly (more
frequently if renal or hepatic impairment); document creatinine clearance if there
is baseline renal impairment or any concerns; document baseline and monthly
audiology exam; follow monthly electrolytes, magnesium and calcium. Question
patient regularly about vestibular complaints and perform serial vestibular exams.
Document peak and trough concentrations at baseline if there is any question
about renal function. Some experts monitor aminoglycoside concentrations
routinely, regardless of renal function. Monitor concentrations serially for
patients with impaired renal function.
Patient instructions Instruct patients to inform their health care provider right away if any of the
and alerting symptoms following occurs:
• Problems with hearing, dizziness or balance
• Rash or swelling of your face
• Trouble breathing
• Decreased urination
• Swelling, pain or redness at your IV site
• Muscle twitching or weakness.

Kanamycin (Km)
Drug class: Aminoglycoside
Activity against TB, Bactericidal: has strong anti-TB activity. Cross-resistance with amikacin and
mechanism of action, some data suggesting cross-resistance with capreomycin; inhibits protein
and metabolism synthesis.
Dose Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week (maximum dose
is generally 1 gram, but a large, well-built person could receive more and should
have concentrations monitored).
>59 years of age: 10 mg/kg/dose (max 750 mg) 5–7 times per week or 2–3 times
per week after initial period. Alternatively, 15 mg/kg/dose, 3 times per week.
Children: 15–30 mg/kg/day (max 1 gram) 5–7 days per week.
 Renal failure/dialysis: 12–15 mg/kg/dose, 3 times weekly.
Markedly obese individuals should have an adjusted dose due to the decreased
distribution of extracellular fluids in adipose tissues. Dosing based on actual
weight will give supratherapeutic concentrations.
Route of administration IV or IM; not absorbed orally.
Preparation 250 mg/ml in vials of 500 mg or 1 gram; 1 gram in 3 ml vial; or 75 mg/vial for
infants. Can be mixed with D5W or normal saline for intravenous infusion. Adult
IV doses should be mixed in at least 100 ml of fluid, and paediatric IV doses
should be mixed to a concentration of at least 5 mg/ml. For intravenous
administration, infuse over 60 minutes for adults; 1–2 hours for children.
Storage The product supplied by the Global Drug Facility does not need storage in in the
refrigerator.
Oral absorption Not absorbed orally; 40–80% of the dose is absorbed intramuscularly.
CSF penetration Minimal and variable CSF penetration – slightly better with inflammed meninges.
Special circumstances Use in pregnancy/breastfeeding: Generally avoided in pregnancy due to
documented congenital deafness. Can be used while breastfeeding.
Use in renal disease: Use with caution. Concentrations should be monitored for
patients with impaired renal function. Interval adjustment is recommended for
renal impairment or dialysis. See section above for dosage under renal disease or
dialysis. The drug is variably cleared by haemodialysis.
Use in hepatic disease: Drug concentrations are not affected by hepatic disease
(except a larger volume of distribution for alcoholic cirrhotic patients with
ascites). Presumed to be safe in severe liver disease; however, use with caution
because patients with severe liver disease may progress rapidly to hepatorenal
syndrome.
Diuretic use: Coadministration of loop diuretics and aminoglycoside
antibiotics carries an increased risk of ototoxicity.
Adverse reactions Nephrotoxicity: Appears to be more nephrotoxic than streptomycin.
Ototoxicity (hearing loss) and vestibular toxicity: Increases with advanced age
and prolonged use; appears to occur slightly more commonly with kanamycin
than with streptomycin and about the same frequency as amikacin. Kanamycin
seems to have slightly less vestibular toxicity.
Contraindications Pregnancy (congenital deafness seen with streptomycin and kanamycin use in
pregnancy); hypersensitivity to aminoglycosides; caution with renal, vestibular or
auditory impairment; patients with intestinal obstructions.
Monitoring Monitor renal function by documenting creatinine at least monthly (more
frequently if renal or hepatic impairment is present); document creatinine
clearance if there is baseline renal impairment or any other concern; document
baseline and monthly audiology exam. Question patient regularly about vestibular
complaints and perform serial vestibular exams.
Patient instructions Instruct patients to inform their health care provider right away if any of the
and alerting symptoms following occurs:
• Problems with hearing, dizziness or balance
• Rash or swelling of your face
• Trouble breathing
• Decreased urination
• Watery or bloody diarrhoea
• Swelling, pain, or redness at your IV site
• Muscle twitching or weakness.

Streptomycin (S)
Drug class: Aminoglycoside
Activity against TB, Bactericidal: inhibits protein synthesis; no significant crossresistance with other
mechanism of action, aminoglycosides.
and metabolism
Dose Adults: 15 mg/kg/day in a single daily dose, 5–7 days per week (maximum dose
is generally 1 g)
>59 years of age: 10 mg/kg/dose (max 750 mg) 5–7 times per week or 2–3 times
per week after the initial period. Alternatively, 15 mg/kg/dose, 3 times per week.
Children: 20–40 mg/kg/day (max 1 gram), 5–7 days per week.
 Renal failure/dialysis: 12–15 mg/kg/dose, 2–3 times weekly (not daily).
Route of administration IV or IM (has been used intrathecally and intraperitoneally). Not absorbed orally.
Preparation 1 gram vial for injection.
Storage Store in the refrigerator
Oral absorption There is no significant oral absorption. Intramuscular absorption might be
delayed if the same site is used consistently.
CSF penetration Variable penetration; appears to penetrate inflammed meninges better.
Special circumstances Use during pregnancy/breastfeeding: Avoided during pregnancy due to
documented cases of congenital deafness. Can be used while breastfeeding.
Use in renal disease: Use with caution. Concentrations should be monitored for
patients with impaired renal function. Interval adjustment is recommended for
renal impairment or dialysis. The drug is variably cleared by haemodialysis.
Use in hepatic disease: Drug concentrations are not affected by hepatic disease
(expect a larger volume of distribution for alcoholic cirrhotic patients with
ascites). Presumed to be safe in severe liver disease; however, use with caution as
patients with severe liver disease may progress rapidly to hepatorenal syndrome.
Diuretic use: Coadministration of loop diuretics and aminoglycoside antibiotics
carries an increased risk of ototoxicity.
Adverse reactions Nephrotoxicity: Less nephrotoxic than amikacin.
Ototoxicity (hearing loss): Increased with advanced age and prolonged use.
Vestibular toxicity.
Local pain with IM injections.
Electrolyte abnormalities, including hypokalaemia, hypocalcaemia, and
hypomagnesaemia.
Contraindications Pregnancy (congenital deafness seen with streptomycin and kanamycin use
during pregnancy); Hypersensitivity to aminoglycosides: caution with renal,
vestibular or auditory impairment.
Monitoring Monitor renal function by documenting creatinine at least monthly (more
frequently if renal or hepatic impairment); document creatinine clearance if there
is baseline renal impairment or any concerns; document baseline and monthly
audiology exam.
Question patient regularly about vestibular complaints and perform serial
vestibular exams. Document peak and trough concentrations at baseline if there is
any question about renal function. Some experts monitor aminoglycoside
concentrations routinely, regardless of renal function. Monitor concentrations
serially for patients with impaired renal function.
Patient instructions Instruct patients to inform their health care provider right away if any of the
and alerting symptoms following occurs:
• Problems with hearing, dizziness or balance
• Rash or swelling of your face
• Trouble breathing
• Decreased urination
• Watery or bloody diarrhoea
• Swelling, pain or redness at your IV site
• Muscle twitching or weakness.

Ethionamide (Eto)/Protionamide (Pto)

Drug class: Carbothionamides group, derivatives of isonicotinic acid
Activity against TB, Weakly bactericidal: blocks mycolic acid synthesis.
mechanism of action,
and metabolism
Dose Adults: 15–20 mg/kg/day frequently divided (max dose 1 gram per day); usually
500–750 mg per day in 2 divided doses or a single daily dose.
Children: 15–20 mg/kg/day usually divided into 2–3 doses (max dose 1 gram per
day). A single daily dose can sometimes be given at bedtime or with the main
meal. Many individuals require gradual ramping up of the dose and treatment for
gastrointestinal upset.
Pyridoxine (vitamin B6): Although there is little supporting data, most MDR-TB
experts recommend that all patients should receive vitamin B6 while taking
ethionamide. Suggested dose for adults is 100 mg and children should receive a
dose proportionate to their weight (1–2 mg/kg/day, with a usual range of 10–50
 mg/day).
Renal failure/dialysis: No change.
Route of administration Oral; not available parenterally
Preparation Coated 250 mg tablet.
Storage Store at room temperature (15–25 °C).
Oral absorption Erratic absorption, possibly due to gastrointestinal disturbances
associated with the medication.
CSF penetration Concentrations approach those in the serum; one paediatric study evaluating drug
concentrations in the CSF suggests that ethionamide should be dosed on the high
end of the range for patients with meningitis.
Special circumstances Use in pregnancy/breastfeeding: Generally avoided during pregnancy due to
reports of teratogenicity; little data about use during breastfeeding – an estimated
20% of the infant therapeutic dose will be passed on to the baby in the breast milk
(dose the infant with vitamin B6 if breastfed).
Use in renal disease: No precautions are required for renal impairment.
Use in hepatic disease: Can cause hepatotoxicity similar to that of isoniazid – use
with caution in liver disease.
Adverse reactions Gastrointestinal upset and anorexia: sometimes intolerable (symptoms are
moderated by food or taking at bedtime). Premedication with an antiemetic like
ondansetron is often helpful.
Low dose Ativan 0.5 mg has also been used successfully. Metallic taste.
Hepatotoxicity.
Endocrine effects: Gynaecomastia, hair loss, acne, impotence, menstrual
irregularity, and reversible hypothyroidism – treat with thyroid replacement.
Neurotoxicity (patients taking ethionamide should take high doses of vitamin
B6). Side effects may be exaggerated in patients also taking cycloserine.
Contraindications Sensitivity to ethionamide.
Monitoring Monitor thyroid stimulating hormone for evidence of hypothyroidism
requiring replacement; therapeutic drug monitoring required if malabsorption is
suspected. Monitor liver function tests.
Patient instructions Take this medicine with food.
and alerting symptoms You must also take a high-dose vitamin B6 supplement while on this drug.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Any problems with your eyes: eye pain, blurred vision, colour blindness or
trouble seeing
• Numbness, tingling or pain in your hands or feet
• Unusual bruising or bleeding
• Personality changes such as depression, confusion or aggression
• Yellowing of your skin or eyes
• Dark-colored urine
• Nausea and vomiting
• Dizziness
• Swollen breasts (in men).

