A-035. Differences in Resistance Mechanisms between Levofloxacin (LVX)-Susceptible / Ciprofloxacin (CIP)-Resistant Proteus mirabilis and Isolates Resistant to Both Drugs

T. A. Davies1, Y. C. Yee2, B. Morrow1, A. Evangelista2;
1Johnson & Johnson Pharmaceutical Res. & Dev. L.L.C., Raritan, NJ, 2Ortho-McNeil Pharmaceutical, Raritan, NJ.

Background: TRUST surveillance has shown that LVX and CIP susceptibilities for most Enterobacteriaceae are similar (≤2% difference) except for Proteus mirabilis in which LVX is more susceptible (S). LVX and CIP susceptibilities to P. mirabilis in 2006 and 2007 were 80.5% vs. 73.1% and 78.4% vs. 72.6%, respectively. Isolates resistant (R) to CIP but S to LVX were compared to isolates that were S or R to both drugs to examine differences in resistance mechanisms. Methods: A total of 38 isolates (9 LVX-S/CIP-S, 14 LVX-S/CIP-R, and 15 LVX-R/CIP-R) were collected from TRUST 2006-2007 and screened for plasmid-mediated fluoroquinolone (FQ)-resistance genes (qnrA, qnrB, qnrS), CIP-inactivating variant of aminoglycoside acetyltransferase [aac(6’)-Ib-cr] and mutations in the quinolone-resistance determining region (QRDR) of gyrA/B and parC/E. Isolates were also screened for efflux using efflux inhibitors in MIC testing. Results: Eight of 9 LVX-S/CIP-S isolates had LVX and CIP MICs of ≤0.06 μg/ml with no QRDR mutations. One LVX-S/CIP-S isolate with 2-4 fold higher FQ MICs had a GyrA S83R change. MICs of the 14 LVX-S/CIP-R isolates ranged 1-2 μg/ml to LVX and 4-16 μg/ml to CIP with ≥2 QRDR mutations (a GyrA S83I or S83R and a ParC S80I or S80R change). A GyrB S464Y or E466D change was also seen in 2 isolates. Of the 15 LVX-R/CIP-R isolates, MIC90s were 128 μg/ml for CIP and 64 μg/ml for LVX, and all have ≥3 QRDR mutations. All 15 isolates had a GyrA S83R or S83I and a ParC S80I or S80R change with one of the following changes: a GyrB S464F or S464Y, a GyrA E87G, or a ParC E84K. The GyrA S83I change was most prevalent (p<0.0001) in LVX-S/CIP-R isolates (93%) than LVX-R/CIP-R (7%) and the ParC S80I change was more prevalent (p=0.0052) in LVX-R/CIP-R isolates (93%) than LVX-S/CIP-R (43%). QnrA/B/S genes were not found in any isolate; efflux and parE mutation were found in 1 isolate each, and aac(6’)-Ib-cr was found in 2 isolates. Conclusions: Resistance or higher MICs to FQs were mainly observed by a minimum of 2 QRDR mutations for CIP and 3 for LVX among the P. mirabilis isolates analyzed. Other mechanisms such as efflux or CIP-modifying enzymes may play a role in elevating CIP MICs.