Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database

Iarikov, Dmitri; Wassel, Ronald T.; Farley, John; Nambiar, Sumathi

doi:10.1007/s40121-015-0092-8

Cited by 64 publications

(55 citation statements)

References 62 publications

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“…Reported adverse events were generally non-serious and expected, without troubling drug/drug interactions. Moreover, safety results from the NIS-FOM are in line with recent reviews corroborating the good safety profile of the substance [6,15]. Given the sodium load of IV fosfomycin, discontinuation of the drug due to accumulating high sodium levels in six cases was reasonable to prevent potentially serious electrolyte imbalances.…”

Section: Discussionsupporting

confidence: 74%

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Current clinical use of intravenous fosfomycin in ICU patients in two European countries

et al. 2019

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Purpose In Europe, intravenous fosfomycin (IV) is used particularly in difficult-to-treat or complex infections, caused by both Gram-positive and Gram-negative pathogens including multidrug-resistant strains. Here, we investigated the efficacy and safety of intravenous fosfomycin under real-life conditions. Methods Prospective, multi-center, and non-interventional study in patients with bacterial infections from 20 intensive care units (ICU) in Germany and Austria (NCT01173575). Results Overall, 209 patients were included (77 females, 132 males, mean age: 59 ± 16 years), 194 of which were treated in intensive care (APACHE II score at the beginning of fosfomycin therapy: 23 ± 8). Main indications (± bacteremia or sepsis) were infections of the CNS (21.5%), community-(CAP) and hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP, 15.3%), bone and joint infections (BJI, 11%), abdominal infections (11%), and bacteremia (10.5%). Most frequently identified pathogens were S. aureus (22.3%), S. epidermidis (14.2%), Enterococcus spp. (10.8%), E. coli (12.3%) and Klebsiella spp. (7.7%). At least one multidrug-resistant (MDR) pathogen was isolated from 51 patients (24.4%). Fosfomycin was administered with an average daily dose of 13.7 ± 3.5 g over 12.4 ± 8.6 days, almost exclusively (99%) in combination with other antibiotics. The overall clinical success was favorable in 81.3% (148/182) of cases, and in 84.8% (39/46) of patients with ≥ 1 MDR pathogen. Noteworthy, 16.3% (34/209) of patients developed at least one, in the majority of cases non-serious, adverse drug reaction during fosfomycin therapy. Conclusion Our data suggest that IV fosfomycin is an effective and safe combination partner for the treatment of a broad spectrum of severe bacterial infections in critically ill patients.

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Section: Discussionsupporting

confidence: 74%

“…Fosfomycin can be used without any age limitations. However, due to the high sodium load (1 g fosfomycin contains 14 mmol (320 mg) sodium), electrolyte imbalances such as hypernatremia or hypokalemia might occur [6,15].…”

Section: Introductionmentioning

confidence: 99%

Current clinical use of intravenous fosfomycin in ICU patients in two European countries

et al. 2019

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“…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).…”

