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Question

Can fosfomycin treat multidrug-resistant urinary tract infections?

Response from Sarah F. Hale, PharmD 

PGY-2 Critical Care and Pediatrics Pharmacy Resident, Albany Medical Center, Albany, New York

Fosfomycin is a phosphonic acid derivative that exhibits bactericidal activity by irreversibly inhibiting the production of bacterial cell wall precursors.^[1] It has a broad spectrum of antimicrobial activity against many gram-negative bacteria including Escherichia coli, Enterobacter species, Serratia marcescens, Pseudomonas aeruginosa, and Klebsiella pneumoniae, with the notable exception ofAcinetobacter baumannii. Fosfomycin also exhibits activity against gram-positive organisms such asStaphylococcus aureus and Enterococcus species (including methicillin-resistant S aureus and vancomycin-resistant Enterococcus).^[2,3]

Fosfomycin tromethamine, the oral salt, is the only formulation marketed in the United States; the parenteral disodium salt of fosfomycin is not available. Fosfomycin tromethamine is a small, lipophilic molecule with an oral bioavailability of 30%-37% and a mean volume of distribution of 136 L.^[4] It distributes particularly well to the kidneys, bladder wall, and prostate and achieves high urinary concentrations within 4 hours that remain high (> 128 mg/L) up to 48 hours after a single 3-g dose.^[3] It is primarily excreted unchanged in the urine, with a mean elimination half-life of 5.7 hours. Use with metoclopramide has been shown to decrease serum and urinary concentrations and should be avoided.^[4]

Fosfomycin tromethamine is approved by the US Food and Drug Administration (FDA) as a single 3-g dose, given orally as a powder sachet dissolved in cool water, for treatment in women with uncomplicated urinary tract infections (UTIs) caused by E faecalis or E coli. ^[4] Adverse effects are generally mild and gastrointestinal in nature, with diarrhea most commonly reported.^[4] Fosfomycin is not recommended or approved for the treatment of pyelonephritis.^[4,5]

Guidelines from the Infectious Diseases Society of America list fosfomycin as a reasonable option for acute uncomplicated cystitis, although they note that it may have inferior efficacy compared with other standard treatment regimens.^[5] However, a meta-analysis by Falagas and colleagues^[6] reported no differences in clinical or microbiological success in treating acute cystitis with fosfomycin vs other antibiotics. Comparable microbiological success was noted also in a limited number of trials in pediatric patients and pregnant women.^[6] Fosfomycin has an FDA pregnancy category B rating and may serve as an alternative for patients with restrictions for other antibiotics.^[6]

The emergence of multidrug-resistant (MDR) organisms such as fluoroquinolone-resistant E coli, extended-spectrum beta-lactamase (ESBL)-producing bacteria, and carbapenem-resistant K pneumoniae has prompted re-evaluation of nontraditional antibiotics, like fosfomycin, and research into its efficacy for treatment of both urinary and systemic infections.^[7,8] Although fosfomycin tromethamine is only indicated for lower UTIs, it has been studied in both uncomplicated and complicated lower UTIs caused by MDR uropathogens.^[6,9-12] Additionally, the parenteral form of fosfomycin has been used worldwide for a variety of infections at doses between 1 g/day and 16 g/day (in divided doses every 6-8 hours).^[7,13]

Among ESBL-producing Enterobacteriaceae, antimicrobial activity of fosfomycin seems to be best retained against E coli, with a reported cumulative susceptibility of 96.8%, and 81.3% for K pneumoniaeisolates using a minimum inhibitory concentration (MIC) susceptibility breakpoint of 64 mg/L or less.^[9]Pullukcu and colleagues^[11] evaluated fosfomycin in 52 patients with lower UTIs caused by ESBL-producing E coli but without leukocytosis or fever. Fosfomycin was dosed off-label as 3 g every other night for 3 doses. Microbiological success was documented in 78.5% of cases with a higher clinical success rate of 94.3%.

Similarly, Falagas and colleagues^[9] summarized clinical cure rates as 93.8% in 2 studies of lower UTIs caused by ESBL-producing E coli, despite a lower rate of microbiological success. A separate analysis evaluated extensively drug-resistant (XDR) Enterobacteriaceae isolates, the majority of which were from urine or lower respiratory tract, with XDR isolates defined as resistant to all but 1 or 2 classes of potentially effective antimicrobials. In vitro susceptibility to fosfomycin was retained in 91.8% of isolates using the MIC breakpoint of 64 mg/L or less.^[12]

The microbiological outcomes of UTIs due to MDR pathogens treated with fosfomycin, including 13 isolates of carbapenem-resistant K pneumoniae, were described by Neuner and colleagues.^[13]Fosfomycin in vitro susceptibility of 92% was observed with a corresponding microbiological cure of 46% (6/13 patients). More patients that developed treatment failure were immunosuppressed or had ureteral stents, suggesting caution in using fosfomycin monotherapy in kidney transplant patients.

