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

Infect Dis Ther DOI 10.1007/s40121-015-0092-8

ORIGINAL RESEARCH

Dmitri Iarikov . Ronald Wassel . John Farley . Sumathi Nambiar

To view enhanced content go to www.infectiousdiseases-open.com Received: August 17, 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com

ABSTRACT agranulocytosis, liver injury, severe skin reactions, and pseudomembranous colitis. Introduction: The growing problem of Subsequent search for AEs where fosfomycin antibacterial resistance resulted in an increased was the primary suspect and the literature interest in fosfomycin, especially its parenteral review did not suggest a higher association of formulation. We reviewed fosfomycin safety fosfomycin with these AEs. The search of bone proﬁle using the Food and Drug marrow toxicity reports did not demonstrate an Administration Adverse Event (AE) Reporting association between aplastic anemia and System (FAERS) and published literature. fosfomycin. The literature review selected 23 Methods: We conducted a FAERS search and trials of parenteral administration of fosfomycin disproportionality analysis of all in 1242 patients including 8 comparative and fosfomycin-associated AEs. We also conducted 15 non-comparative trials. For oral fosfomycin, a FAERS search for AEs implicating fosfomycin only prospective comparative trials (n = 28) in as the primary suspect and a search of reports of 2743 patients were included. The most frequent fosfomycin-associated bone marrow toxicity. AEs associated with parenteral fosfomycin We then review the literature for publications included rash, peripheral phlebitis, reporting AEs associated with fosfomycin by hypokalemia, and gastrointestinal disorders. conducting PubMed searches. Serious AEs such as aplastic anemia, Results: The disproportionality analysis of all anaphylaxis, and liver toxicities were reported FAERS reports of fosfomycin-associated AEs infrequently. Gastrointestinal disorders were produced a higher than expected frequency of the most common AEs associated with oral

Electronic supplementary material The online fosfomycin. version of this article (doi:10.1007/s40121-015-0092-8) Conclusion: The identified AEs were consistent contains supplementary material, which is available to authorized users. with the safety profile of fosfomycin. No new safety signals related to either parenteral or oral & D. Iarikov ( ) Á R. Wassel Á J. Farley Á S. Nambiar fosfomycin were identified. US Food and Drug Administration, Silver Spring, MD, USA e-mail: [email protected] Infect Dis Ther

