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. 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. 3 PK/PD: AUIC and Selected Resistance 0 25 75 50 100 Probability of remaining susceptible 05101520 Days from initiation of Therapy AUIC<100 AUIC>101 Thomas JK, Antimicrobial Agents Chemother. 42: 521-527, 1998.

4. 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. 5 Time (hours) Vancomycin serum concentration 30 8 2 0.5 Vancomycin 1 gm q 12hr: 2 pks of 30 mcg/ml in 24 hrs AUC 24 =254 120 MIC 90 MIC 50 Peak:MIC=60, AUIC=508 Peak:MIC=3.75, AUIC=32 Peak:MIC=15, AUIC=127

6. 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. 7 0102030 Day of Eradication 0 20 40 60 80 100 Percent Culture Positive AUIC >400 AUIC <400 P=0.0402 Moise & Schentag. Am J Health Sys Pharmacy: October 2000 Suppl. Comparison of Vancomycin days to eradication for MRSA Infections free AUIC=140

8. 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. 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. 10 Synercid Killing Curves w/w.o. Vancomycin Growth Control Vancomycin 1 2 3 4 5 6 7 8 9 10 11 04812162024 Test tube time-kill curves; MRSA 67 was used. Time (h) 1 2 3 4 5 6 7 8 9 10 11 04812162024 Log 10 CFU/ml Synercid plus Vancomycin B. High Inocula A. Low Inocula

11. 11 In Vivo Synergy: Quinupristin/Dalfopristin Plus Vancomycin Against MLS B C 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 (MLS B C) and Q-susceptible (MLS B I/MLS B S) 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 Pavie, et al. ICAAC 2000. Abstract 1006. *rabbit endocarditis model MLS B C = macrolide-lincosamide-streptogramin B–constitutively resistant MRSA = methicillin-resistant Staphylococcus aureus MLS B I = macrolide-lincosamide-streptogramin B–inducibly resistant MLS B S = macrolide-lincosamide-streptogramin B–susceptible MIC = minimal inhibitory concentration

12. 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. 13 Outcomes Clinical Success Micro Eradication Mean Vanco Days Prior Q/D + Vanco 83.3% (n=12) 15.7 Vanco HD 70.6% (n=17) 72.2% (n=18) 5.9 Vanco TD 56.0% (n=25) 57.7% (n=26) 5.5 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 02468101214 Day 0 20 40 60 80 100 Percent Culture Positive Quinu/Dalfo Plus Vanco (n=12) Vancomycin HD (n=17) Vancomycin TD (n=15) 14 Day (% Culture Positive)

15. 15 % of patients remaining culture-positive Days of treatment 0 2 4 6 8 10 12 14 0 2 4 6 8 10 12 14 0 100 75 50 25 AUIC 125-250 AUIC > 250 AUIC < 125 Ciprofloxacin: Eradication vs AUIC 24 Forrest A, Antimicrobial Agents Chemother 37:1073–1081, 1993.

16. 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. 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. 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. 19 Clinical Trials are Designed to Assure Equivalence.... A. Time, days % Cured 0 50 100 10 50 B This is When we Determine Outcomes in Most Trials...... C. Nightingale, 1998

20. 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. T he 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. 21 Delta, power and sample size on a dichotomous vs continuous endpoint Dichotomous (cure / failure) Continuous (T to Erad vs AUIC) Power90% Delta10%+ 1 day Variability: Type I two tailed error -SD = 20-40% Cure Rate (%)85-90% (clinical)80% (MicroErad) at median Terad 3d # pts per group to conclude A=B 1532<10 to ~ 90 # pts per group to conclude A>>B inf<10 to ~ 90

22. 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. 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. 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..