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

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

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

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 105 - 106 fold after transfer - specific plasmid pheromone shut down s Clewell Cell 1993; 77: 9-12

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

Second Case of Fully Vancomycin-Resistant S. aureus (MIC-32 mg/ml) Detroit MIC > 128 mg/ml Hershey, PA MIC= 32 mg/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

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?

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

ICU BSI: Increased Mortality with Inadequate Antimicrobial Therapy Risk for death AOR Inadeq. Rx 6.9 Vasopres 3.0 No. organ fail 2.3 Risk for inad. Rx Candida 52 Prior AB 2.1  ALB 1.3  CVC days 1.03 62% Mortality (%) 29% Adequate Inadequate (n=345) (n=147) therapy Ibrahim et al Chest 2000; 118: 146-55

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

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

Hypothetical Argument: Recombinant Human Activated Protein C for Severe Sepsis and Septic Shock 30.8% 24.7% 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 15.4% 9.3% 15.4% 15.4%

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