Para-aminosalicyclic acid (PAS)

Drug class: Salicylic acid – anti-folate
Activity against TB, Bacteriostatic.
mechanism of action,
and metabolism
Dose Adults: 8–12 g per day divided 2–3 times per day
Children: 200–300 mg/kg/day divided 2–4 times per day
Renal failure/dialysis: No change
Route of administration Oral; should be given sprinkled on or stirred into yogurt or similar food. Not
available parenterally in the US
Preparation 4 g per packet
Storage Packets should be kept in the refrigerator or freezer
Oral absorption Incomplete absorption – sometimes requires increased doses to achieve
therapeutic concentrations
CSF penetration Poorly penetrates the meninges (somewhat better with inflammation)
Special circumstances Use during pregnancy/breastfeeding: Not studied, but no teratogenicity known.
There is little data regarding use during breastfeeding.
Use in renal disease: Inactive metabolite is cleared by the kidneys. The package
insert says to avoid with severe renal failure.
Other authorities believe it can be used with caution (toxicity of metabolite not
known)
Use in hepatic disease: Use with caution; 0.5% incidence of hepatotoxicity
Adverse reactions Gastrointestinal distress
Rare hepatotoxicity and coagulopathy
Reversible hypothyroidism (increased risk with concomitant use of ethionamide);
treat with thyroid replacement
Contraindications Pregnancy (relative).
Monitoring Monitor TSH, electrolytes, blood counts and liver function tests.
Patient instructions Sprinkle granules over apple-sauce or yogurt or swirl in acidic juices (tomato,
and alerting symptoms grape, grapefruit, cranberry, apple or orange).
Do not chew the granules. Take with food if desired. Do not use the packet if it is
puffed up or if the granules are discoloured.
Gastrointestinal discomfort and diarrhoea usually improve over time. The shells
of the granules may be seen in the stool, which is normal.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Skin rash, severe itching or hives
• Severe abdominal pain, nausea or vomiting
• Unusual tiredness or loss of appetite
• Black stools or bleeding.

Isoniazid (Inh)
Drug class: Isonicotinic acid hydrazide
Activity against TB, Bactericidal: Especially for rapidly dividing cells. Affects mycolic acid
mechanism of action, (cell wall) synthesis. Inclusion of isoniazid in the regimen of patients with
and metabolism strain W MDR-TB was also associated with improved outcomes.
Dose Adults: 4–6 mg/kg/day (oral or IV); usual adult dose 300 mg daily;
high dose isoniazid (600 to 1500 mg daily) used for patients with low-level
isoniazid resistance or documented isoniazid resistance other than due to the Kat
G gene mutation.
Children: 10–15 mg/kg/day up to 300 mg (oral or IV);
– Patient <30 kg: 7 to 15 mg/kg once daily
– Patient ≥30 kg: 4 to 6 mg/kg once daily
– Maximum dose: 300 mg daily
Renal failure/dialysis: 300 mg once daily or 900 mg thrice weekly.
Pyridoxine (vitamin B6) should be used when high-dose isoniazid is administered
and in patients with diabetes, uraemia, HIV infection, seizure disorders, alcohol
abuse, malnutrition or peripheral neuropathy.
Additionally, pregnant and postpartum women and exclusively breastfed infants
should receive vitamin B6 while taking isoniazid. (Normal dose of pyridoxine
when used prophylactically for prevention of neuropathy in patients taking
isoniazid is 10–25 mg/day.)
Route of administration Oral, IV or IM.
Preparation 50 mg, 100 mg or 300 mg scored or unscored tablets; 50 mg/5 ml oral suspension
in sorbitol; solution for injection is 100 mg/ml. When given IV, dilute in 25 ml
normal saline and infuse as a slow bolus over 5 minutes. Since compatibility
information is not available, do not infuse “piggyback” with other drugs through
a shared IV line.
Storage Suspension must be kept at room temperature (15–25 °C).
Oral absorption Well absorbed orally or intramuscularly; best absorbed on an empty stomach; up
to 50% reduction in peak concentration with a fatty meal.
CSF penetration Concentration equivalent to plasma in inflammed meninges. 20% of
concentrations in plasma in noninflammed meninges.
Special circumstances Use in pregnancy/breastfeeding: Safe during pregnancy; safe during
breastfeeding (both baby and mother should receive pyridoxine supplementation).
Up to 20% of the infant therapeutic dose will be passed on to the baby in the
breast milk.
Use in renal disease: No dose adjustment for renal failure, but pyridoxine
supplementation should be used.
Use in hepatic disease: May exacerbate liver failure. Use with caution.
Drug Interactions: Isoniazid is a CYP3A4 inhibitor. Isoniazid may increase the
concentrations of certain cytochrome P450 enzyme substrates, including
phenytoin and carbamazepine.
Adverse reactions Hepatitis (age-related).
Peripheral neuropathy.
Hypersensitivity reactions.
Other reactions, including optic neuritis, arthralgias, CNS changes, druginduced
lupus, diarrhoea, and cramping with liquid product.
Drug Interactions Monitor concentrations of phenytoin or carbamazepine in patients receiving those
drugs (increases phenytoin concentrations and risk of hepatotoxicity with
carbamazepine), especially when undergoing isoniazid monotherapy. Rifampin
tends to lower concentrations of these drugs and balance the effect of isoniazid.
Contraindications Patients with high-level isoniazid resistance who have failed an isoniazid-
containing regimen should not receive isoniazid. History of allergic reaction to
isoniazid.
Monitoring Clinical monitoring of all patients on isoniazid is essential. Routine laboratory
monitoring is not recommended for patients receiving isoniazid monotherapy for
latent TB infection. For patients receiving multiple TB drugs or other hepatotoxic
drugs, or with underlying liver disease (including viral hepatitis), baseline liver
function testing is recommended.
Follow-up liver function testing is determined by baseline concerns and
symptoms of hepatotoxicity.
Patient instructions Instruct patients to inform their health care provider right away if any of the
and alerting symptoms following occurs:
• Loss of appetite for a few days that does not go away
• Tiredness, weakness
• Moderate stomach pain, nausea or vomiting
• Numbness, pain or tingling of your fingers or toes
• Blurred vision, eye pain
• Yellow skin or eyes or dark-colored urine.

Rifampin (R)
Drug class: rifamycin
Activity against TB, Bactericidal: inhibits protein synthesis; cross-resistance with other rifamycins.
mechanism of action,
and metabolism
Dose Adults: 10 mg/kg/dose up to 600 mg (oral or IV).
Children: 10-20 mg/kg/dose up to 600 mg (oral or IV).
Renal failure/dialysis: No adjustment required.
Concomitant medications: Dosage adjustment may be required for concurrent
medications, including warfarin. After stopping rifampin, warfarin dosage may
require downward adjustment to prevent toxicity. Concurrent treatment with most
antiretroviral drugs is not recommended, as antiretroviral drug concentrations are
substantially reduced. Rifampin plasma concentrations are not affected by most
other drugs.
Route of administration Oral or IV.
Preparation 150 and 300 mg capsules; lyophilized powder for injection: 600 mg/vial; contents
of capsules can be mixed with liquid or semi-soft vehicles. Extemporaneously
prepared oral solutions have unproven homogeneity and shelf life. Immediate
administration of the dose after mixing capsular contents in a vehicle is ideal.
Storage Capsules and powder should be kept at room temperature (15–25 °C); powder
suspended in saline is stable for 24 hours; powder suspended in dextrose
 solutions is stable for 4 hours
Oral absorption Usually absorption is rapid but may be delayed or decreased by high-fat meals.
CSF penetration Rifampin CSF penetration is variable and typically achieves only 10–20% of
serum concentrations in CSF (may be better in the face of inflammed meninges),
but this may still be an important contribution to the regimen. Some authors
recommend increased doses of rifampin in patients with TB meningitis.
Special circumstances Use during pregnancy/breastfeeding: Recommended for use during pregnancy;
can be used while breastfeeding.
Use in renal disease: Can be used without dose adjustment.
Use in hepatic disease: Use with caution as it can be associated with
hepatotoxicity.
Adverse reactions Many drug interactions.
Orange staining of body fluids
Rash and pruritus
Gastrointestinal upsets, flu-like syndrome (usually only with intermittent
administration).
Hepatotoxicity.
Haematologic abnormalities (thrombocytopenia, haemolytic anaemia).
Contraindications Rifamycin allergy; due to drug interactions, may be contraindicated with
concurrent use of certain drugs.
Monitoring Liver function monitoring if appropriate (if given with other hepatotoxic
medications or if there are symptoms of hepatotoxicity); monitor drug
concentrations of interacting medications.
Patient instructions Best taken without food; if it irritates the stomach, try taking it with a small
and alerting symptoms amount of food. It is normal for urine, tears and other secretions to turn an orange
color when taking this medicine. Soft contact lenses may become discolored
while on this medicine.
Make sure your doctor knows all the medicines you take because many drugs can
interfere with this one. Avoid the use of oral hormone-based birth control
methods because rifampin may decrease their effectiveness.
Instruct patients to inform their health care provider right away if any of the
following occurs:
• Unusual tiredness or loss of appetite
• Severe abdominal upset
• Fever or chills

