Intravenous Fosfomycin for Systemic Multidrug-Resistant Infections

AUG 20, 2020
The alarming increase in rates of antibiotic resistance has necessitated the exploration of alternative treatment strategies, among them reevaluation of previously approved agents like fosfomycin. Fosfomycin is recommended as a frontline agent for uncomplicated urinary tract infection1 in current Infectious Diseases Society of America guidelines,2 but it also demonstrates efficacy for multidrug-resistant urinary tract infections (UTIs).3 With the continued rise of drug resistance, along with limited availability of novel antimicrobial agents, there is interest in reappraising IV fosfomycin for the treatment of systemic MDR infections.

Fosfomycin is available in 2 oral formulations, fosfomycin tromethamine and fosfomycin calcium, and one IV formulation, fosfomycin disodium.5 It exerts its bactericidal effects through the irreversible inactivation of uridine diphosphate N-acetylglucosamine-GlcNAc enolpyruvyl transferase, an essential first step in bacterial cell wall synthesis.6 Fosfomycin has a wide spectrum of activity, including both Gram-positive organisms—ie, Streptococcus spp., Enterococcus faecalis, E faecium, Staphylococcus aureus, and S epidermidis—and Gram-negative organisms—ie, Escherichia coli, Salmonella spp., Shigella spp., Enterobacter spp., Citrobacter spp., Klebsiella spp., Proteus spp., and Serratia marcescens.6 Due to its unique mechanism of action, cross-resistance is uncommon; therefore, fosfomycin retains in vitro activity against many MDR organisms including methicillin-resistant S aureus (MRSA), vancomycin-resistant enterococci, and extended-spectrum beta-lactamase (ESBL)-producing and carbapenemase-producing nterobacterales.

Despite its broad spectrum of activity, some notable pathogens, including Acinetobacter spp., Stenotrophomonas maltophilia, Burkholderia cepacia, Bacteriodes spp., Chlamydia spp., Vibrio fischeria, Mycobacterium tuberculosis, Staphylococcus capitis, Staphylococcus saprophyticus, and Morganella morganii are intrinsically resistant to fosfomycin.10,11 Intrinsic resistance has been linked to mutations in the MurA gene, recycling of peptidoglycan, and chromosomal expression of abrp expressed by some species of A baumannii, leading to decreased membrane permeability.12 Additionally, acquired resistance has been noted through decreased fosfomycin absorption, enzymatic inactivation, and target site modification.12 Despite these concerns, susceptibility testing is not routinely performed by clinical microbiology laboratories. This is largely driven by the fact that agar dilution, the reference testing method, is a laborious process requiring Mueller‐Hinton agar plates supplemented with glucose-6-phospate.13 In addition, complicating matters is the poor performance of automated and routine manual susceptibility testing methods, compared with standard agar dilution methods, in predicting resistance among MDR Enterobacterales isolates such as E coli and K pnuemoniae. Such methods proved to perform poorly, with high major error (ie, false susceptible) rates.14 Furthermore, in the United States, breakpoints exist only for urinary E coli and Enterococcus faecalis isolates using disk diffusion and agar dilution methods.

Fosfomycin is a concentration-dependent, bactericidal antibiotic with a prolonged post antibiotic effect in vitro. A small compound with a low molecular weight, it is hydrophobic and has negligible protein binding, leading to excellent penetration in bladder tissue.5,10 The IV formulation has also been proven to penetrate lung tissue, pleural fluid, cerebral spinal fluid, and aqueous humor. 15 The volume of distribution for IV fosfomycin is 0.3 L/kg, but it increases significantly in critically ill patients.15 Fosfomycin is nearly entirely cleared through glomerular filtration and is excreted largely unchanged in the urine. It has a favorable safety profile with primarily mild and self-limiting adverse effects (AEs). The most common AEs include gastrointestinal symptoms such as nausea, vomiting, and diarrhea in less than 10% of patients. Additional AEs with the IV formulations include transient increase in transaminases and  hypernatremia and/or hypokalaemia.

