Rationalization of

Antibiotic Selection in
Sepsis
Soedarsono, Tutik Kusmiati

Departemen Pulmonologi dan Ilmu Kedokteran Respirasi

FK Unair – RSUD Dr. Soetomo
Leading Causes of Global Deaths from Infectious Diseases

Fauci AS et al. N Engl J Med 2012;366:454-461

High Mortality with Pneumonia
and Severe Sepsis
• Pneumonia with severe sepsis are one of the
most common, most serious problems in the
ICU.
• Pneumonia with severe sepsis are associated
with high mortality rates.
• Inadequate therapy for Pneumonia with severe
sepsis increases mortality.
Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.
Richards MJ et al. Crit Care Med 1999;27:887-892.
Ibrahim EH et al. Chest 2000;118:146-155.
Van der Poll T. Lancet Infectious Diseases 2001;1:165-174.
Bernard GR et al. N Engl J Med 2001;344:699-709.
Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.
 Initial “Inadequate Therapy” In Critically Ill
Patients with Serious Infections

Myth
• There is time to start with one therapy and then escalate later,
if needed.
Fact
• Inadequate initial antimicrobial therapy increases mortality.
• Changing from inadequate to appropriate therapy may not
decrease mortality.
• Initially delayed appropriate antibiotic therapy (IDAAT) is
inadequate therapy.

Kollef MH et al. Chest 1999;115:462-474.

Ibrahim EH et al. Chest 2000;118:146-155.
Iregui M et al. Chest 2002;122:262-268.
Mortality* Associated with Initial Inadequate Therapy in
Critically Ill Patients with Serious Infections in the ICU

Alvarez-Lerma,1996 Initial adequate

therapy
Rello, 1997
Initial inadequate
Kollef, 1999 therapy
Kollef, 1998
Ibrahim, 2000
Luna, 1997
Mortality*
0% 20% 40% 60% 80% 100 %
*Alvarez-Lerma F et al. Intensive Care Med 1996;22:387-394.
Rello J et al. Am J Respir Crit Care Med 1997;156:196-200.
Kollef MH et al. Chest 1999; 115:462-474
Kollef MH et al. Chest 1998;113:412-420.
Ibrahim EH at al. Chest 2000;118:146-155.
Luna CM et al. Chest 1997;111:676-685.
Mortality Impact of Inadequate Therapy
Bacteraemia
Adequate

Kang** Inadequate

Zaragoza

Valles*

Ibrahim

0 20 40 60 80
*Community-acquired bacteraemia
**Resistant Gram-negative microorganisms

Ibrahim, et al. Chest 2000;118:146–155;

Valles, et al. Chest 2003;123:1615–1624;
Zaragoza, et al. Clin Microbiol Infect 2003;9:412–418;
KangI, et al. Antimicrob Agents Chemother 2005;49:760–766
Mortality Impact of Inadequate Therapy
Severe sepsis and septic shock

Garnacho-Montero

Harbarth
Adequate
MacArthur Inadequate

Dhainaut

0 20 40 60 80

Garnacho-Montero, et al. Crit Care Med 2003;31:2742–2751;

Harbarth, et al. Am J Med 2003;115:529–535;
MacArthur, et al. Clin Infect Dis 2004;38:284–288;
Dhainaut, et al. Crit Care Med 2003;31:2291–2301
 Effect of inappropriate antibiotics
on survival
Appropriate Inappropriate
OR (95% CI)
(n=4579) (n=1136)
Survived 52 10.3 9.45 (7.74 – 11.54)
P value
Immuno-
15 19.8 < 0.05
suppressed*
COPD 13.6 14.1 < 0.05
Dialysis 7.3 10.7 < 0.05
All numbers expressed as % unless otherwise specified
* Immunosuppression = chemotherapy or chronic steroids (>10mg prednisone daily)

Chest 2009;136:1237-48
 Inadequate/Inapproriate Antibiotic
Therapy Severe Pneumonia Patients Leads
to Increase in:

• Mortality
• Morbidity
• Length of hospital stay (LOS)
• Resistance selection
• Cost burden
 The Importance of
Early Appropriate Therapy
• Early adequate therapy, before bacteriologic data are known, leads to
an improved outcome. Delays in appropriate therapy do not improve
outcome. Even if BAL gives accurate data, it comes too late to affect
outcome.
100 * Mortality pre-BAL

80
% Mortality

Mortality post-BAL

60
*
40 *P<0.01

20

0
Adequate Inadequate

Adapted from Luna CM et al. Chest 1997;111:676-685.