Keywords: Fosfomycin; Fosfomycin adverse patients with heart failure or those on events; Fosfomycin safety hemodialysis [2]. Adverse reactions such as angioedema, aplastic anemia, cholestatic INTRODUCTION jaundice, and hepatic necrosis have been reported postmarketing [1]. Fosfomycin, discovered in Spain in 1969, is a Because of the growing problem of cell wall-acting antibacterial drug that inhibits antibacterial resistance, there has been an the formation of N-acetylmuramic acid, a increased interest in fosfomycin use, especially precursor of peptidoglycan. Fosfomycin has its parenteral formulations [6]. This review been available in Europe since the 1970s and summarizes the safety profile of fosfomycin was approved in the United States in 1996 [1]. using the Food and Drug Administration In the US, it is approved as a 3-g sachet of (FDA) Adverse Event (AE) Reporting System fosfomycin tromethamine to be given orally as (FAERS) and published literature with an a single dose for uncomplicated cystitis due to emphasis on AEs associated with its parenteral susceptible strains of Escherichia coli and formulations. Enterococcus faecalis. In Europe, fosfomycin is also available as fosfomycin disodium for METHODS intravenous (IV) administration and is used for various infections at doses of 12–16 g/day (up to The FAERS database was queried for domestic 24 g/day), divided into 3–4 doses. and foreign cases of AEs reported with oral or IV In vitro, fosfomycin is active against formulations. The FAERS contains information Enterococci including vancomycin-resistant on AE and medication error reports submitted strains, E. coli, methicillin-resistant to FDA. AEs and medication errors are coded to Staphylococcus aureus, Citrobacter diversus, terms in the Medical Dictionary for Regulatory Citrobacter freundii, Enterobacter aerogenes, Activities (MedDRA) terminology. Klebsiella oxytoca and Klebsiella pneumoniae, We conducted three FAERS searches. The including some carbapenem-resistant strains, first search included reports regardless of Proteus mirabilis and vulgaris, and Serratia whether fosfomycin was implicated as the marcescens [2]. Some extended spectrum primary suspect. The period for the search was beta-lactamase-producing strains of E. coli and from 1996 through September 2012. Data K. pneumoniae are susceptible to fosfomycin [3, retrieved by this search were subjected to a 4]. Fosfomycin is variably active against disproportionality analysis (henceforth referred Pseudomonas aeruginosa and Acinetobacter spp. to as a ‘data mining analysis’). This analysis [2, 4, 5]. aims to detect over-represented associations of The oral formulation of fosfomycin is drug–event combinations in the FAERS. The considered to have a favorable safety profile analysis used Empirica SignalÒ software (version with gastrointestinal disturbances being the 7.3.3.3.2.359, Oracle, Redwood Shores, CA, most commonly associated adverse event [1, USA) and the Multi-item Gamma Poisson 2]. An IV formulation of fosfomycin, Shrinker (MGPS) data mining algorithm for all fosfomycin disodium, is associated with a high events associated with fosfomycin use [7]. sodium intake which could be a limitation in MGPS generates adjusted relative reporting Infect Dis Ther ratios, also known as Empirical Bayes Geometric of significant fibrosis on bone marrow Mean (EBGM) values, for the entire FAERS examination [9]. database. The EBGM is the value of a ratio of We then supplemented the results of the the observed to expected number of AEs FAERS searches by the literature review of the indicating the strength of reporting safety profile of fosfomycin. The review was relationships among all drug–AE combinations conducted by searching articles in English with in the database. Importantly, the process does the term ‘‘fosfomycin’’ via PubMed. We not adjust for reporting bias. conducted a systematic review aiming to The EBGM value provides a stable estimate of evaluate for possible imbalances in the the relative reporting ratio of any AE for a frequency of AEs associated with fosfomycin as particular drug relative to all other drugs and compared to other antibacterial drugs with the AEs in FAERS. MGPS also calculates lower and focus on fosfomycin AEs over-represented in the upper 90% confidence intervals (CI) for the data-mining analysis and on safety signals EBGM scores, denoted as EB05 and EB95, associated with IV administration of respectively. The higher the EBGM value for a fosfomycin. particular drug–AE combination, the higher is The reports of clinical trials, meta-analyses, the reporting association between that drug and systematic reviews, and case reports of AEs AE in the database. Drug–AE pairs with an EB05 associated with fosfomycin were selected. (lower bound of the 90% CI for the EBGM) [1 Individual trials were selected if they included indicate AEs that occur above the expected rate. greater than 10 patients. For parenteral Furthermore, one may estimate that events with formulations of fosfomycin, all clinical trials an EB05 [2 occur at least twice the expected were selected for analysis and for oral ratio relative to the other drugs and events in formulations only prospective comparative the database. For our data mining analysis, we trials were selected. References of the selected selected reports of events with an EB05 [1. articles were also reviewed. The database was Subsequently, we conducted a FAERS search most recently accessed on July 9, 2015. for reports of AEs where fosfomycin was considered to be the primary suspect [8]. Compliance with Ethics Guidelines A separate FAERS search was conducted for all cases of possible bone marrow toxicity with This article is based on previously conducted the terms of agranulocytosis, neutropenia, studies and does not involve any new studies of febrile neutropenia, aplastic anemia, bone human or animal subjects performed by any of marrow failure, aplasia pure red cell, and the authors. No identifiable patient data were pancytopenia associated with the use of provided or accessed. fosfomycin. This separate query was prompted by a case of aplastic anemia that was reported to RESULTS the FDA. Aplastic anemia was defined as a combination of hemoglobin level \10 g/dl, Data mining for all AEs with EB05[1 associated segmented polymorphonuclear and band cells with fosfomycin that were reported to FAERS count \1.5 9 109/l, platelet count \100 9 109/ identified a total of 559 reports for 69 events. l), and histological evidence of decreased Two events had an EB05 score greater than cellularity, absence of infiltration and absence 8—pseudomembranous colitis, 5 reports, EBGM Infect Dis Ther

