Sepsis:Optimalization of Antibiotic TreatmentDivision of Tropical and Infectious DiseaseDepartment of Internal Medicine Faculty of Medicine Sriwijaya University

dr. Rizky Perdana,SpPD,KPTI,FINASIM

Updated Definition SepsisInfection (documented/suspected) + systemic manifestationsSevere sepsisSepsis + sepsis-induced organ dysfunction or tissue hypoperfusionSepsis-induced hypotensiona systolic BP(SBP)

Sepsis: A Continuum of DiseasesSIRSSepsis-induced HypotensionSevere SepsisSepsisInfectionSeptic ShockBone, 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

SEPSISHosts 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

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 diseaseModerate diseaseSevere diseaseNicolasora N, Kaul DR. Infectious disease emergencies. Med Clin N Am 92. 2008Why Mortality Remains High??

Systemic ManifestationsI. General variablesFever (38.3C)Hypothermia (core temperature 36C)Heart rate > 90/min or 2 SD above normal value for ageTachypneaAltered mental statusSignificant 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 diabetesDellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Systemic ManifestationsII. Inflammatory variablesLeukocytosis (WBC count >12,000/L)Leukopenia (WBC count 10% immature WBC Plasma CRP >2 SD above normal valuePlasma PCT >2 SD above normal valueDellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

Criteria of Organ DysfunctionAterial hypotension (MAP70%CI>3.5 L/mt/m2Arterial hypoxemia (PaO2/FiO2 1.5 or aPTT > 60 sec)IleusThombocytopenia 4 mg?dLHyperlactatemia >3 mmol/LDecrease capilary fillSCCM/ESICM/ACCP/ATS/SISInternational Sepsis Definition Cofence,2001Emergency Medicine 2010

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2008Initial resuscitationDiagnosisAntibiotic therapySource controlFluid therapyVasopressorsInotropic therapySteroids Recombinant human activated protein CBlood 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 SepsisDeathCourtesy 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 SurvivalInfectionInflammation/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 TherapyIntravenous therapy should be started within the first hour, after appropriate cultures have been obtainedInitial empiric therapy using de-escalation strategyAntimicrobial should be reassessed 48-72 hours based on microbiological data and clinical improvementDellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Crit Care Med 2008; 36(1): 296-327

*Consideration When Choosingan Antibacterial AgentMicrobiology Mechanism of action Antibacterial spectrumDrugPK Absorption Distribution Metabolism Excretion Optimal dosing regimenConcentrationat infection sitePathogen MICPD Time vs. concentration dependent killing Bactericidal vs. bacteriostatic activity Tissue penetration Persistence of antibacterial effectOutcome Clinical efficacy Bacterial eradication Compliance with dosing regimen Tolerability Rate of resolution Prevention of resistance (Scaglione, 2002)

*Antibiotic Usage in Clinical Practice

Empirical Initial AntibioticsDepends on :Presumed site of infectionSuspected or known pathogensGrams stain resultsPreviously have been documented to colonize or infect the patientLocal resistance patternsLimited spectrum of antibiotics availableAllergiesCostHost 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 UtilizationObtain appropriate microbial sample for culture and special stainFollow up: temp, WBC, CXR, PaO2/FiO2, haemodynamic, organ functionSearch for superinfection, abscess formation, non-infectious caused of feverKollef, Drugs 2003;63 (20): 2157YesNo

Empirical Antimicrobial Therapy in SepsisCunha BA, et al. In: Cunha BA, et al. Antibiotic essentials. 2008.

SourcePreferred TherapyAlternate therapyUnknown sourceMeropenemPiperacillin/tazobactamFluoroquinolones +Metronidazole / clindamycinCAPQuinoloneCeftriaxone2nd gen cephalosporinCefepimeNosocomial pneumoniaMeropenemLevofloxacinPiperacillin/tazobactam

Empirical Antimicrobial Therapy in SepsisCunha BA, et al. In: Cunha BA, et al. Antibiotic essentials. 2008.

