Antibiotic Development Strategies to

Understand and Label Microbial

Endpoints such as Slow killing,
resistance and Failure,
AUIC Dosing and Success via Synergy
Jerome J. Schentag, PharmD
University at Buffalo
Buffalo, New York
Schentag@buffalo.edu
 Introduction

• Yesterday, we considered trial design

conditions to establish one antibiotic for all.
• Today, I wish to discuss the trial design
issues if our goal becomes one antibiotic for
each.
• I will then show that the two approaches work
well together to answer the questions of
antibiotic efficacy for resistant microbes.

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Probability of remaining susceptible
PK/PD: AUIC and Selected Resistance
Thomas JK, Antimicrobial Agents Chemother. 42: 521-527, 1998.
100

75 AUIC>101

50

25 AUIC<100

0
0 5 10 15 20
Days from initiation of Therapy 3
 PK/PD trials of Antibiotics
• Small numbers of patients yield very robust
data
• Time considerations dominate over one-time
sampling
• The more range you have in the data, the
better the ability of PK/PD to establish
correlations
• Antibiotics are very good models, because the
bacteria can be treated like a drug receptor.
• Drug effects are the key to applications of
PK/PD 4
 Vancomycin 1 gm q 12hr:
2 pks of 30 mcg/ml in 24 hrs
Vancomycin serum concentration

30 AUC24=254

8 Peak:MIC=3.75, AUIC=32

2 Peak:MIC=15, AUIC=127 MIC90

0.5 Peak:MIC=60, AUIC=508 MIC50

0 12
Time (hours)
5
MRSA: Issues With Appropriately
Dosed Vancomycin?
• MRSA MICs are usually 0.5 to 1.0 mcg/ml
– Slow killing of organisms in vitro and in vivo
– Recent MICs are 2.0 mcg/ml, a 2-4 fold loss of activity
• MRSA MBCs are increasingly 4-32 mcg/ml
– Staphylococci that are not yet VISA or VRSA, but no longer
responding to vancomycin
– Slow cidal..and getting progressively slower?
• Protocol Study; Find these cases and study them
using PK/PD; offer solutions while vancomycin is still
in the mix of options

6
Comparison of Vancomycin days to
eradication for MRSA Infections
100
Percent Culture Positive AUIC <400
80

60

40
AUIC >400
20 free AUIC=140

0
0 10 20 30
P=0.0402 Day of Eradication
Moise & Schentag. Am J Health Sys Pharmacy: October 2000 Suppl. 7
 Study Design Issues
• MRSA is seldom eradicated quickly, and improvements in
activity could yield shorter T-erad
• Once established, this organism will persist in blood and
soft tissues, despite therapy
• Weak antimicrobial action (vancomycin) keeps the patient
from death, but dissemination continues to foreign bodies,
bone, heart valves, etc.
• Accept only MRSA positive patients on vanco for at least
5 days with continued CX positive
– Enroll pts who continued on vanco for retrospective controls
– Enroll pts who have vanco dose increased (additivity control) and
follow for changes in time to eradication
– Enroll pts who have same vanco dose but add another ABX
(synergy test)
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 Strategies for MRSA failing
vancomycin after 5 days Tx
• In the Vancomycin failure patient with MIC ~ 2.0:
– Raise the vancomycin dose; target peaks of 50 and troughs
of 20 mcg/ml; higher if we dare…
– Vancomycin at conventional doses (troughs ~ 10) in
Combination therapy: Target Synergy
• Rifampin
• Aminoglycosides
• Oxacillin
• Linezolid
• Synercid

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 Synercid Killing Curves w/w.o. Vancomycin

Test tube time-kill curves; MRSA 67 was used.

11
11
A. Low Inocula B. High Inocula
10
10
9
9
Growth Control 8
8
Log 10 CFU/ml

Synercid 7
7
Vancomycin
6
6
Synercid
5
5 plus Vancomycin
4
4
3
3
2
2
1
1
0 4 8 12 16 20 24
0 4 8 12 16 20 24
Time (h) Time (h) 10
 In Vivo Synergy:
Quinupristin/Dalfopristin Plus Vancomycin Against
MLSBC Strains of MRSA for Endocarditis*
• Quinupristin/dalfopristin (Q/D) plus vancomycin was significantly
(P<.05) more active than either agent alone against both Q-
resistant (MLSBC) and Q-susceptible (MLSBI/MLSBS)
Staphylococcus aureus in animal models
• Enhanced cidal activity and sterilization of valvular vegetations
• Mechanism of synergy unclear
• Q/D plus vancomycin at 1 x MIC was synergistic against
Q-susc. S aureus and additive against Q-Res. S aureus
*rabbit endocarditis model
MLSBC = macrolide-lincosamide-streptogramin B–constitutively resistant
MRSA = methicillin-resistant Staphylococcus aureus Pavie, et al. ICAAC 2000. Abstract 1006.
MLSBI = macrolide-lincosamide-streptogramin B–inducibly resistant
MLSBS = macrolide-lincosamide-streptogramin B–susceptible 11
MIC = minimal inhibitory concentration
 Vancomycin Failure Study
• Enrollment of Vancomycin treatment failures (CX
remain positive after 5 days at rec. levels)
– Retrospective collection of vancomycin failures treated with
normal troughs ~10 mcg/ml
– Retrospective collection of vancomycin failures treated with
vancomycin troughs ~20 mcg/ml
– Prospective collection of vancomycin at troughs of ~ 20 mcg/ml
– Prospective collection of Synercid added to vancomycin at
troughs of ~10 mcg/ml
• All of the above collected if organism was available, site
would do serial cultures, and sites would fill out CRFs.