 Early, appropriate antibiotics
§ Early = within 1 hour after recognition
of potential septic shock

§ Appropriate = in vitro activity against

pathogen
§ Route of administration
§ Dose and frequency
§ Penetration
§ Cidality
Crit Care Clin 2011;27:53-76
 Early, appropriate antibiotics 2

§ Appropriate, can be interpreted:

§ The chosen antimicrobial agent is:

• on the formulary
• in the treatment guideline or clinical pathway
§ The pathogen is:
• susceptible to the antimicrobial agent
§ The patient:
• is not allergic to the prescribed antimicrobial agent
• has not had a previous adverse event to the
prescribed agent

Crit Care Clin 2011;27:53-76

 Other factors to consider in
defining appropriate therapy

– Microbiologic data
– Monotherapy vs combination therapy
– Dose and dosing frequency
– Penetration
– Timing
– Toxicity
– Risk of influencing resistance
– Prior antibiotic use
Kollef MH. Clin Infect Dis 2000;31(Suppl 4):S131-S138.
Ibrahim EH et al. Chest 2000;118:146-155.
13
 What is Adequate
Antimicrobial Therapy ?

• The regimen is administered at

dosages such that minimally
acceptable PK/PD targets are
attained.
 [C]
PK infection
site Outcome
Drug n Absorption
n Distribution Pathogen • Bacterial counts
n Metabolism MIC • Mortality
n Excretion
• Rate of symptom
resolution/
PD symptom-free period
• Time-dependent killing
• Concentration-dependent killing
• Post-antibiotic effect
[C], concentration;
MIC, minimum inhibitory
concentration;
PD, pharmacodynamics;
PK, pharmacokinetics
Pharmacodynamics

Clin Inf Dis 1998;26:1-12

Crit Care Clin 2011;27:1-18
Crit Care Clin 2011;27:19-34
Crit Care Med 2009;37:840-51
 Pattern of Activity Antibiotics Goal of Therapy PK/PD Parameter

Type I Aminoglycosides Maximize 24h-AUC/MIC

Concentration-dependent killing and Daptomycin concentrations Peak/MIC
Prolonged persistent effects Fluoroquinolones
Ketolides

Type II Carbapenems Maximize duration T>MIC

Time-dependent killing and Cephalosporins of exposure
Minimal persistent effects Erythromycin
Linezolid
Penicillins
Type III Azithromycin Maximize amount of 24h-AUC/MIC
Time-dependent killing and Clindamycin drug
Moderate to prolonged persistent Oxazolidinones
effects. Tetracyclines
Vancomycin
 Considerations for Successful
Antimicrobial Therapy

Tissue penetration
PK/PD
parameters

Cmax
(Peak)
Concentration

Potent bactericidal
activity
AUC

Time >
MIC
Tissue concentration: what is the
relevance to know it?

Tissue concentration is one of the most

important information needed to assure
that the antimicrobial concentration is high
enough to inhibit the growth of pathogen
at the site of infection
Factors affecting tissue penetration
of antimicrobials
• Concentration of antimicrobial in blood
• Molecular size of antimicrobial
• Protein binding of antimicrobial
• Lipid solubility of antimicrobial
• Ionic charge of antimicrobial
• Antimicrobial binding to exudate or tissue
• Presence of inflammation
• Active transport mechanism
• Pathway of excretion of antimicrobial

(Marie et al, 2000)

21
 PROTEIN BINDING

• Drug in plasma is available as protein-bound

and unbound (free) drug
• Only unbound drug can diffuse into tissues
• Only unbound drug is able to kill or inhibit
the growth of bacteria

19
Protein binding of some antimicrobials
Drug PB Drug PB
(%) (%)
• Gentamicin 10
• Cefotaxime 30
• Piperacillin 30
• Ceftriaxone 95
• Ceftazidime 15 • Amikacin 4
• Cefpirome 10 • Ciprofloxacin25
• Cefepime 19 • Vancomycin 30
 Antibiotic choice: Etiological agent
• Most probable agents: based on epidemiology
and clinical experience
• Importance of local antibiotic resistance data
• Resistance patterns varies
– From country to country
– From hospital to hospital in the same country
– From unit to unit in the same hospital
– With time
• Regional/country data useful only for
following trends, NOT guide empirical therapy
Fraction of total patients Effect of timing on survival

