Review
Fosfomycin for the treatment of infections caused by multidrug-resistant non-fermenting Gram-negative bacilli: a systematic review of microbiological, animal and clinical studies

https://doi.org/10.1016/j.ijantimicag.2009.03.009Get rights and content

Abstract

The treatment of multidrug-resistant (MDR), extensively drug-resistant or pandrug-resistant non-fermenting Gram-negative bacterial infections constitutes a challenge in an era of few new antibiotic choices. This mandates the re-evaluation of already existing antibiotics such as fosfomycin. We systematically reviewed the literature to assess the clinical and microbiological effectiveness of fosfomycin in the treatment of these infections by searching PubMed, Scopus and the Cochrane Library databases. In 23 microbiological studies identified, 1859 MDR non-fermenting Gram-negative bacterial isolates were examined. The susceptibility rate to fosfomycin of MDR Pseudomonas aeruginosa isolates was ≥90% and 50–90% in 7/19 and 4/19 relevant studies, respectively. Cumulatively, 511/1693 (30.2%) MDR P. aeruginosa isolates were susceptible to fosfomycin. Serotype O12 isolates exhibited greater susceptibility. Only 3/85 (3.5%) MDR Acinetobacter baumannii and 0/31 MDR Burkholderia spp. isolates were susceptible to fosfomycin. Variable criteria of susceptibility were used in the included studies. Fosfomycin was synergistic in combination with a β-lactam, aminoglycoside or ciprofloxacin in 46/86 (53.5%) MDR P. aeruginosa isolates. One animal study found a good therapeutic effect of the combination fosfomycin/gentamicin against MDR P. aeruginosa endocarditis. In six clinical studies, 33 patients with MDR P. aeruginosa infections (mainly pulmonary exacerbations of cystic fibrosis) received fosfomycin (25/33 in combination with other antibiotics); 91% of the patients clinically improved. In conclusion, fosfomycin could have a role as a therapeutic option against MDR P. aeruginosa infections. Further research is needed to clarify the potential utility of this agent.

Introduction

In an era of extensive bacterial drug resistance, especially among non-fermenting Gram-negative species such as Pseudomonas aeruginosa and Acinetobacter baumannii [1], emphasis should be given not only to the development of new drugs but also to the re-evaluation of older and ‘forgotten’ drugs [2], [3], [4]. Fosfomycin is a drug representing the latter category, discovered almost 40 years ago. It inhibits bacterial cell wall biosynthesis by inactivating the UDP-N-acetyl-glucosamine-3-o-enolpyruvultransferase [5].

The oral form of this broad-spectrum antibiotic [6] has principally been used in the treatment of uncomplicated urinary tract infections (UTIs) in the USA, the UK and other countries. However, the intravenous form has been used for indications beyond UTIs in only a few countries such as Germany, France, Spain and Japan [7]. Recent data suggest that it may be considered as an alternative in the treatment of Gram-negative and Gram-positive infections other than of UTIs [7], [8].

Thus, we sought to evaluate human and animal studies that examined the clinical effectiveness and/or microbiological activity of fosfomycin against multidrug-resistant (MDR), extensively drug-resistant (XDR) or pandrug-resistant (PDR) non-fermenting Gram-negative bacilli.

Section snippets

Literature search

We systematically searched PubMed, Scopus and the Cochrane Library databases up to January 2009. The keywords used were (fosfomycin OR phosphomycin OR phosphonomycin) AND (drug resistance OR Pseudomonas OR Acinetobacter OR Stenotrophomonas OR Burkholderia). Bibliographies of relevant articles were also hand-searched.

Study selection

Studies were selected if they included microbiological, animal experimental or clinical data on the effect of fosfomycin against MDR non-fermenting Gram-negative pathogens such as

Results

The process of study selection is depicted as a flow diagram in Fig. 1. A total of 30 studies published between 1985 and 2008 were included in the review [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. Twenty-three of these are microbiological studies on the activity of fosfomycin against clinical isolates of MDR non-fermenting Gram-negative bacteria [8], [9], [10],

Discussion

The main finding of our review is that fosfomycin may play a role in the treatment of infections caused by MDR P. aeruginosa. One has to acknowledge that relatively few studies have examined the clinical or microbiological effects of fosfomycin on infections due to MDR non-fermenting Gram-negative bacilli. Interestingly, the great majority of relevant studies regard P. aeruginosa, whilst there is a dearth of relevant data for MDR A. baumannii, Burkholderia spp. and Stenotrophomonas spp.

The

Conclusions

Fosfomycin could potentially be considered in the treatment of infections caused by MDR P. aeruginosa if established therapeutic options are not available. An appreciable number of studies have documented good antimicrobial activity of fosfomycin against MDR P. aeruginosa isolates, which is difficult to quantitate given the lack of universally accepted specific species-related susceptibility breakpoints. The antimicrobial activity of fosfomycin against MDR P. aeruginosa may also be enhanced in

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