Sepsis:

Optimalization of Antibiotic
Treatment
dr. Rizky Perdana,SpPD,KPTI,FINASIM

Division of Tropical and Infectious Disease

Department of Internal Medicine Faculty of Medicine Sriwijaya
University

Updated Definition

Sepsis

Severe sepsis

Sepsis + sepsis-induced organ dysfunction or tissue

hypoperfusion

Sepsis-induced hypotension

Infection (documented/suspected) + systemic

manifestations

a systolic BP(SBP) <90 mmHg or MAP <70 mmHg or

SBP >40 mmHg or <2 SD below normal for age in
the absence of other cause of hypotension

Septic Shock

Sepsis-induced hypotension persisting despite

adequate fluid resuscitation

Bone, et al. 1992 Chest 101:1644-1655

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-

Sepsis: A Continuum of Diseases

Septic Shock

Sepsis-induced Hypotension

Severe Sepsis

Sepsis
SIRS
Infection

Bone, et al. 1992 Chest 101:1644-1655

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med

SEPSIS
Hosts reaction to systemic invading
microbes involves a rapidly amplifying
inflammatory signals and responses that may
spread beyond the invaded tissue.
When counterregulatory control mechanisms
are overwhelmed, homeostasis may fail, and
dysfunction of major organ may supervene.
Further imbalance response related to
hypotension and septic shock with multiple
organ dysfunction leads to increasing deaths

Why Mortality Remains High??

(A) INFECTIOUS AGENT (S) :
toxin & other
virulence factors

(B) HOST DEFENSES :

natural barriers, humoral
& cell-mediated immunity

(C) UNFAVORABLE HOST FACTORS

Increasing age
Breakdown of barriers
Acquired immunodeficiency syndrome
Diabetes melitus
Cancer
Asplenia
End-organ disease
Neutropenia, lymphopenia
Chemotherapy, steroids & other
Immunosuppressive agents
e
Mild diseas ase
e dise
t
a
r
e
d
o
M
disease
e
r
e
v
e
S

Death

(D) MANAGEMENT
Resuscitative and supportive
measures
Appropriate and timely antibiotics
Targeted diagnostics
Closer monitoring (triaging)
Source control or anatomic repair :
surgery, interventional radiology, etc.
Reduction of immunosuppression
Adjunctive medical therapy
(e.g. IVIG, activated protein C, etc.)

Health
Nicolasora N, Kaul DR. Infectious disease emergencies. Med Clin N Am 92. 2008

Systemic Manifestations
I. General variables

Fever (38.3C)
Hypothermia (core temperature 36C)
Heart rate > 90/min or 2 SD above normal value for age
Tachypnea
Altered mental status
Significant edema or positive fluid balance (20 mL/kg over 24
hrs)
Hyperglycemia (plasma glucose 140 mg/dL or 7.7 mmol/L) in
the absence of diabetes

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Systemic Manifestations
II. Inflammatory variables
Leukocytosis (WBC count >12,000/L)
Leukopenia (WBC count <4000/L)
Normal count with >10% immature WBC
Plasma CRP >2 SD above normal value
Plasma PCT >2 SD above normal value

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Criteria of Organ Dysfunction

Aterial hypotension (MAP<70)

SCVO2 >70%
CI>3.5 L/mt/m2
Arterial hypoxemia (PaO2/FiO2 <300)
Acute oliguria (urine output<0.5ml/kg/h for at least 2 hours)
Creatinin increase >0.5mg/dL
Coagulation abnormalites (INR >1.5 or aPTT > 60 sec)
Ileus
Thombocytopenia <100.000/uL
Hyperbilirubinemia >4 mg?dL
Hyperlactatemia >3 mmol/L
Decrease capilary fill
SCCM/ESICM/ACCP/ATS/SIS
International Sepsis Definition Cofence,2001
Emergency Medicine 2010

Surviving Sepsis Campaign:

International Guidelines for
Management of Severe Sepsis and Septic Shock, 2008

A.
B.
C.
D.
E.
F.
G.
H.
I.
J.

Initial resuscitation
Diagnosis
Antibiotic therapy
Source control
Fluid therapy
Vasopressors
Inotropic therapy
Steroids
Recombinant human activated protein C
Blood product administration

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Antibiotics and Sepsis:

Necessary But Not Sufficient for Survival

Infection

Inflammation/Coagulation
Activation
Severe Sepsis

Death

Appropriate antibiotics
reduce mortality by
10%-15%; mortality
remains 28%-50%
Kreger BE et al. Am J Med 1980;68:332-43.
Meehan TP et al. JAMA 1997;278:2080-4.
Opal SM et al. Crit Care Med 1997;25:1115-24.
Pittet D et al. Am J Respir Crit Care Med 1996;153:684-93.
Simon D et al. Crit Care Clin 2000;16:215-31.
Courtesy of the National Initiative in Sepsis Education. Copyright 2002
Thomson Advanced Therapeutics Communications (ATC) and Vanderbilt
University School of Medicine. All rights reserved.

