Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae.
- Crémieux AC St Louis Hospital, Paris 7 University, Paris, France.
- Dinh A UMR 1173, Versailles Saint-Quentin University, Versailles, France.
- Nordmann P Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science and Medicine, INSERM European Unit (IAME, France), Swiss National Reference Center for Emerging Antibiotic Resistance (NARA), University of Fribourg, Fribourg, Switzerland.
- Mouton W Team 'Staphylococcal pathogenesis', International Centre for Infectiology Research, INSERM U1111 - CNRS UMR5308 - ENS Lyon - Lyon 1 University, Lyon, France.
- Tattevin P Pontchaillou University Hospital, Rennes, France.
- Ghout I AP-HP, Ambroise Paré University Hospital, Boulogne, France.
- Jayol A Medical and Molecular Microbiology Unit, Department of Medicine, Faculty of Science and Medicine, INSERM European Unit (IAME, France), Swiss National Reference Center for Emerging Antibiotic Resistance (NARA), University of Fribourg, Fribourg, Switzerland.
- Aimer O Department of Pharmacy, Raymond-Poincaré University Hospital, Garches, France.
- Gatin L UMR 1173, Versailles Saint-Quentin University, Versailles, France.
- Verdier MC Pontchaillou University Hospital, Rennes, France.
- Saleh-Mghir A UMR 1173, Versailles Saint-Quentin University, Versailles, France.
- Laurent F Team 'Staphylococcal pathogenesis', International Centre for Infectiology Research, INSERM U1111 - CNRS UMR5308 - ENS Lyon - Lyon 1 University, Lyon, France.
- 2019-07-03
Published in:
- The Journal of antimicrobial chemotherapy. - 2019
Animals
Anti-Bacterial Agents
Carbapenem-Resistant Enterobacteriaceae
Colistin
Disease Models, Animal
Dose-Response Relationship, Drug
Drug Resistance, Bacterial
Drug Resistance, Multiple, Bacterial
Drug Synergism
Drug Therapy, Combination
Klebsiella Infections
Klebsiella pneumoniae
Microbial Sensitivity Tests
Osteomyelitis
Rabbits
English
OBJECTIVES
In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs).
METHODS
KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin.
RESULTS
In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37.
CONCLUSIONS
In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.
In a new experimental model of carbapenemase-producing Klebsiella pneumoniae osteomyelitis we evaluated the efficacy of colistin alone and in various combinations and examined the emergence of colistin-resistant strains and cross-resistance to host defence peptides (HDPs).
METHODS
KPC-99YC is a clinical strain with intermediate susceptibility to meropenem (MIC = 4 mg/L) and full susceptibility to gentamicin, colistin and tigecycline (MICs = 1 mg/L) and fosfomycin (MIC = 32 mg/L). Time-kill curves were performed at 4× MIC. Osteomyelitis was induced in rabbits by tibial injection of 2 × 108 cfu. Treatment started 14 days later for 7 days in seven groups: (i) control; (ii) colistin; (iii) colistin + gentamicin; (iv) colistin + tigecycline; (v) colistin + meropenem; (vi) colistin + meropenem + gentamicin; and (vii) colistin + fosfomycin.
RESULTS
In vitro, colistin was rapidly bactericidal, but regrowth occurred after 9 h. Combinations of colistin with meropenem or fosfomycin were synergistic, whereas combination with tigecycline was antagonistic. In vivo, colistin alone was not effective. Combinations of colistin with meropenem or fosfomycin were bactericidal (P < 0.001) and the addition of gentamicin enhanced the efficacy of colistin + meropenem (P = 0.025). Tigecycline reduced the efficacy of colistin (P = 0.007). Colistin-resistant strains emerged in all groups except colistin + fosfomycin and two strains showed cross-resistance to HDP LL-37.
CONCLUSIONS
In this model, combinations of colistin plus meropenem, with or without gentamicin, or colistin plus fosfomycin were the only effective therapies. The combination of colistin and tigecycline should be administered with caution, as it may be antagonistic in vitro and in vivo.
- Language
-
- English
- Open access status
- green
- Identifiers
-
- DOI 10.1093/jac/dkz257
- PMID 31263884
- Persistent URL
- https://sonar.ch/global/documents/93197
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