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
Origin - N.Am., Europe, India, Mid East, Russia
Strains - Salmonella (48%); Shigella (32%),
E. coli (7%)
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
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

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 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> 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

6. 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

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)33
case fatality = 82%
total cases 13 20 16 15
No. patients 14 9 9 4 3 1
recovered
age strata
Skinner & Keefer
Arch Int. Med 1941; 68:

9. 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:

10. 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 10
CNS S.aureus* Enterococcus Candida
n= n= n= n=934
* ~50% resistant to Methicillin
Edmond et al CID 1999; 29:239-44

11. 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
scenarios
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%
The absolute difference
in mortality
( = 6.1%)
corresponds to a 20%
reduction in crude
mortality and a 40%
reduction in attributable
mortality.
See: NEJM 2001; 344:
15.4% %
15.4% %

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