Overview Antimicrobial Stewardship

regarding to Pharmacokinetic and

Pharmacodynamic of Antibiotics

DR. Dr. Latre Buntaran Sp.MK(K)

Clinical Microbiologist Consultant
Antibiotic Resistance
• A worldwide problem1
• Associated with increased morbidity, mortality,
and hospital costs1
• Occurs in both hospitals and the community2
• Results from factors such as antibiotic misuse1
 Pola Mikroorganisme di ICU & HCU
januari - Juni 2017 (N : 80)
ICU
35
43%
30

25

20

15

11% 13%
10
9%
6%
5 4% 4% 4%
1% 3%
1.3% 1% 1%
0

Pola kuman & resistensi – Latre 2017

Sensitifitas Acinetobacter baumanii di ICU-HCU

Pola kuman & resistensi – Latre 2017

 Persentase MDR Acinetobacter baumanii

MDR Non MDR

Acinetobacter Non MDR Acinetobacter
baumanii 5% baumanii
95% 5%

Pola kuman & resistensi – Latre 2017

Sensitifitas Pseudomonas aeruginosa di ICU-HCU

Pola kuman& resistensi – Latre 2017

Persentase MDR Pseudomonas aeruginosa

MDR
Non MDR Pseudomonas
Pseudomonas aeruginosa
aeruginosa 48%
52%

Pola kuman & resistensi – Latre 2017

Sensitifitas Klebsiella pneumoniae di ICU-HCU

Pola kuman & resistensi – Latre 2017

 Persentase Klebsiella pneumoniae
ESBL Producer, Non ESBL Producer & carbapenemase producer

20%
36%

44%

Klebsiella pneumoniae Non ESBL producer Klebsiella pneumoniae ESBL producer Klebsiella pneumoniae Carbapenemase producer

Pola kuman & resistensi – Latre 2017

 CRKP isolated from 88 patients
Carbapenem-susceptible K. pneumoniae in 373 patients
5
#-fold increase in the risk of acquisition

4.27
3.9
4

1.87 1.83
2

1
P=0.026 P=0.042 P<0.001 P=0.029
0
Prior FQ exposure Prior carbapenem ICU admission Exposure to at least 1
exposure ABX drug prior to
isolation of K.
pneumoniae
Hussein K, et al. Infect Control Hosp Epidemiol. 2009;30:666-671.

Gram-negative Infections
 Persentase Escherichia coli
ESBL Producer & Non ESBL Producer

Escherichia coli Escherichia coli 33%

Non ESBL producer ESBL producer
67% 33%

Pola kuman & resistensi – Latre 2017

Sensitifitas Staphylococcus aureus di ICU-HCU

Pola kuman & resistensi – Latre 2017

 MRSA & MSSA

Staphylococcus aureus
76%
14

12

10

6 24%

0
MRSA MSSA

Pola kuman & resistensi – Latre 2017

 • Pseudomonas aeruginosa
– AmpC production, efflux pumps (MexAB-OprM, etc), outer membrane porin
changes (i.e., loss of OprD), Metallo-Beta-Lactamase production (e.g., blaVIM,
blaIMP), gyrA/parC mutations, aminoglycoside-modifying enzymes (AME), ESBL /
KPC production
• Acinetobacter species
– AmpC, ESBL (TEM-1, SHV-type, CTX-M-type), and serine (blaOXA) and metallo
(blaVIM, blaIMP) carbapenemase production, outer membrane porin changes,
AME, gyrA/parC mutations, efflux pumps
• Enterobacteriaceae (Klebsiella species, E. coli, Enterobacter
species)
– ESBL, Klebsiella-producing-carbapenemase (KPC-2, -3, -4, etc.) production,
New Delhi Metallo-Beta-Lactamase (NDM-1, -2), AmpC, outer membrane porin
changes, plasmid mediated quinolone resistance gene (qnrA)
• Other multidrug resistant, non-fermentative bacteria
– Stenotrophomonas maltophilia, Burkholdheria cepacia complex
Bonomo RA, et al. Clin Infect Dis 2006;43:S49-56, Nicasio AM, et al. Pharmacotherapy 2008;28:235-49
Gram-negative Infections
 Potential Determinants
 Pathogen and microbial ecology
 Physician’s prescribing practice
 Population characteristics
 Politics and healthcare policy 
antimicrobial stewardship
 Prevention and Control Measures

 Infection prevention / control

 Identify cases.
 Clean hands.
 Isolate and use barrier precautions.
 Separate colonized/infected and noncolonized patients.
 Clean and control of environmental or other potential sources.
 Antimicrobial stewardship
 Limitations of Infection Control

 Difficult with bacteria that colonize gastrointestinal tract.

