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IT 5 - Sepsis - MEG
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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