Nama : Carta A.

Gunawan
TTL : Berau, 4 Maret 1968
Pendidikan : - Dokter FK UNAIR 1992
- Spesialis Penyakit Dalam
FK UNSRAT 2003
- Konsultan Penyakit Tropik-Infeksi
2006
- Program Doktor FK UGM 2014
Pekerjaan : - Staf SMF Penyakit Dalam
FK UNMUL/ RSUD A. Wahab Sjahranie
Samarinda
Organisasi : - IDI
- PAPDI
- PETRI
- PERDALIN
- PKWI
- PUSKI
- ISID Council Member
 ANTIMICROBIAL THERAPY
IN SEPSIS

CARTA GUNAWAN
DEPARTMENT OF INTERNAL MEDICINE
MULAWARMAN UNIVERSITY/ A. WAHAB SJAHRANIE GENERAL HOSPITAL
SAMARINDA
 Sepsis : life-threatening organ dysfunction
caused by dysregulated host responses to
infections
 Septic shock : sepsis with circulatory and
cellular/ metabolic dysfunction
 Affecting millions of people each year, and
killing one in four
 Early identification and appropriate
management in the initial hours improves
outcomes
Rhodes et al. Crit Care Med 2017;15 (3): 486-552
MANAGEMENT OF SEPSIS
ANTIMICROBIAL THERAPY
 When to initiate empirical antimicrobial
therapy in sepsis ?
SSC Guidelines 2016

Administration of IV antimicrobials as soon as

possible after recognition, within one hour,
for both sepsis and septic shock

Each hour delay is associated with a measureable

increase in mortality

Rhodes et al. Crit Care Med 2017;15 (3): 486-552

 Empirical antimicrobial therapy in sepsis
SSC Guidelines 2016

Use empiric broad-spectrum therapy with one or

more antimicrobials
to cover all likely pathogens (including bacterial,
and potentially fungal or viral coverage)

Empiric antimicrobial therapy be narrowed once

pathogen identification and sensitivities
established and/ or adequate clinical
improvement noted
Rhodes et al. Crit Care Med 2017;15 (3): 486-552
DIAGNOSIS OF INFECTION AND
ANTIMICROBIAL THERAPY
 Predisposing conditions (trauma, surgery, elderly,
immunosupression)
 Two or more blood culture and other sites potential
sources of infection
 Intravenous antibiotic therapy should be given
within one hour of identifying sepsis
 Routine empiric anti-fungal therapy NOT
recommended except for patients with high risk of
invasive candidiasis
 Antimicrobial regimen should be reassessed after
48 to 72 hours
 Risk Factors for Invasive Candidiasis

◦ Immunocompromised status
(neutropenia, chemotherapy, transplant, DM,
chronic liver failure, chronic kidney failure)
◦ Prolonged invasive vascular devices
(hemodialysis catheter, CVP)
• Total parenteral nutrition
• Necrotizing pancreatitis, recent major surgery
(particularly abdominal)
• Prolonged administration of broad spectrum
antibiotic
• Prolonged hospital/ ICU admission
◦ Recent fungal infection and multisite colonization
Rhodes et al. Crit Care Med 2017;15 (3): 486-552
Candida Score > 2.5 : 6-fold increase in relative risk
for developing invasive candidiasis
ANTIBIOTIC TREATMENT IN SEPSIS
Consideration in choosing appropriate antibiotic
 Anatomic site associated with typical pathogen,
the ability of antimicrobial to penetrate that site
 Prevalent pathogens in the community, hospital
or hospital ward
 The resistant patterns of those prevalent
pathogens
 Immune defects (neutropenia, HIV infection,
defect of immunoglobulin, complement,
leucocyte function or production)
 Age and comorbidities (diabetes, liver or renal
failure, invasive devices)
ANTIBIOTIC TREATMENT IN SEPSIS

 Empiric antibiotic should be broad-spectrum that

may cover gram positives, gram negatives and
anaerobes
 Change to narrow spectrum antibiotic based on
culture results
ANTIBIOTIC TREATMENT IN SEPSIS
 Poor outcomes are associated with inadequate
or inappropriate antimicrobial or delay in giving
antimicrobial therapy
 Inappropriate AB selection in sepsis are
common (32 %) with markedly increase mortality
(34 % vs 18 %)
(Leibovici et al. Antimicrob Agents Chemother 1997; 41: 1127)

 The time to initiation of appropriate antimicrobial

therapy was the strongest predictor of mortality
(Kumar et al. Crit Care Med 2006; 34: 1589)
ANTIBIOTIC TREATMENT IN SEPSIS
SSC Guidelines 2016
Carbapenem (meropenem, imipenem-cilastatin,
doripenem), or

Piperacillin-tazobactam, ticarcillin-clavulanate, or

3rd or 4th generation cephalosporins

+
Vancomycin, teicoplanin
(when risk factors for MRSA exist)

Macrolide or fluoroquinolone (significant risk of

Legionella spp infection)
Six Risk Factors Independently
Associated With MRSA Infection

 Previous hospitalization
(within the last 12 months)
 Longer LOS before infection
 Surgery
 Enteral feedings
 Use of broad spectrum antibiotics
 Immunocompromised
Graffunder EM et al. J Antimicrob Chemother. 2002;49:999-1005.
ANTIBIOTIC TREATMENT IN SEPSIS
SSC Guidelines 2016

