title: Synergistic activity of colistin plus rifampin against colistin-resistant KPC-producing Klebsiella pneumoniae.
abstract: Infections caused by carbapenem-resistant KPC-producing Klebsiella pneumoniae are responsible for high rates of mortality and represent a major therapeutic challenge, especially when the isolates are also resistant to colistin. We used the checkerboard method to evaluate the synergistic activity of 10 antibiotic combinations against 13 colistin-resistant KPC-producing K. pneumoniae isolates (colistin MIC range of 8 to 128 mg/liter). Colistin plus rifampin was the only combination that demonstrated consistent synergistic bacteriostatic activity against 13/13 strains tested, reducing the colistin MIC below the susceptibility breakpoint (MIC ≤ 2 mg/liter) in 7/13 strains at rifampin concentrations ranging from 4 to 16 mg/liter. Bactericidal synergistic activity was also documented for 8/13 tested strains. Other antimicrobial combinations with carbapenems, gentamicin, and tigecycline showed variously synergistic results. Colistin plus rifampin also exhibited bacteriostatic synergistic activity against 4/4 colistin-susceptible KPC-producing K. pneumoniae isolates (colistin MIC range of 0.5 to 2 mg/liter) and 4/4 ertapenem-resistant extended-spectrum beta-lactamase (ESBL)-producing K. pneumoniae isolates (ertapenem MIC range of 16 to 32 mg/liter). Collectively, our data suggest that colistin plus rifampin is the most consistently synergistic combination against KPC-producing K. pneumoniae isolates, including colistin-resistant strains. Colistin-rifampin combinations may have a role in the treatment of multidrug-resistant K. pneumoniae and may possibly slow the selection of heteroresistant subpopulations during colistin therapy.
authors.affiliation: UO Malattie Infettive, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Tascini
authors.forename: Enrico
authors.initials: E
authors.lastname: Tagliaferri
authors.forename: Tommaso
authors.initials: T
authors.lastname: Giani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Leonildi
authors.forename: Sarah
authors.initials: S
authors.lastname: Flammini
authors.forename: Beatrice
authors.initials: B
authors.lastname: Casini
authors.forename: Russell
authors.initials: R
authors.lastname: Lewis
authors.forename: Simone
authors.initials: S
authors.lastname: Ferranti
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Rossolini
authors.forename: Francesco
authors.initials: F
authors.lastname: Menichetti
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D003091:Colistin / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D000077727:Ertapenem; D005798:Genes, Bacterial; D005839:Gentamicins / Q000494:pharmacology; D007711:Klebsiella pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D012293:Rifampin / Q000494:pharmacology*; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D005839:Gentamicins; D047090:beta-Lactams; D001618:beta-Lactamases; C063912:carbapenemase; C108449:oxacillinase; D000077727:Ertapenem; D012293:Rifampin; D003091:Colistin