Amoxicillin/Clavulanate (Amx/Clv)
Drug class: Penicillin/beta-lactam inhibitor
Activity against TB, Conflicting and limited reports, but possible early bactericidal activity.
mechanism of action, Clavulanate is a beta-lactam inhibitor. Amoxicillin component is renally excreted
and metabolism and clavulanate is cleared by the liver.
Dose Expressed in amoxicillin component
Adult (and child >30 kg): 80 mg/kg/day in 2 divided doses
Child under 30 kg: 80 mg/kg/day in 2 divided doses
Maximum dose: 3000 mg daily
Preparation and An oral drug with different preparations:
administration • 875 mg amoxicillin/125 mg clavulanic acid tablet (ratio 7:1)
• 400 mg amoxicillin/57 mg clavulanic acid/5 ml, powder for oral
suspension (ratio 7:1)
• 500 mg amoxicillin/62.5 mg clavulanic acid tablet (ratio 8:1)
• 500 mg amoxicillin/62.5 mg clavulanic acid/5 ml, powder for oral
suspension (ratio 8:1).
Storage Tablets are stable at room temperature (15–25 °C); reconstituted suspension
should be stored in the refrigerator and discarded after 7 days.
Oral absorption Good oral absorption, best tolerated and well absorbed when taken at the start of
a standard meal.
CSF penetration Approximately 5% of the plasma concentration reaches the CSF.
Special circumstances Use in pregnancy/breastfeeding: Probably safe in pregnancy (no known risk); can
 be used while breastfeeding.
Use in renal disease: Amoxicillin is renally excreted and the dose should be
adjusted for renal failure. For creatinine clearance 10–30 ml/min dose 1000 mg as
amoxicillin twice daily; for creatinine clearance <10 ml/min dose 1000 mg as
amoxicillin once daily. It is cleared by dialysis, so should be dosed after dialysis
– single dose every 24 hours and after each dialysis session.
Use in hepatic disease: Clavulanate is cleared by the liver, so care should be used
when using in patients with liver failure.
Adverse reactions Common: Diarrhoea and abdominal discomfort are most common.
Nausea and vomiting.
Uncommon: Hypersensitivity and rash. Rare side-effects have been reported in
other organ systems.
Contraindications Penicillin allergy; use with caution with cephalosporin allergies.
Monitoring No specific monitoring is required.
Patient instructions Take at beginning of a meal
and alerting symptoms Instruct patients to inform their health care provider right away if any of the
following occurs:
• Rash or swelling
• Trouble breathing
• Severe diarrhoea.

Annex 3 Summary of known cross-resistance between anti-TB drugs (10)

Rifamycins All rifamycins (rifampicin and rifabutin) have high levels of cross-resistance.
Isoniazid There is high cross-resistance between isoniazid and ethionamide if the inhA
mutation is present.
Aminoglycosides and polypeptides Amikacin and kanamycin have (very) high cross-resistance.
Amikacin/kanamycin and capreomycin can have cross-resistance, which is
associated with the rrs mutation (clinical implications are not clear).
Streptomycin has low cross-resistance with amikacin/kanamycin and
capreomycin.
Fluoroquinolones Fluoroquinolones are believed to have variable cross-resistance between
themselves, with in vitro data suggesting that later-generation
fluoroquinolones (levofloxacin, gatifloxacin, moxifloxacin) remain
effective when lower generation fluoroquinolones (ofloxacin) are
demonstrating resistance. It is unknown if the in vitro data translates into
clinical relevance.
When levofloxacin (a third generation fluoroquinolone) is demonstrating
resistance, it is not known if fourth generation quinolones (moxifloxacin and
gatifloxacin) remain effective, and their use in such cases is not standardized.
It is not known if cross-resistance is complete between fourth generation
fluoroquinolones (i.e. between moxifloxacin and gatifloxacin), but is
generally considered complete in vitro studies.
Laboratories should test isolates for resistance to each fluoroquinolone used
by their TB programme
Thiamides Prothionamide and ethionamide have 100% cross-resistance.

Annex 4 Adjustment of anti-TB drugs in renal insufficiency (10)

Drug Recommended dose and frequency for patients with Creatinine clearance <30
ml/min or for patients receiving haemodialysis (unless otherwise indicated
dose after dialysis)
Isoniazid No adjustment necessary
Rifampicin No adjustment necessary
Pyrazinamide 25–35 mg/kg per dose three times per week (not daily)
Ethambutol 15–25 mg/kg per dose three times per week (not daily)
Rifabutin Normal dose can be used, if possible monitor drug concentrations to avoid
toxicity.
Rifapentine No adjustment necessary
Streptomycin 12–15 mg/kg per dose two or three times per week (not daily)
Capreomycin 12–15 mg/kg per dose two or three times per week (not daily)
Kanamycin 12–15 mg/kg per dose two or three times per week (not daily)
Amikacin 12–15 mg/kg per dose two or three times per week (not daily)
Ofloxacin 600–800 mg per dose three times per week (not daily)
Levofloxacin 750–1000 mg per dose three times per week (not daily)
Moxifloxacin No adjustment necessary
Gatifloxacin 400 mg three times a week
Cycloserine 250 mg once daily, or 500 mg/dose three times per week
Terizidone Recommendations not available
Prothionamide No adjustment necessary
Ethionamide No adjustment necessary
Para-aminosalicylic acide 4 g/dose, twice daily maximum dose
Bedaquiline No dosage adjustment is required in patients with mild to moderate renal
impairment (dosing not established in severe renal impairment, use with
caution).
Delamanid No dosage adjustment is required in patients with mild to moderate renal
impairment (dosing not established in severe renal impairment, use with
caution).
Linezolid No adjustment necessary
Clofazimine No adjustment necessary
Amoxicillin/clavulanate For creatinine clearance 10–30 ml/min dose 1000 mg as amoxicillin
component twice daily; for creatinine clearance <10 ml/min dose 1000 mg as
amoxicillin component once daily
Imipenem/cilastin For creatinine clearance 20–40 ml/min dose 500 mg every 8 hours; for
creatinine clearance <20 ml/min dose 500 mg every 12 hours
Meropenem For creatinine clearance 20–40 ml/min dose 750 mg every 12 hours; for
creatinine clearance <20 ml/min dose 500 mg every 12 hours
High dose isoniazid Recommendations not available
Clarithromycin 500 mg daily

Annex 5 Activities for monitoring treatment response (10)

Monitoring evaluation
Evaluation by clinician
Treatment adherence and tolerance
Sputum smears and culture
Weight
Height
Drug susceptibility testing
Chest radiograph
Recommended frequency
During the intensive phase: Every day during the first weeks if
hospitalized and at least every week if treated as outpatient, until the
treatment is well tolerated.
Once stable, the patient is seen twice a month or once a month.
During the continuation phase: Monthly assessments unless there is a
medical necessity to see the patient more often. The DOT supporter
sees the patient daily between consultations and signals any concerns
to the clinician.
Daily at every DOT encounter by the DOT provider.
Monitoring smears and culture monthly throughout treatment.
(Note: programmes with limited resources may choose to do monthly
smears and cultures until conversion and then monthly smears with
every other month cultures.)
At baseline, then every two weeks for first three months and then
monthly.
At start of treatment for all (to be able to assess BMI throughout
treatment); monthly for children (to assess growth).
At baseline for first- and second-line anti-TB drugs. Repeat DST for
patients who remain culture-positive or revert after month four (see
Chapter 3 for more information on DST).
At baseline, and then every six months.

