# Presentation: 744027

## New Drug Application NDA 21-572/S-008 Cubicin® (daptomycin for injection)

**Microbiology: Increased Daptomycin MICs During Therapy**
**Peter Coderre, PhD, MBA**
**CDER, DAIOP**
**Anti-Infective Drugs Advisory Committee Meeting**
**Rockville, Maryland**
**March 6, 2006**

## Increased Daptomycin MICs

**Increasing daptomycin MICs documented *****in vitro*****, *****in vivo*****, in the literature and during this clinical trial**
**Currently: *****S. aureus***** isolates with a       ****MIC ≤ 1 ********g/ml**** are considered ****susceptible**** to daptomycin**
**Breakpoints for intermediate and resistant isolates have yet to be established**

## Increased Daptomycin MICs

***What are the implications of increasing daptomycin MICs during treatment with daptomycin for infective endocarditis and bacteremia?***
**In patients with persistent or relapsing bacteremia, *****S. aureus***** demonstrated increasing daptomycin MICs (****≥**** 1 ********g/ml) during or after therapy with the drug.  **

## Changes in MICs for Relapsing or Persistent Bacteremia Patients#

|  | MIC >1 | > 2 steps | MRSA | MSSA |
| --- | --- | --- | --- | --- |
| daptomycin arm (N=20) | 9/20 (45.0%) | 9/20 (45.0%) | 12/20 (60.0%)* | 11/20 (55.0%)* |
| comparator arm (N=10) | 1/10 (10.0%) | 0/10  (0%) | 8/10 (80.0%) | 2/10 (20.0%) |
|  |  |  |  |  |

- 3 patients had both MSSA and MRSA
- # FDA Analysis

## Distribution of Terminal MICs for Daptomycin Treated Patients (ITT) by Clinical Outcome

|  |  |  | MIC (g/ml) |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
|  | 0.12 | 0.25 | 0.5 | 1 | 2 | 4 |
| clinical success (N=53) | 1  (1.9%) | 36 (67.9%) | 14 (26.4%) | 2  (3.8%) | 0  (0%) | 0   (0%) |
| clinical failure (N=59) | 1  (1.7%) | 34 (57.6%) | 15 (25.4%) | 3  (5.1%) | 5 (8.5%) | 1 (1.7%) |
| total (N=112) | 2  (1.8%) | 70 (62.5%) | 29 (25.9%) | 5  (4.4%) | 5 (4.5%) | 1 (0.9%) |

## Clinical Failures in Daptomycin Arm with Increased Daptomycin MICs

| Case # | Final Diagnosis | Organism | Baseline | High  | MIC Step |
| --- | --- | --- | --- | --- | --- |
|  |  |  | MIC | MIC | Increase |
| 009-212 | complicated bacteremia | MRSA | 0.25 | 2 | 3 |
| 010-152 | complicated RIE | MSSA | 0.25 | 4 | 4 |
| 015-105 | complicated bacteremia | Both | 0.25 | 2 | - |
| 017-037 | left IE | Both | 0.25 | 2 | - |
| 027-183 | left IE | MRSA | 0.5 | 2 | 2 |
| 324-136 | complicated bacteremia | MRSA | 0.5 | 2 | 2 |
| 300-111 | left IE | MRSA | 0.25 | 1 | 2 |
| 300-246 | left IE | MRSA | 0.25 | 1 | 2 |

## Frequency of Increased MICs and Non-Susceptibility/Resistance to Daptomycin or Vancomycin in Patients during Therapy^

|  | N, % ↑  | N, % ↑  | N, % developed  | N, % developed  |
| --- | --- | --- | --- | --- |
|  | Dapto  MIC | Vanco MIC | DaptoNS | VancoR |
| IEAC successes |  |  |  |  |
| daptomycin (N=53) | 17 (32.1%)* | 12 (22.6%)* | 0 (0%)* | 0 (0%)* |
| comparator (N=48) | 11 (22.9%) | 13 (27.1%) | 1 (2.1%) | 0 (0%) |
| IEAC failures |  |  |  |  |
| daptomycin (N=67) | 23 (34.3%) | 16 (24.2%)* | 6 (9.0%) | 0 (0.0%)* |
| comparator (N=65) | 12 (18.5%)* | 17 (26.2%)* | 0 (0.0%)** | 0 (0.0%)** |

- *determination of MICs not done for one patient; **determination of MICs not done for two patients; *** one or more dilution increase; ^ contains non-evaluable patients as failures

## Overview of Isolates with Treatment Associated Decreases in Daptomycin Susceptibility Following Commercial Availability

| Isolate/N | Source | Daptomycin | MIC (g/ml) |
| --- | --- | --- | --- |
| S.aureus | blood | 0.25 | 1 |
| S.aureus | * | 0.25 | 4 |
| S.aureus--5 | blood | 0.5 | 4 |
| S.aureus | ** | 0.5 | 4 |
| S.aureus | blood | 1 | 2--4 |
| S.aureus |  | 0.5 | 8 |
| MRSA |  | 0.25 | 1.5 |
| E. faecium | urine/blood | 4 | 32 |
| E. faecium | blood | 4 | > 32 |
| VRE*** | blood |  | 4 |
| VRE*** |  |  | 8 |

