Clinical Trials of Anti-Clinical Trials of Anti-Infectives for Highly Resistant Infectives for Highly Resistant

MicroorganismsMicroorganisms

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 genesHughes & DattaNature 1981; 302:725

Intercontinental Spread of a New Antibiotic Resistance Gene on an Epidemic Plasmid

. . ..

.

.

..

Seattle

Los AngelesChicago Syracuse

BostonPhiladelphiaGainesville

Miami

. Caracas, Venezuela

GeneGenegent.resistancegent.resistance2”-nucleotidyl transferase2”-nucleotidyl transferaseidentical Eco R1identical Eco R1 fragment sizesfragment sizes

All produce TEM 1All produce TEM 1 and OXA and OXA -lactamase-lactamase

O’Brien et alScience 1985; 230: 87

Enterococci Contain Sex-PheromoneInduced Plasmid Transfer

Plasmid containingdonor

Plasmid freerecipient

consenting (responsive)- synthesize proteinadhesin facilitatingmating

secrete family of heat-stableprotease pheromones (5 to 6) - 7 or 8 AAresult - transfer frequently 105 - 106 foldafter transfer - specific plasmid pheromone shut down

s

ClewellCell 1993; 77: 9-12

First Case of Fully Vancomycin-Resistant S. aureus (MIC> 128g/ml)

DetroitDetroitVRSAResistance: vanco, teico, oxacillinSusceptible: chloro, linezolid

synercid, minocyclinetrimeth-sulfa

Mechanism: Van A geneFrom enterococcus

40 y old womanDM, PVD, CRIOn Dialysis3 mo: chronic foot ulcer4/02: MRSA BSI6/02: exit site infVRSA

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

Detroit Detroit MIC > 128 g/ml

70 yr obese man500 lbs L ext amputation 2 osteo ‘952 yrs: ®L ext ulcer -

VRE and MRSASept 02: osteo

VRSA/S. aureus/S. maltophilia/GBSVan A gene

L

Hershey, PAHershey, PAMIC= 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)

0

5

10

15

20

25

30

35

10 20 30 40 50 60 70 80

total cases

recovered

13

33

2016 15 14

9

349

4 40 0 1

0

No.

pat

ien

ts

case fatality = 82%

age strataSkinner & KeeferArch 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%

Mor

tali

ty (

%)

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

pro

por

tion

of

BS

I (%

)

0

proportion

crude mortality

crudemortality (%)

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

8070

60

50

40

30

20

10

all-

cau

se (

cru

de)

mor

talit

y -

per

cen

t-

Attributable mortality of resistance geneAttributable mortality of infectionMortality from underlying disease

infectionandno Rx

infection and Rx

infection and no Rx

resistancegene

resistancegene

infectionand Rx

effect ofexisting Rx

1 2 3 4 5 scenarios

effect ofexisting Rx

Wenzel RP JID 1998; 178:917-9

Hypothetical Argument: Recombinant Human Activated Protein C for Severe

Sepsis and Septic Shock

control HAPC

0

5

10

15

20

25

30

35

attributable mortality

mortality of underlying disease

30.8%24.7%

15.4% 9.3%

15.4% 15.4%

The absolute differencein mortality (30.8 - 24.7 = 6.1%)corresponds to a 20%reduction in crudemortality and a 40%reduction in attributablemortality.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