Annex 6 Baseline and routine monitoring for patients on MDR-TB regimens (10)
Monitoring evaluation Recommended frequency
Serum creatinine At baseline; then monthly if possible while receiving an injectable agent.
Every one to three weeks in HIV infected patients, diabetics and other
high-risk patients.
Serum potassium Monthly while receiving an injectable agent. Every one to three weeks in
HIV infected patients, diabetics and other high-risk patients.
Serum magnesium and calcium Check magnesium and calcium blood levels whenever hypokalaemia is
diagnosed.
At baseline and then monthly if on bedaquiline or delamanid.
Repeat if any electrocardiogram (ECG) abnormalities develop
(prolonged QT interval).
Thyroid stimulating Every three months if receiving ethionamide/ prothionamide and p-
hormone (TSH) aminosalicylic acid (PAS). Every six months if receiving ethionamide/
prothionamide or PAS, but not both together.
TSH is sufficient for screening for hypothyroidism and it is not
necessary to measure hormone thyroid levels. Monthly monitoring for
clinical signs/symptoms of hypothyroidism is also necessary.
Liver serum enzymes (SGOT, Periodic monitoring (every 1–3 months) in patients receiving
SGPT) pyrazinamide for extended periods or for patients at risk for, or with
symptoms of hepatitis. For HIV-infected patients monthly monitoring is
recommended.
For patients on bedaquiline, monitor monthly.
For patients with viral hepatitis, monitor every one to two weeks for the
first month and then every one to four weeks.
HIV testing At baseline, and repeat if clinically indicated.
Pregnancy tests At baseline for women of childbearing age, and repeat if indicated.
Haemoglobin and white blood If on linezolid, monitor weekly at first, then monthly or as needed based
cell count on symptoms; there is little clinical experience with prolonged use of
linezolid.
For HIV-infected patients on zidovudine, monitor monthly initially and
then as needed based on symptoms.
Lipase Indicated for work-up of abdominal pain to rule out pancreatitis in
patients on linezolid, bedaquiline.
Lactic acid Indicated for work up of lactic acidosis in patients on linezolid or
antiretroviral treatment (ART).
Serum glucose If receiving gatifloxacin, monitor fasting blood glucose at baseline and
monitor monthly. Educate/remind patients on signs and symptoms of
hypoglycaemia and hyperglycaemia monthly.
Audiometry (hearing test) Baseline audiogram and then monthly while on an injectable agent. Ask
patients about changes in hearing at every clinic visit and evaluate their
ability to participate in normal conversation.
Vision tests For patients on long-term ethambutol or linezolid perform at least a
visual acuity test with Snellen charts and colour vision test at baseline
(as a small percentage of the population has colour blindness). Repeat
the test for any suspicion of change in acuity or colour vision.
Educational, psychological and At baseline by personnel trained in health education,
social consultation psychological and social issues relevant to TB management; during
treatment and repeat as indicated. Refer to social worker, psychologist or
psychiatrist when indicated.
ECG An ECG should be obtained before initiation of treatment with
bedaquiline or delamanid, and at least 2, 4, 8, 12, and 24 weeks after
starting treatment. Monitoring ECGs should be done monthly if taking
other QT prolonging drugs (i.e moxifloxacin, clofazimin).

Annex 7 Adverse effects, suspected agent(s) and management strategiesa (10)

