2042. Efficacy of colistin alone and in various combinations for the treatment of carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis
Session: Poster Abstract Session: Antimicrobial Resistant Infections: Treatment
Saturday, October 29, 2016
Room: Poster Hall
Posters
  • Poster ID week_20161017_igt-PT.pdf (570.9 kB)
  • Background: Optimal treatment (Tx) of carbapenemase-producing Enterobacteriaceae infections is poorly defined. We evaluated the efficacy of colistin alone and in combinations in a new experimental model of carbapenemase-producing K. pneumoniae (CR-Kp) osteomyelitis.

    Methods: KPC-99YC is a clinical strain intermediate to meropenem (MIC 4 mg/L), and susceptible to gentamicin (MIC 1 mg/L), colistin, and tigecyclin (MIC 0.5 mg/L). Plasma antibiotic concentrations were measured in rabbits, to select doses equivalent to those used in humans (H). Time-kill curves were performed at 4 x MIC. An osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent, followed by 109 CFU/mL (0.2ml) of KPC-99YC. Tx was started at day 14, for 7 days, in 6 groups (12 rabbits/group): (1) control, (2) group C: colistin 150 000 IU/kg tid (equivalent to 3 M IU tid in H), (3) group CG: colistin + gentamicin, 30 mg/kg im od (5 mg/kg od in H), (4) group CT: colistin + tigecyclin 14 mg/kg im bid (50 mg bid in H), and (5) group CM: colistin + meropenem 80 mg/kg sc tid (1 g tid in H), (6) group CMG. Bone samples were quantitatively cultured, and tested for colistin resistance.

    Results: In vitro, colistin bactericidal effect was inhibited when combined with T, and enhanced when combined with M or G (>2 log10 CFU). Bone samples were sterile in 0/11, 1/11, 1/12, 2/12, 1/12 and 7/10 rabbits in control, C, CG, CT, CM, and CMG groups, respectively. Median [interquartile range] bacterial concentrations (log10 CFU/g) in bones were 5.4 [3.5, 6.1] (C), 4.9 [4.4, 5.6] (CG), 6.6 [6, 7.2] (CT), 4.5 [3.9, 5.2] (CM), 1.5 [1.5, 4], and 5.7 [4.6, 6.1] (controls). Bacterial concentrations were lower in CM and CMG groups as compared to controls (p=0.049 and 0.001), and higher in CT group as compared to C (p=0.01). C or CT were not better than controls (p>0.2). Colistin-resistant strains were detected in groups C, CT, CG but not in CM and CMG.

    Conclusion: Addition of meropenem to colistin was the only effective therapy and prevented emergence of colistin-resistance, in agreement with the concept that i) colimycin should always be combined; ii) penems are the best companion drugs, whenever MIC<8 mg/L. The combination of colistin and tigecyclin was less effective than colistin alone, suggesting an antagonistic effect in vitro and in vivo. 

    Pierre Tattevin, MD, PHD1, Azzam Saleh-Mghir, PhD2, Aurelien Dinh, MD3, Laure Gatin, MD3, William Mouton, MD4, Idir Ghout, Dr5, Jacques Ropers, PhD6, Marie-Clémence Verdier, MD7, Frédéric Laurent, PhD4, Patrice Nordmann, MD, PhD8 and Anne-Claude Crémieux, Pr3, (1)Pontchaillou University Hospital, Rennes, France, (2)UMR 1173 Université Versailles St-Quentin, Garches, France, (3)Garches Univ. Hosp., Garches, France, (4)Lyon Univ. Hosp., Lyon, France, (5)URC Paris-Ouest Laboratoire de Bio statistiques, Hôpital Ambroise Paré, Boulogne-Billancourt, France, (6)Versailles UNiv., Versailles, France, (7)PONTCHAILLOU UNIV. HOSP., Rennes, France, (8)Fribourg Univ. Hosp., Fribourg, Switzerland

    Disclosures:

    P. Tattevin, None

    A. Saleh-Mghir, None

    A. Dinh, None

    L. Gatin, None

    W. Mouton, None

    I. Ghout, None

    J. Ropers, None

    M. C. Verdier, None

    F. Laurent, None

    P. Nordmann, None

    A. C. Crémieux, None

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