The emergence of resistance is a reasonable concern when evaluating fosfomycin for clinical use. Despite its high propensity towards mutations in vivo, the same has not been observed in clinical practice.^[14] Both the use of a single-dose treatment course for UTIs and the acidic environment in urine reduce the probability of resistance emerging in uropathogens. It has also been suggested that the mutations that cause resistance to fosfomycin may confer a detrimental biological cost that decreases pathogen virulence.^[14]

A recent meta-analysis of fosfomycin revealed no emergence of resistance in clinical trials evaluating the treatment of UTIs.^[6] However, use of fosfomycin for infections beyond the urinary tract may be more prone to potential resistance. For example, resistance rates between 2.3% and 6.7% have been reported in studies of oral and parenteral fosfomycin for treatment of other infections, including respiratory tract infections and osteomyelitis.^[14] Resistance may be particularly of concern when treating P aeruginosa. ^[14]

Fosfomycin provides an appropriate treatment option for uncomplicated UTIs, with comparable clinical efficacy to other first-line agents, nitrofurantoin and trimethoprim-sulfamethoxazole. As a single-dose oral regimen that achieves excellent urinary concentrations, it is both convenient and effective. With its broad spectrum of in vitro activity, interest in using fosfomycin for treatment of MDR infections has been renewed. Given its low rates of resistance and the available evidence, fosfomycin may serve as a useful option for oral treatment of MDR uropathogens. Further research into the most appropriate dosing regimen and duration of fosfomycin for MDR UTIs is needed.

References

1. Hendlin D, Stapley EO, Jackson M, et al. Phosphonomycin, a new antibiotic produced by strains of streptomyces. Science. 1969;166:122-123. Abstract

2. Lu CL, Liu CY, Huang YT, et al. Antimicrobial susceptibilities of commonly encountered bacterial isolates to fosfomycin determined by agar dilution and disk diffusion methods. Antimicrob Agents Chemother. 2011;55:4295-4301. Abstract

3. Patel SS, Balfour JA, Bryson HM. Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections. Drugs. 1997;53:637-656. Abstract

4. Monurol® [package insert]. Cadempino, Switzerland: Zambon Switzerland Ltd.; 2011.

5. Gupta K, Hooton TM, Naber KG, et al. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52:e103-e120. Abstract

6. Falagas ME, Vouloumanou EK, Togias AG, et al. Fosfomycin versus other antibiotics for the treatment of cystitis: a meta-analysis of randomized controlled trials. J Antimicrob Chemother. 2010;65:1862-1877. Abstract

7. Popovic M, Steinort D, Pillai S, Joukhadar C. Fosfomycin: an old, new friend? Eur J Clin Microbiol Infect Dis. 2010;29:127-142.

8. Roussos N, Karageorgopoulos DE, Samonis G, Falagas ME. Clinical significance of the pharmacokinetic and pharmacodynamic characteristics of fosfomycin for the treatment of patients with systemic infections. Int J Antimicrob Agents. 2009;34:506-515. Abstract

9. Falagas ME, Giannopoulou KP, Kokolakis GN, Rafailidis PI. Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008;46:1069-1077. Abstract

10. Falagas ME, Kastoris AC, Kapaskelis AM, Karageorgopoulos DE. Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: a systematic review. Lancet Infect Dis. 2010;10:43-50. Abstract

11. Pullukcu H, Tasbakan M, Sipahi OR, Yamazhan T, Aydemir S, Ulusoy S. Fosfomycin in the treatment of extended spectrum beta-lactamase-producing Escherichia coli-related lower urinary tract infections. Int J Antimicrob Agents. 2007;29:62-65. Abstract

12. Falagas ME, Maraki S, Karageorgopoulos DE, Kastoris AC, Mavromanolakis E, Samonis G. Antimicrobial susceptibility of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae isolates to fosfomycin. Int J Antimicrob Agents. 2010;35:240-243. Abstract

13. Neuner EA, Sekeres J, Hall GS, van Duin D. Experience with fosfomycin for treatment of urinary tract infections due to multidrug-resistant organisms. Antimicrob Agents Chemother. 2012;56:5744-5748. Abstract

14. Karageorgopoulos DE, Wang R, Yu XH, Falagas ME. Fosfomycin: evaluation of the published evidence on the emergence of antimicrobial resistance in gram-negative pathogens. J Antimicrob Chemother. 2012;67:255-268.Abstract