Adverse Effect Suspected Suggested management strategies Comments
Agent(s)
Rash, allergic Any drug 1. For serious allergic reactions, stop all 1. History of previous drug
reaction and therapy pending resolution of reaction. In the allergies should be carefully
anaphylaxis case of anaphylaxis manage with standard reviewed. Any known drug
emergency protocols. allergies should be noted on
 2. Eliminate other potential causes of allergic the treatment card.
skin reactions (like scabies or other 2. Flushing reaction to
environmental agents). rifampicin or pyrazinamide
3. For minor dermatologic reactions, various is usually mild and resolves
agents may be helpful and allow continuation with time. Antihistamines
of the medication. They include can be used. Hot flushes,
• Antihistamines itching, palpitations
• Hydrocortisone cream for localized rash can be caused with isoniazid
• Prednisone in a low dose of 10 to 20 mg per and tyraminecontaining
day for several weeks can be tried if other foods (cheese, red wine). If
measures are not helpful this occurs advise patients to
• Phototoxicity may respond to sunscreens, but avoid foods that precipitate
these can also cause rash the reaction.
• Dry skin may cause itching (especially in 3. Any of the drugs can
diabetics), liberal use of moisturizing lotion is cause hives (urticaria). To
recommended. Dry skin is a common and identify the drug, introduce
significant problem with clofazimine. the drugs one at a time.
4. Once the rash resolves, reintroduce In the case of hives a
remaining drugs, one at a time with the one desensitization attempt can
most likely to cause the reaction last. be made (methods are
Consider not reintroducing even as a challenge described elsewhere.
any drug that is highly likely to be the cause. 4. Any drug that resulted in
5. Suspend permanently any drug identified to anaphylaxis or Stevens–
be the cause of a serious reaction. Johnson syndrome should
never be reintroduced, not
even as a challenge.
Nausea and Eto, Pto, PAS, 1. Assess for danger signs including 1. Nausea and vomiting are
vomiting Bdq, H, E, Z, dehydration, electrolyte disturbances and universal in early weeks of
Amx/Clv, Cfz, hepatitis. Initiate rehydration therapy if therapy and usually abate
Dlm indicated and correct any electrolyte with time on treatment and
disturbances. If there is blood in the vomit, adjunctive therapy. Some
check haemoglobin and treat for possible nausea and even vomiting
bleeding ulcers. may need to be tolerated at
2. Initiate a step-wise approach to manage least in the initial period.
nausea and vomiting. 2. Creatinine and electrolytes
• Phase 1: Adjust medications and conditions should be checked if
without lowering the overall dose: vomiting is severe. Give
––Give Eto/Pto at night intravenous fluids and
––Give Eto or PAS twice or thrice daily replace electrolytes as
––Give a light snack (biscuits, bread, rice, tea) needed.
before the medications 3. Another strategy is to stop
––Give PAS two hours after other anti-TB the responsible medicine for
drugs. two or three days and then
Phase 2: Start antiemetic(s): add it back gradually
––Metoclopramide 10 mg, 30 minutes before increasing the dose (advise
anti-TB medications. the patient that the medicine
––Ondansetron 8 mg, 30 minutes before the will be increased back to
anti-TB drugs and again eight hours after. a therapeutic dose in a
Ondansetron can either be used on its own or manner that will be better
with metoclopramide. (If ondansetron is not tolerated).
available, promethazine can be used.) For 4. Odansetron is a serotonin
refractory nausea give 24 mg, 30 minutes 5-HT3 receptor antagonist
before the dose can be tried. and considered to have
Phase 3: Decrease dose of the suspected drug strong antiemetic properties.
by one weight class if this can be done without It is on the WHO essential
compromising the regimen. It is rarely drug list. A number of other
necessary to suspend the drug completely. antiemetics from this class of
serotonin 5-HT3 receptor
antagonists exist. Trying
different antiemetics, even if
from the same class may be
 helpful for some patients.
Odansetron prolongs the QT
interval; avoid the use of
odansetron with bedaquiline
or delamanid.
5. For patients particularly
anxious about the nausea,
(and with “anticipatory
nausea and vomiting”) a
small dose of an anti-anxiety
medicine (5 mg of diazepam)
can help when given 30
minutes prior to the intake of
anti-TB drugs.
Gastritis and PAS, Eto, Pto, 1. Abdominal pain can also be associated with 1. Severe gastritis, as
abdominal pain Cfz, FQs, H, serious adverse effects, such as pancreatitis, manifested by blood in the
E, lactic acidosis and hepatitis. If any of these are vomit or stool is relatively
and Z suspected, obtain appropriate laboratory tests to rare, but should be always
confirm and suspend the suspected agent. treated to facilitate
2. If symptoms are associated consistent with adherence to treatment.
gastritis (epigastric burning or discomfort, a 2. If antacids must be used,
sour taste in mouth associated with reflux) they should be carefully
initiate medical therapy with the use of H2- timed so as to not interfere
blockers (ranitidine 150 mg twice daily or 300 with the absorption of
mg once daily) or proton-pump inhibitors fluoroquinolones (take two
(omeprazole 20 mg once daily). Avoid the use hours before or three hours
of antacids as they decrease absorption of after anti-TB drugs).
fluoroquinolones. 3. Stop any nonsteroidal anti-
3. For severe abdominal pain stop suspected inflammatory drugs
agent(s) for short periods of time (one to seven the patient may be taking.
days). 4. Diagnose and treat for
4. Lower the dose of the suspected agent, if this Helicobacter pylori
can be done without compromising the infections.
regimen. 5. Severe abdominal distress
5. Discontinue the suspected agent if this can has been reported with the
be done without compromising the regimen. use of clofazimine. Although
these reports are rare, if this
occurs, clofazimine should
be suspended.
Diarrhoea and/ PAS, Eto/Pto 1. Encourage patients to tolerate some degree 1. Consider other causes of
or flatulence of loose stools and flatulence. diarrhoea:
2. Encourage fluid intake. • Pseudo-membranous colitis
3. Treat uncomplicated diarrhoea (no blood in related to broad-spectrum
stool and no fever) with loperamide 4 mg by antibiotics (such as the
mouth initially followed by 2 mg after each fluoroquinolones) is a
loose stool to a maximum of 10 mg per 24 serious and even life
hours. threatening condition. Fever,
4. Check serum electrolytes (especially bloody diarrhoea, intense
potassium) and dehydration status if diarrhoea abdominal pain and
is severe. increased white blood cells
5. Fever and diarrhoea and/or blood in the are warning signs of possible
stools indicate that diarrhoea may be secondary pseudomembranous colitis.
to something other than the simple adverse • Parasites and common
effect of anti-TB drugs. waterborne pathogens in
the area should be evaluated
in the patient and treated.
• Lactose intolerance,
especially if patient has been
exposed to new foods in a
hospital not normally part of
their diet.
 2. Loperamide can be used in
children over two years of
age.
Hepatitis Z, H, R, 1. If enzymes are more than five times the 1. History of previous drug
Pto/Eto, and upper limit of normal, stop all hepatotoxic hepatitis should be carefully
PAS drugs and continue with at least three non analysed to determine the
hepatotoxic medications (for example, the most likely causative
injectable agent, fluoroquinolone and agent(s); these drugs should
cycloserine). If hepatitis worsens or does not be avoided in future
resolve with the three-drug regimens.
regimen, then stop all drugs. 2. Viral serology should be
2. Eliminate other potential causes of hepatitis done to rule out other
(viral hepatitis and alcohol induced hepatitis aetiologies of hepatitis if
being the two most common causes) and treat available, especially to
any that is identified. hepatitis A, B and C.
3. Consider suspending the most likely agent 3. Alcohol use should be
permanently. investigated and alcoholism
Reintroduce remaining drugs, one at a time addressed.
with the least hepatotoxic agents first, while 4. Generally, hepatitis due to
monitoring liver function by testing the medications resolves upon
enzymes every three days, and if the most discontinuation of the
likely agent is not essential consider not suspected drug.
reintroducing it.
Hypo- Eto/Pto, PAS 1. Most adults will require 100–150 mcg of 1. Symptoms of
thyroidism levothyroxine daily. Start levothyroxine in the hypothyroidism include
following manner: fatigue, somnolence, cold
• Young healthy adults can be started on 75– intolerance, dry skin, coarse
100 mcg daily hair, and constipation, as
• Older patients should begin treatment with 50 well as occasional depresion
mcg daily and inability to concentrate.
• Patients with significant cardiovascular 2. Do not start treatment
disease should start at 25 mcg daily. unless TSH is above 1.5–
2. Monitor TSH every one to two months and 2.0 times of the upper normal
increase the dose by 12.5–25 mcg until TSH limit.
normalizes. Adjust the dose more slowly in the 3. It is completely reversible
elderly and in patients with cardiac conditions. upon discontinuation of PAS
and/or ethionamide/
protionamide.
4. The combination of
ethionamide/protionamide
with PAS is more frequently
associated with
hypothyroidism than when
each individual drug is used.
Arthralgia Z, Bdq, 1. Initiate therapy with nonsteroidal anti- 1. Symptoms of arthralgia
Fluoroquinolo inflammatory drugs (indomethacin 50 mg twice generally diminish over
nes daily or ibuprofen 400 to 800 mg three times a time, even without
day). intervention.
2. Lower the dose of the suspected agent (most 2. Uric acid levels may be
commonly pyrazinamide) if this can be done elevated in patients on
without compromising the regimen. pyrazinamide. There is little
3. Discontinue the suspected agent if this can evidence to support the
be done without compromising the regimen. addition of allopurinol for
arthralgias, although if
gout is present it should be
used.
3. If acute swelling, redness
and warmth are present in a
joint, consider aspiration for
diagnosis of gout, infections,
autoimmune diseases, etc.
Tendonitis and Fluoro- 1. If significant inflammation of tendons or 1. Tendon rupture with
tendon rupture quinolones tendon sheaths occur: fluoroquinolone use is more
• Consider stopping fluoroquinolones likely in patients doing new
• Give a non steroidal anti-inflammatory drug physical activities and more
(ibuprofen 400 mg four times daily) common among older
• Rest the joint. patients and diabetics.
2. If treatment failure is likely without the 2. Tendon rupture is
fluoroquinolone relatively rare in patients on
• Reduce dose if possible MDR-TB regimens with
• Ensure joint is strictly rested fluoroquinolones.
• Inform patient of the possible risk of tendon
rupture and discuss the risks and benefits of
ongoing use of the fluoroquinolone.
Electrolyte Cm, Km, Am, 1. Check potassium. 1. If severe hypokalaemia is
disturbances S 2. If potassium is low, also check for present, consider
(hypokalaemia magnesium and calcium (if unable to check for hospitalization.
and magnesium, consider empiric treatment with 2. Amiloride, 5–10 mg daily,
hypo- magnesium in all cases of hypokalaemia). or spironolactone, 25 mg
magnesaemia) 3. Replace electrolytes as needed. Dose oral daily, may decrease
electrolytes apart from fluoroquinolone as they potassium and magnesium
can interfere with fluoroquinolone absorption. wasting, and thus useful in
refractory cases.
3. Oral potassium
replacements can cause
significant nausea and
vomiting. Oral magnesium
may cause diarrhoea.
Nephrotoxicity S, Km, Am, 1. Discontinue the suspected agent. 1. History of diabetes or
(renal toxicity) Cm 2. Consider using capreomycin if an renal disease is not a
aminoglycoside had been the prior injectable contraindication to the use of
drug in the regimen. agents listed here, although
3. Consider other contributing aetiologies (non patients with these
steroidal anti-inflammatory drugs, diabetes, comorbidities may be at
other medications, dehydration, congestive increased risk for developing
heart failure, urinary obstruction, etc.) and renal failure.
address as indicated. 2. Renal impairment may be
4. Follow creatinine (and electrolyte) levels permanent.
closely, every one to two weeks.
5. Consider dosing the injectable agent two to
three times a week if the drug is essential to the
regimen and the patient can tolerate (close
monitoring of creatinine). If the creatinine
continues to rise despite twice/thrice a week
dosing, suspend the injectable agent.
5. Adjust all TB medications according to the
creatinine clearance.
Vestibular S, Km, Am, 1. If early symptoms of vestibular toxicity 1. Ask the patient about
toxicity Cm, appear, change the dosing of the injectable tinnitus and unsteadiness
(tinnitus and Cs, FQs, H agent to twice/thrice a week. Also, consider every week.
dizziness) Eto, using capreomycin if an aminoglycoside had 2. Fullness in the ears and
Lzd been the prior injectable in the regimen. intermittent ringing are early
3. If tinnitus and unsteadiness worsen with the symptoms of vestibular
above adjustment, stop the injectable agent. toxicity.
This is one of the few adverse reactions that 3. A degree of disequilibrium
cause permanent intolerable toxicity and can can be caused by Cs, FQs,
necessitate discontinuation of a class of agents. Eto/Pto, INH or linezolid.
Some clinicians will stop all
drugs for several days to see
if symptoms are attributed to
these drugs. Symptoms of
vestibular toxicity generally
 do not improve on
withholding medications.
Peripheral Cs, Lzd, H, S, 1. Correct any vitamin or nutritional 1. Patients with comorbid
neuropathy Km, Amk, deficiencies. Increase pyridoxine to the disease (e.g. diabetes, HIV,
Cm, H, maximum daily dose (200 mg per day). alcohol dependence) may be
Fluoro- 2. Consider whether the dose of cycloserine can more likely to develop
quinolones, be reduced without compromising the regimen. peripheral neuropathy, but
rarely Pto/Eto, If isoniazid is being used (especially high dose these conditions are not
E isoniazid), consider stopping it. If possible, contraindications to the use
switching the aminoglycoside to capreomycin of the agents listed here.
may also be helpful. 2. Neuropathy may be
3. Initiate medical therapy: irreversible but many
• Nonsteroidal anti-inflammatory drugs or patients experience
acetaminophen may help alleviate symptoms. improvement when the
• Therapy with tricyclic antidepressants such as offending agents are
amitriptyline (start with 25 mg at bedtime, the suspended. The neuropathy
dose may be increased to a maximum of 150 associated with linezolid is
mg) can be tried. Do not use tricyclic common after prolonged use
antidepressants with selective serotonin and often permanent. For this
reuptake inhibitors and anti depressant drugs. reason, suspension of this
• Carbamazepine, an anticonvulsant, at 100 to drug should be strongly
400 mg twice daily can be tried. considered when neuropathy
• Gabapentin (used off-label) at 300 mg thrice a develops due to linezolid.
day; it can be used at a maximum dose of 3600
mg/day in three or four divided doses.
4. Rarely, medication may be discontinued, but
only if an alternative drug is available and the
regimen is not compromised.
Headache Cs, Bdq, Rule out more serious causes of headache 1. Headaches are common
including meningitis, and other infections of during the initial months of
the central nervous system. (HIV co-infected MDR-TB therapy. They can
patients should receive a head computed present as migraine or cluster
tomography scan and cerebrospinal fluid headaches.
analysis). 2. To minimize headaches at
Start analgesics like ibuprofen or paracetamol. the start of therapy,
Also encourage good hydration. Consider low cycloserine can be started at
dose tricyclic antidepressants for refractory lower doses of 250–500 mg
headaches. and gradually increased over
one to two weeks to achieve
the target dose.
3. Headaches due to
cycloserine and bedaquiline
are usually self-limited.
4. Pyridoxine (vitamin B6)
should be given to all
patients receiving
cycloserine to help prevent
neurotoxicity. The
recommended dose is 50 mg
for every 250 mg of
cycloserine prescribed.
Depression Psychological 1. Assess and address underlying emotional and 1. Socioeconomic conditions
and socioeconomic issues. and chronic illness should
socioeconomic 2. Assess patients for coexisting substance not be underestimated as
circumstances, abuse and refer to treatment if appropriate. contributing factors to
chronic 3. Initiate individual counselling (or group depression.
disease, Cs, counselling if the patient is sputum smear and 2. Depressive symptoms may
fluoro- culture negative). fluctuate during therapy and
quinolones, 3. When depression is more significant, initiate may improve as illness is
H, Eto/Pto antidepressant therapy (amitryptiline, successfully treated.
fluoxetine or similar). 3. History of previous
 Tricyclic antidepressants and selective depression is not a
serotonin reuptake inhibitors should be given contraindication to the use of
together and should not be given to patients on agents listed but may
linezolid. increase the likelihood of
4. Lower the dose of the suspected agent if this depression developing
can be done without compromising the during treatment. If
regimen. (Reducing the dose of cycloserine and significant depression is
ethionamide to 500 mg daily to see if the present at the start of
depression is lessened is a common strategy). treatment, avoid a regimen
5. Discontinue the suspected agent if this can with cycloserine, if possible.
be done without compromising the regimen. 4. Question the patient
regarding suicidal ideation
any time the depression is
judged to be more than
mild.
Suicidal CS, H, Eto/Pto 1. Hospitalize the patient and put under 24-hour 1. Keep the patient in the
ideation surveillance. hospital until risk of suicide
2. Discontinue cycloserine. has passed.
3. Request psychiatric consultation. 2. If no improvement occurs
4. Initiate antidepressant therapy. after holding cycloserine,
5. Lower the dose of Eto/Pto to 500 mg daily hold H and/or Eto/Pto.
until the patient is stable.
Psychotic Cs, H, 1. Stop the suspected agent for a short period of 1. Some patients will need to
symptoms fluoro- time (1–4 weeks) while psychotic symptoms continue antipsychotic
quinolones are brought under control. treatment throughout MDR-
The most likely drug is cycloserine followed by TB treatment (and
high dose isonizaid. discontinued upon
2. If moderate to severe symptoms persist, completion of treatment).
initiate antipsychotic therapy (haloperidol). 2. Previous history of
3. Hospitalize in a ward with psychiatric psychiatric disease is not
expertise if patient is at risk to himself/herself a contraindication to
or others. cycloserine, but its use may
4. Increase pyridoxine to the maximum daily increase the likelihood of
dose (200 mg per day). psychotic symptoms
5. Lower the dose of the suspected agent (most developing during treatment.
commonly cycloserine to 500 mg a day) if this 3. Some patients will tolerate
can be done without compromising the cycloserine with an
regimen. antipsychotic drug but this
6. Discontinue the suspected agent if this can should be done in
be done without compromising the regimen. consultation with a
7. Once all symptoms resolve and patient is off psychiatrist, as these patients
cycloserine, antipsychotic therapy can be will need to be under special
tapered off. If cycloserine is continued at a observation; this should only
lower dose, antipsychotic therapy may need to be done when there is no
be continued and any attempts of tapering off other alternative.
should be done after referring to a psychiatrist 4. Psychotic symptoms are
trained in the adverse effects of second-line generally reversible upon
anti-TB drugs. completion of MDR-TB
treatment or cessation
of the offending agent.
5. Always check creatinine
in patients with new onset
psychosis. A decrease in
renal function can result in
high blood levels of
cycloserine, which can
cause psychosis.
Seizures Cs, H, 1. Hold cycloserine, fluoroquinolones and 1. An anticonvulsant is
fluoro- isoniazid pending resolution of seizures. generally continued until
quinolones 2. Initiate anticonvulsant therapy MDR-TB treatment is
(carbamazepine, phenytoin or valproic acid are completed or suspected agent
 most commonly used). is discontinued.
3. Increase pyridoxine to the maximum daily 2. History of previous
dose (200 mg per day). seizure disorder is not a
4. Check serum electrolytes including contraindication to the use of
potassium, sodium, bicarbonate, calcium, agents listed here if a
magnesium and chloride. patient’s seizures are well
5. When seizures have resolved, restart controlled and/or the patient
medications one at a time. Cycloserine should is receiving anticonvulsant
not be restarted unless it is absolutely essential therapy.
to the regimen. If cycloserine is reinitiated, start (Do not include cycloserine
a dose one weight band lower. if an alternative drug is
available.)
3. Patients with history of
previous seizures may be at
increased risk for
development of seizures
during MDR-TB therapy.
5. Always check creatinine
in patients with new onset
seizures. A decrease in renal
function can result in high
blood levels of cycloserine,
which can cause seizures.
Adjusting the dose of
cycloserine in the presence
of low creatinine may be all
that is needed to control the
seizures.
Optic neuritis E, Eto/Pto, 1. Stop ethambutol. Do not restart. 1. The most common drug
Lzd, 2. Refer patient to an ophthalmologist. responsible is ethambutol
Cfz, rifabutin, and it usually reverses with
H, S cessation of the drug.
2. Improve diabetes control
in diabetic patients.
Metallic taste Eto/Pto, Clr, 1. Encourage the patient to tolerate this side 1. Normal taste returns when
FQs effect. treatment is stopped.
2. Sucking hard candy or chewing gum can be
helpful.
Gynaecomastia Eto/Pto 1. Breast enlargement can be a troublesome 1. Resolution occurs after
Eto/Pto side effect of Eto/Pto therapy, especially for treatment is stopped.
male patients. Galactorrhoea has also been
reported.
2. Encourage patients to tolerate this side
effect.
Alopecia H, Eto/Pto 1. Hair loss can occur or there can be 1. Significant cosmetic
significant thinning of the hair, but this is change has not been
temporary and not progressive during reported.
treatment.
2. Encourage patients to tolerate this side
effect.
Superficial Fluoroquinolo 1. Topical antifungal agents or short-course 1. Vaginal or penile
fungal infection nes oral antifungal drugs are helpful. candidiasis, oral thrush or
and thrush and other 2. Exclude other diseases if response to cutaneous candidiasis in skin
antibiotics treatment is not prompt (such as HIV). folds may occur with
with antibiotic treatment.
antibacterial
properties
Lactic acidosis Lzd 1. Stop linezolid if lactic acidosis occurs. 1. Lactic acidosis can be
monitored with a blood
test that measures lactic acid.
Dysglycaemia Gfx, Eto/Pto 1. Stop gatifloxacin and replace with different
and latergeneration fluoroquinolone like
hyperglycaemia moxifloxacin.
2. Treat diabetes as needed. Good glucose
control is important during treatment.
QT Bdq, Dlm, Any patient found to have a QTc value greater 1. The QT interval is
prolongation Fluoro- than 500ms should be managed carefully. measured from the end of the
quinolones, • Repeat ECG and confirm the prolongation. QRS complex to the
clarithromycin • Bedaquiline and delamanid are drugs that beginning of the T wave on a
clofazimine should be stopped for QTc value greater than standard ECG. The QT is
500ms. Consider stopping other drugs that corrected for heart rate,
prolong the QT interval. which is referred to as the
• Check potassium, calcium and magnesium QTc and calculated by
levels. most ECG machines. A
Electrolyte levels should be maintained in the normal QTc is generally
normal range in any patients with an elevated <440ms.
QT interval. 2. Values above QTc 440ms
• It is suggested to maintain potassium levels of are referred to as prolonged.
more than 4 mEq/l and magnesium levels of Patients with prolonged QTc
more than 1.8 mg/dl. are at risk for developing
• Avoid other drugs that increase the QT cardiac arrhythmias like
interval. torsades de pointes, which
Monitor the patient’s renal and hepatic function can be life threatening.
and adjust the dose of fluoroquinolones if Patients with QTc greater
impairment is present. than 500ms are at the
Consider suspension of fluoroquinolone if risk greatest risk for developing
of torsades de pointes outweighs the benefits of these arrhythmias.
the drug. 3. The fluoroquinolones
cause prolongation of the
QTc. Moxifloxacin and
gatifloxacin cause the
greatest QTc prolongation,
while levofloxacin and
ofloxacin have a lower risk.
4. Currently, ECG
monitoring prior to initiation
and during MDR-TB therapy
is only required with the
use of bedaquiline,
delamanid, or when two
drugs known to prolong QT
(e.g.moxifloxacin,
clofazimine) are combined in
the same regimen.
Haematological Lzd Stop linezolid if myelosuppression 1. Haematological
abnormalities (suppression of white blood cells, red blood abnormalities (leukopenia,
cells or platelets) occurs. thrombocytopenia, anaemia,
Consider restarting with a lower dose of red cell aplasia, coagulation
linezolid (300 mg instead of 600 mg) if abnormalities, and
myelosupression resolves and if linezolid is eosinophilia) can rarely
considered essential to the regimen. occur with a number of other
Consider nondrug related causes of the anti-TB drugs.
haematological abnormality. 2. There is little experience
Consider blood transfusion for severe anaemia. with prolonged use of
linezolid.