Hospital mortality and inappropriate initial antimicrobial therapy (IIAT)

according to classification of infection source.
(P < 0.001 for differences in hospital mortality and IIAT)

Scott T. Micek, Emily C. Welch, Junaid Khan, Mubashir Pervez, Joshua A. Doherty, Richard M. Reichley,
and Marin H. Kollef
Antimicrob. Agents Chemother., May 2010; 54: 1742 - 1748.

Hospital spending and adjusted mortality

rates for patients with sepsis vary
substantially, but higher hospital
expenditures are not associated
with better survival.

Tara Lagu, Michael B. Rothberg, Brian H. Nathanson, Penelope S. Pekow,

Jay S. Steingrub, and Peter K. Lindenauer
Arch Intern Med, 2011; 171: 292 - 299.

Antibiotic Therapy

Intravenous therapy should be started

within the first hour, after appropriate
cultures have been obtained
Initial empiric therapy using de-escalation
strategy
Antimicrobial should be reassessed 48-72
hours based on microbiological data and
clinical improvement

Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1):
296-327

Consideration When Choosing

an Antibacterial Agent
Outcome

Microbiology
Mechanism of action

at infection site

Concentration
Antibacterial spectrum

Drug
PK
Absorption

Distribution
Metabolism
Excretion
Optimal dosing
regimen

(06/16/15
Scaglione,
2002)

Pathogen MIC
PD

Clinical efficacy
Bacterial eradication
Compliance with
dosing regimen
Tolerability
Rate of resolution
Prevention of resistan

Time vs. concentration

dependent killing
Bactericidal vs. bacteriostatic
activity
Tissue penetration
Persistence of antibacterial effect

Antibiotic Usage in
Clinical Practice

06/16/15

Empirical Initial Antibiotics

Depends on :

Presumed site of infection

Suspected or known pathogens
Grams stain results
Previously have been documented to colonize or infect
the patient
Local resistance patterns
Limited spectrum of antibiotics available
Allergies
Cost
Host factor

Strategy For Empirical Treatment

Patient
Outpatient

risk

Deescalation

dysfunction

Pohan HT, 2005

Hospitalized

Stable condition

Severe or high

Escalation

Antibiotic selection based on

Susceptibility and resistance pattern
Immunity status, co morbidity and organ

Antibiotic monotherapy or combination

De-escalation Approach to
Antimicrobial Utilization
Obtain appropriate microbial sample
for culture and special stain

Follow up: temp, WBC, CXR, PaO2/FiO2,

haemodynamic, organ function

Search for
superinfection,
abscess
formation,
non-infectious
caused of
fever

No
Yes

Kollef, Drugs 2003;63 (20): 2157

Empirical Antimicrobial Therapy in Sepsis

Source

Preferred Therapy

Alternate therapy

Unknown
source

Meropenem
Piperacillin/tazobactam

Fluoroquinolones +
Metronidazole / clindamycin

CAP

Quinolone
Ceftriaxone

2nd gen cephalosporin

Cefepime

Nosocomial
pneumonia

Meropenem
Levofloxacin
Piperacillin/tazobactam

Cunha BA, et al. In: Cunha BA, et al. Antibiotic essentials.

Empirical Antimicrobial Therapy in Sepsis

Source
Intraabdominal
/ pelvic source

Preferred Therapy

Alternate therapy

Meropenem
Fluoroquinolones
(Ciprofloxacin /
Piperacillin/tazobactam
Levofloxacin) +
Ertapenem
Ceftriaxone + Metronidazole Metronidazole / Clindamycin

Urosepsis
Communityacquired

Meropenem
Piperacillin/tazobactam

Fluoroquinolones
(Ciprofloxacin /
Levofloxacin)
Aminoglycoside +
Ampicillin / Vancomycin

Urosepsis
Nosocomial

Meropenem
Piperacillin/tazobactam

Aztreonam
Cefepime
Amikacin

Cunha BA, et al. In: Cunha BA, et al. Antibiotic essentials. 2008.