SourcePreferred TherapyAlternate therapyIntraabdominal / pelvic sourceMeropenemPiperacillin/tazobactamErtapenemCeftriaxone + MetronidazoleFluoroquinolones (Ciprofloxacin / Levofloxacin) +Metronidazole / ClindamycinUrosepsis Community-acquiredMeropenemPiperacillin/tazobactamFluoroquinolones (Ciprofloxacin / Levofloxacin)Aminoglycoside + Ampicillin / VancomycinUrosepsis NosocomialMeropenemPiperacillin/tazobactamAztreonamCefepimeAmikacin

Empirical Antimicrobial Therapy in Sepsis (Combination Therapy) 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.

Antibiotic% Susceptible to at least one antibiotic plus:NoneCiprofloxacinGentamicinCefepime83.486.489.9Imipenem or meropenem89.792.494.2Piperacillin-tazobactam79.687.091.4

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, TeicoplaninOxazolidinones: LinezolidStreptogramin: Quinopristin-DalfopristinGycylcycline: TygelcyclinCephalosporine gen. V : Ceftobiprole,cetrarolinAlternative : Cotrimoxazole, Minocycline, Fluoroquinolones,RifampicinCombination treatment : Cotrimoxazole + Rifampicin Minocyclin + Rifampicin

Antimicrobial Treatment for MRSA

GlycopeptideVancomycin (500 mg q6h OR 1 g q12h) Teicoplanin (400 mg IV, then 200 mg/d IV/IM)OxazolidinonesLinezolid (600 mg q12h IV/PO)StreptograminQuinopristin-DalfopristinGlycylcyclineTigecycline (100 mg IV, then 50 mg IV q12h)AlternativeCotrimoxazole, Minocycline, Fluoroquinolones, RifampicinCombinationCotrimoxazole + RifampicinMinocyclin + Rifampicin

Antimicrobial Treatment forESBL-producing Organisms

Beta-lactam / beta-lactam inhibitorPiperacillin-tazobactam, Cefoperazone-sulbactam , Amoxicillin-clavulanatCarbapenemImipenem, Meropenem,Doripenem ErtapenemFluoroquinoloneCiprofloxacin, Levofloxacin AminoglycosidesAmikasinMonobactamAztreonam

Antimicrobial Treatment forPseudomonas aeruginosa

Antipseudomonas CephalosporinCeftazidime, Cefepime, Cefpirome

Beta-lactam / beta-lactam inhibitorPiperacillin-tazobactamCarbapenemImipenem, Meropenem, DoripenemAntipseudomonas fluoroquinoloneCiprofloxacin, Levofloxacin

AminoglycosidesAmikasin, Tobramycin, GentamisinMonobactamAztreonam

Novel Combinations for Multiresistant AcinetobacterTygecyclinePolymyxin B + Carbapenem Polymyxin B + RifampinPolymyxin B + Carbapenem + RifampinYoon. AAC. 2004.

Suitable empirical monotherapy :

Empirical Antimicrobial Treatment forFebrile NeutropeniaCEFTAZIDIMEPIPERACILIN TAZOBACTAMCARBAPENEMSPaul 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 strainsexhibiting in vitro carbapenemnonsusceptibility and/or harboring theblaKPC gene show high sensitivity toGentamycinJonas 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.

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

****When a patient presents with infection, or when activation of inflammation or coagulation occurs following infection, it is possible to use appropriate antibiotic therapy to reduce the risk of mortality. Under these circumstances, use of an appropriate antibiotic regimen can reduce the evolution to sepsis by approximately 50%. The point is that appropriate antibiotic therapy is best used to stop the evolution to severe sepsis, not when severe sepsis has already set in. Early recognition of sepsis syndrome, along with prompt administration of broad-spectrum antibiotics and surgery where needed, is the cornerstone of therapy for patients with sepsis.28