Annex 8 Commonly used ancillary medications (10)

Indication Drug
Nausea, vomiting, upset stomach Metoclopramide, dimenhydrinate, prochlorperazine, promethazine,
odansetron (and other serotonin 5-HT3 receptor antagonist)
Heartburn, acid indigestion, sour H2-blockers (ranitidine, cimetidine, famotidine, etc.), proton pump
stomach, ulcer inhibitors (omeprazole, lansoprazole, etc.).
Avoid antacids because they can decrease absorption of fluoroquinolone
Oral candidiasis Fluconazole, clotrimazole lozenges, nystatin suspension
Diarrhoea Loperamide
Depression Selective serotonin reuptake inhibitors (fluoxetine, sertraline), tricyclic
antidepressants (amitriptyline)
Severe anxiety Lorazepam, diazepam
Seizures Phenytoin, carbamazepine, valproic acid, phenobarbital
Prophylaxis of neurological Pyridoxine (vitamin B6)
complications of cycloserine and
isoniazid
Peripheral neuropathy Amitriptyline, gabapentin
Vestibular symptoms Meclizine, dimenhydrinate, prochlorperazine, promethazine
Musculoskeletal pain, arthralgia, Ibuprofen, paracetamol, codeine
headaches
Cutaneous reactions, itching Hydrocortisone cream, calamine, caladryl lotions
Systemic hypersensitivity reactions Antihistamines, corticosteroids
Bronchospasm Inhaled beta-agonists, inhaled corticosteroids (beclomethasone, etc.), oral
steroids, injectable steroids
Hypothyroidism Levothyroxine
Electrolyte wasting Potassium, magnesium and calcium replacement therapy
(oral and intravenous formulations)