Empirical Antimicrobial Therapy in Sepsis

(Combination Therapy)

Antibiotic

% Susceptible to at least one

antibiotic plus:

Cefepime

None Ciprofloxacin
83.4
86.4

Gentamicin
89.9

Imipenem or meropenem

89.7

92.4

94.2

Piperacillin-tazobactam

79.6

87.0

91.4

Scott T. Micek, Emily C. Welch, Junaid Khan, Mubashir Pervez, Joshua A. Doherty,
Richard M. Reichley, and Marin H. Kollef Antimicrob. Agents Chemother., May
2010; 54: 1742 - 1748.

Antimicrobial Treatment
for MRSA

Based on Microbiological and susceptibility test Staph. Aureus

resistant
to methicilin or oxacillin (MIC > 4 ug/ml).
Antibiotic for MRSA :
Glycopeptide
: Vancomycin, Teicoplanin
Oxazolidinones : Linezolid
Streptogramin : Quinopristin-Dalfopristin
Gycylcycline
: Tygelcyclin
Cephalosporine gen. V
: Ceftobiprole,cetrarolin
Alternative
: Cotrimoxazole, Minocycline,
Fluoroquinolones,Rifampicin
Combination treatment
: Cotrimoxazole + Rifampicin
Minocyclin + Rifampicin

Antimicrobial Treatment for MRSA

Glycopeptide

Vancomycin (500 mg q6h OR 1 g q12h)

Teicoplanin (400 mg IV, then 200 mg/d
IV/IM)

Oxazolidinones

Linezolid (600 mg q12h IV/PO)

Streptogramin

Quinopristin-Dalfopristin

Glycylcycline

Tigecycline (100 mg IV, then 50 mg IV q12h)

Alternative

Cotrimoxazole, Minocycline,
Fluoroquinolones, Rifampicin

Combination

Cotrimoxazole + Rifampicin
Minocyclin + Rifampicin

Antimicrobial Treatment for

ESBL-producing Organisms
Beta-lactam / beta- Piperacillin-tazobactam,
lactam inhibitor
Cefoperazone-sulbactam ,
Amoxicillin-clavulanat
Carbapenem

Imipenem,
Meropenem,Doripenem
Ertapenem

Fluoroquinolone

Ciprofloxacin, Levofloxacin

Aminoglycosides
Monobactam

Amikasin
Aztreonam

Antimicrobial Treatment for

Pseudomonas aeruginosa
Antipseudomonas
Cephalosporin

Ceftazidime, Cefepime, Cefpirome

Beta-lactam / betalactam inhibitor

Piperacillin-tazobactam

Carbapenem

Imipenem, Meropenem, Doripenem

Antipseudomonas
fluoroquinolone

Ciprofloxacin, Levofloxacin

Aminoglycosides

Amikasin, Tobramycin, Gentamisin

Monobactam

Aztreonam

Novel Combinations for Multiresistant

Acinetobacter

Tygecycline
Polymyxin B + Carbapenem
Polymyxin B + Rifampin
Polymyxin B + Carbapenem + Rifampin

Yoon. AAC. 2004.

Empirical Antimicrobial Treatment

for
Febrile Neutropenia
Suitable empirical monotherapy :
CARBAPENEMS
PIPERACILIN
TAZOBACTAM
CEFTAZIDIME
Paul M, Yahav D, Fraser A, Leibovici L, Empirical antibiotic monotherapy for febrile
neutropenia: systematic review and meta-analysis of randomized controlled
trials
J. Antimicrob. Chemother, 2006; 57: 176 - 189.

Antimicrobial Treatment for

Klebsiela pneumoniae
Carbapnemase and Other
Carbapenemase Bacteria
Characteristics of Enterobacteriaceae
strains
exhibiting in vitro carbapenem
nonsusceptibility and/or harboring the
blaKPC gene show high sensitivity to
Gentamycin
Jonas Marschall, Robert J. Tibbetts, W. Michael Dunne, Jr., Jonathan G. Frye,
Victoria J. Fraser, and David K. Warren
J. Clin. Microbiol., Jan 2009; 47: 239 - 241.

Conclusion

Sepsis is systemic inflammatory response to severe

infection which has high mortality
One way to reduce mortality is initial rapid and appropriate
antimicrobial therapy
Strategy to choose appropriate therapy is De-escalation
strategy:
Using broad-spectrum potent empiric antibiotic which is
sensitive in vitro based on local data
Short duration and narrow down based on culture result
and clinical improvement
Ideal criteria for empiric therapy: broad spectrum, based
on site of infection, local data, right dosage & duration,
combination therapy if indicated