 Resource intensive.
 Compliance often sub–optimal.
 Definition

An ongoing effort by a health care institution to

optimize antimicrobial use among hospitalized patients
in order to :
 Improve patient outcomes.
 Ensure cost-effective therapy.
 Reduce adverse sequelae of antimicrobial use (including antimicrobial
resistance).

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship. Clin Infect Dis 2007; 44: 159–77.
 Hypothesis

 Antibiotic prescribing behaviors can be changed.

 Antibiotic use is a primary cause of resistance.
 A reduction in use will reduce or slow resistance.
 Appropriate use can improve outcomes and costs.

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 159–77.
 Goals of Antimicrobial Stewardship

 Optimizing clinical outcomes while minimizing unintended

consequences of antimicrobial use.
 Reducing health care costs without adversely impacting quality
of care.

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 159–77.
 Goals of Antimicrobial Stewardship (AMS)

• Improve patient outcomes

• Optimize selection, dose and duration of treatment

• Reduce adverse drug events including secondary

infection (e.g. C. difficile infection)

• Reduce morbidity and mortality

• Limit emergence of antimicrobial resistance

• Reduce length of stay

• Reduce health care expenditures

Dellit TH, et. al. Clin Infect Dis. 2007;44:159-177
 Target Outcomes

 Reduction in total or targeted antimicrobial use.

 Increase in appropriate drug use.
 Improvement in susceptibility profiles of hospital pathogens.
 Improvement in clinical markers (such as reduced length of
stay).

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 159–77.
 Comprehensive Evidence – Based
Stewardship Program
1. Multidisciplinary antimicrobial stewardship team.
2. Collaboration between antimicrobial stewardship team,
hospital infection control, pharmacy & therapeutics
committees / their equivalents.
3. Support & collaboration of hospital administration, medical
staff leadership & local providers.
4. Hospital administrative support.
5. Health care information technology in the form of electronic
medical records.
6. Computer–based surveillance.
7. Microbiology laboratory.
8. Process measures and outcome measures.
IDSA/SHEA. Guidelines for developing an instutional program to enhance antimicrobial stewarship..
Clin Infect Dis 2007; 44: 159–77.
 Core Members for Antimicrobial
Stewardship Team
 An infectious diseases physician.
 A clinical pharmacist with infectious diseases
training.
 A clinical microbiologist.
 An information system specialist.
 An infection control professional.
 Hospital epidemiologist.
IDSA/SHEA. Guidelines for developing an instutional program to
enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 159–77.
Strategies to implement AMS
Guiding Document for Antimicrobial stewardship
IDSA – AMS Guidelines
 Antimicrobial Stewardship Strategies

• Primary Strategies: IDSA Grading System for Ranking

Recommendations in Clinical Guidelines
1. Formulary restriction and preauthorization (BII)
2. Prospective audit with intervention
and feedback.(AI)

• Secondary Strategies:
1. Education.(AII)
2. Guidelines and clinical pathways (AI)
3. Antimicrobial cycling.(CII)
4. Antimicrobial order forms (BII)
5. Streamlining or de-escalation (AII)
6. IV to Oral Conversion (AI)

Dellit TH, et. al. Clin Infect Dis. 2007;44:159-177

 Antimicrobial Stewardship Team
and Its responsibilities

Team Responsibilities
• Infectious Disease (ID) Physician • Establish an antibiotic formulary

• Clinical Pharmacist with ID training • Produce antibiotic guidelines

• Clinical Microbiologist • Develop and implement educational

programs
• Support from hospital
administration • Audit, surveillance of antibiotic use

