Pharmacodynamics of colistin and fosfomycin: a 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae

Objectives: KPC-producing Klebsiella pneumoniae are an emerging public health problem around the globe. We defined the combinatorial pharmacodynamics and ability to suppress resistance of two 'old' antibiotics, fosfomycin and colistin, in time-kill experiments and hollow-fibre infection models (HFIM). Methods: Two KPC-2-producing K. pneumoniae isolates were used: one susceptible to both colistin and fosfomycin (KPC 9A: MICcolistin 0.25 mg/L and MICfosfomycin a parts per thousand<currency>8 mg/L) and the other resistant to colistin and susceptible to fosfomycin (KPC 5A: MICcolistin 64 mg/L and MICfosfomycin 32 mg/L). Time-kill experiments assessed an array of colistin and fosfomycin concentrations against both isolates. Colistin and fosfomycin pharmacokinetics from critically ill patients were simulated in the HFIM to define the pharmacodynamic activity of humanized regimens over 5 days against KPC 9A. Results: In time-kill experiments, synergy was demonstrated for all colistin/fosfomycin combinations containing > 8 mg/L fosfomycin against the double-susceptible KPC strain, 9A. Synergy versus KPC strain 5A was only achieved at the highest concentrations of colistin (4 mg/L) and fosfomycin (512 mg/L) at 48 h. In the HFIM, colistin or fosfomycin monotherapies resulted in rapid proliferation of resistant subpopulations; KPC 9A regrew by 24 h. In contrast to the monotherapies, the colistin/fosfomycin combination resulted in a rapid 6.15 log(10) cfu/mL reduction of KPC 9A by 6 h and complete suppression of resistant subpopulations until 120 h. Conclusions: Colistin and fosfomycin may represent an important treatment option for KPC-producing K. pneumoniae otherwise resistant to traditional antibiotics.