Fosfomycin was first isolated in Spain in 1969, and was introduced in Europe throughout the 1970s.25 It is a small molecule from a unique drug class that acts by inhibiting pyruvyl transferase. This enzyme is responsible for synthesising the precursors of peptidoglycan, the key component of the bacterial cell wall. Uptake in the USA was initially limited due to problems with susceptibility testing, but this was standardised in 1983.
Fosfomycin trometamol, an oral formulation that can be taken as a single 3 g dose, was introduced in 1995. In many countries it is now a first-line treatment option for uncomplicated urinary tract infection in women.22 This single-dose regimen is attractive due to better adherence and is generally well tolerated. While transient gastrointestinal disturbance can occur, serious adverse events are rare.26
In Australia, fosfomycin was only previously available via the Special Access Scheme. The Therapeutic Goods Administration has now approved it for acute uncomplicated lower urinary tract infection, in females more than 12 years of age, caused by susceptible organisms (Enterobacteriaceae including E. coli, and Enterococcus faecalis).
Susceptibility testing for fosfomycin is available, but can be complicated and is not necessarily routine in Australian microbiology laboratories. Fosfomycin is most active against E. coli, and minimum inhibitory concentrations are typically low.27-29 Other urinary pathogens such as Klebsiella, Proteus, Citrobacter, Enterobacter, Pseudomonas and Enterococcus have variable susceptibility.30-32 Morganella morganii and Acinetobacter are typically resistant.28 Urinary concentrations following a single 3 g dose are generally sufficient to treat patients infected with susceptible organisms, although some recent data suggest more variability in urinary concentrations than previously thought.33,34
As fosfomycin has a unique structure there is minimal cross-resistance with other antibiotics. At present, many multidrug resistant isolates remain susceptible to fosfomycin, even in geographic regions where there has been widespread use of the drug.35,36 No comprehensive studies examining fosfomycin susceptibility have been conducted in Australia.
While resistant subpopulations of bacteria may develop with fosfomycin exposure, resistant strains do not seem to easily survive in vivo.32,37-40 However, there are multiple resistance mechanisms and there are reports of increasing resistance correlating with higher fosfomycin usage in Spain.32,41-43 Plasmid-mediated resistance, which could disseminate more readily, has been described in Japan,44 and among livestock45 and pets46 in China.
Efficacy and safety
Historically, the clinical efficacy of fosfomycin was thought to be similar to antibiotics such as trimethoprim, trimethoprim/sulfamethoxazole, fluoroquinolones, beta-lactams and nitrofurantoin, with reported cure rates of 75–90%.47-51 However, methodological flaws in the older studies may have resulted in clinical efficacy being overestimated. A recent large randomised trial found a lower clinical cure rate with fosfomycin compared with nitrofurantoin (58% vs 70%, p=0.004).19 While some recent observational studies have demonstrated fosfomycin efficacy in uncomplicated urinary tract infection caused by resistant organisms,52-56 including non-inferiority to carbapenems,57,58 there are reports of treatment failures particularly with Klebsiella.59
As low serum concentrations lead to treatment failures, fosfomycin is not appropriate for patients with bacteraemia or upper urinary tract infections such as pyelonephritis. Occasionally, longer courses have been used to treat complicated urinary tract infection, for example as completion therapy when there are no oral alternatives to intravenous antibiotics.57 There is also an emerging role in prostatitis and perioperative prophylaxis for urological procedures in men.60-62 Specialist infectious diseases input should be sought for these complex cases if off-label use or prolonged courses of therapy are being considered.
Fosfomycin is generally well tolerated, with adverse events rare and usually transient. Gastrointestinal events (9% diarrhoea, 4% nausea) have been most commonly reported with rare reports of other more serious problems.26 Co-administration with metoclopramide can lower serum and urinary concentrations and should be avoided, but there are few other problematic drug interactions. Fosfomycin is classified in pregnancy category B2. It is not recommended in breastfeeding as small amounts are excreted in breast milk. Given there are minimal data on use in children under 12 years of age, it is not advised for this group.
In Australia, we currently recommend reserving fosfomycin for the treatment of uncomplicated urinary tract infection in patients when the standard first-line drugs are not an option. Part of the rationale behind this is to minimise the emergence of resistance and prolong the usefulness of fosfomycin for patients without alternative options.35 As resistance to other drugs inevitably rises and local experience increases, fosfomycin may become a first-line option in the future.