• Hospital epidemiologist • Review of interventions and monitor

compliance
• Infection control professional

Dellit TH, et. al. Clin Infect Dis. 2007;44:159-177

www.leadstewardship.orgg
Key Performance Indicators (KPIs) of an AMS
programme
Structural Indicators
Process Indicators
Clinical/cost Outcome Indictors
 Structure Indicators
• Top 5 Structrural Indicators are:

• Structure Indicators: describe 1. Hospital multi-disciplinary antibiotic

management team (AMT)
organisation and resources,
communication and evaluation 2. Antimicrobial Drug formulary with annual
updates
tools available at hospital level
for implementing a multi-modal, 3. Annual update of local clinical guidelines for
empirical therapy based on review of local
multi-disciplinary stewardship resistance data
programme
4. Local clinical guidelines for surgical antibiotic
prophylaxis

5. Clinical guidelines for IV to oral switch

Buyle FM etal. Eur J Clin Microbiol Infect Dis (2013) 32:1161-

1170
Antibiotic Strategy International (ABS) Quality Indicators Team-
EU
 Process Indicators

• Process measures are direct

measures of the quality of
antibiotic prescription. Eg:AB
therapy and prophylaxis
(including choice, timing, dose
and duration) adherence to
treatment guidelines

www.ashpadvantage.com/stewardship
American society of health System Pharmacists
 Clinical / Cost Outcome Indicators

• Clinical Outcomes (length of stay, Infection related mortality)

• Change in resistance patterns (eg ESBL incidence) outcome

• Utilization and Cost outcomes

• The best way to showcase the difference in these outcome

measures is to show the Pre-AMS and Post AMS difference
Implementation and Impact of AMS
 Role of Infectious Diseases Physicians

 As a supervisor.
 To ensure :
 Therapeutic guidelines.
 Antimicrobial restriction policies.
 Other measures.
 based on the best evidence & practice and not put patients at
risk.

IDSA/SHEA. Guidelines for developing an instutional program to

enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 159–77.
Appropriateness of the Empirical Treatment
According to the Treating Physician

Byl B. Clin Infect Dis 1999; 29: 60–6.

Appropriateness of the treatment given at the time when
blood–isolate gram stain &
antimicrobial susceptibility test results were available,
according to the treating physician.

Laboratory test Proportion (% of total) of P

results appropriate treatments by value
IDSs Other
physicians
Gram stain 249/258 (97) 94/106 (89) 0.008
Antimicrobial 265/265 (100) 84/87 (97) 0.015
susceptibility

Byl B. Clin Infect Dis 1999; 29: 60–6.

 Role of Clinical Microbiologist
Summary data on antimicrobial resistance rates

Current burden of antimicrobial resistance in the hospital

Antimicrobial Clinicians
Stewardship Team

Better selection of
Antimicrobial restriction
empirical therapy
IDSA/SHEA. Guidelines for developing an instutional program to
enhance antimicrobial stewarship.. Clin Infect Dis 2007; 44: 159–77.
45
 PPRA ( AMSP ):
Class on Antibiotics Policy

Classification of antibiotics
Class A : Not restricted
Class B : Not restricted, under
supervision
Class C : Restricted
Implementation
Evaluation and surveillance
Auditing
 Classification of Antibiotics
Class A Class B Class C
Aminoglicoside Cephalosporine Vancomycine
Penicillin gen III Teicoplanin
Cephalosporin gen.I,II Fluoroquinolone Linezolide
Chloramphenicol gen III-IV Cefepime
Fucidic acid Sulperazone Cefpirome
Lincosamide Aztreonam Ceftazidime
Macrolide Pip-Tazo
Nitroimidazol Carbapenem
Fluoroquinolone Tigecycline
gen.I,II
Tetracyline
TMP-SMX
Fosfomicin
Polypeptide
Implementation of Antimicrobial
Policy in Hospital

Community Hospital
infection infection
Outpatient Class A Class A

Inpatient Mild
WARD Moderate Class B Class C
Severe

ICU Class B/C Class C

Treatment Option Against ESBL

Kuman/Specimen JUMLAH % sensitivitas

FOSFOMYCIN
Klebsiella pneumoniae Non ESBL producer 4 75%
Klebsiella pneumoniae ESBL producer 5 80%