57.4 and agranulocytosis, 16 reports, EBGM (n = 8), vascular purpura (n = 3), rash 25.8. Two events had an EB05 score from [4 maculopapular (n = 6), rash erythematous to 8—toxic skin eruption, 7 events, EBGM 16.1 (n = 6), dermatitis allergic (n = 3), and face and hepatocellular injury, 10 reports, EBGM 10. edema (n = 8). Eighteen events had EB05 score from[2to4. Subsequent FAERS query for events where These AEs were mainly related to fosfomycin was considered to be the primary hypersensitivity reactions, liver and bone suspect identified a total of 146 reports. There marrow toxicity. AEs related to were 31 domestic and 115 foreign reports; in hypersensitivity reactions included drug 132 cases fosfomycin was given by oral and in 5 reaction with eosinophilia and systemic cases by IV or intramuscular routes; the route of symptoms, 6 reports, EBGM 9.2; Stevens administration was not reported in 9 reports. In Johnson syndrome, 11 reports, EBGM 6.7; the majority of cases, fosfomycin was used for eosinophilia, 8 reports, EBGM 6.7; drug the treatment of urinary tract infections (UTI) eruption, 6 reports, EBGM 5.4; urticaria, 18 (n = 131). reports, EBGM 3.6. Table 1 presents the most frequently AEs with EB05 score from [2 to 4 related to reported AEs (case count of [3). Events related liver toxicity included hepatitis, 14 reports, to lack of efficacy or those that were deemed EBGM 6.1; hepatic function abnormal, 12 non-significant are not included. reports, EBGM 4.8; alanine aminotransferase Gastrointestinal disorders and allergic increased, 16 reports, EBGM 4.6; aspartate reactions were reported most frequently. aminotransferase increased, 13 reports, EBGM There were a total of 38 reports of allergic 3.8. reactions associated with fosfomycin, although AEs with EB05 score from [2 to 4 related to no reports of severe skin reactions such as bone marrow toxicity included pancytopenia, Stevens Johnson syndrome or drug rash with 13 reports, EBGM 5.7; leukopenia, 16 reports, eosinophilia and systemic symptoms were EBGM 5.4; thrombocytopenia, 19 reports, retrieved by this query. EBGM 4.4; neutropenia, 13 reports, EBGM 4. The seven cases of fetal toxicities reported The other AEs with EB05 score from [2to4 included stillbirth (1), pyelocalyceal dilation included blood urea increased, 10 reports, (1), interventricular septal defect and EBGM of 4.6; blood lactate dehydrogenase micrognathia (1), spina bifida (1), hydrocele increased, 8 reports, EBGM 4.2; disseminated (1), congenital pulmonic stenosis and patent intravascular coagulation, 7 reports, EBGM 4.2; foramen ovale (1), and cranial bone defect with hypokalemia, 8 reports, EBGM 3.9; and pyrexia, exencephaly (1). 33 reports, EBGM 3.1. The FAERS search for all cases of cytopenia Review of the events with EB05 score from associated with fosfomycin identified 50 [1 to 2 revealed that many of these events were reports. Analysis of these cases identified one related to hypersensitivity reactions including case that met criteria for aplastic anemia. anaphylactic reaction (n = 5), anaphylactic The majority of cases described isolated shock (n = 4), toxic epidermal necrolysis decreases in white blood cell count (n = 25). (n = 4), dermatitis exfoliative (n = 6), acute Time to onset of cytopenia ranged from 1 to generalized exanthematous pustulosis (n = 3), 116 days with a median of 11 days. All patients drug hypersensitivity (n = 6), hypersensitivity received other medications that could be Infect Dis Ther

