Edward L. Goodman, MDCore Faculty

Hospital EpidemiologistJune 27, 2013

OutlineRecognition and ImpactGrades of recommendationsNon-antimicrobial managementAntimicrobial managementInfection PreventionAntibiotic Stewardship

TerminologySystemic Inflammatory Response Syndrome (SIRS)

Temp > 38 or < 36HR > 90RR > 20 or PaCO2 < 32WBC > 12 or < 4 or Bands > 10%

SepsisThe systemic inflammatory response to infection.

Severe SepsisOrgan dysfunction secondary to Sepsis.e.g. hypoperfusion, hypotension, acute lung injury, encephalopathy, acute kidney injury, coagulopathy.

Septic ShockHypotension secondary to Sepsis that is resistant to adequate fluid administration and associated with hypoperfusion.

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 1644–1655.

TWO out of four criteriaacute change from baseline

Infection, SiRS, Sepsis

Bone, R., Balk, R., Cerra, F., Dellinger, R., Fein, A., Knaus, W., Schein, R., et al. (1992). Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest, 101(6), 1644–1655.

Sepsis PathogenesisUnbalanced Immune Reaction

Tissue Factor

Procoagulant State

MicrovascularThrombosis

Mediators of Inflammation

ROS

Vasodilation CapillaryLeak

Organ failure in sepsis

Vincent, J.-L., Sakr, Y., Sprung, C. L., Ranieri, V. M., Reinhart, K., Gerlach, H., Moreno, R., et al. (2006). Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine, 34(2), 344–353.

P/FPlateletsBiliBPGCSCr/UOP

Critical Care Medicine 2013;41:580

Grading of Recommendations, Assessment, Development and EvaluationGRADE SYSTEM

Strength of Evidence (A – D)Level of Recommendation (1 or 2)

ManagementInitial Resuscitation

FluidsPressors

Microbial DiagnosisAntimicrobial Therapy

Primer on AntibioticsSource ControlInfection Prevention

Summary

Other Supportive Measures

Other Supportive

Other Supportive

Microbiology and Antibiotic Primer 101Three classes of major bacterial pathogens

that need to be considered in septic patientsGram Positive CocciGram Negative RodsStrict Anaerobes

Gram Positive CocciStaphylococcus aureus

50% are MRSABeta hemolytic streptococci

Always penicillin susceptibleViridans streptococci

Usually penicillin or ceftriaxone susceptibleEnterococcus species

E faecium is always penicillin resistant, often vancomycin resistant

Facultative Gram Negative Rods (Enterobacteraciae)Most common pathogens are E coli and

KlebsiellaIncreasing resistance includes ESBL, Kpc

SPICE Organisms (Serratia, Indole Positive Proteus, Citrobacter, Enterobacter)Possess Amp C resistance genes which can be

induced or selected

Strictly Aerobic Gram NegativesPseudomonas aeruginosa

Inherently resistant to many classes of drugs Possess Amp C genes (also SPICE organism), many

other beta lactamases, efflux pumps and altered porin channels

Can become even more resistant Even to carbapenemases!

Acinetobacter speciesInherently MDRCan become totally resistant, even to colistin!

Strict AnaerobesMost common pathogens are Bacteroides

fragilis and fusobacterium speciesProduce beta lactamases

Resistant to penicillins and older cephalosporins Susceptible to BL/BLI, cefoxitin, carbapenems,

metronidazole, clindamycin

Classes of Antibiotics to Use Initially in SepsisBeta Lactams*

Broad Spectrum Penicillins = piperacillin/tazobactam3 or 4th Generation Cephalosporins

Non anti-pseudomonal = ceftriaxone or cefotaxime Anti-pseudomonal = ceftazidime or cefepime

Carbapenems Non anti-pseudomonal = ertapenem Anti-pseudomonal = meropenem

Monobactams = aztreonam Only for “beta lactam” allergic No gram positive or anaerobic activity Anti-pseudomonas activity comparable to ceftazidime

* Avoid combinations of beta lactams

AminoglycosidesGentamicin/tobramycin (7 mg/kg/day)

Cover most enterobacteraciae and pseudomonasNot as resistant to aminoglycoside modifying

enzymesAmikacin (20 mg/kg/day)

More resistant to aminoglycoside modifying enzymes

Should be the “Go To AG”Once MIC’s available, can de-escalate to other

class (BL, FQ)Rarely need more than 1-2 days of AGNephro/oto-toxicity are unlikely

VancomycinOnly active against GPCSlowly bactericidalPharmacodynamic parameter = AUC/MIC

Goal of >=400Need loading dose for serious infections: 25

mg/kg AWTrough >15 achieves AUC/MIC of >400 when

MIC <2For OSSA, less effective than beta lactams

What is Missing?Fluoroquinolones

Only empiric indication in sepsis would be as part of combination therapy for severe CAP

Not empirically for UTI, intra-abdominal or SSTI

Why not?25-30+% of E coli in ICU are resistant!35% of Pseudomonas in ICU are resistant

When to Cover for MRSASevere purulent SSTINecrotizing pneumonia/empyemaCentral line associated(Known MRSA carriers?)

Go To Drug = Vancomycin

When to Cover for PseudomonasSevere COBPD/bronchiectasis

Frequent ABXSteroid dependentKnown airway colonization

Neutropenic septic leukemic(Burn patients)

Combination Rx for Pseudomonas? (Andrew Faust, PharmD)Only indicated to ensure coverage until MICs are

available Does not prevent resistance from developing Synergy is not clinically relevant

What combinations are optimal in ICU isolates 2012?

Pip/Tazo

P/T 66.67%

P/T + FQ 73.34%

P/T + Gent

89.34%

P/T + Tobra

96.00 %

P/T + Amik

97.30%

Cefepime

CPM 54.67%

CPM + FQ

61.33%

CPM + G 82.67%

CPM + T 89.33%

CPM + A 93.34%

Ceftazidime

CTZ 57.33%

CTZ + FQ 64.00%

CTZ + G 84.00%

CTZ + T 90.67%

CTZ + A 93.33%

Sepsis is “always” a secondary diagnosis: where is it coming from?

Septic Patients are not Immune to Hospital Acquired Infections!“Bundles”GuidelinesRecent literature

Prevent CLABSI

Prevent Ventilator Adverse Events

Prevent CAUTI

Sepsis Guidelines 2013

Antibiotic StewardshipGet appropriate cultures before starting ABXPick empiric therapy based on likely source

and organism(s)Once meaningful cultures are available, use

susceptibilities to de-escalate therapyLimit duration of therapy to evidence based

recommendations when possible

Thanks toAndrew Faust, PharmDTerri Smith, PharmD, Sharon Williamson,

MT(ASCP), CICMichael H. Hooper, MD, Eastern Virginia

Medical SchoolSurviving Sepsis Campaign. Dellinger et al.

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