1. Correspondence: msalbur@hotmail.com
Bactericidal Activity of Fosfomycin against NDM-1 producing Enterobacteriaceae M. Albur, A. Noel, K. Bowker, A. MacGowan BCARE, Department of Microbiology, North Bristol NHS Trust, Bristol, UK
Correspondence:
Introduction:
Results:
Table 2. AUBKC: Sensitive v/s Resistant
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 options1. 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 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 acts by inhibiting the initial step involving phospoenolpyruvate synthetase. It inhibits the synthesis of peptidoglycan by blocking the formation of N-acetylmuramic acid2. 
In this study we looked at antimicrobial activity of fosfomycin against NDM-1 producing Enterobacteriaciae.
•The comparative mean TKC at different concentrations for sensitive and resistant isolates are shown in Fig 2a & 2b.
•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. There was grow back in Ctrough & Css concentrations at 24-48hours but no detectable re-growth at Cmax.
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 with 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: The mean AUBKC was significantly lower in sensitive isolates than resistant isolates (Table 2).
Conc.Of fosfomycin
Sensitive isolates
Resistant isolates
Growth control
311.4  110.5
286  112.3
Cmax (250mg/L)
31  17.7
208  121.7
Css (20mg/L)
146.8  120.3
254.4  122.3
Ctrough (5mg/L)
253  108.8
282.7  120.8
Discussion:
This study shows the bactericidal activity of fosfomycin against NDM-1 producing Enterobacteriaciae, at concentrations which can be achieved with systemic (intravenous) administration of fosfomycin (4-8gm i.v. TDS in an average built adult with normal renal function).
Against the sensitive isolates, there was 3-4 log-kill at 3-6 hrs at all concentrations, with no re-growth at peak concentration.Even against the resistant strains, there was log-kill by 6hr at Cmax and 2 log-kill by 6hr at Css. The cumulative bactericidal activity as estimated by AUBKC was significantly low (indicating superior bactericidality) at all concentrations for sensitive strains as compared to resistant strains. AUBKC for resistant strains showed modest but significant activity at Cmax and Css as compared to growth control indicating some activity.
Although, there are no clinical studies to confirm this data, 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 with mainly urinary tract infections4.
Fig.2a
Methodology:
•Bactericidal activity of fosfomycin was assessed by time-kill methodology using initial inoculums of 10^6CFU/ml in Muller-Hinton broth at 0, 1, 3, 6, 12, 24 and 48 hr time-points.
Area under the bacterial kill curve (AUBKC)
over 48hrs was calculated.
•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 (EUCAST breakpoint 64mg/L) .
•Pharmacokinetically achievable free drug serum concentrations were derived from the limited PK/PD data currently available3.The following concentrations reflecting peak (Cmax) 250mg/L, steady-state (Css) 20mg/L, and trough (Cmin) 5mg/L were used.
Fig.2b
Conclusion:
Fosfomycin showed a concentration dependent bactericidal activity against NDM-1 producing Enterobacteriaceae, especially against sensitive strains.
Fosfomycin susceptibility should be tested against NDM-1 producing Enterobacteriaceae, since it would be a useful systemic therapeutic option especially against sensitive strains.
Table 1 MICs of the isolates
References:
Strain No.
Isolate ID
Fos.MIC 1
E.coli 2 3
K. pneumoniae
>128 4 5
K. oxytoca 6 7 8
0.5 9
ATCC (E.coli)
<0.12
Fig.1 Structure of fosfomycin
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3) Kucers’ The Use of Antibiotics, 6th Edition.
ASM press. Editor: Lindsay. Grayson.
4) Falagas M.E. et al Lancet Infect Dis 2010;10:
43-50