Annex 9 Potential overlapping and additive toxicities of ART and anti-TB treatment (10)
TOXICITY ANTIRETROVIRAL ANTI-TB AGENT COMMENTS
AGENT
Skin rash ABC, NVP, EFV, H, R, Z, Do not re-challenge with ABC (can
d4T and others PAS, result in life-threatening anaphylaxis).
Fluoroquinolones, Do not re-challenge with any agent
And others that may have caused Stevens-
Johnson syndrome.
Also consider co-trimoxazole as a
cause of skin rash if the patient is
receiving this medication.
Thioacetazone is contraindicated
in HIV because of the risk of
lifethreatening rash.
Peripheral d4T, ddI Lzd, Cs, H, Avoid use of D4T or ddI in
neuropathy aminoglycosides combination with Cs or Lzd because
Eto/Pto, E of an increased risk of peripheral
neuropathy;
If these agents must be used
in combination and peripheral
neuropathy does develop, replace
antiretrovirals with a less neurotoxic
agent.
Patients taking H, Cs or Lzd should
receive prophylactic pyridoxine.
Central nervous EFV Cs, H, Eto/Pto, EFV has a high rate of CNS side
system (CNS) FQ effects (dizziness, impaired
toxicity concentration, depersonalization,
abnormal dreams, insomnia and
confusion) in the first 2–3 weeks of
use, but typically resolve on their
own. If these effects do not resolve,
 consider substitution of the agent.
At present, there are limited data on
the use of EFV with Cs; concurrent
use is the accepted practice as
long as there is frequent monitoring
for central nervous system toxicity.
Frank psychosis can occur with Cs
but is rare with EFV alone; other
causes should always be ruled out.
Depression EFV Cs, FQ, H, Severe depression can be seen
Eto/Pto in 2.4% of patients receiving EFV.
Consider substitution of EFV if
severe depression develops.
Headache AZT, EFV Cs, Bdq Rule out more serious causes
of headache, such as bacterial
meningitis, cryptococcal
meningitis, central nervous
system toxoplasmosis, etc. Use of
analgesics (ibuprofen, paracetamol)
and good hydration may help.
Headaches secondary to AZT, EFV
and Cs are usually self-limited.
Nausea and RTV, d4T, NVP, Eto/Pto, PAS, H, Persistent vomiting and abdominal
vomiting and most others Bdq, Dlm, E, Z pain may be a result of developing
and others lactic acidosis (especially common
with long-term d4T use) and/or
hepatitis secondary to medications.
Abdominal pain All antiretrovirals Eto/Pto, PAS Abdominal pain is a common
have been adverse effect and often benign;
associated with however, abdominal pain may be an
abdominal pain early symptom of severe side-effects,
such as pancreatitis, hepatitis or
lactic acidosis (especially common
with long-term d4T use.
Pancreatitis d4T, ddI Lzd Avoid use of these agents together.
If an agent causes pancreatitis,
suspend it permanently and do
not use any of the potentially
pancreatitis-producing antiretrovirals
(d4T or ddI) in the future.
Also consider gallstones or
excessive alcohol use as potential
causes of pancreatitis.
Diarrhoea All protease Eto/Pto, PAS, Diarrhoea is a common adverse
inhibitors, FQ effect. Also consider opportunistic
ddI (buffered infections as a cause of
formulation) diarrhoea, or Clostridium difficile
(pseudomembranous colitis).
Hepatotoxicity NVP, EFV, H, R, E, Z, Bdq, Also see Section on hepatotoxicity
all protease PAS, Eto/ Pto, treatment related to second-line
inhibitors (RTV > FQ anti-TB drugs. When severe, stop
others), both the ART and TB medications,
all NRTIs and restart the TB medications first.
Also consider co-trimoxazole as a
cause of hepatotoxicity if the patient
is receiving this medication.
Also rule out viral aetiologies as
cause of hepatitis (hepatitis A, B, C,
and CMV).
Lactic acidosis d4T, ddI, AZT, 3TC Lzd If an agent has caused
hyperlactataemia (i.e. high lactate)
 or lactic acidosis, replace it with
an agent less likely to cause lactic
acidosis.
Note: the goal should always be
early detection and management
of hyperlactataemia to prevent
development of lactic acidosis.
Renal toxicity TDF (rare) Aminoglycosides, TDF may cause renal injury with the
Cm characteristic features of Fanconi
syndrome, hypophosphataemia,
hypouricaemia, proteinuria,
normoglycaemic glycosuria and, in
some cases, acute renal failure.
Avoid TDF in patients receiving
aminoglycosides or Cm. If TDF
is absolutely necessary, serum
creatinine and electrolytes should
be monitored frequently (at least
every two weeks).
Even without the concurrent use
of TDF, HIV-infected patients have
an increased risk of renal toxicity
secondary to aminoglycosides
and Cm. Frequent creatinine
and electrolyte monitoring is
recommended.
In the presence of renal insufficiency,
antiretrovirals and anti-TB
medications need to have their
doses adjusted.
Nephrolithiasis IDV None No overlapping toxicities regarding
nephrolithiasis have been
documented between ART and
anti-TB medications. Adequate
hydration prevents nephrolithiasis in
patients taking IDV. If nephrolithiasis
develops while on IDV, substitute
with another protease inhibitor.
Electrolyte TDF (rare) Cm, Diarrhoea and/or vomiting
disturbances amino-glycosides can contribute to electrolyte
disturbances.
Even without the concurrent use
of TDF, HIV-infected patients have
an increased risk of both renal
toxicity and electrolyte disturbances
secondary to aminoglycosides
and Cm.
Bone marrow AZT Lzd, R, Rfb, H Monitor blood counts regularly.
suppression Replace AZT if bone marrow
suppression develops. Consider
suspension of Lzd.
Also consider co-trimoxazole as a
cause if the patient is receiving this
medication.
Consider adding folinic acid
supplements, especially if the
patient is receiving co-trimoxazole.
Optic neuritis ddI E, Eto/Pto (rare) Suspend agent responsible for optic
neuritis permanently and replace
with an agent that does not cause
optic neuritis.
Hyperlipidaemia Protease None No overlapping toxicities regarding
inhibitors, EFV hyperlipidaemia have been
documented between antiretrovirals
and anti-TB drugs.
Lipodystrophy NRTIs (especially None No overlapping toxicities regarding
d4T and ddI) lipodystrophy have been documented
between antiretrovirals and anti-TB
drugs.
Dysglycaemia Protease Gfx, Eto/Pto Protease inhibitors tend to
(disturbed inhibitors cause insulin resistance and
blood sugar hyperglycaemia. Eto/Pto tends to
regulation) make insulin control in diabetics
more difficult, and can result in
hypoglycaemia and poor glucose
regulation.
Hypothyroidism d4T Eto/Pto, PAS There is potential for overlying
toxicity, but evidence is mixed.
Several studies show subclinical
hypothyroidism associated with
some antiretrovirals, particularly
stavudine (d4T). PAS and Eto/
Pto, especially in combination, can
commonly cause hypothyroidism.
Arthralgia Indinavir, Z, Bdq Protease inhibitors can cause
other protease arthralgia and there have been
inhibitors case reports of more severe
rheumatologic pathology.
Arthralgias are very common with
Z and has been reported as one of
the most frequent adverse effects
(>10%) in controlled clinical trials
with Bdq
QT ART has been Bdq, Dlm, Mfx, ARV therapy does appear to confer
Prolongation associated with Gfx, Cfz, Lfx, Ofx a significant increased risk of QTc
QTc prolongation prolongation in HIV-positive patients
but data is sparse. The additive
effects of combining ART with the
known second-line anti-TB drugs in
respect to QTc prolongation is not
known.
Note: Drugs that are more strongly associated with the listed toxicities appear in bold lettering.

Annex 10 Baseline and routine monitoring for patients on MDR-TB regimens (10)
MONITORING RECOMMENDED FREQUENCY
EVALUATION
Serum creatinine At baseline; then monthly if possible while receiving an injectable agent. Every
one to three weeks in HIV infected patients, diabetics and other high-risk
patients.
Serum potassium Monthly while receiving an injectable agent. Every one to three weeks in HIV
infected patients, diabetics and other high-risk patients.
Serum magnesium and Check magnesium and calcium blood levels whenever hypokalaemia is
calcium diagnosed. At baseline and then monthly if on bedaquiline or delamanid.
Repeat if any electrocardiogram (ECG) abnormalities develop (prolonged QT
interval).
Thyroid stimulating Every three months if receiving ethionamide/prothionamide and p-
hormone (TSH) aminosalicylic acid (PAS). Every six months if receiving ethionamide/
prothionamide or PAS, but not both together.
 TSH is sufficient for screening for hypothyroidism and it is not necessary to
measure hormone thyroid levels. Monthly monitoring for clinical
signs/symptoms of hypothyroidism is also necessary.
Liver serum enzymes Periodic monitoring (every 1–3 months) in patients receiving pyrazinamide for
(SGOT, SGPT) extended periods or for patients at risk for, or with symptoms of hepatitis. For
HIV-infected patients monthly monitoring is recommended.
For patients on bedaquiline, monitor monthly.
For patients with viral hepatitis, monitor every one to two weeks for the first
month and then every one to four weeks.
HIV testing At baseline, and repeat if clinically indicated.
Pregnancy tests At baseline for women of childbearing age, and repeat if indicated.
Haemoglobin and white If on linezolid, monitor weekly at first, then monthly or as needed based on
blood cell count symptoms; there is little clinical experience with prolonged use of linezolid.
For HIV-infected patients on zidovudine, monitor monthly initially and then as
needed based on symptoms.
Lipase Indicated for work-up of abdominal pain to rule out pancreatitis in patients on
linezolid, bedaquiline, D4T, ddI or ddc.
Lactic acid Indicated for work up of lactic acidosis in patients on linezolid or antiretroviral
treatment (ART).
Serum glucose If receiving gatifloxacin, monitor fasting blood glucose at baseline and monitor
monthly. Educate/remind patients on signs and symptoms of hypoglycaemia and
hyperglycaemia monthly.
Audiometry (hearing Baseline audiogram and then monthly while on an injectable agent. Ask patients
test) about changes in hearing at every clinic visit and evaluate their ability to
participate in normal conversation.
Vision tests For patients on long-term ethambutol or linezolid perform at least a visual acuity
test with Snellen charts and colour vision test at baseline (as a small percentage
of the population has colour blindness). Repeat the test for any suspicion of
change in acuity or colour vision.
Educational, At baseline by personnel trained in health education, psychological and social
psychological issues relevant to TB management; during treatment and repeat as indicated.
and social consultation Refer to social worker, psychologist or psychiatrist when indicated.
ECG An ECG should be obtained before initiation of treatment with bedaquiline or
delamanid, and at least 2, 4, 8, 12, and 24 weeks after starting treatment.
Monitoring ECGs should be done monthly if taking other QT prolonging drugs
(i.e moxifloxacin, clofazimin).

