1. Clinical Trials of Anti- Infectives for Highly Resistant Microorganisms Richard P. Wenzel, M.D., M.Sc. Professor and Chairman Department of Internal Medicine Medical College of Virginia Virginia Commonwealth University

2. Conjugative Plasmids in the Pre-Antibiotic Era E.D.G. Murray - Enterobacteriaceae 1917-54 Origin - N.Am., Europe, India, Mid East, Russia Strains - Salmonella (48%); Shigella (32%), E. coli (7%) 1917-41 Genetic transfer function (plasmids) - 24% Amp ® in 2%; tetra ® 9% No plasmids had resistance genes Hughes & Datta Nature 1981; 302:725

3. Intercontinental Spread of a New Antibiotic Resistance Gene on an Epidemic Plasmid....... Seattle Los Angeles Chicago Syracuse Boston PhiladelphiaGainesville Miami. Caracas, Venezuela Genegent.resistance 2”-nucleotidyl transferase identical Eco R1 fragment sizes fragment sizes All produce TEM 1 All produce TEM 1 and OXA  -lactamase and OXA  -lactamase O’Brien et al Science 1985; 230: 87

4. Enterococci Contain Sex-Pheromone Induced Plasmid Transfer Plasmid containing donor Plasmid free recipient consenting (responsive) - synthesize protein adhesin facilitating mating secrete family of heat-stable protease pheromones (5 to 6) - 7 or 8 AA result -  transfer frequently 10 5 - 10 6 fold after transfer - specific plasmid pheromone shut down s Clewell Cell 1993; 77: 9-12

5. First Case of Fully Vancomycin- Resistant S. aureus (MIC> 128  g/ml) Detroit VRSA Resistance: vanco, teico, oxacillin Susceptible: chloro, linezolid synercid, minocycline trimeth-sulfa Mechanism: Van A gene From enterococcus 40 y old woman DM, PVD, CRI On Dialysis 3 mo: chronic foot ulcer 4/02: MRSA BSI 6/02: exit site inf VRSA

6. Second Case of Fully Vancomycin- Resistant S. aureus (MIC-32  g/ml) Detroit Detroit MIC > 128  g/ml 70 yr obese man 500 lbs L ext amputation 2 osteo ‘95 2 yrs: ®L ext ulcer - VRE and MRSA Sept 02: osteo VRSA/S. aureus/S. maltophilia/GBS Van A gene L Hershey, PA MIC= 32  g/ml

7. A Clinical Trial for VRSA Rx What gold standard? vanco ®; meth ® possibly trimeth-sulfa vs other What comparators? a) synercid b) linezolid c) daptomycin d) combinations Why scientific base to choose comparators?

8. Significance of Bacteremia Caused by Staphylococcus Aureus (n=122) total cases recovered 13 33 20 16 15 14 9 3 4 9 4 0 1 0 No. patients case fatality = 82% age strata Skinner & Keefer Arch Int. Med 1941; 68: 851-75

9. ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy Risk for death AOR Inadeq. Rx6.9 Vasopres3.0 No. organ fail2.3 Risk for inad. Rx Candida52 Prior AB2.1  ALB1.3  CVC days1.03 Adequate Inadequate (n=345) (n=147) therapy 29% 62% Mortality (%) Ibrahim et al Chest 2000; 118: 146-55

10. Rank Order of Nosocomial U.S.Bloodstream Infections and Mortality SCOPE Surveillance System 40 30 20 10 CNS S.aureus* Enterococcus Candida n=3908 n=1928 n=1354 n=934 proportion of BSI (%) 0 proportion crude mortality crude mortality (%) 32 21 16 25 11 32 8 40 Edmond et al CID 1999; 29:239-44 * ~50% resistant to Methicillin

11. Attributable Mortality: The Promise of Better Antimicrobial Therapy 80 70 60 50 40 30 20 10 all-cause (crude) mortality - percent- Attributable mortality of resistance gene Attributable mortality of infection Mortality from underlying disease infection and no Rx infection and Rx infection and no Rx resistance gene resistance gene infection and Rx effect of existing Rx 1 2 3 4 5 scenarios effect of existing Rx Wenzel RP JID 1998; 178:917-9

12. Hypothetical Argument: Recombinant Human Activated Protein C for Severe Sepsis and Septic Shock 30.8% 24.7% 15.4% 9.3% 15.4% The absolute difference in mortality (30.8 - 24.7 = 6.1%) corresponds to a 20% reduction in crude mortality and a 40% reduction in attributable mortality. See: NEJM 2001; 344: 699-709

13. Clinical Trials of Anti-Infectives for Highly Resistant Microorganisms Important Urgent Complex Need to do power estimates cognizant of attributable mortality Gold standard and comparator drugs - challenging decision Feasible