Table 1 Most frequently reported MedDRA preferred implicated in the development of bone marrow terms toxicities. There was no obvious correlation Event preferred terms Total cases between development of cytopenia and a total Gastrointestinal disorders dose of fosfomycin and in several cases Diarrhea 19 cytopenia developed after a single dose of the Vomiting 15 drug. Nausea 11 One case involved a 68-year-old female who Abdominal pain 8 took one fosfomycin 3-g sachet for UTI. Allergic reactions Concomitant medications included Urticaria 14 itraconazole and ciproﬂoxacin. One week after Hypersensitivity 7 receiving fosfomycin the patient was found to 9 Pruritus 7 have a decrease in platelet count to 70 9 10 /l. Anaphylactic reaction 6 On day 17 after fosfomycin administration 9 Dermatitis allergic 4 platelet count was 27 9 10 /l, WBC was 9 Cardiac, Vascular, Respiratory, and General disorders 1.7 9 10 /l and hematocrit was 33. Bone Dyspnea 12 marrow aspiration reported changes Dizziness 8 ‘‘consistent with aplastic anemia’’. Filgrastim Fatigue 7 and epoetin alfa were administered and Malaise 7 hematological abnormalities resolved by day Hypotension 6 44 after fosfomycin dosing. Respiratory failure 5 Pyrexia 5 Literature Search Palpitations 4 Bone marrow toxicity The search resulted in selection of 20 trials of a Aplastic anemia 5 parenteral fosfomycin and 25 trials of oral Platelet count decreased 4 fosfomycin. Details of the retrieved articles are White blood cell count decreased 4 presented in Tables 2 and 3. Nervous system-related disorders The trials of parenteral fosfomycin reported Headache 5 on 1242 patients enrolled in 8 comparative, 7 Loss of consciousness 5 prospective non-comparative, and 8 Others retrospective non-comparative trials. A total of Maternal drugs affecting fetus 7 2052 patients were enrolled in prospective Hepatitis 5 comparative trials of oral formulations of Renal failure 4 fosfomycin. Our review included 6 trials in Preferred terms included in 146 FAERS reports; a report may 254 pediatric patients (3 trials of parenteral and contain more than one preferred term; PTs are grouped by 3 of oral fosfomycin) and 5 trials in 291 the authors PT preferred terms, MedDRA Medical Dictionary for pregnant patients (all received oral fosfomycin). Regulatory Activities, FAERS Food and Drug The eight comparative trials of parenteral Administration Adverse Event Reporting System a fosfomycin enrolled 664 patients in the Subsequent review of the reports revealed that one case met criteria for aplastic anemia fosfomycin and 626 patients in the Table 2 Adverse events associated with parenteral use of fosfomycin in individual trials

References Trial design FOM Patients’ gender FOM dosing regimen FOM COMP FOM AE COMP AE N and age total N No of events (%) n (%) Indication dose Regimen Andaker et al. [15] Prospective N = 259 F and M; mean age 67 years FOM IV 16 g N = 258 5% (12/259) 4% (11/258) randomized 8g? metronidazole 1 g Prophylaxis of infection after Doxycycline ? Death 2% (5/259) Death 2% (5/259) controlleda once and FOM 8 g 8 h colorectal surgery metronidazole once later Urticaria/purpura Urticaria 1% (2/258) 1% (3/259) Nausea 0.5% (1/258) Nausea 1% (3/ Leucopenia 0.5% 259) (1/258) Thrombophlebitis Vaginitis 0.5% (1/ 0.5% (1/259) 258) Pulmonary edema 0.5% (1/258) Ishizaka et al. [13] Prospective N = 101 F and M [20 years FOM IV 2 g once ? 2g 14 g N = 101 3 (3%) 6 (6%) randomized twice daily 9 3 days Prevention of infection after Cefotiam 9 4 days Eosinophilia—2 Eosinophilia—2 (2%) controlled urological surgery Follow-up 14 days (2%) Elevated LDH—1 Elevated LDH—1 (1%) (1%) Elevated GTP—1 (1%) GI disorders—2 (2%) Nohr et al. [10] Prospective N = 84 F and M 24–90 years FOM IV 8g N = 88 2 (2%) 7 (8%) randomized 8g? metronidazole 1 g Prophylaxis of infection after Bacitracin ? neomycin 9 2 days Rash—1 (1%) Rash—1 (1%) controlled once colorectal surgery ? metronidazole and GI disorders—1 GI disorders—6 (7%) ampicillin once (1%) Chareancholvanich Prospective N = 56 F and M 57–86 years FOM IV 2 g 12 h apart 4g N = 56 0% (0/56) 0% (0/56) [14] randomized Prevention of surgical infection Follow-up 6 months Cefuroxime, 3 g total divided controlled after elective total knee in 3 doses q 8 h arthroplasty netDsTher Dis Infect Table 2 continued Ther Dis Infect