Annex 11. Adverse events of clinical significance or special interest for aDSM
1. All serious adverse events (SAEs).
2. All AEs of special interest (suggested list):
–– Peripheral neuropathy (paraesthesia)
–– Psychiatric disorders and central nervous system toxicity (e.g. depression, psychosis,
suicidal intention, seizures)
–– Optic nerve disorder (optic neuritis) or retinopathy
–– Ototoxicity (hearing impairment, hearing loss)
–– Myelosuppression (manifested as anaemia, thrombocytopenia, neutropenia or
leukopenia)
–– Prolonged QT interval (Fridericia correction; see (8))
–– Lactic acidosis
–– Hepatitis (defined as increases in alanine aminotransferase (ALT) or aspartate
aminotransferase (AST) ≥5x the upper limit of normal (ULN), or increases in ALT
or AST ≥3x ULN with clinical manifestations, or increases in ALT or AST ≥3x ULN
with concomitant increase in bilirubin ≥1.5x ULN)
–– Hypothyroidism
–– Hypokalaemia
–– Pancreatitis
–– Phospholipidosis
–– Acute kidney injury (acute renal failure).
3. Adverse events leading to treatment discontinuation or change in drug dosage.
4. Adverse events not listed above but judged as otherwise clinically significant by the
clinician.

Annex 12. Clinical and laboratory testing schedule for active tuberculosis drug-safety monitoring and management
(aDSM) (from 11)
Month 1 1 1 1 1 1 1 1 1 1 2 2 2 2
0 1 2 3 4 5 6 7 8 9 24
0 1 2 3 4 5 6 7 8 9 0 1 2 3
Date
Clinical
screen
Visual acuity
Simple
hearing test
Audiogram
Neuro &
psychiatric
investigation
s
Serum
creatinine
ALT (SGPT)
AST (SGOT)
Bilirubin
Alkaline
phospatase
gamaGT
ECG
Lipase
Amylase
Potassium
Magnesium
Calcium
Albumin
CBC
Blood
glucose
Thyroid
tests: TSH

Annex 13 Informed Consent Part I:

Medication guide for patients taking bedaquiline tablets
Read this medication guide before you start taking bedaquiline and each time before your monthly
visit. This information does not tell your health care provider about your medical treatment or any
medical conditions.
What is the most important information i should know about bedaquiline?
Bedaquiline is a drug used to treat multidrug-resistant tuberculosis (MDR-TB) lungs in people with
limited treatment options. MDR-TB is a serious disease that can result in death and for which there
are few treatment choices. More people treated with bedaquiline cleared TB from their sputum
compared to people who did not receive bedaquiline. In one clinical trial, fewer deaths were seen in
people who were not treated with bedaquiline compared to people who did receive bedaquiline.
It is important to complete the full course of treatment of bedaquiline and your other TB medicines
and not skip doses. Skipping doses may decrease the effectiveness of the treatment and increase the
likelihood that your TB disease will not be treatable by bedaquiline or other medicines.
Bedaquiline can cause serious side-effects.
• Heart rhythm problems can happen with bedaquiline.
It is not known if bedaquiline is safe in:
• Children under 18 years of age
• Pregnancy
• In patients with heart, kidney, liver or other health problems.
Before you take bedaquiline, tell your health care provider if:
• You have had an abnormal heart rhythm or other heart problems.
• Anyone in your family has or has had a heart problem called ‘congenital long QT syndrome’
• You have liver or kidney problems or any other medical conditions, including HIV infection.
• You are pregnant or plan to become pregnant. It is not known if bedaquiline will harm your
unborn baby.
• You are breastfeeding or plan to breastfeed. It is not known if bedaquiline passes into breast milk.
You and your health care provider should decide if you will take bedaquiline or breastfeed.
• You are taking any prescription and non-prescription medicines, vitamins and herbal supplements.
How should I take bedaquiline?
• Bedaquiline must always be taken with other medicines to treat TB. Your health care provider will
decide which other medicines you should take with bedaquiline.
• Always take bedaquiline with a light meal.
• Swallow the tablets whole with water.
• Take bedaquiline for a total of 24 weeks (6 months).
• Week 1 and Week 2: Take 400 mg (4 tablets) once a day, 7 days a week
• Week 3 to Week 24: Take 200 mg (2 tablets) three times a week. For example, you may take
bedaquiline on Monday, Wednesday and Friday of every week.
• You will need to take your other TB medicines for longer than 24 weeks, and at least for 20
months in total (the injectable drug is usually given for up to 8 months).
• Your treatment will be provided under directly observed treatment (DOT), with a patient-centred
approach, which means that a health care provider will accompany you during the treatment and
that your information, psychological and material needs will be addressed in order to enable your
adherence to treatment.
• Do not skip bedaquiline doses. If you skip doses, or do not complete the total 24 weeks of
bedaquiline your treatment may not work as well and your TB may be harder to treat.
• If for some reason you miss a dose, inform the person responsible for your treatment right away,
they will tell you what to do.
What should I avoid while taking bedaquiline?
• You should not drink alcohol while taking bedaquiline.
• There are some medications that cannot be taken safety with bedaquiline.
Make sure to inform your doctor if you are taking medicines or if medicines are recommended to
you by a health care practitioner while you are on treatment for TB with bedaquiline.
What are the possible side-effects of bedaquiline?
• Serious heart rhythm changes. Tell your health care provider right away if you have a change in
your heartbeat (a fast or irregular heartbeat), or if you faint. Your heart will be monitored
periodically with a machine that checks that the heart rhythm is normal.
• Liver problems (hepatotoxicity). Liver toxicity can present in many ways. Tell your doctor of
symptoms such as nausea or vomiting, stomach pain, fever, weakness, itching, unusual tiredness,
loss of appetite, light coloured stools, dark colored urine, yellowing of your skin or yellowing of the
white of your eyes.
• Other side-effects of bedaquiline include nausea, joint pain, headache, an abnormal laboratory test
associated with damage to the pancreas, coughing up blood, chest pain, loss of appetite, and/or rash.
It is possible that it may also cause some problems that we are not aware of. However, you will be
followed closely for any unwanted effects or any problems. Other medicines to decrease the
symptoms of the side-effects or reactions may also be given. Always tell your health care provider
of any side-effects or problems you are having. Sometimes because of side-effects bedaquiline or
other drugs may need to be stopped.
What monitoring tests do I need while on bedaquiline?
• You will need the same monitoring test that all patients on MDR-TB treatment
need. In addition, you will need heart monitoring, extra blood tests for the liver
and your electrolytes. Consult with your health-care provider about the appropriate
schedule of all your monitoring tests and regular doctor visits.
General information about the risk versus the benefit of taking bedaquiline
• RISK: It is possible that you will be at greater risk of not feeling well than you would otherwise
because of certain side-effects due to the drug. It is possible that adverse side-effects could be
serious and even result in death.
• BENEFIT: There is a greater chance that you will be cured of tuberculosis than if you did not take
the medicine. You will possibly also become better very much sooner than if you only took the
standard medicines for treatment of resistant TB. Also, it is probably less likely that the drugs you
are taking will develop resistance if you are taking bedaquiline.
Confidentiality and sharing of information
• Because bedaquiline is a new drug for which we have limited experience, we are collecting
information on patients taking it.
• The information that we collect from you will be kept confidential and no one but the clinical staff
will be able to see your medical information.
• Any information collected to help us better use the drug in future patients will be unlinked to your
name (made anonymous) before we share or analyse it.
Right to refuse or withdraw
• You do not have to agree to take bedaquiline if you do not wish to do so and refusing to accept the
drug as part of your treatment schedule.
• If you agree to take bedaquiline, you may choose to discontinue it at any point for any reason
without losing any of your rights as a patient here. Your treatment at this clinic will not be affected
in any way.

Contact person
If you have any questions, you may contact any of the following persons:
Name_____________________________. Title_______________. Phone____________.
Name_____________________________. Title_______________. Phone____________.
Name_____________________________. Title_______________. Phone____________.
Name of responsible physician: ____________________________________________
Name of clinic/hospital/institution: ________________________________________

BOX A4.1.9
Informed Consent Part II:
Certificate of consent
I have read the provided information, or it has been read to me. I have had
the opportunity to ask questions about it and any questions that I have asked have
been answered to my satisfaction. I consent to receive bedaquiline for treating the
drug-resistant tuberculosis disease that I am suffering from.
Name of Patient: _____________________________________________________
Signature of Patient: ______________________________________________________
Date: _________________________________