Pharmacodynamics of colistin and fosfomycin

A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae

Miao Zhao, Zackery P Bulman, Justin R Lenhard, Michael J Satlin, Barry N Kreiswirth, Thomas J. Walsh, Amanda Marrocco, Phillip J Bergen, Roger L Nation, Jian Li, Jing Zhang, Brian Tsuji

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17 Citations (Scopus)

Abstract

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 0.25mg/L and MICfosfomycin ≥ 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 log10 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.

Original languageEnglish
Article numberdkx070
Pages (from-to)1985-1990
Number of pages6
JournalJournal of Antimicrobial Chemotherapy
Volume72
Issue number7
DOIs
Publication statusPublished - 1 Jul 2017

Cite this

Zhao, M., Bulman, Z. P., Lenhard, J. R., Satlin, M. J., Kreiswirth, B. N., Walsh, T. J., ... Tsuji, B. (2017). Pharmacodynamics of colistin and fosfomycin: A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae. Journal of Antimicrobial Chemotherapy, 72(7), 1985-1990. [dkx070]. https://doi.org/10.1093/jac/dkx070
Zhao, Miao ; Bulman, Zackery P ; Lenhard, Justin R ; Satlin, Michael J ; Kreiswirth, Barry N ; Walsh, Thomas J. ; Marrocco, Amanda ; Bergen, Phillip J ; Nation, Roger L ; Li, Jian ; Zhang, Jing ; Tsuji, Brian. / Pharmacodynamics of colistin and fosfomycin : A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae. In: Journal of Antimicrobial Chemotherapy. 2017 ; Vol. 72, No. 7. pp. 1985-1990.
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title = "Pharmacodynamics of colistin and fosfomycin: A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae",
abstract = "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 0.25mg/L and MICfosfomycin ≥ 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 log10 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.",
author = "Miao Zhao and Bulman, {Zackery P} and Lenhard, {Justin R} and Satlin, {Michael J} and Kreiswirth, {Barry N} and Walsh, {Thomas J.} and Amanda Marrocco and Bergen, {Phillip J} and Nation, {Roger L} and Jian Li and Jing Zhang and Brian Tsuji",
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Zhao, M, Bulman, ZP, Lenhard, JR, Satlin, MJ, Kreiswirth, BN, Walsh, TJ, Marrocco, A, Bergen, PJ, Nation, RL, Li, J, Zhang, J & Tsuji, B 2017, 'Pharmacodynamics of colistin and fosfomycin: A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae', Journal of Antimicrobial Chemotherapy, vol. 72, no. 7, dkx070, pp. 1985-1990. https://doi.org/10.1093/jac/dkx070

Pharmacodynamics of colistin and fosfomycin : A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae. / Zhao, Miao; Bulman, Zackery P; Lenhard, Justin R; Satlin, Michael J; Kreiswirth, Barry N; Walsh, Thomas J.; Marrocco, Amanda ; Bergen, Phillip J; Nation, Roger L; Li, Jian; Zhang, Jing; Tsuji, Brian.

In: Journal of Antimicrobial Chemotherapy, Vol. 72, No. 7, dkx070, 01.07.2017, p. 1985-1990.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacodynamics of colistin and fosfomycin

T2 - A 'treasure trove' combination combats KPC-producing Klebsiella pneumoniae

AU - Zhao, Miao

AU - Bulman, Zackery P

AU - Lenhard, Justin R

AU - Satlin, Michael J

AU - Kreiswirth, Barry N

AU - Walsh, Thomas J.

AU - Marrocco, Amanda

AU - Bergen, Phillip J

AU - Nation, Roger L

AU - Li, Jian

AU - Zhang, Jing

AU - Tsuji, Brian

PY - 2017/7/1

Y1 - 2017/7/1

N2 - 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 0.25mg/L and MICfosfomycin ≥ 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 log10 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.

AB - 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 0.25mg/L and MICfosfomycin ≥ 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 log10 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.

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U2 - 10.1093/jac/dkx070

DO - 10.1093/jac/dkx070

M3 - Article

VL - 72

SP - 1985

EP - 1990

JO - Journal of Antimicrobial Chemotherapy

JF - Journal of Antimicrobial Chemotherapy

SN - 0305-7453

IS - 7

M1 - dkx070

ER -