599. In vitro Activity of Doripenem Alone and in Multi-Agent Combinations Against Extremely Drug-Resistant Gram-Negative Bacilli (XDR-GNB)
Session: Poster Abstract Session: Novel Antimicrobial Agents
Friday, October 21, 2011
Room: Poster Hall B1
  • IDSA_Dori_XDR MbD Results_FINAL_10.04.11.pdf (378.1 kB)
  • Background: Reliance on imipenem and meropenem to treat infections with multidrug-resistant Acinetobacter baumannii (AB) and Klebsiella pneumoniae (KP) has been accompanied by rising rates of carbapenem-resistant isolates, including those with KP carbapenemases (KPCs). We evaluated the efficacy of doripenem alone and in combination with other antimicrobial agents against XDR-AB and KPC-positive XDR-KP.


    Methods: XDR-GNB [susceptible to ≤1 first-line agents by Vitek 2, excluding polymyxin B (PB) or tigecycline (TIG)] associated with hospital-acquired infections in ICU patients from January 2008-March 2010 were studied. Susceptibility and synergy testing were performed using commercially prepared broth microdilution panels for 48 AB and 48 KP. CLSI and FDA breakpoints (when applicable) were used as interpretive susceptibility criteria. For doripenem multi-agent combinations, we determined fractional inhibitory concentration [synergy: ≤0.5 for 2 agents, ≤0.75 for 3 agents] and MIC lowering effect [MIC for doripenem and/or additional agent(s) lowered to a clinically achievable concentration].


    Results: All 96 XDR-GNB were resistant to doripenem (MIC50&90 were both >128 g/ml for AB; 16 g/ml and 64 g/ml for KP) and 99% were non-susceptible to rifampin (RIF), 99% to levofloxacin (LEV), and 61% to amikacin (AMI). Most were susceptible to PB (100% AB, 88% KP) and TIG (73% AB, 89% KP). The 2-agent combinations with the most synergistic activity were doripenem with RIF (11%) and doripenem with AMI (7%). Combinations of doripenem with LEV, PB, or TIG were synergistic for ≤3%. The 3-agent combinations of doripenem with PB and RIF and doripenem with PB and TIG were synergistic for 15% and 5%, respectively. We observed a large MIC lowering effect for doripenem with PB alone (93%) and in both 3-drug combinations (99% with PB and RIF, 95% with PB and TIG). MIC lowering for doripenem with AMI, RIF, or TIG occurred for 20%, 15%, and 10% of isolates, respectively, but did not occur with LEV.

    Conclusion: XDR-GNB were highly resistant to doripenem, and doripenem drug combinations were not synergistic for the majority of isolates. However, an MIC lowering effect for doripenem was seen for most isolates using combinations with PB, including PB and RIF.


    Subject Category: A. Antimicrobial agents and Resistance

    Sarah A. Clock, PhD, Setareh Tabibi, MS, Luis Alba, BS and Lisa Saiman, MD, MPH, Columbia University, New York, NY


    S. A. Clock, Ortho-McNeil-Janssen Pharmaceuticals, Inc.: Research Contractor, Research support

    S. Tabibi, Ortho-McNeil-Janssen Pharmaceuticals, Inc.: Research Contractor, Research support

    L. Alba, Ortho-McNeil-Janssen Pharmaceuticals, Inc.: Research Contractor, Research support

    L. Saiman, Ortho-McNeil-Janssen Pharmaceuticals, Inc.: Research Contractor, Research support

    Findings in the abstracts are embargoed until 12:01 a.m. EST Thursday, Oct. 20 with the exception of research findings presented at IDSA press conferences.