# Presentation: 100425

## 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

**.**

**. .**

**.**

**.**

**.**

-  **.**

**.**

**Seattle**

**Los Angeles**

**Chicago**

**Syracuse**

**Boston**

**Philadelphia**

**Gainesville**

**Miami**

**. ****Caracas,**
** ****Venezuela**

**Gene**
**gent.resistance**
**2”-nucleotidyl transferase**
**identical Eco R1**
**          ****fragment sizes**
**      ****All produce TEM 1**
**      ****and OXA ********-lactamase**

- O’Brien et al
*Science *1985; 230: 87

## Enterococci Contain Sex-Pheromone

_**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

## 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**

## Second Case of Fully Vancomycin-Resistant S. aureus (MIC-32 g/ml)

**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**

## 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)

**total cases**

**recovered**

**13**

**33**

**20**

**16**

**15**

**14**

**9**

**3**

**4**

**9**

**4        4**

**0         0**

**1**

**0**

**No. patients**

**case fatality = 82%**

**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**

**Adequate   Inadequate**
**  ****(n=345)       (n=147)**
**          ****therapy**

**29%**

**62%**

**Mortality (%)**

- Ibrahim et al *Chest *2000; 118: 146-55

## 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**

## 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

## Hypothetical Argument: Recombinant Human Activated Protein C for Severe Sepsis and Septic Shock

**30.8%**
**	****	****24.7%**

**15.4%               9.3%**
**15.4%              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

## 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**