Kuman/Specimen % sensitivitas
JUMLAH
FOSFOMYCIN
Escherichia coli Non ESBL producer 9 100%
Escherichia coli ESBL producer 9 100%
 Antimicrobial Stewardship : Patient Risk Stratification
Patient type 1 Patient type 2 Patient type 3
1. 90 hari terakhir tidak ada kontak dengan 1. 90 hari terakhir terdapat kontak 1. Di rawat di rumah Sakit (> 5 hari) dan/
lingkungan medis dengan lingkungan medis1,A atau dilakukan tindakan invasif3,6,7,8

DAN ATAU ATAU

2. 90 hari terakhir tidak mengkonsumsi 2. 90 hari terakhir pernah mengkonsumsi 2. Penggunaan antibiotik dalam jangka
obat-obatan jenis antibiotik obat-obatan jenis antibiotik1,2 waktu ≤ 30 hari sebelum masuk rumah
sakit3,6,7,8
DAN ATAU
ATAU
3. Usia muda, dan tidak ada penyakit 3. Usia tua (≥ 65 tahun) dengan
penyerta penyakit penyerta1,B 3. Penyakit penyerta yang mengarah
pada kondisi immunocompromised3,6,7,8,C
A 90 hari terakhir di rawat di rumah sakit/nursing home stay (dengan/ tanpa tindakan tindakan invasif minimal ), Pasien Dialysis, Home Care
B Diabetes, Asma , Bronkritis Kronis, Penyakit Kardiovascular dll.
C AIDS, Neutropenia, Penggunaan Immunosuppressants. Catatan: Structural lung diseases seperti Bronchiectasis , Cystic fibrosis juga merupakan faktor resiko terjangkitnya Pseudomonas

• Berisiko rendah terhadap bakteri multi- • Berisiko tinggi ESBL • Berisiko tinggi Pseudomonas,
drug resistant Acinetobacter, MRSA5, Enterococcus

Resisten pada semua golongan penisilin /

semua golongan sefalosporin / co-resistance
• Berisiko rendah ESBL kuinolon dan aminoglikosida

• Berisiko rendah Pseudomonas • Berisiko rendah Pseudomonas,

Acinetobacter, MRSA5, Enterococcus

• Rekomendasi: antibiotik spektrum sempit • Rekomendasi: Golongan karbapenem • Golongan karbapenem yang mencakup
yang tidak mencakup Pseudomonas Pseudomonas (Imipenem / Meropenem) 9
Contoh: (Ertapenem) 5 dengan / tanpa
• Penisilin spektrum sempit • Golongan kuinolon spektrum luas
(Levofloxasin / Ciprofloxasin)10 atau
• Sefalosporin generasi 1/2 Aminoglikosida (Amikasin)
• *hindari penggunaan berlebihan karena
dapat menyebabkan produksi ESBL) • MRSA: Glycopeptida (Vancomysin,
Teikoplanin)11,12; Oksazolidinon (Linezolid)14
• Kuinolon spektrum sempit
• VRSAF/VREF: Glycylcycline (Tigesiklin) 14,15
• Makrolid

DESBL = Extended Spectrum Beta Lactamase EMRSA = Methicillin resistant Staphylococcus aureus FVRSA / VRE = Vancomycin resistant Staph. aureus / Enterococcus
Concentration dependent killing activity and moderate to
prolonged persistent effects
 More rapid killing effect against micro organisms than low
concentrations
 Allows the administrations of high doses with widely separated
frequencies of administration

 Aminoglycosides
 Doses of these antimicrobials administered to critically ill patients are
frequently insufficient
Rea RS, et al. Suboptimal aminoglycoside dosing in critically ill patients. Ther
Drug Monit 2008; 30: 674-81

YUMC
Concentration dependent killing activity and moderate to
prolonged persistent effects
 Fluoroquinolones
 Cut off of 125 for the AUC/MIC ratio has been proposed
 In critical ill patients, very complex given that pharmacokinetics of these
and multiple variation related to changes in renal function and high inter-
individual variability

