# Presentation: 736935

## Antibiotic Development Strategies to Understand and Label Microbial Endpoints such as Slow killing, resistance and Failure,  AUIC Dosing and Success via Synergy

**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.

## PK/PD: AUIC and Selected Resistance

**PK/PD: AUIC and Selected Resistance**

** ****0**

**25**

**75**

-  **50**

-   **100**

**Probability of remaining susceptible**

**0**

**5**

**10**

**15**

**20**

**Days from initiation of Therapy**

**AUIC<100**

**AUIC>101**

**Thomas JK, Antimicrobial Agents Chemother. 42: 521-527,  1998.**

## 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

## Time (hours) 

- Time (hours)

- Vancomycin serum concentration

- 30

- 8

- 2

- 0.5

- Vancomycin 1 gm q 12hr:
- 2 pks of 30 mcg/ml in 24 hrs
- AUC24=254

- 12

- 0

**MIC****90**

**MIC****50**

- Peak:MIC=60,    AUIC=508

- Peak:MIC=3.75,    AUIC=32

- Peak:MIC=15,   AUIC=127

## 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

## Comparison of Vancomycin days to eradication for MRSA Infections

- 0

- 10

- 20

- 30

- 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

## 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)

## 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

## Synercid Killing Curves w/w.o. Vancomycin

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**8**

**9**

**1**

**0**

**1**

**1**

**0**

**4**

**8**

**1**

**2**

**1**

**6**

**2**

**0**

**2**

**4**

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

**Time (h)**

**Log 10 CFU/ml**

**Synercid**

**Synercid **
**plus Vancomycin**

- B. High Inocula

- A. Low Inocula

## 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*

**Pavie, et al. ICAAC 2000. Abstract 1006.**

- *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

## 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.

## Outcomes

- <footer>

- <date/time>

**Outcomes**

|  | Clinical Success | Micro Eradication | Mean Vanco Days Prior |
| --- | --- | --- | --- |
| Q/D + Vanco | 83.3%(n=12) | 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 Day (% Culture Positive)

- <footer>

- <date/time>

- 0

- 2

- 4

- 6

- 8

- 10

- 12

- 14

- 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)**

## Ciprofloxacin: Eradication vs AUIC24

**% of patients remaining culture-positive**

**Days of treatment**

** ****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.**

## 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

## 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

## 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?**

## Clinical Trials are Designed to Assure Equivalence....

**A**

**.**

**Time, days**

**% Cured**

**0**

**50**

**100**

**10**

**5**

**0**

**B**

**This is When we**
**Determine Outcomes **
**in Most Trials......**

**C. Nightingale, 1998**

## 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

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

|  | Dichotomous      (cure / failure) | Continuous             (T to Erad vs AUIC) |
| --- | --- | --- |
| Power | 90% | 90% |
| Delta | 10% | + 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 |

## 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.

## 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.

## 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..