Sepsis:Sepsis:Optimalization of AntibioticOptimalization of Antibiotic

TreatmentTreatment

Division of Tropical and Infectious DiseaseDivision of Tropical and Infectious DiseaseDepartment of Internal Medicine Faculty of Medicine Department of Internal Medicine Faculty of Medicine Sriwijaya Sriwijaya

University University

dr. Rizky Perdana,SpPD,KPTI,FINASIM

Updated Definition Updated Definition SepsisSepsis

Infection (documented/suspected) + Infection (documented/suspected) + systemic systemic manifestationsmanifestations

Severe sepsisSevere sepsis Sepsis + sepsis-induced Sepsis + sepsis-induced organ dysfunctionorgan dysfunction or or tissue tissue

hypoperfusionhypoperfusion Sepsis-induced hypotensionSepsis-induced hypotension

a systolic BP(SBP) <90 mmHg or MAP <70 mmHg or a systolic BP(SBP) <90 mmHg or MAP <70 mmHg or SBP SBP >40 mmHg or <2 SD below normal for age in >40 mmHg or <2 SD below normal for age in the absence of other cause of the absence of other cause of hypotensionhypotension

Septic ShockSeptic Shock Sepsis-induced hypotension persisting despite Sepsis-induced hypotension persisting despite

adequate fluid adequate fluid resuscitationresuscitation

Bone, et al. 1992 Chest 101:1644-1655Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-

327

Sepsis: A Continuum of DiseasesSepsis: A Continuum of Diseases

SIRS

Sepsis-induced Hypotension

Severe Sepsis

Sepsis

Infection

Septic Shock

Bone, et al. 1992 Chest 101:1644-1655Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

SEPSISHost’s 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

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

virulence factors

(B) HOST DEFENSES : natural barriers, humoral & cell-mediated immunity

(C) UNFAVORABLE HOST FACTORSIncreasing ageBreakdown of barriersAcquired immunodeficiency syndromeDiabetes melitusCancerAspleniaEnd-organ diseaseNeutropenia, lymphopeniaChemotherapy, steroids & otherImmunosuppressive agents

(D) MANAGEMENTResuscitative and supportive

measuresAppropriate and timely antibioticsTargeted diagnosticsCloser monitoring (triaging)Source control or anatomic repair :

surgery, interventional radiology, etc.Reduction of immunosuppressionAdjunctive medical therapy

(e.g. IVIG, activated protein C, etc.)

Death Health

Mild disease

Moderate disease

Severe disease

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

Why Mortality Remains High??

Systemic Manifestations

I. General variables Fever (38.3°C) Hypothermia (core temperature 36°C) 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/μL) Leukopenia (WBC count <4000/μL) 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)Aterial hypotension (MAP<70) SCVO2 >70%SCVO2 >70% CI>3.5 L/mt/m2CI>3.5 L/mt/m2 Arterial hypoxemia (PaO2/FiO2 <300)Arterial hypoxemia (PaO2/FiO2 <300) Acute oliguria (urine output<0.5ml/kg/h for at least 2 Acute oliguria (urine output<0.5ml/kg/h for at least 2

hours)hours) Creatinin increase Creatinin increase >>0.5mg/dL0.5mg/dL Coagulation abnormalites (INR >1.5 or aPTT > 60 sec)Coagulation abnormalites (INR >1.5 or aPTT > 60 sec) IleusIleus Thombocytopenia <100.000/uLThombocytopenia <100.000/uL Hyperbilirubinemia >4 mg?dLHyperbilirubinemia >4 mg?dL Hyperlactatemia >3 mmol/LHyperlactatemia >3 mmol/L Decrease capilary fillDecrease capilary fill

SCCM/ESICM/ACCP/ATS/SISInternational Sepsis Definition Cofence,2001

Emergency Medicine 2010

Surviving Sepsis Campaign:Surviving Sepsis Campaign: International Guidelines for International Guidelines for

Management of Severe Sepsis and Septic Shock, 2008Management of Severe Sepsis and Septic Shock, 2008

A. Initial resuscitationB. DiagnosisC. Antibiotic therapyD. Source controlE. Fluid therapyF. VasopressorsG. Inotropic therapyH. Steroids I. Recombinant human activated protein CJ. 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

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.

Appropriate antibioticsreduce mortality by 10%-15%; mortality remains 28%-50%

Severe SepsisSevere Sepsis

DeathDeath

Courtesy of the National Initiative in Sepsis Education. Copyright © 2002 Thomson Advanced Therapeutics Communications™ (ATC) and

Vanderbilt University School of Medicine. All rights reserved.

Antibiotics and Sepsis:Necessary But Not Sufficient for Survival

Appropriate antibioticsdecrease evolution tosevere sepsis by ~50%

InfectionInfection

Inflammation/Coagulation ActivationInflammation/Coagulation Activation

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 Intravenous therapy should be started started within the first hourwithin the first hour, , after appropriate after appropriate cultures cultures have been obtainedhave been obtained

Initial empiric therapy using Initial empiric therapy using de-escalation de-escalation strategystrategy

Antimicrobial should be Antimicrobial should be reassessed 48-72 reassessed 48-72 hourshours based on based on microbiological data and microbiological data and clinical improvementclinical improvement

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

04/18/23

Consideration When Choosingan Antibacterial Agent

Microbiology Mechanism of action Antibacterial spectrum

DrugPK

Absorption Distribution Metabolism Excretion Optimal dosing regimen

Concentrationat infection site

Pathogen MIC

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

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

(Scaglione, 2002)

04/18/23

Antibiotic Usage in Clinical Practice

Empirical Initial Antibiotics

Depends on : Presumed site of infection Suspected or known pathogens Gram’s 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 Hospitalized

