Jerome J. Schentag, PharmD University at Buffalo Buffalo, New York Schentag@buffalo.edu

1. 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

2. 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.

3. PK/PD: AUIC and Selected Resistance Thomas JK, Antimicrobial Agents Chemother. 42: 521-527, 1998. 100 AUIC>101 75 Probability of remaining susceptible 50 25 AUIC<100 0 0 5 10 15 20 Days from initiation of Therapy

4. 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

5. Vancomycin 1 gm q 12hr: 2 pks of 30 mcg/ml in 24 hrs AUC24=254 30 Peak:MIC=3.75, AUIC=32 8 Vancomycin serum concentration Peak:MIC=15, AUIC=127 2 MIC90 0.5 Peak:MIC=60, AUIC=508 MIC50 0 12 Time (hours)

6. 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

7. Comparison of Vancomycin days to eradication for MRSA Infections 100 AUIC <400 80 60 Percent Culture Positive 40 AUIC >400 free AUIC=140 20 0 0 10 20 30 P=0.0402 Day of Eradication Moise & Schentag. Am J Health Sys Pharmacy: October 2000 Suppl.

8. 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)

9. 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

10. 1 1 1 0 9 8 G r o w t h C o n t r o l 7 V a n c o m y c i n 6 5 4 3 2 1 0 4 8 1 2 1 6 2 0 2 4 Time (h) Synercid Killing Curves w/w.o. Vancomycin Test tube time-kill curves; MRSA 67 was used. B. High Inocula 1 1 A. Low Inocula 1 0 9 8 Log 10 CFU/ml Synercid 7 6 Synercid plus Vancomycin 5 4 3 2 1 0 4 8 1 2 1 6 2 0 2 4 Time (h)

11. 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 MLSBI = macrolide-lincosamide-streptogramin B–inducibly resistant MLSBS = macrolide-lincosamide-streptogramin B–susceptible MIC = minimal inhibitory concentration • Pavie, et al. ICAAC 2000. Abstract 1006.

12. 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.

13. Outcomes Q/D, quinupristin/dalfopristin; Vanco, vancomycin; Vanco HD, “high-dose” vancomycin; VancoTD; traditionally dosed vancomycin N, number of evaluable patients used in analysis

14. 14 Day (% Culture Positive) 100 80 60 Percent Culture Positive 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

15. Ciprofloxacin: Eradication vs AUIC24 Forrest A, Antimicrobial Agents Chemother 37:1073–1081, 1993. 100 75 AUIC < 125 50 % of patients remaining culture-positive AUIC 125-250 25 AUIC > 250 0 0 2 4 6 8 10 12 14 Days of treatment

16. 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

17. 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

18. 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?

19. Clinical Trials are Designed to Assure Equivalence.... . 100 A This is When we Determine Outcomes in Most Trials...... % Cured 50 B C. Nightingale, 1998 0 0 5 10 Time, days

20. 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

21. Delta, power and sample size on a dichotomous vs continuous endpoint

22. 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.

23. 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.

24. 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..