References Trial design FOM Patients’ gender FOM dosing regimen FOM COMP FOM AE COMP AE N and age total N No of events (%) n (%) Indication dose Regimen Sirijatuphat and Prospective N = 47 F and M 31–96 years FOM IV 4 g every 12 h plus colistin at 5 mg 56–168 g N = 47 28-days all cause 28-days all Thamlikitkul randomized of colistin base activity/kg 9 median mortality 46.8% cause Treatment of Colistin at 5 mg of colistin [17] controlled duration 12 days (range 3–14) mortality carbapenem-resistant base activity/kg 9 median AKI- 53.4% 57.4% Acinetobacter baumannii duration 12 days (range Abnormal liver tests infection including 3–56) AKI— 12.8% pneumonia (79%), 59.6% primary bacteremia, UTI, Abnormal cIAI, SSI liver tests 12.8% Lindhagen et al. Prospective N = 30 Prophylaxis of infection FOM 2 g ? metronidazole 0.5 g 32 g N = 28 0% (0/30) 0% (0/28) [16] randomized after elective colorectal Q6 h 9 3 days for the total dose of FOM Cephalotin ? metronidazole 9 controlled surgery of 32 g and metronidazole of 8 g 3 days for the total dose of cephalotin of 32 g and metronidazole of 8 g Nissen et al. [12] Prospective N = 17 F and M C 18 years of age FOM IV 4 g every 8 h ? AMP 1 g q 6 h About N = 15 Peripheral 0 randomized 180 g phlebitis—2 Mean age 57 years Mean treatment duration 5.5 days Gentamicin 80 mg every controlled (12%) 8h? AMP1gq6h Pneumonia requiring ‘‘mild transient’’ mechanical ventilation in AST elevation—1 22 out 32 patients (6%) Pontiki et al. Prospective N = 66 F and M 56.7 ± 17.2 years FOM IV ? colisitin (n = 32), tigecycline About NA Hypokalemia 10 NA [31] non-comparative (age ± SD) (n = 19), gentamicin (n = 15), 336 g (15.2%) meropenem (n = 12), and Infections due to resistant Renal toxicity 3 piperacillin-tazobactam (n = 4) for pathogens including (4.5%) median duration of 14 days (IQR primary bacteremia 8–17 days) at a median dose 24 g/day Thrombocytopenia (n = 18), VAP (n = 14), (IQR 16–24 g/day) 4 (6%) CR-BSI (n = 7), cIAI, UTI, meningitis. Diarrhea 2 (3%) Rash 1 (1.5%) Neutropenia 1 (1.5%) Meissner et al. Prospective N = 60 F and M 17–78 years FOM IV 10 g once, then 5 g 3 times daily 50–420 g NA Peripheral NA [20] non-comparative phlebitis—7 Chronic post-traumatic Mean duration 13.9 days (5–28) (12%) osteomyelitis GI disorders—4 (7%) Exanthema—2 (3%) Table 2 continued

References Trial design FOM Patients’ gender FOM dosing regimen FOM total COMP FOM AE COMP AE N and age dose N No of events (%) n (%) Indication Regimen Stengel et al. [21] Prospective N = 52 F and M C18 years; mean age FOM IV 8-24 g 9 14 days (range 3–40) Varied NA Nausea and rash—4 NA non-comparative 63 years in combination with carbapenems and (8%) other b-lactams, quinolones, DFI with high risk of major clindamycin amputation Rio et al. [32] Prospective N = 16 Rescue therapy for MRSA FOM IV 2 g every 6 h plus imipenem 1 g 48–900 g NA Deaths—5 (31%); 1 NA non-comparative bacteremia or infective every 6 h death due to sodium endocarditis (n = 12) overload, Median duration 28 days (range 4–75) hypernatremia and acute renal failure was considered FOM related Leucopenia—1 Sodium overload—3 Portier et al. [18] Prospective N = 16 8 days–73 years (five children IV 50 mg/kg 3–4 times daily for About NA Neutropenia—3 (19%) NA non-comparative aged 8 days 14 years) 11–21 days in combination with 115–295 g (not specified) cefotaxime 25 mg/kg 3–4 times daily Meningitis (3); bone and joint AST increase—1 (6%) infections (6); persistent (not specified) bacteremia (7) Mirakhur et al. [19] Prospective N = 15 F and M mean age 23 years FOM IV 5 g three times daily Varied NA Nausea—1 (7%) NA non-comparative (18–37) Mean course length Pulmonary exacerbations of 16.6 days (7–36); mean 2 courses per Pseudomonas aeruginosa patient (range 1–3), infection in patient with cystic fibrosis FOM given in combination with 1–2 other intravenous antibacterial drugs Michalopoulos et al. Prospective N = 11 Adults FOM IV 2–4 g every 72–320 g NA 0 (0%) NA [22] non-comparative 6h9 14 ± 5.6 days in combination Carbapenem-resistant Klebsiella with colistin, gentamicin, or pneumoniae infections: VAP, piperacillin/tazobactam BSI, UTI, and wound infection netDsTher Dis Infect Table 2 continued Ther Dis Infect