In countries where IV fosfomycin is readily available, it has frequently been used in combination,17 usually as part of salvage treatment, for susceptible MDR organisms. 6,18,19 In the treatment of MRSA, fosfomycin, in combination with daptomycin or imipenem, has been of great interest due to evidence of synergy in vitro.20 Clinical data include case series21 and prospective studies, but these have been limited by sample size22 and flawed enrollment process.23 A multicenter, open-label, randomized phase 3 study (NCT01898338) evaluating the addition of fosfomycin to daptomycin for MRSA bacteremia is currently underway.24 For MDR Gram-negative isolates, fosfomycin has been evaluated in vitro in combination with several agents. Synergy has been demonstrated with colistimethate,25 carbapenems,25 and aminoglycosides.26 Similarly, clinical data on the efficacy of IV fosfomycin for MDR Gram-negative infections (Enterobacterales and P aeruginosa) stem from observational studies without comparative control arms in which fosfomycin was administered mainly in combination with other agents.

Phase 1 and 2/3 clinical trials have been completed as part of the new drug application to the FDA for the approval of Contepo (fosfomycin for injection).4,29,30 In the recent ZEUS trial, a multicenter, double-blind, randomized, noninferiority study, fosfomycin was found to be noninferior to piperacillin–tazobactam in the treatment of complicated urinary tract infections and acute pyelonephritis.30 While a significant proportion of E. coli isolates (73%) were phenotypically determined to be producers of ESBL, more robust trials are needed in the setting of MDR infections. The FOREST study (NCT02142751), a phase 3, randomized, controlled, multicenter, open-label trial, aims to compare IV fosfomycin with meropenem or ceftriaxone in patients with bacteremia secondary to UTIs caused by MDR E. coli (including ESBL producers).31

One major uncertainty about IV fosfomycin and its role in the anti-infective armamentarium is concern for the potential emergence of resistance during therapy, in particular among P aeruginosa.32 Given the high spontaneous mutation rate for fosfomycin resistance in vitro, its use as part of combination therapy maybe be prudent to reduce the risk of development of fosfomycin resistance during therapy while maximizing treatment outcomes among MDR infections. Recently, the addition of ceftazidime–avibactam to IV fosfomycin has shown promise in the prevention of the emergence of resistance among those patients with high bacterial burdens.

Fosfomycin’s unique mechanism of action, which makes cross-resistance uncommon and allows for synergy with other antibiotics, coupled with its excellent capacity for diffusion to various tissues and its well-tolerated safety profile, grants it considerable versatility as a therapeutic option for systemic MDR therapies. However, its efficacy and utility as a stand-alone agent (as opposed to its use in combination with other agents) in the treatment of MDR infections remains unclear and will need to be elucidated through careful investigation. Moreover, issues such as the emergence of resistance and susceptibility testing standards will need to be concurrently addressed. Given the above limitations of IV fosfomycin, its logical niche in our MDR therapeutic arsenal will likely be exclusively as a synergetic agent in combination rather than a stand-alone therapy.

CR, carbapenem resistant; ESBL, extended-spectrum beta-lactamases; KPC, Klebsiella pneumoniae carbapenemase; MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus aureus; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; VRE, vancomycin-resistant enterococci.

Ahmed Babiker, MBBS, is an assistant professor, Department of Medicine, Division of Infectious Disease, Emory University School of Medicine, with a secondary appointment in the Department of Pathology and Laboratory Medicine. Dr. Babiker sees patients on the Infectious Diseases inpatient consult at Emory University Hospital and serves as the associate director of the Investigational Clinical Microbiology Laboratory and a medical director of the Emory University Molecular Laboratory.

Daniel Anderson, PharmD, is an internal medicine and infectious diseases pharmacist at Augusta University Medical Center in Augusta, Georgia.
 
References

1.         Arana DM, Ortega A, González-Barberá E, et al; Spanish Antibiotic Resistance Surveillance Programme Collaborating Group. Carbapenem-resistant Citrobacter spp. isolated in Spain from 2013 to 2015 produced a variety of carbapenemases including VIM-1, OXA-48, KPC-2, NDM-1 and VIM-2. J Antimicrobial Chemotherapy. 2017;72(12):3283-3287. doi:10.1093/jac/dkx325
2.         Gupta K, Hooton TM, Naber KG, et al; Infectious Diseases Society of America;  European Society for Microbiology and Infectious Diseases.. 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(5):e103-e120. doi:10.1093/cid/ciq257

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