Terminology Systemic Inflammatory Response Syndrome (SIRS) Temp > 38 or < 36 HR > 90 RR > 20 or PaCO2 < 32 WBC > 12 or 10% Sepsis The systemic inflammatory response to infection. Severe Sepsis Organ dysfunction secondary to Sepsis. e.g. hypoperfusion, hypotension, acute lung injury, encephalopathy, acute kidney injury, coagulopathy. Septic Shock Hypotension 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 criteria acute 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 Pathogenesis Unbalanced Immune Reaction Tissue Factor Procoagulant State Microvascular Thrombosis Mediators of Inflammation ROS Vasodilation Capillary Leak
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/F Platelets Bili BP GCS Cr/UOP
Microbiology and Antibiotic Primer 101 Three classes of major bacterial pathogens that need to be considered in septic patients Gram Positive Cocci Gram Negative Rods Strict Anaerobes
Gram Positive Cocci Staphylococcus aureus 50% are MRSA Beta hemolytic streptococci Always penicillin susceptible Viridans streptococci Usually penicillin or ceftriaxone susceptible Enterococcus species E faecium is always penicillin resistant, often vancomycin resistant
Facultative Gram Negative Rods (Enterobacteraciae) Most common pathogens are E coli and Klebsiella Increasing 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 Negatives Pseudomonas 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 species Inherently MDR Can become totally resistant, even to colistin!
Strict Anaerobes Most common pathogens are Bacteroides fragilis and fusobacterium species Produce beta lactamases Resistant to penicillins and older cephalosporins Susceptible to BL/BLI, cefoxitin, carbapenems, metronidazole, clindamycin
Classes of Antibiotics to Use Initially in Sepsis Beta Lactams* Broad Spectrum Penicillins = piperacillin/tazobactam 3 or 4 th 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
Aminoglycosides Gentamicin/tobramycin (7 mg/kg/day) Cover most enterobacteraciae and pseudomonas Not as resistant to aminoglycoside modifying enzymes Amikacin (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 AG Nephro/oto-toxicity are unlikely
Vancomycin Only active against GPC Slowly bactericidal Pharmacodynamic parameter = AUC/MIC Goal of >=400 Need loading dose for serious infections: 25 mg/kg AW Trough >15 achieves AUC/MIC of >400 when MIC <2 For 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 MRSA Severe purulent SSTI Necrotizing pneumonia/empyema Central line associated (Known MRSA carriers?) Go To Drug = Vancomycin
When to Cover for Pseudomonas Severe COBPD/bronchiectasis Frequent ABX Steroid dependent Known 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/T66.67% P/T + FQ73.34% P/T + Gent89.34% P/T + Tobra96.00 % P/T + Amik97.30% Cefepime CPM54.67% CPM + FQ61.33% CPM + G82.67% CPM + T89.33% CPM + A93.34% Ceftazidime CTZ57.33% CTZ + FQ64.00% CTZ + G84.00% CTZ + T90.67% CTZ + A93.33%
Sepsis is “always” a secondary diagnosis: where is it coming from?
Septic Patients are not Immune to Hospital Acquired Infections! “Bundles” Guidelines Recent literature
Antibiotic Stewardship Get appropriate cultures before starting ABX Pick empiric therapy based on likely source and organism(s) Once meaningful cultures are available, use susceptibilities to de-escalate therapy Limit duration of therapy to evidence based recommendations when possible
Thanks to Andrew Faust, PharmD Terri Smith, PharmD, Sharon Williamson, MT(ASCP), CIC Michael H. Hooper, MD, Eastern Virginia Medical School Surviving Sepsis Campaign. Dellinger et al. Critical Care Medicine 2013;41;580-637