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 Outcomes

Clinical Micro Mean Vanco

Success Eradication Days Prior

83.3% 83.3%
Q/D + Vanco 15.7
(n=12) (n=12)

70.6% 72.2%
Vanco HD 5.9
(n=17) (n=18)

56.0% 57.7%
Vanco TD 5.5
(n=25) (n=26)
Q/D, quinupristin/dalfopristin; Vanco, vancomycin; Vanco HD, “high-dose” vancomycin;
VancoTD; traditionally dosed vancomycin N, number of evaluable patients used in analysis
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 14 Day (% Culture Positive)
100
Percent Culture Positive

80

60

40

20
Vancomycin TD (n=15)
Vancomycin HD (n=17)
0 Quinu/Dalfo Plus Vanco (n=12)
0 2 4 6 8 10 12 14
Day

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 Ciprofloxacin: Eradication vs AUIC24
Forrest A, Antimicrobial Agents Chemother 37:1073–1081, 1993.

100
% of patients remaining culture-

75
AUIC < 125

50

AUIC 125-250
25
AUIC > 250
positive

0
0 2 4 6 8 10 12 14

Days of treatment 15
 PK/PD
• Targets Bacterial Killing in the Individual Patient when
concentration exceeds the killing threshold of 80%
above the MIC
– Explains Clinical Failure as a failure to eradicate the
organism
– Explains selection of a resistant strain when it occurs
– Can use these methods to detect effects of antibiotics in
combination, as antagonism, synergy or additivity
• Very Little is left as Random Noise when PK/PD is
linked to bacterial outcome.
– AUIC accounts for over 80% of the variability in outcomes in
a logistic regression model
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 Micro Cure as a Surrogate?
• When the patient reaches clinical cure status, and
there is nothing to culture, the micro outcome of the
patient is recorded as “micro cure”
• This form of “micro cure” is can be employed in over
80% of patients in equivalence trials of old vs. new
antibiotics
• The use of this surrogate for “micro cure” removes
any hope of finding differences in eradication or the
emergence of selected resistance
• “Micro cure” on non culture is uninformative at best,
there is no information on speed of eradication, time
to events, or inoculum reduction
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So, Why do the FDA regulatory
approval trials not see these
differences in Clinical Cure Rates
..between two Antibiotic AUICs
That differ in Killing Rate so
Dramatically?

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 Clinical Trials are Designed to Assure Equivalence....

100
A
.
Cured

This is When we
50 Determine Outcomes
B
%

in Most Trials......

C. Nightingale, 1998

0
0 5 10
Time, days 19
ABX Equivalence vs Superiority
• Current trend is how many do we need to conclude
ABX are equivalent. Because of Delta of 10%, we now
need twice as many patients to conclude equivalence
– With this you get FDA approval but you can’t sell it for more.
• Antibiotics are never equivalent. In the real world, one
is always better. The right endpoint can differentiate almost
any antibiotic from any other, with only small numbers of patients
• Patient by Patient, the better ABX kills the pathogen
faster and/or prevents the selection of resistant sub-
populations
• Compare these methods

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 Delta, power and sample size on a
dichotomous vs continuous endpoint
Dichotomous Continuous
(cure / failure) (T to Erad vs AUIC)
Power 90% 90%

Delta 10% + 1 day

Variability: Type I - SD = 20-40%

two tailed error
Cure Rate (%) 85-90% (clinical) 80% (MicroErad) at
median Terad 3d
# pts per group to 1532 <10 to ~ 90
conclude A=B
# pts per group to inf <10 to ~ 90
conclude A>>B 21
Alternative View from the Front

• Obscured in every NDA of 5000 patients,

there are ~100 who, if you listen (i.e. PK/PD)
will teach you everything that is truly
important about the drug.
• We should not allow our statistically driven
quest for equivalence to silence those voices.

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 Recommendations
• Change the endpoint of antibiotic action, from Clinical
to Microbiological
• Express Efficacy as time to eradication to handle
static vs cidal, and time dependent vs conc
dependent killing in vivo
• Resistance protection or facilitation vs achieved
serum concentrations and AUICs
• Substantial lowering of drug development costs and
faster time to NDA approval
• Still need to deal with safety issues and numbers, but
standard equivalence design can accomplish this.
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 Disclosures - J.J. Schentag
• Much of the MRSA study is the work of
Pamela A. Moise, PharmD
• Research Support: Bayer, Aventis,
Pharmacia, Wyeth-Ayerst, Versicor, Lilly,
Pfizer, GSK, Bristol Myers, Roche, Eisai
• Consultant: Bayer, Aventis, Versicor, Eisai
• Stock/Options: None of the above
• This trip was paid out of my own pocket..

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