Empiric combination therapy (at least two

antibiotics of different classes) aimed to the most
likely bacterial pathogens for the initial management
of septic shock

de-escalation with discontinuation within the first few days in

response to clinical improvement and/ or evidence of
infection resolution

Fluoroquinolone,
b-lactam + Aminoglycoside,
Macrolide
Dosage of Antibiotics in Sepsis

 Meropenem 1000 mg q 6-8 h,

Doripenem 500-1000 mg q8h
 Ciprofloxacin 400 mg q 8h,
Levofloxacin 750 mg q d
 Piperacillin-tazobactam 4.5 g q 8h
 Cefepime 2 g q 8-12h
 Gentamicin 7 mg/kg/d
 Linezolid 600 mg q 12h
 Vancomycin 15 mg/kg q 12h
 How long duration treatment ?
Approximately 7-10 days

Longer courses in patients with slow clinical

response, undrainable foci of infections,
bacteriemia with S. aureus, some fungal and viral
infections, immunologic deficiencies, including
neutropenia

Shorter courses in patients with rapid clinical

resolution

Daily assessment for de-escalation

Spectrum of antibiotics
Gram positives Gram negatives
Tigecycline
Carbapenems
Ceftobiprole
Quinupristin-
dalfopristin
Telithromycin
Glycopeptides
Daptomycin
Linezolid
Aztreonam
Polymixins
Pharmacokinetic and pharmacodynamic
(PK/PD) of antimicrobial
• Cmax/MIC ratio
Cmax • AUC/MIC ratio
• Time above MIC

Area Under
the Curve

MIC

Time
ANTIBIOTIC KILLING EFFECT
 Concentration-dependent (Cmax/ MIC or
AUC/ MIC)
(quinolones, aminoglycosides, macrolides,
ketolides, metronidazole)
maximizes plasma level
 Time-dependent (T > MIC)
(penicillins, cephalosporins, aztreonam,
carbapenems, glycopeptides, macrolides,
linezolid, clindamycin)
maximizes T > MIC
Fluoroquinolone spectrum of activity

Gram – Gram +

Strong Levofloxacin Levofloxacin

Ciprofloxacin Moxifloxacin
Gemifloxacin

Moderate Moxifloxacin Ciprofloxacin

Gemifloxacin Ofloxacin
Ofloxacin

Weak Norfloxacin Norfloxacin

Levofloxacin

 More active than ciprofloxacin against gram-

positive organisms such as S. pneumonia,
S. aureus
 Active against : Legionella pneumophila,
Chlamydia spp, Mycoplasma pneumonia,
Haemophilusn influenzae, Moraxella catarrhalis
 Less active than ciprofloxacin in vitro against
enteric gram negative bacilli and Pseudomonas
aeruginosa
Levofloxacin 500 mg vs 750 mg
CARBAPENEMS
 B-lactam group, inhibits cell wall synthesis
 Active against gram positives, gram negatives, anaerobes
(ultra broad spectrum)
 Imipenem slightly more active against gram positives
 Meropenem, ertapenem, doripenem : > active against
gram negatives
 Time-dependent killing agents (T > MIC)
 Drug of choice to treat serious infections caused by
cephalosporin-resistant Enterobacteriaceae, P. aeruginosa
(except ertapenem), Acinetobacter sp. (except ertapenem)
 NOT active against MRSA, MRSE, Enterococcus faecium,
Legionella sp., Chlamydia sp., M. pneumonia, P. cepacia,
Stenotrophomas maltophilia
Doripenem
• Drug of choice for treating serious infections (nosocomial
pneumonia, ventilator-associated pneumonia, complicated
intra-abdominal infection, sepsis) caused by
P. aeruginosa, ESBL-producing Enterobacteriaceae
• In vitro more active than imipenem and meropenem
against P. aeruginosa, active against some pseudomonal
isolates resistant to other carbapenems (29 %)
• Can be given by extended infusion of 4 hour (time above
MIC 49 %) with good stability to maximize bactericidal
effect
• Lower risk of resistance compared with other
carbapenems
 Conclusion :
From this meta-analysis,
we can conclude that
Doripenem is as valuable
Well-tolerated than
empirical antimicrobial
Agents for complicated
Intra-abdominal infection
cUTI, acute billiary tract
infection and
nosocomial pneumonia
Doripenem extended-infusion
“ Do not save your best antibiotics for
the postmortem room”

“The use of empirical therapy with

the most effective broad-spectrum agents
available is justified in severely ill patients
who may not survive until the causative
pathogens are identified.”

D.J. Bihari FRCP, RC Spencer FRCP, 1995.

Bacterial infections in Intensive Care. Medicom (UK)
Antifungal for systemic fungal infections

Polyenes (liposomal amphotericin-B)

Triazoles (fluconazole, voriconazole,

posaconazole)

Echinocandins (caspofungin, anidulafungin,

micafungin)
Algorithm for Empiric Therapy
Source Control
SSC Guidelines 2016

 Identify a specific anatomic diagnosis of

infection and source control intervention
as soon as possible
 Prompt removal of intravascular access
devices that are a possible source of
sepsis after other vascular access has
been established
SUMMARY
 Sepsis is medical emergency with high mortality
rate
 Sepsis, severe sepsis and septic shock should be
treated early and aggressively
 The cornerstones of sepsis therapy are rapid
administration of broad-spectrum antibiotic
targeting all likely pathogens, prompt removal of
the source of infection, supportive treatment
 For antimicrobial selection, consider : host
condition, severity of disease, suspected
pathogens, availability of antimicrobial agents
THANK YOU