 Using a Monte Carlo dosing simulation, doses of 400mg every 8-12hrs

givento 1-2 patients did not reach the necessary killing concentrations
for P.aeruginosa, A.baumannii strains

Khachman D, et al. Optimizing ciprofloxacin dosing in intensive care unit patients

through the use of population pharmacokinetic-pharmacodynamic analysis and
Monte Carlo simulations. J Antimicrob Chemother 2011; 66: 1798-809

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Time dependent killing activity and minimal persistent effects

 Maintain blood concentrations above MIC for prolonged time periods

 T>MIC ratio is the pK.pD predictor of efficacy of these antibacterials

and to attain the best values of this parameter

 These drugs should be given by continuous infusion

 B- lactams
 Constant controversy
 Penicillin, monobactams, cephalosporins, carbapenems
 No relation to the survival, continuous infusion vs extended infusion
 Continous or extended infusion of β-lactam antibacterials leads to
similar clinical results

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2) Time dependent killing activity and minimal persistent effects

 Linezolid
 T>MIC and AUC/MIC are the pK/pD predictors of efficacy

 With continuous infusion, AUC/MIC 80-120 more frequently than with

intermittent infusion

 According to pK/pD parameters, continuous infusion has theoretically

advantages over intermittent infusion in this population
Adembri C, et al. Linezolid pharmacokinetic/ pharmacodynamic profile in critically ill
septic patients: intermittent versus continuous infusion. Int J Antimicrob Agents
2008; 31: 122-9

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Time dependent killing activity and moderate to prolonged persistent
effects
 Glycopeptides (Vancomycin, Teicoplanin)
 Significant controversy in regarding the efficiency by which vancomycin
kills GPB and the potential misuse of the drug

 In humans, AUC/MIC value >350 was an independent factor associated

with clinical success in patients with S.aureus proven lower respiratory
tract infection

 Difficulty in obtain multiple serum vancomycin concentration,

 Cmin monitoring has been recommended as the most accurate and
practical method

 The duration of effect is longer and the possibility of regrowth of micro-

organisms during the dosing interval is more limited

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How to optimize antibiotic administration in critically ill patient

 1) β-lactams
 Active against most organisms recovered form ICU patients

 Drug levels are insufficient in patients with severe infections

 Cefepime(2g taken every 12hr) concentrations were more than 70%

above target concetnrations in less than half of patients with sepsis
Ambrose PG, Owens Jr RC, Garvey MJ, et al. Pharmacodynamic considerations in the
treatment of moderate to severe pseudomonal infections with cefepime. J Antimicrob
Chemother. 2002;49:445–5
 Cefepime (2g every 8hr), recently

 Serum cefepime and ceftazidime levels below therapeutic levels after a

few hours in most cases in septic patients with normal renal function
Lipman J, Gomersall CD, Gin T, et al. Continuous infusion ceftazidime in intensive
care: a randomized controlled trial. J Antimicrob Chemother. 1999;43:309–11.

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How to optimize antibiotic administration in critically ill patient

 1) β-lactams
 Piperacillin concentration, above therapeutic levels for most of the time
interval in patients with sepsis
 Administration of piperacillin by continuous infusion, with a loading
dose, achieved superior pharmacodynamic targets compared with
conventional bolus dosing in septic patients
Roberts JA, et al. First-dose and steady-state population pharmacokinetics and
pharmacodynamics of piperacillin by continuous or intermittent dosing in critically
ill patients with sepsis. Int J Antimicrob Agents 2010, 35:156–163.

 Meropenem concentration, adequate in most of the studies in critically ill

patients
 But in severe infection,mostly after cardiac surgery, meropenem had
adequate serum concentration for at least 50% of the time in patients
with normal and impaired renal function
Kitzes-Cohen R, Farin D, Piva G, et al. Pharmacokinetics and pharmacodynamics of
meropenem in critically ill patients. Int J Antimicrob Agents. 2002;19:105–10.