## Recent Literature Reporting Clinical Failures with Daptomycin Treatment

| Organism | Condition | Source | Dose | Highest  | Reference |
| --- | --- | --- | --- | --- | --- |
|  |  |  | (mg/kg) | MIC (g/ml) |  |
| MRSA | bacteremia | blood | 4 | 2 | Mangili et al., 2005 |
| MRSA | osteomyelitis | blood | 6 | 4 | Hayden et al., 2005 |
| MRSA | bacteremia | blood | 8 | 4 | Skiest, 2006 |
| MRSA | bacteremia | blood | 6 | 4 | Marty et al., 2006 |
| E. faecium | bacteremia | blood | 6 | >32 | Sabol et al., 2005 |
| E. faecium | fever | blood | none | 4 | Lesho et al., 2006 |
| E. faecalis (VRE) | bacteremia | blood | * | 16 | Munoz-Price, et al., 2005 |
| E. faecalis (VRE) | febrile neutropenia | blood | ?? | ?? | Long et al., 2005 |
| *400 mg q48h |  |  |  |  |  |

## Surveillance Data

| Species | Study/Year | N |  |  Daptomycin MIC Distribution  n (%)
 MIC (g/ml) |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  | ≤ 0.12 | 0.25 | 0.5 | 1 | 2 |
| MSSA | 2000-1 | 1601 | 304 (18.9%) | 1165 (72.7%) | 131 (8.2%) | 1 (0.1%) | 0   (0%) |
|  | 2002 | 1547 | 83 (5.4%) | 1140 (73.7%) | 319 (20.6%)  | 3 (0.2%) | 2 (0.1%) |
|  | 2003 | 2894 | 229 (7.9%) | 2371 (81.9%) | 285 (9.9%) | 8 (0.3%) | 1 (<0.1%) |
|  | 2003-4 | 3284 | 70 (2.1%) | 1891 (57.6%) | 1297 (39.5%) | 25 (0.8%) | 1 (<0.1%) |
| MRSA | 2000-1 | 639 | 51 (7.9%) | 396 (61.9%) | 187 (29.3%) | 5 (0.8%) | 0 (0%) |
|  | 2002 | 1076 | 20 (1.9%) | 655 (60.9%)  | 388 (36.1%) | 13 (1.2%) | 0 (0%) |
|  | 2003 | 1468 | 40 (2.7%) | 963 (65.6%) | 452 (30.8%) | 13 (0.9%) | 0 (0%) |
|  | 2003-4 | 1976 | 10 (0.5%) | 878 (44.4%) | 1047 (52.9%) | 40 (2.0%) | 1 (<0.1%) |

- Source: Table 2.7.2-24, NDA 21-572 SN008

## S. aureus MIC Distributions: 2004-2005 (2004: n = 317; 2005: n = 359)

** **

**0.9%**

**3.3%**

**0**

**10**

**20**

**30**

**40**

**50**

**60**

**70**

**80**

**90**

**100**

_**< **_**1 (********g/ml)**

**> 1 (********g/ml)**

**MIC Group**

**% of Total**

**99.1%**

**96.7%**

- Source: Focus Technologies

-         2004              2005

-         2004              2005

## In Vivo Evidence

**Sponsor data from rabbits, mice, rats for bacteremia, endocarditis, fibrin clot, etc.**
**In rabbit model, daptomycin more efficacious than vancomycin, however, ****diminished susceptibility developed during therapy**** —due to selection by sub-inhibitory concentrations of daptomycin in vegetations**
**Silverman et al. (2001): extensive clinical use required to establish if resistance will be a major clinical problem**

## In Vitro Evidence

**Spontaneous mutations rare; no known transferable elements**
**Liebowitz et al.  (1988): stable resistant organisms after multiple passages in increasing [daptomycin] and after chemical mutagenesis— ****isolates 16X higher than parental isolates**
**Kaatz et al. (1990): Dapto****R**** mutants were Van****S****, Amp****S**** but ****cross-resistance to Nisin**

## In Vivo Evidence--Biofilms

**Evidence for pathogenesis of biofilms in IE is strong**
**60% of daptomycin penetrates vegetation but 90% is protein bound; therefore, expect < 60% penetration**
**Vegetations manifest biofilm-like antibiotic resistance that cannot be completely explained by poor penetration of antimicrobials**
**Composition of the valve biofilm has direct bearing on clinical outcomes**
**Results demonstrate association between biofilm composition and clinical manifestations—IE can be manipulated by targeting biofilm development**

## Summary

**On therapy (endocarditis):**** increasing daptomycin MICs particularly among persisting or relapsing bacteremia**
**On therapy (all-comers):**** increasing daptomycin MICs among clinical failures**
**Surveillance data****: increasing daptomycin MICs over time; more reports in literature (2005-6) showing daptomycin resistance**
***In vivo*****: rabbit model, daptomycin more efficacious than vancomycin but diminished daptomycin susceptibility during therapy**
** *****In vitro*****: bacteria develop resistance at sub-inhibitory concentrations; cross-resistance to nisin, but not vancomycin or ampicillin; biofilms—subinhibitory concentrations?**