Time from hypotension onset (hours)

Crit Care Med 2006;34:1589-96
 Barriers to timely antibiotics
§ Delayed recognition of sepsis and septic shock
• Infection
• Hypotension

§ Inappropriate antimicrobial therapy

• Failure to use start order
• Unrecognized risk factors for MDR pathogens
• No specifications for order of administration
• Logistical delays
Crit Care Clin 2011;27:53-76
 Combination therapy vs.
monotherapy for septic shock
Mortality rate *
Monotherapy Combination Rx
HR (95% CI)
(n=1223) (n=1223)
28-Day, % 36.3 29 0.77 (0.67 – 0.88)
ICU, % 35.7 28.8 0.75 (0.63 – 0.88)
Hospital, % 47.8 37.4 0.69 (0.59 – 0.81)
# deaths
All Gram + , % 39.9 30.7 0.73 (0.58 – 0.92)
All Gram - , % 34.5 28.2 0.79 (0.67 – 0.94)
* Propensity score adjusted

Crit Care Med 2010;38:1773-85

 Guideline recommendations
§ Combination empirical therapy for the following
patients (grade 2B):

• Neutropenic with severe sepsis and for patients

with difficult-to-treat, multidrug-resistant bacterial
pathogens

• Severe infections associated with respiratory

failure and septic shock

Crit Care Med 2013;41:580-637

Initial Antibiotic Therapy in Severe
Infection is….

EMPIRIC

IMMEDIATE
APPROPRIATE
ADEQUATE
ATS/IDSA Severe CAP score. The presence of one major, or three
or more of nine minor criteria should warrant consideration for
critical care dmission
 Aetiology of CAP ICU patients
§ Bacteraemia in 9%,
mainly
S. pneumoniae (80%)
§ Mortality: 7%
§ S. pneumoniae had the
highest number of deaths
§ Gram-negative
enterobacteria, P.
aeruginosa, S. aureus and
mixed aetiologies had the
highest mortality rates
Cillóniz et al. Thorax 2011; 66: 340-6
 Etiologi Severe CAP di RSDS
• Penelitian di RSUD Dr. Soetomo
melaporkan bahwa bakteri paling banyak
menjadi penyebab severe CAP antara
lain: Acinetobacter baumannii 40/122
(33%), Klebsiella pneumonia 23/122
(19%), dan Pseudomonas aeruginosa
16/122 (13%).
Tesis. Departemen Pulmonologi dan Ilmu Kedokteran Respirasi Universitas Airlangga – RSUD
Dr. Soetomo. Surabaya 2018
 2007 ATS-IDSA guidelines-ICU
CAP Inpatient Therapy

Intensive Care Unit

No Pseudomonas Risk Pseudomonas Risk

No b-lactam
Allergy
b-lactam Allergy No b-lactam Allergy b-lactam Allergy

Anti-pseudomonal,
antipneumococcal b-lactam /
carbapenem
No b-lactam +
+
Either advanced Respiratory Aztreonam
Cipro / Levo 750
macrolide Fluoroquinolone +
OR
OR + Respiratory
Anti-pseudomonal, antipneumoccal
Respiratory Aztreonam b-lactam / carbapenem Fluoroquinolone
Fluoroquinolone +
+
Aninoglycoside Aminoglycoside
+
Azithromycin
* Regimen selected will depend on nature of recent antibiotic therapy (Moxi, Levo 750)
Mandell LA, et al. Clin Infect Dis 20017; 44: S27-72
Pathophysiological alterations during critical illness and their
potential effect on pharmacokinetics of antimicrobial agents

Advanced Drug Delivery Reviews. 2014; 77: 3–11

 Physicochemical properties of antimicrobials and
dosage requirements in the presence of severe sepsis

Advanced Drug Delivery Reviews. 2014: 77: 3–11

Strategies to Improve Efficacy and Limit Resistance
for Time Dependent
v Increase T > MIC : IV bolus (1 hour) followed continous infusion (3-4 h)
v Intermittent IV bolus : risk of bacterial regrowing (white dotted line)

Bacterial Regrowing
 De Escalation Strategy
q Initial appropriate - adequate therapy through :

