Review
What is the relevance of fosfomycin pharmacokinetics in the treatment of serious infections in critically ill patients? A systematic review

https://doi.org/10.1016/j.ijantimicag.2013.05.018Get rights and content

Abstract

As treatment options for critically ill patients with multidrug-resistant bacteria diminish, older antibiotics such as fosfomycin are being investigated for use as last-resort drugs. Fosfomycin is a broad-spectrum antibiotic with activity both against Gram-positive and Gram-negative bacteria. The aim of this review was to examine the effectiveness of current fosfomycin dosing strategies in critically ill patients. These patients can be subject to pathophysiology that can impact antibiotic pharmacokinetic (PK) profiles and potentially the effectiveness of their treatment. As a hydrophilic drug with negligible protein binding, fosfomycin is eliminated almost entirely by glomerular filtration and is subject to patient renal function. If altered as seen in augmented renal clearance, renal function in a critically ill patient may lead to low blood concentrations and predispose patients to the risk of treatment failure. If altered as seen in acute kidney injury, toxic blood concentrations may develop. Fosfomycin has a volume of distribution comparable with β-lactams and aminoglycosides and may therefore increase in critically ill patients. Altered dosing strategies may be required to optimise dosing given these PK changes, although the current paucity of data on fosfomycin in critically ill patients prevents accurate dosing guidance being recommended at this time.

Introduction

The escalation of antibiotic resistance is a significant and immediate global health concern. An increasing prevalence of multidrug-resistant (MDR) Gram-negative bacteria is steadily reducing the number of antibiotics available that can be used as effective treatment for many infections. Whilst serious Gram-negative infections are commonly treated with carbapenem antibiotics, infections are caused by resistant bacteria, such as those producing the increasingly described New Delhi metallo-β-lactamase (NDM), meaning that normal treatment options will result in an increased likelihood of treatment failure [1], [2]. Reports of NDM-producing and similarly resistant bacteria are becoming increasingly common in the USA, Europe, Asia-Pacific and Middle East regions.

Fosfomycin is a broad-spectrum antibiotic with bactericidal activity against Gram-negative and Gram-positive bacteria. It was first discovered in Spain in 1969 and was used for the treatment of urinary tract infections [3]. Fosfomycin is structurally unrelated to other antibiotics: it is a small (138 Da), highly hydrophilic phosphonic acid and, with negligible protein binding [2], exhibits excellent penetration into tissue [4].

The bacterial killing mechanism of fosfomycin is to inhibit the synthesis of peptidoglycan found in the inner cell wall of bacteria. Fosfomycin is very well tolerated, with only minor adverse effects, with hypokalaemia being the most frequent [5]. These characteristics support the effectiveness of fosfomycin for the treatment of MDR pathogens as a last-line antibiotic and, as such, it has been used extensively in critically ill patients in some countries in these circumstances [6].

Despite its favourable chemical characteristics, there has been some debate over what appears to be the rapid development of in vitro resistance with fosfomycin monotherapy [7]. However, in countries where fosfomycin has been used in clinical practice for many years, little change in resistance patterns has been described [8]. Resistance may also be driven by low drug exposures, as has been demonstrated for quinolones and β-lactams [9], especially in association with what can be the relatively long duration of treatment with fosfomycin [6].

As a treatment reserved for the critically ill, changes in fosfomycin pharmacokinetics can significantly impact concentrations at the site of infection, thus dose alterations may be required to ensure that optimal exposures are achieved. The aim of this paper was to examine the published data describing the pharmacokinetics of fosfomycin in critically ill patients and to review the effectiveness of current dosing strategies.

Section snippets

Literature search

The Web of Knowledge and PubMed databases were systematically searched up to October 2012. The keyword searches were ‘fosfomycin’ OR ‘phosphomycin’ OR ‘phosphonomycin’ AND ‘critical care’ OR ‘intensive care’ OR ‘sepsis’, with the search limited to English language papers only. The bibliographies of relevant articles were also reviewed. Studies were selected if they included pharmacokinetic (PK) data on fosfomycin as well as a review of current microbiological or clinical data to report a

Pharmacokinetics in intensive care unit (ICU) versus non-ICU patients

The effect of pathophysiological changes in critical illness on pharmacokinetics can be described via the changes that occur to PK parameters, specifically to clearance (CL) and the volume of distribution (Vd). Such changes can impact fosfomycin concentrations at the site of infection, which in turn may potentially reduce its bactericidal activity.

Pharmacodynamics

Bacterial killing by fosfomycin is categorised pharmacodynamically as time-dependent and, as such, maintaining concentrations above the minimum inhibitory concentration (MIC) of the target pathogen for extended periods is required for optimum activity [12]. Static time–kill studies of fosfomycin tromethamine suggest that it kills 99% of Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae and Citrobacter freundii within 2.9 h when fosfomycin concentrations are 2×

Conclusion

This systematic review has found that there is limited information available on the pharmacokinetics of fosfomycin in critically ill patients. The lack of data could be considered problematic given the serious nature of infections requiring use of this last-line antibiotic. When comparing the PK data of healthy volunteers with critically ill patients, significant changes in the Vd and CL of fosfomycin are evident. These data emphasise that standard dosing, particularly in line with the earliest

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