References Trial design FOM Patients’ gender FOM dosing regimen FOM total COMP FOM AE COMP AE N and age dose N No of events (%) n (%) Indication Regimen Hernandez Retrospective N = 99 M and F 7–74 years (No. of N = 39 Varied NA Rash—1 (1%) NA Casado [26] non-comparative children is not reported) IV 8–16 g 9 4 days, then IM At risk of bone fracture infection 2–8 g 9 2–6 days, then PO or established osteomyelitis 2–4 g 9 2–6 days N = 60 IM or PO, doses are not speciﬁed Florent et al. Retrospective N = 72 M and F 55 ± 19 years FOM IV 12 g a day in 86% of cases with About NA 27 (38%) NA [23] non-comparative a median duration of 11 days; 132 g Infections of bone and joint Hypokalemia—19 co-administered with another (n = 33); CNS (n = 11); ear (26%) antibacterial in all cases and sinus (n = 9); UTI Injection site pain—3 (n = 9); bacteremia (n = 5); (4%) SSTI (n = 4); pneumonia (n = 1) Heart failure—2 (3%) Hypertension—2 (3%) ALT elevated—1 (1.4%) Gallardo et al. Retrospective N = 33 M and F 10–79 years IM/IV 4–6 daily 9 5 days in the cIAI IM/IV Historical control; but Petechial rash—1 Not [28] non-comparative (n = 29) group and IM 3–6 daily no safety data are (3%) reported cIAI (n = 29) 18–30 g (n = 4) in the SSI group reported for the e SSI (n = 4 ) control Ruiz Garcia Retrospective N = 31 Females 16–39 years FOM IM 4 g/day (N = 29) 28–84 g NA 0 NA et al. [30] non-comparative Endometritis FOM IV 8–12 g/day (N = 2) for 7 days Hutzler et al. Retrospective N = 30 M and F 4–77 years IM or PO 20–200 g NA Pain at the injection NA [24] non-comparative site 1 (3%) UTI (n = 13), pneumonia 2–8 g daily (100–230 mg/kg/day) (n = 14), osteomyelitis divided in 4 doses given every Transaminase (n = 2), septicemia (n = 1) 6h9 5–58 days elevation—2 (7%) Eosinophilia—1 (3%) Menendez et al. Retrospective N = 27 M and F 11–80 years Parenterally N = 19 28–168 g NA Rash—1 (4%) NA [27] non-comparative Pneumonia and bronchitis PO N = 8 (calcum salt) Diarrhea—1 (4%) 4–12 g daily for 1–2 weeks; Table 2 continued