Getting it Right the First Time

• Hitting Hard - Fast , Big dose and combination if possible
• antimicrobial selection based on empiric or local ecology
• optimize the antibiotic dose and time of administration

q Adjust antibiotic based on susceptibility test and

administer the shortest possible
DE-ESCALATION THERAPY
INNITIAL
BROAD SPECTRUM
HIGH DOSE
EMPIRIC COVERAGE
RE ASSESS WHEN
switch to MICROBIOLOGICAL
DATA AVAILABLE

TARGETED
(NARROW / DEDICATED)
SPECTRUM
 Algorithm for De-escalation Antibiotic
Patient on empiric antibiotic

Obtained appropriate microbial Daily assessment until day 3

culture and special stain Temperatur, WBC,PCT, Pa02/Fi02 ratio, CXR

Clinical not improving Clinical improving

or getting worse

De-escalation
Escalation

further investigation
microbiology culture (+) microbiology culture (-)

wrong diagnosis narrowing antibiotic maintain antibiotic

wrong organism (suggested monoterapi)
complication
Clinical assessment does not support presence of infection
“ STOP ANTIBIOTIC “
Total cohort

Adequte empirical Ab

Montero GJ et al ICM 2014

 VAP: Therapy Modifications and
Mortality
50 De-escalated (n=88)
Mortality (%)

40
No change (n=245)
30
20 Escalated (n=61)
10
0

100

80
% patterns of
modification

60

40

20

0
Quinolone Ureidopenicillin/ Cefepime Carbapenem
monobactam
Kollef. Chest 2006;129:1210–1218
 Advantage Outcomes of
De-escalation Strategy

• Stop progression of disease à reduce

mortality
• Reduces hospital length of stay
• Minimize resistance
• More cost effective
Short course therapy : outcome

60-day mortality : 25% vs 28% ; p = 0.57

 The Continuum of Appropriete
Antimicrobial Use

Obtain culture De-escalating according to cultures Stop antibiotics

Empiric selection Dose and route as soon as it is
Dose and route Plan duration appropriate

0 days 3 days n days

 The role of procalcitonin
§ Procalcitonin levels can be used to support
shortening of duration of antimicrobial therapy
in sepsis patients
§ Decisions on initiating, altering, or discontinuing
antimicrobial therapy
§ should never be made solely on the basis of changes
in any biomarker, including procalcitonin
§ Procalcitonin levels can be used to support the
discontinuation of empiric antibiotics in patients
who initially appeared to have sepsis
 Nomogram for antibiotic usage
CAP diagnosis
PCT concentration

< 0.25 μg/mL > 0.25 - ≤ 0.5 μg/mL ≥ 0.5 - < 1 μg/mL ≥ 1 μg/mL

Antibiotics Antibiotics Antibiotics Antibiotics

strongly discouraged encouraged strongly
discouraged encouraged

Christ-Crain et al. A J Respir Crit Care Med 2006; 174: 84-93

 Summary
• Early appropriate-adequate antimicrobial therapy
(within 1 hour after diagnosis) should be
administration in severe infection (combination if
possible).
• Host characteristic, source of infection and local
ecology are determinants of choice empirical
antimicrobial therapy.
• Antimicrobial therapy is still the primary
causative treatment of severe pneumonia.
 Summary (cont’d)

• Use of PK/PD principles to optimize dosing in

order to minimize risk of failure and emerge of
bacterial resistant.
– PK /PD of antibiotics is essential to reach
successfull treatment outcome without toxicity
effect
• The antibiotic must be sensitive & eradicate the
pathogen quickly, not promote resistance, not
allergic, and has not had a previous adverse
event
 Summary (cont’d)
Importance of adequate and
appropriate antimicrobial
treatment : Ongoing bacterial proliferation and
inflammation
Selection of drug resistent
microorganisms
Adequate antimicrobial treatment

Inadequate antimicrobial
Increased

treatment
Mortality
Decreased

Rapid reduction of bacterial load Limitation

of inflammatory response
Thorax 2002 ; 57 : 366 - 371
 Summary (cont’d)
The factors should be considered
when choosing an antibiotic :
Excellent activity
against targeted
pathogens

Favourable PK/PD
profile, a low potential
Recommended in for resistance
clinical guidelines development and
good tissue
penetration
Antibiotic

Favourable safety High bacteriological

profile efficacy

Patient risk factors

Mandell et al. Clin Infect Dis 2007; 44: S27-72

Woodhead et al. Clin Microbiol Infect 2011; 17(Suppl 6): E1–E59
Lim et al. Thorax 2009: 64 (Suppl 3): iii1–iii55