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How to optimize antibiotic administration in critically ill patient

 Monitoring of several antibiotics in a large cohort of ICU septic patients,

showing that dose adjustments are necessary to optimize drug
concentrations in most of them

 Early phase of sepsis, broad-spectrum β-lactams should be

administered more frequently or in doses larger than suggested in non
septic patients with a dramatic increased of therapy costs

 Continous infusion or extended β-lactam infusion are required to

optimize pathogen exposure to bactericidal concentrations of these
drugs
 Roberts JA, Lipman J: Pharmacokinetic issues for antibiotics in The critically ill
patients. Crit Care Med 2009, 37:840–851

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How to optimize antibiotic administration in critically ill patient

 2) Vancomycin
 Higher than recommended doses of vancomycin were necessary to
optimize drug concentrations and rescue patients from septic shock d/t
GPB
 Administration of the conventional dose of vancomycin(15mg/kg of BW
every 12hr) would probably fail to achieve therapeutic drug
concentraions in the majority of critically ill patients
 Continuous infusion with 30mg/kg daily dosage has been proposed to optimize
PD vancomycin
Pea F, Viale P. Should the currently recommended twice-daily dosing still be considered the
most appropriate regimen for treating MRSA ventilator-associated pneumonia with
vancomycin? Clin Pharmacokinet. 2008;47:147–52.

 Continuous infusion, faster time to achieve target drug concentrations,

lower daily dose, reduced therapy costs than intermittent dose
Wysocki M, et al. Continuous versus intermittent infusion of vancomycin in severe
Staphylococcal infections: prospective multicenter randomized study. Antimicrob Agents
Chemother. 2001;45:2460–7.
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How to optimize antibiotic administration in critically ill patient

 Clinical superiority of continuous infusion of vancomycin in a subgroup

of patients with VAP d/t MRSA
Rello J, Sole-Violan J, Sa-Borges M, et al. Pneumonia caused by methicillin-
resistant Staphylococcus aureus treated with glycopeptides. Crit Care Med.
2005;33:1983–7.

 Continuous infusion with a 30mg/kg daily dosage has been proposed to

optimize PD vancomycin
Pea F, Viale P. Should the currently recommended twice-daily dosing still be
considered the most appropriate regimen for treating MRSA ventilator-associated
pneumonia with vancomycin? Clin Pharmacokinet. 2008;47:147–52.

 Slower onset of nephrotoxicity

Ingram PR, Lye DC, Fisher DA, et al. Nephrotoxicity of continuous versus
intermittent infusion of vancomycin in outpatient parenteral antimicrobial therapy.
Int J Antimicrob Agents. 2009;34:570–4.

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Right Time
 Duration of antibiotic therapy

 The optimal duration of antibiotic therapy for bacteremia is

unknown. There appears to be some evidence that would
suggest that there is no significant difference in mortality,
clinical and microbiological cure between shorter
durations i.e. 5 – 7 days versus 8 -21 days in critically ill
patients with bacteremia.
 Appropriate empirical antibiotic therapy of ventilator-associated pneumonia: 8 vs. 15 days.

Deresinski S Clin Infect Dis. 2007;45:S177-S183

© 2007 by the Infectious Diseases Society of America

 Multidrug resistance
 MDR pathogens : resistant to > 3 classes of drugs
 ESBL
 Amp- C lactamase
 Carbapenamase
Doyle JS, Buising KL, Thursky KA, et al. Epidemiology of infections acquired in
intensive care units. Semin Respir Crit Care Med 2011; 32: 115-38
Strategies to optimize the use of antimicrobials in the ICU

 1) De-escalation therapy

 2) Antibacterial cycling

 3) Pre-emptive therapy

 4) Use of pharmacokinetic/pharmacodynamic parameters for dose

adjustment

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 De-escalation therapy

 Initial administration of broad spectrum empirical treatment

 To cover pathogens, most frequently related to the infection
 Rapid adjustment of antibacterial treatment once the causative
pathogen has been identified
 Objective
 Lower morbidity and mortality by an early achievement of an
appropriate empirical treatment
 Limit the appearance of bacterial resistance by a reduced antibacterial
pressure
 Condition that needed-strategy
 Epidemiolgical map of the bacterial ecosystem including susceptibility
pattern of the most frequent pathogen
 Rapid response of microbiological studies
 Compliance with the recommendation of adjusting initial empirical
treatment to definite microbiological diagnosis
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 De-escalation therapy