Section: Fosfomycinmentioning

confidence: 99%

Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems

Gardiner¹,

Stewardson²,

Abbott³

et al. 2019

Aust Prescr

110

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Uncomplicated urinary tract infection is one of the most common indications for antibiotic use in the community. However, the Gram-negative organisms that can cause the infection are becoming more resistant to antibiotics. Many multidrug resistant organisms retain susceptibility to two old antibiotics, nitrofurantoin and fosfomycin. Advantages over newer drugs include their high urinary concentrations and minimal toxicity. Fosfomycin is a potential treatment option for patients with uncomplicated urinary tract infection due to resistant organisms. Nitrofurantoin may be more effective and can be used for urinary infections in pregnant women. Nitrofurantoin Nitrofurantoin has been available since 1953, and in Australia since the 1970s. Its exact mechanism of action is not well understood and presumably multifactorial. Nitrofurantoin requires reduction by bacterial enzymes producing 'highly reactive electrophilic' metabolites. These then inhibit protein synthesis by interfering with bacterial ribosomal proteins. 11 Nitrofurantoin has 80% oral bioavailability, and approximately 25% is excreted unchanged in the urine, with only a small portion reaching the colon. 12 Like fosfomycin, therapeutic concentrations are only reached in the urinary tract, 13 so the clinical use of nitrofurantoin is limited to the treatment of uncomplicated urinary tract infection in women. Administration with food results in higher urinary concentrations and fewer gastrointestinal adverse effects. Antimicrobial activity Nitrofurantoin is active against common causes of urinary tract infection including E. coli, Citrobacter and Enterococcus. Klebsiella and Enterobacter are less reliably susceptible. Serratia, Acinetobacter, Morganella, Proteus and Pseudomonas are usually resistant. 14 Overall, resistance to nitrofurantoin is uncommon and many multidrug resistant organisms retain susceptibility. 15-17 Australian data are limited, but studies suggest resistance rates in E. coli of 1-2%. 4,6

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“…Aminotransferase level elevations were also commonly observed in the ZEUS phase III clinical trial, although none progressed to more severe hepatic‐related complications, and all resolved at the end of therapy . A review of the FDA Adverse Events Reporting System for fosfomycin also noted similar aminotransferase level elevation rates (1–2%) . Other events noted in a phase I open‐label trial of an IV fosfomycin 8‐g dose were bradycardia (28.6%), defined as heart rate of 54 beats/minute or lower and hypocalcemia (10.7%) These treatment‐related adverse events resolved by the end of the study with the exception of one case of mild hypocalcemia and one case of anemia.…”

Section: Safety and Tolerabilitymentioning

confidence: 78%

“…8 A review of the FDA Adverse Events Reporting System for fosfomycin also noted similar aminotransferase level elevation rates (1-2%). 108 Other events noted in a phase I open-label trial of an IV fosfomycin 8-g dose were bradycardia (28.6%), defined as heart rate of 54 beats/minute or lower and hypocalcemia (10.7%) 43 These treatment-related adverse events resolved by the end of the study with the exception of one case of mild hypocalcemia and one case of anemia. No other laboratory abnormalities were observed in this study.…”

Section: Safety and Tolerabilitymentioning

confidence: 99%

Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide

2019

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Fosfomycin was initially discovered in 1969 but has recently gained renewed interest for the treatment of multidrug‐resistant (MDR) bacterial infections, particularly in the United States. Its unique mechanism of action, bactericidal activity, broad spectrum of activity, and relatively safe and tolerable adverse effect profile make it a great addition to the dwindling antibiotic armamentarium. Fosfomycin contains a three‐membered epoxide ring with a direct carbon to phosphorous bond that bypasses the intermediate oxygen bond commonly present in other organophosphorous compounds; this structure makes the agent unique from other antibiotics. Despite nearly 50 years of parenteral fosfomycin use in Europe, fosfomycin has retained stable activity against most pathogens. Furthermore, fosfomycin demonstrated in vitro synergy in combination with other cell wall–active antibiotics (e.g., β‐lactams, daptomycin). These combinations may offer respite for severe infections due to MDR gram‐positive and gram‐negative bacteria. The intravenous (IV) formulation is currently under review in the United States, and apropos, this review collates more contemporary evidence (i.e., studies published between 2000 and early 2019) in anticipation of this development. The approval of IV fosfomycin provides another option for consideration in the management of MDR infections. Its unique structure will give rise to a promising epoxide epoch in the battle against MDR bacteria.

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Adverse Events Associated with Fosfomycin Use: Review of the Literature and Analyses of the FDA Adverse Event Reporting System Database

Cited by 64 publications

References 62 publications

Current clinical use of intravenous fosfomycin in ICU patients in two European countries

Current clinical use of intravenous fosfomycin in ICU patients in two European countries

Nitrofurantoin and fosfomycin for resistant urinary tract infections: old drugs for emerging problems

Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide

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