Antimicrobial activity of fosfomycin against NDM-1 producing Enterobacteriacia

Mahableshwar S Albur, Alan Noel, Karen Bowker, Alasdair P MacGowan

Research output: Contribution to conferenceConference Abstract

Abstract

Introduction:
Antibiotic resistance is a growing problem worldwide, at the same time the number of new antibacterial drugs in development with a potential to treat multi-drug resistant bacterial infections is on the decline. Recently emerged multi-drug resistant (MDR) bacteria such as NDM1 metallo-B-lactamase producing coliforms have very limited or no therapeutic options. Hence, there is an urgent need to explore therapeutic strategies against the emerging MDR-bacteria by using the currently available antimicrobial agents before newer agents become available.
Fosfomycin (originally named phosphonomycin) is a phosphonic acid derivative and was discovered in Spain way back in 1969. Fosfomycin has a unique chemical structure (Fig.1) with a very low molecular weight and negligible protein binding. It is bactericidal against both gram positive and gram negative organisms, and act by inhibiting the initial step involving phospoenolpyruvate synthetase. It inhibits the synthesis of peptidoglycan by blocking the formation of N-acetylmuramic acid.
In this study we looked at antimicrobial activity of fosfomycin against NDM-1 producing Enterobacteriaciae.

Methodology:
•Bactericidal activity of fosfomycin was assessed by time-kill methodology.
•8 well characterised strains of NDM-1 producing Enterobacteriaceae and one control strain E.coli (ATCC 13353) were used.
•MIC was determined by CLSI microdilution method using Muller-Hinton broth supplemented with 25mg/L of Glucose-6-phosphate (G6P). (Table1)
•Four of the isolates were resistant, and four were sensitive to fosfomycin
•Pharmacokinetically achievable free drug serum concentrations were used.
•The following concentrations (derived from limited PK/PD data currently available) reflecting peak (Cmax) 250mg/L, steady-state (Css) 20mg/L, and trough (Cmin) 5mg/L were used.
•Bactericidal activity of fosfomycin was tested at 0, 1, 3, 6, 12, 24 and 48 hr time-points along with a growth control (GC).

Results:
•Against sensitive strains: Fosfomycin showed excellent bactericidal activity with a mean log drop in bacterial count (CFU/ml) at 3hr (–2.930.34, -2.260.53, -1.770.45), and (-4.030.35, -3.530.52, -2.940.40) at 6hr respectively for Cmax, Css, and Ctrough concentrations. There was grow back in Ctrough & Css concentrations at 24-48hours but no detectable regrowth at Cmax conc.
•Against resistant strains: Fosfomycin showed good bactericidality at Cmax with a mean log-kill of -2.380.52 at 3hr, and –3.610.64 at 6hr. Modest cidality at Css concentration a mean log-kill of –0.920.85 at 3hr, and –2.100.34 at 6hr, but no activity at Ctrough concentration. There was grow-back in all concentrations by 24hrs.
•AUBKC sensitive v/s resistant strains: As expectedly, the mean AUBKC was significantly lower in sensitive isolates than resistant isolates.

Discussion:
This study shows bactericidal activity of fosfomycin against NDM-1 producing Enterobacteriaceae, especially against sensitive strains at concentrations which can be achieved with systemic (intravenous) administration of fosfomycin (8gm i.v. TDS in average built adult with normal renal function).
Although, there are no clinical studies looking at this very specific angle, a recent systematic review on fosfomycin has shown a good antimicrobial activity against ESBL-producing Enterobacteriaceae (96.8% of 1657 E. coli, and 81.3% of 748 K. pneumoniae isolates tested susceptible) and good clinical effectiveness in 75 out of 80 (93.8%) patients.
Conclusion:
Fosfomycin has a good bactericidal activity against susceptible strains of NDM-1 producing Enterobacteriaceae.
Original languageEnglish
PagesP1821
Number of pages1
Publication statusPublished - 31 Mar 2012
EventECCMID 2012 - London, United Kingdom
Duration: 30 Mar 20123 Apr 2012

Conference

ConferenceECCMID 2012
CountryUnited Kingdom
CityLondon
Period30/03/123/04/12

Keywords

  • Fosfomycin, NDM-1, Bactericidality

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    Albur, M. S., Noel, A., Bowker, K., & MacGowan, A. P. (2012). Antimicrobial activity of fosfomycin against NDM-1 producing Enterobacteriacia. P1821. Abstract from ECCMID 2012, London, United Kingdom.