Efficacy of colistin alone and in various combinations for the treatment of experimental osteomyelitis due to carbapenemase-producing Klebsiella pneumoniae

Abstract

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.

Colistin Heteroresistance in Klebsiella Pneumoniae Isolates and Diverse Mutations of PmrAB and PhoPQ in Resistant Subpopulations

“…The combination of meropenem and colistin has been suggested to treat multidrug-resistant K. pneumoniae infections [28]. The results of our time–kill assays showed that monotherapy with colistin may be problematic for the treatment of infections caused by colistin-heteroresistant K. pneumoniae .…”

Fosfomycin as Partner Drug for Systemic Infection Management. A Systematic Review of Its Synergistic Properties from In Vitro and In Vivo Studies

“…Based on literature data, susceptibility was defined as a MIC ≤ 1 µg/mL for Enterococcus spp. [71]. Rifampin showed synergistic activity in association with FOS against Enterococcus spp., resulting in synergistic effect in 20−100% of cases.…”

“…Synergism rates were not unanimous on all studies but was reported in 23/29 papers. Synergisms rate were 100% in 2 in vitro studies against K. pneumoniae [50,71] and 2 in vivo studies respectively against A. baumannii and E.coli [72,73]. The overall effect was indifferent on most isolates of P. aeruginosa and Enterobacterales.…”

Efficacy of generic meropenem products in combination with colistin in carbapenemase-producing Klebsiella pneumoniae experimental osteomyelitis

“…KPC-99YC is a clinical strain of carbapenemase-producing K. pneumoniae, intermediate to meropenem (MIC, 4 mg/L), and susceptible to colistin (MIC, 1 mg/L) [13,14]. This strain belongs to the epidemic clone ST-258.…”