 Applicability of this strategy, failed

 Absence of microbiological results
 Isolation of multi-resistant pathogens preventing de-escalation
 Reluctance of some clinicians to change antibacterials in patients with a
favorable clinical course despite persistence of severity of illness

 Despite limitations, antibacterial de-escalation therapy has been

recommended
 ATS guideline for the management of adults with hospital acquired, ventilator
associated, and healthcare associated pneumonia, AJRCCM 2005;171:388-416

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 Recommendations for starting/stopping antibiotics based on the PRORATA study.21 Adapted
from Figure 1 in Bouadma et al.21.

Kibe S et al. J. Antimicrob. Chemother. 2011;66:ii33-ii40

© The Author 2011. Published by Oxford University Press on behalf of the British Society for
Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com
 Antibacterial cycling

 The scheduled rotation of one class of antibacterials

 One or more different classes with comparable spectra of activity
 Different mechanisms of resistance

 Some weeks and a few months

 Objective
 Reduce the appearance of resistances by replacing the antibacterial
before they occur and preserving its activity to be re-introduced in the
hospital in a later cycle

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 Pre-emptive therapy

 The administration of antimicrobials in certain patients at very high

risk of opportunistic infections before the onset of clinical signs of
infection
 Developed in hematological patients and/or transplant recipients based
on the use of serological tests that advanced the diagnosis of some
infections
 CMV, aspergillosis
 In critical illness patients to patients at high risk of candidemia or
invasive candidiasis
: In the absence of serological test to establish an early diagnosis of
invasive candidiasis, different scores based on clinical and/or
microbiological data

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 A bedside scoring system (Candida score) for preemptive antifungal treatment in
nonneutropenic critically ill patients with Candida colonization. Crit Care Med 2006; 34: 730-7

 In a large cohort of nonneutropenic critically ill patients in whom Candida colonization was
prospectively assessed, a “Candida score” >2.5 accurately selected patients who would
benefit from early antifungal treatment.

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Drugs 2012; 72

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 Agent Class FDA Status Timing Company
Cephalosporin/β
Ceftolozane/ta Approved for FDA Approved 12/19/14;
-lactamase HABP/VABP study underway
Merck
zobactam inhibitor cUTI and cIAI

Approved for
Ceftazidime/avi Cephalosporin/β Phase-3 results to be
-lactamase cUTI and cIAI submitted in 2015 for labeling Actavis
bactam inhibitor update
(limited use)
Positive P-3 top-line results
Fully synthetic Tetraphase
Eravacycline Phase III reported; Phase-3 results
fluorocycline expected mid- 2015 Pharmaceuticals

Carbapenem/β-
Meropenem/R Phase-3 trial results expected The Medicines
lactamase Phase III in 2016
PX7009 Company
inhibitor
Next-generation Final data collection
Plazomicin Phase III estimated January 2017
Achaogen
aminoglycoside
Carbapenem/β-
Imipenem/rele Phase-3 studies planned to
lactamase Phase II initiate in 2015
Merck
bactam inhibitor
Gram-negative Infections
 clavulanic acid sulbactam tazobactam

Inhibit some Class A beta-lactamases

avibactam relebactam RXP7009

Inhibit Class A and C beta-lactamases (e.g., ESBLs, KPC, ampC)

Variable Class D inhibition; no Class B (metallo beta-lactamase) inhibition
Gram-negative Infections
 The selection window hypothesis

Mutant prevention concentration (MPC)

(to inhibit growth of the least susceptible, single step
Plasma concentrations mutant)

Mutant Selection MIC

Selective concentration (SC)
window to block wild-type bacteria

All bacteria Growth of only the most

inhibited Growth of all
resistant subpopulation
bacteria
Nice buiatric 2006-87
 SUMMARY
 Antibiotics are amongst the most commonly used
therapies in critical care
 Optimising antibiotic use improves patient outcomes
 Optimising antibiotic use should minimise pressures on
emerging antibiotic resistance
 Is antibiotic stewardship the answer?