References Trial design FOM Patients’ gender FOM dosing regimen FOM COMP FOM AE COMP AE N and age total N No of events (%) n (%) Indication dose Regimen Children Corti Retrospective N = 70 Children \16 years of IV 200 mg/kg daily Varied N = 33 FOM Exanthema— et al. comparative age acute 14 (42%) FOM (23) Mean duration 2.5–3 weeks Flucloxacillin, amoxicillin, Exanthema—0 [11] hematogenous b amoxicillin/clavulanic Diarrhea—7 FOM?(47) osteomyelitis Diarrhea—1 (4%) acid, clindamycin (21%) Leucopenia —0c Leucopenia— FOM? 3 (9%)c Exanthema—10 (21%) Diarrhea—1 (2%) Leucopenia—1 (2%) Baquero Retrospective N = 26 (number F and M Serratia IV 75 mg/kg every 6 h for Varied NA 0—‘‘no signiﬁcant side effects’’ NA et al. non-comparative of treatments in marcescens bacteremia 2–4 weeks, FOM alone [29] 24 patients) (n = 6), in combination with Children; 22 out of 24 gentamicin (n = 18) and were \1 year including carbenicillin (2)f 11 \1 month Llorens Retrospective N = 24 Children of 11 months 200 mg/kg/day given in 4 Varied NA Transient ‘‘slight’’ transaminase NA et al. non-comparative to 12 years injections every 6 h; IV—10, elevation—6 (25%)—resolved [25] IM—14; co-administered with without stopping FOM Pneumonia, empyema, ampicillin in 1 case bronchitis Nicolau syndrome—1 (4%)d Duration 4–23 days

