Clinical%20Trials%20of%20Anti-Infectives%20for%20Highly%20Resistant%20Microorganisms

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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

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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 302725
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Intercontinental Spread of a New Antibiotic
Resistance Gene on an Epidemic Plasmid
Gene gent.resistance 2-nucleotidyl
transferase identical Eco R1 fragment
sizes All produce TEM 1 and OXA
b-lactamase
Seattle
.
Syracuse
.
Chicago
.
. .
.
Los Angeles
Boston
Philadelphia
Gainesville
.
.
Miami
. Caracas, Venezuela
OBrien et al Science 1985 230 87
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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
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First Case of Fully Vancomycin-Resistant S.
aureus (MICgt 128mg/ml)
VRSA Resistance vanco, teico, oxacillin Susceptib
le 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
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Second Case of Fully Vancomycin-Resistant S.
aureus (MIC-32 mg/ml)
Detroit MIC gt 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
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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?

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Significance of Bacteremia Caused by
Staphylococcus Aureus (n122)
33
case fatality 82
total cases
13
20
16
15
14
No. patients
9
9
4
4 4
3
0 0
1
recovered
0
age strata
Skinner Keefer Arch Int. Med 1941 68 851-75
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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

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Mortality ()
29
Adequate Inadequate (n345) (n147)
therapy
Ibrahim et al Chest 2000 118 146-55
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Rank Order of Nosocomial U.S.Bloodstream
Infections and MortalitySCOPE Surveillance System
proportion
40
crude mortality
proportion of BSI ()
30
crude mortality ()
20
32 21 16 25 11 32
8 40
10
0
CNS S.aureus Enterococcus
Candida n3908 n1928 n1354
n934
50 resistant to Methicillin
Edmond et al CID 1999 29239-44
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Attributable Mortality The Promise of Better
Antimicrobial Therapy
Attributable mortality of resistance gene
80
Attributable mortality of infection
Mortality from underlying disease
70
effect of existing Rx
60
resistance gene
effect of existing Rx
50
resistance gene
40
infection and no Rx
all-cause (crude) mortality - percent-
infection and no Rx
infection and Rx
infection and Rx
30
20
10
1 2 3
4 5
scenarios
Wenzel RP JID 1998 178917-9
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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
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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