1612. Evaluation of RPX2003 alone and in combination with RPX7009, a serine beta-lactamase inhibitor (BLI), against P. aeruginosa (PSA)
Session: Poster Abstract Session: Novel Antimicrobial Agents
Saturday, October 20, 2012
Room: SDCC Poster Hall F-H
Background:

RPX2003 (a carbapenem) is being developed in combination with the BLI RPX7009. The objective of these studies was to evaluate the impact of known intrinsic carbapenem resistance mechanisms in PSA on the sensitivity to RPX2003, and to determine the in vivo PK-PD properties of RPX2003 against strains with different levels of sensitivity to the drug.

Methods: Isogenic mutants of PSA with various combinations of efflux, porin and beta-lactamase mutations were tested against RPX2003 alone or with RPX7009 (fixed at 4 mg/L) and comparator carbapenems using CLSI broth microdilution reference methods. The PK-PD of RPX2003 was studied in a neutropenic mouse thigh infection model using five PSA strains with MICs ranging from 0.25 –16 mg/L.  Mice were infected with ~106 CFU/thigh and treated over 24 hours, and CFU determined.

Results:

RPX2003 had MICs of 0.25 mg/L against wild type strain of PSA and MIC was not increased by overexpression of any of the four major Mex efflux pumps. AmpC overexpression increased MICs by 2 to 4-fold, and deletion of OprD resulted in a 16-fold increase in MIC (from 0.25 µg/ml to 4 µg/ml). The combination of OprD deletion and AmpC overexpression (with or without efflux) produced strains with MICs of only 8 µg/ml for RPX2003 or DOR, but of 16-32 µg/ml for IMI and MER. Addition of the BLI RPX7009 was not associated with potentiation RPX2003 against PSA in vitro.  In the mouse thigh infection model, free RPX2003 %T>MIC was the PK-PD index associated with antibacterial effects, and the avg magnitude of the index required for static, 1-, or 2- log drops in CFU counts was 22, 27, and 35, respectively. The magnitude of the index was similar across the 64-fold range in MICs.

 

 

MICs (µg/ml)

Description

RPX2003

IMI

MER

DOR

wt

0.25

2

0.5

0.5

MexAB-OprM up, ΔampC

0.13

0.25

1

1

ΔOprD

4

16

2

2

MexAB-OprM up, ΔOprD

4

16

4

4

AmpC up, ΔOprD

8

16

8

8

MexAB-OprM and AmpC up

0.5

1

2

2

MexAB-OprM and AmpC up, ΔOprD

8

16

32

8

Conclusion:

RPX2003 is a potent anti-pseudomonal agent, with a significant loss of potency observed only with combinations of resistance mechanisms other than efflux. PK-PD studies in mice show that free RPX2003 %T>MIC is linked to efficacy, and the magnitude of the index is independent of RPX2003 MIC.

Mojgan Sabet, PhD, Pharm., Rempex Pharmaceuticals, Inc, San Diego, CA, Paula King, MPH, Biol, Rempex Pharmaceuticals, Inc., SAN Diego, CA, Ziad Tarazi, BS, Pharm., Rempex Pharmaceuticsals, Inc, San Diego, CA, Donxu Sun, PhD, Biol., Rempex Pharnaceuticals, Inc, San Diego, CA, David Griffith, BS, Pharm., Rempex Pharmaceuticals, Inc., San Diego, CA, Olga Lomovskaya, PhD, Biol, Rempex Pharmaceuticals, Inc, San Diego, CA and Michael Dudley, PharmD, FIDSA, Rempex Pharmaceuticals, San Diego, CA

Disclosures:

M. Sabet, None

P. King, None

Z. Tarazi, None

D. Sun, None

D. Griffith, None

O. Lomovskaya, None

M. Dudley, None

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