Stable condition Severe or high risk

Escalation

Deescalation

Antibiotic selection based on Susceptibility and resistance pattern Immunity status, co morbidity and organ

dysfunction

Antibiotic monotherapy or combination

Pohan HT, 2005

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

Kollef, Drugs 2003;63 (20): 2157

Yes

No

Empirical Antimicrobial Therapy in Sepsis

SourceSource Preferred TherapyPreferred Therapy Alternate therapyAlternate therapy

Unknown Unknown sourcesource

MeropenemMeropenem

Piperacillin/tazobactamPiperacillin/tazobactam

Fluoroquinolones +Fluoroquinolones +

Metronidazole / clindamycinMetronidazole / clindamycin

CAPCAP QuinoloneQuinolone

CeftriaxoneCeftriaxone

22ndnd gen cephalosporin gen cephalosporin

CefepimeCefepime

Nosocomial Nosocomial pneumoniapneumonia

MeropenemMeropenem

LevofloxacinLevofloxacin

Piperacillin/tazobactamPiperacillin/tazobactam

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

Empirical Antimicrobial Therapy in Sepsis

SourceSource Preferred TherapyPreferred Therapy Alternate therapyAlternate therapy

Intraabdominal Intraabdominal / pelvic source/ pelvic source

MeropenemMeropenem

Piperacillin/tazobactamPiperacillin/tazobactam

ErtapenemErtapenem

Ceftriaxone + MetronidazoleCeftriaxone + Metronidazole

Fluoroquinolones Fluoroquinolones (Ciprofloxacin / (Ciprofloxacin / Levofloxacin) +Levofloxacin) +

Metronidazole / ClindamycinMetronidazole / Clindamycin

Urosepsis – Urosepsis – Community-Community-

acquiredacquired

MeropenemMeropenem

Piperacillin/tazobactamPiperacillin/tazobactam

Fluoroquinolones Fluoroquinolones (Ciprofloxacin / (Ciprofloxacin / Levofloxacin)Levofloxacin)

Aminoglycoside + Aminoglycoside + Ampicillin / VancomycinAmpicillin / Vancomycin

Urosepsis – Urosepsis – NosocomialNosocomial

MeropenemMeropenem

Piperacillin/tazobactamPiperacillin/tazobactam

AztreonamAztreonam

CefepimeCefepime

AmikacinAmikacin

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:

None Ciprofloxacin Gentamicin

Cefepime 83.4 86.4 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

GlycopeptideGlycopeptide Vancomycin (500 mg q6h OR 1 g q12h) Teicoplanin (400 mg IV, then 200 mg/d IV/IM)

OxazolidinonesOxazolidinones Linezolid (600 mg q12h IV/PO)

StreptograminStreptogramin Quinopristin-Dalfopristin

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

AlternativeAlternative Cotrimoxazole, Minocycline, Fluoroquinolones, Rifampicin

CombinationCombination Cotrimoxazole + RifampicinMinocyclin + Rifampicin

Beta-lactam / beta-lactam inhibitor

Piperacillin-tazobactam, Cefoperazone-sulbactam , Amoxicillin-clavulanat

Carbapenem Imipenem, Meropenem,Doripenem Ertapenem

Fluoroquinolone Ciprofloxacin, Levofloxacin

Aminoglycosides Amikasin

Monobactam Aztreonam

Antimicrobial Treatment forESBL-producing Organisms

Antipseudomonas Antipseudomonas CephalosporinCephalosporin

Ceftazidime, Cefepime, Cefpirome

Beta-lactam / beta-Beta-lactam / beta-lactam inhibitorlactam inhibitor

Piperacillin-tazobactam

CarbapenemCarbapenem Imipenem, Meropenem, Doripenem

Antipseudomonas Antipseudomonas fluoroquinolonefluoroquinolone

Ciprofloxacin, Levofloxacin

AminoglycosidesAminoglycosides Amikasin, Tobramycin, Gentamisin

MonobactamMonobactam Aztreonam

Antimicrobial Treatment forPseudomonas aeruginosa

Novel Combinations for Multiresistant Acinetobacter

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

Yoon. AAC. 2004.

Suitable empirical monotherapy :

Empirical Antimicrobial Treatment for

Febrile Neutropenia

CEFTAZIDIME

PIPERACILIN TAZOBACTAM

CARBAPENEMS

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 carbapenemnonsusceptibility and/or harboring theblaKPC gene show high sensitivity toGentamycin

Jonas Marschall, Robert J. Tibbetts, W. Michael Dunne, Jr., Jonathan G. Frye, Victoria J. Fraser, and David K. WarrenJ. Clin. Microbiol., Jan 2009; 47: 239 - 241.

Conclusion SepsisSepsis is is systemicsystemic inflammatory response to inflammatory response to severe severe

infection infection which has which has high mortality high mortality One way to reduce mortality is One way to reduce mortality is initial rapid and appropriate initial rapid and appropriate

antimicrobial therapyantimicrobial therapy Strategy to choose appropriate therapy is Strategy to choose appropriate therapy is De-escalation De-escalation

strategystrategy:: Using Using broad-spectrum potent empiric broad-spectrum potent empiric antibiotic which is antibiotic which is

sensitive in vitro based on local datasensitive in vitro based on local data Short duration and narrow down Short duration and narrow down based on culture result based on culture result

and clinical improvementand clinical improvement Ideal criteria Ideal criteria for empiric therapy: for empiric therapy: broadbroad spectrum, based spectrum, based

on site on site of infectionof infection, local data, local data, right , right dosage & durationdosage & duration, , combinationcombination therapy if indicated therapy if indicated