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Initiation of Inappropriate Antimicrobial Therapy Results in a Fivefold Reduction of Survival in Human Septic Shock

Kumar. A. Chest. 2009 Nov;136(5):1237-48. doi: 10.1378/chest.09-0087

Clinical Question

  • In patients with septic shock, what is the relationship between appropriateness of initial empiric antimicrobial therapy and survival?

Design

  • Retrospective observational study
  • Pre-determined rules for assessing appropriateness of antimicrobial agents. For unanticipated scenarios not covered by these pre-determined rules, two infectious disease/critical physicians who were blinded to outcome, reviewed the data to determine appropriateness of antimicrobials
  • Patients identified from ITU registries or ICD coding

Setting

  • 22 hospitals in Canada, USA, Saudi Arabia
  • 1996-2006

Population

  • Inclusion:
    • Adult patients with septic shock as defined by:
      • Documented or suspected infection
      • Persistent hypotension requiring pressor therapy
      • ≥2 of the following
        • HR >90
        • RR >20 or PCO2 <32mmHg
        • Temp <36°C or >38°C
        • WCC <4 or >12 or >10% band forms
  • Exclusion: none defined
  • n=5715
    • Patient characteristics
      • Mean age: 62.6 years
      • 56.3% male
      • Mean APACHE II score: 25.2
      • Treatment with:
        • Drotrecogin-alfa: 2.2%
        • Low-dose steroid: 27.1%
      • Indication for source control: 43.4%
      • Community acquired infections 55%
      • Documented infection: 82.2%
      • Suspected infection without either plausible pathogen isolated, or definitive radiological, surgical, autopsy or biopsy evidence of infection: 17.8%
    • Comparing patients who received appropriate vs. inappropriate antimicrobials
      • Co-morbidities
        • Immunosuppressive chemotherapy or long term steroid therapy: 15% vs. 19.8%, p<0.05
        • COPD: 13.6% vs. 14.1%
        • Chronic renal failure: 14.6% vs. 21.6%, p<0.01
        • Long-term dialysis dependent” 7.3% vs. 10.7%
      • Clinical site infections
        • Pneumonia: 38.1% vs. 37.2%
        • Intra-abdominal 30.1% vs. 30%
        • Genitourinary: 10.9% vs. 7.3%, p<0.01
        • Skin and soft tissue: 8.1% vs. 4.6%, p<0.01
        • Intravascular catheter: 3.4% vs. 5.5%, p<0.01
        • Systemically disseminated infection (including yeast and TB): 1.7% vs. 6.8%, p<0.01
      • Primary microbiological pathogen
        • Gram negative: 53.9% vs 34.4%, p<0.01
        • Gram positive: 33.9% vs. 31.8%
          • S. aureus: 13.2% vs. 19.7%, p<0.05
        • Yeast/fungi: 6.5% vs. 28.8%, p<0.01
        • Anaerobes: 4.3% vs. 2.1%, p<0.05

Intervention

  • Appropriate antimicrobial administered
    • Defined as positive if:
      • The first new antimicrobial agent given following recurrent/persistent hypotension or an antimicrobial initiated within 6 hours of the administration of the 1st new antimicrobial had:
        • in vitro activity appropriate for isolated pathogen
        • Or for culture negative shock, antimicrobial administered consistent with accepted norms modified for local flora

Control

  • Inappropriate or no antimicrobial administered

Outcome

  • Primary outcome: survival to hospital discharge (included discharge to chronic care facility)
    • 43.7%
  • Secondary outcomes:
    • Appropriate antimicrobials initiated in 80.1%
    • Comparing appropriate vs. inappropriate antimicrobials
      • Survival to hospital discharge was significantly improved (52% vs. 10.3%, OR 9.45, 95% C.I. 7.74-11.54, p<0.0001)
      • Multivaribale logistic regression analysis performed to correct potential confounding variables: survival remained significantly improved (OR 8.99, 95% C.I. 6.60-12.23, p<0.0001)
  • Subgroup analysis
    • Significantly improved mortality in patients treated with appropriate vs. inappropriate antimicrobials when analysis restricted to:
      • Culture positive cases (OR 6.95, 95% C.I. 3.11-15.52)
      • Gram positive cocci (n=1356), p<0.0001
      • Gram negative bacilli (n=2002), p<0.0001
      • Anaerobes (n=156), p=0.0048
      • Yeast (n=443), p<0.0001

Authors’ Conclusions

  • In patients with septic shock, ~20% are initially treated with inappropriate antimicrobial therapy. This is associated with a 5-fold decrease in survival.

Strengths

  • Large sample size, multi-centre
  • Pre-determined rules for determining appropriateness of antimicrobials
  • Some known biases are adjusted for by the multivariate analyses, suggesting that the observed effect is likely to be real, even if exact magnitude cannot be determined from this study
  • Simple statistical approach
  • Large effect size (OR 6.95-9.45) so clinically relevant
  • Similar results found in all subgroups thereby giving us confidence in results

Weaknesses

  • Retrospective analysis, therefore confounded by multiple biases
  • Irrespective of unknown biases, the cases and controls definitely differed significantly according to parameters which are very likely to have affected the outcome: specifically patients who didn’t receive appropriate antibiotics were more likely to have been immunosuppressed,  have had surgical complications, line infections, disseminated infections and hard to treat / highly pathogenic organisms (P aeruginosa, S aureus,  yeasts/fungi)
  • The study give no data on patients lost to follow up; this could be an additional source of bias
  • In the case of culture negative infections the gold standard (2 or 3 expert opinions / concordance with guidelines) is weak, although similar to that seen in clinical practice
  • Duration of follow up is not stated
  • Indication for source control in >40% but it was not stated if this was performed
  • Data is historical: some as early as 1996. Overall mortality is very high based on current standards

The Bottom Line

  • In adult patients with septic shock inappropriate initial choice of empiric antibiotic therapy is associated with ~5-fold absolute reduction in survival, even after correction for co-morbidities, clinical presentation and organism. The effect size is greatest in patients with primary blood stream infections, urinary tract infections, and infections due to anaerobes or yeasts.

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