1. Antibiotic Resistance why do we care? Thursday 1/10/2008

2. Reasons why we might care If resistant bugs cause higher mortality If resistant bugs cause greater morbidity If resistant bugs are more costly to treat If resistant bugs cause additional disease Resistance ≠ Virulence Do we have evidence for any of these? Is it true for any resistant bug?

3. How could resistance impact the outcomes? If resistance is associated with virulence. –Resistance genes alter fitness –Resistant genes may be associated with virulent genes If there is a delay in administration of appropriate antibiotic Rx. If treatments of resistant bacteria are more toxic or less efficient (ie vancomycin).

4. Different perspectives of the impact of resistance Hospital / third party payer / the patient / society. Patient vs. Society Resistance also effects patients who did not have infection from resistant organism: –Broader agents are used for initial empirical Rx. -> more expensive more toxic less effective have deleterious effects on other commensal bacteria

5. Different societies: The Netherlands Boston ???

6. Studies reporting increased morbidity/mortality due to MRSA OutcomeResultsAuthorJournal Mortality (meta analysis) OR 1.93 Cosgrove et al. CID 2002 Mortality NS (OR 0.72 95%CI 0.39- 1.96) Cosgrove et al. Infect Control Hosp Epidemiol 2005 LOS HR 1.29 (1.05-1.59) Hospital charges ME (multiplicative effect) 1.36 (1.06-1.75) Clinical failure VISA vs. MRSA Correlation resistance & clin failure r=0.828 (p<0.001) Neoh et al.Ann Clin Microbiol Antimic 2007 Clinical Failure CA-MRSA vs. CA- MSSA OR 3.4 (95%CI 1.7-6.9) Davis et al.JCM 2007

7. Comparison of mortality associated with MRSA vs. MSSA / Cosgrove et al. CID 2002

8. Mortality rates of staphylococcal bacteremia over time / Dancer SJ JAC 2007

9. Studies reporting impaired outcomes due to VRE OutcomeResultAuthorJournal Mortality (VRE clinical isolate) 17% vs. 6% mortality (RR 2.13) Carmeli et al. Arch Intern Med 2002 LOS15.1d vs. 8.5d (RR 1.73) Hospital costs$52,449 vs $31,915 (RR 1.4) Surgery18% vs. 10% (RR 2.74) Transfer to institution51% vs 35% (RR 2.01) Matched cohort study

10. Studies reporting impaired outcomes due to VRE (cont’) OutcomeResultAuthorJournal Mortality (meta-analysis) OR 2.52 (95%CI 1.87-3.39) DiazGranados et al. CID 2005 Mortality (VRE bacteremia) Attributable mortality 37% Edmond et al.CID 1996 MortalityOR 3.47 (95%CI 1.47 – 8.19) Linden et alCID 1996 Mortality (VRE bacteremia) 52% vs. 27% (p<0.001) Bhavnani et alDiag. microbiol. Infect. Dis. 2000 Mortality (VRE bacteremia) OR 8.3 (95%CI 1.9-35.3) Ghanem et al.Infec Cont Hosp Epi 2007

11. Meta-analysis VRE vs. VSE / DiazGranados et al. CID 2005

12. Studies reporting impaired outcomes due to PRSP OutcomeResultAuthorJournal S. pneumoniae 19A MDR Treatment failure Pichichero et al. JAMA 2007 Clinical failureOR 1.03, 95%CI 0.49-1.9 Cardoso et al. Arch. Dis. Childhood 2007 Short-term Mortality Meta-analysis OR 1.3 95%CI1.08-1.59, higher for specific subgroups (bacteremic, PRSP, not all PNSSP) Tleyjeh et al CID 2006 MortalityNot increased - International prospective study Yu et al. CID 2003 MortalityNot increased - 10y prospective study in spain Pallares et al. NEJM 1995

13. Meta-analysis PNSSP vs. PSSP – CID 2006 Tleyjeh et al

14. Studies reporting impaired outcomes due to other resistant pathogens PathogenResultAuthorJournal P. aeruginosaMortality R.R 3.0 95%CI 1.2-7.8 2nd bacteremia RR 9.0 95%CI 2.7-30 Carmeli et al.Arch Intern Med. 1999 Enterobacter spp. (3 rd gen Cephalosp) Mortality (RR 5.02 p=.01) LOS (1.5fold, p<.001) Economic outcomes (attributable hospital charge $29,379) Cosgrove et al.Arch Intern Med 2002

15. In the aftermath of early Ab success: 1960s - US surgeon General William H. Stewart: “(it) is time to close the book on infectious disease and declare the war against pestilence won”. 2007 - despite Ab –Infectious diseases the 2nd-leading cause of death worldwide –3rd -leading cause in US. The reason - global spread of microbial resistance to antimicrobial therapies.

16. So - we do care, yet… Do all these studies correctly measure what they aim to? Do we know this for all bugs? For all antibiotic classes? What are the correct designs to measure these?