AC amoxicillin clavulanate, AE adverse events, AKI acute kidney injury, ALP alkaline phosphatase, ALT alanine aminotransferase, AMP ampicillin, AST aspartate aminotransferase, BSI bloodstream infection, CA cefuroxime axetil, cIAI complicated intra-abdominal infection, CNS central nervous system, COMP comparator, CR-BSI catheter-related bloodstream infection, CTX cotrimoxazole, DFI diabetic foot infection, F female, FOM fosfomycin, F-up follow-up, GI gastrointestinal, GTP c-guanosine triphosphate, IM intramuscularly, IQR interquartile range, IV intravenously, LDH lactate dehydrogenase, M male, MRSA methicillin-resistant Staphylococcus aureus, NA not applicable, PO orally, SSTI skin and soft tissue infection, TID three times daily, TMP trimethoprim, UTI urinary tract infection, VAP ventilator-associated pneumonia a Including blinded and open label trials b FOM? fosfomycin was combined with flucloxacillin (38), amoxicillin (2), amoxicillin/clavulanic acid (4), clindamycin (2), and with gentamicin (1) c Leucopenia was defined as a leukocyte count \1G/l d Nicolau syndrome—necrosis of the skin and underlying tissues at the site on intramuscular injection e Additional 21 patients received FOM orally f Patients could receive more than one course of treatment netDsTher Dis Infect Table 3 Adverse associated with oral use of fosfomycin in individual trials Ther Dis Infect References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of dose Regimen events (%) therapy Stein et al. Prospective N = 375 Uncomplicated UTI PO 3g N = 374 20 (5.3%) 21 (5.6%) [59] randomized F C12 years 3 g once Nitrofurantoin 9 7 days GI GI disorders 9 controlleda Follow-up 4-6 weeks disorders (2%) b 12 (3%) Vaginitis 6 (1.6%) Vaginitis 7 Dizziness 3 (0.8%) (1.8%) Lista et al. Prospective N = 359 Prophylaxis in PO 6g N = 312 GI GI disorders 9 [57] randomized transrectal prostate 3 g twice 48 h apart Ciprofloxacin 9 5 days disorders (2.9%) controlled biopsy 10 Follow-up 3 months Anaphylaxis 1 (2.8%) (0.3%) Periti et al. Prospective N = 256 Prophylaxis in PO 6g N = 419 12/256 33 (8%) [58] randomized transurethral 3 g twice 27 h apart Amoxicillin n = 207 (5%) Amoxicillin controlled prostatic surgery (before and after 3g9 2 q 24 h GI 17/207 (8%) surgery) disorders CTX GI disorders—15 Follow-up 2 weeks 8 (3%) (7%) n = 212 Allergy 4 Allergy—2 (2%) 1.92 g 9 2 q 24 h (1.5%) CTX 16/212/ (7.5%) all GI disorders Table 3 continued References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of dose Regimen events (%) therapy Naber et al. Prospective N = 250 Uncomplicated PO 3g N = 246 17 (6.8%) 17 (6.9%) [35] randomized UTI 3 g once Ofloxacin GI disorders—16 Ofloxacin 7 controlled F 18–75 years Follow-up 4 weeks n = 119 (6.4%) (5.9%), all GI disorders CTX Rash—1 (0.4%) CTX 10 (7.9%); n = 127 GI disorders—8 (6%) Headache—1 Exanthema—1 Rudenko Prospective N = 166 Prophylaxis of PO 54 g N = 151 2 (1%) 4 (2.6%) and randomized recurrent 3 g every Placebo Dyspnea—1 Rash—1 (0.7%) Dorofeyev controlled uncomplicated 10 days 9 6 months (0.6%) GI disorders—1 [33] UTI Follow-up 360 days Rash—1 (0.6%) (0.7%) F 25–63 years Cough—1 (0.7%) Joint pain— 1(0.7%) Van Prospective N = 113 Uncomplicated PO 3g N = 114 65 (58%) 37 (32%) Pienbroek randomized UTI 3 g once Nitrofurantoin GI disorders—47 GI disorders—24 et al. [47] controlled F [18 years Follow-up 6 weeks 9 7 days (42%) (21%) CNS—8 (7%) CNS—7 (6%) Urogenital—4 Skin—1 (1%) netDsTher Dis Infect (3%) Other—5 (4)% Skin—2 (2%) Other—4 (3%) Table 3 continued Ther Dis Infect References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of dose Regimen events (%) therapy Neu [71] Prospective N = 80 Uncomplicated PO 3g N = 78 GI disorders 9 (11.5%) randomized UTI 3 g once Amoxicillin 3 g once 7 (9%) GI disorders—8 controlled F 18–65 years Follow-up 16–32 days (10%) Rash—1 (1%) Boerema and Prospective N = 79 Uncomplicated PO 3g N = 79 16 (20%) 2 (2.5%) Willems randomized UTI 3 g once Norfloxacin 9 7 days GI GI disorders—2 [37] controlled F 16–50 years of Follow-up 6 weeks disorders— (2.5%) age 14 (18%) Fatigue—1 (1.3%) Dizziness -1 (1.3%) Ceran et al. Prospective N = 77 Uncomplicated PO 3g N = 65 GI GI disorders—2 [53] randomized UTI 3 g once Ciprofloxacin 9 5 days disorders— (3.1%) controlled 3 (3.9%) F 18–65 years Follow-up 60 days Costantini Prospective N = 76 Prophylaxis of PO 36 g N = 71 8 (10%) 5 (7%) et al. [34] randomized recurrent UTI 3 g weekly 9 12 weeks Prulifloxacin one tablet GI GI disorders—2 controlled F58± 16.7 years Follow-up 12 months weekly 9 12 weeks disorders— (3%) (age ± SD) 7 (9%) Vaginitis—3(4%) Vaginitis—1 (1.3%) Table 3 continued References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of dose Regimen events (%) therapy Cooper Prospective N = 72 Dysuria PO 3g N = 69 6 (8%) 7 (10%) et al. [38] randomized M and F 3 g once Amoxicillin GI disorders—5 GI disorders—3 controlled 17–75 years Follow-up 1 month clavulanate 9 5 days (7%) (4%) Rash—1 (1.4%) Vaginitis—3 (4%) Rash—1 (1.5%) Elhanan Prospective N = 58 Uncomplicated PO 3g N = 54 0 (0%) 3 (5.5%) et al. [48] randomized UTI 3 g once Cephalexin 9 5 days Vaginitis—3 controlled F [16 years Follow-up 1 month Selvaggi Prospective N = 45 Uncomplicated PO 3g N = 44 0 (%) 0 (%) [39] randomized UTI 3 g once Norfloxacin once controlled F 16–70 years Follow-up 3 weeks Crocchiolo Prospective N = 38 Uncomplicated PO 3g N = 35 GI disorders—3 2 (6%) [40] randomized UTI 3 g once CTX 9 3 days (8%) Rash—1 controlled F 16-70 years Follow-up 30 days Asthenia—1 De Jong Prospective N = 33 Uncomplicated PO 3g N = 30 9 (27%) 8 (27%) et al. [46] randomized UTI 3 g once Norfloxacin 9 5 days GI disorders—8 GI disorders 5 controlled F [16 years Follow-up 30 days (24%) (17%) Dizziness—1 (3%) Dizziness—1 (3%) Headache—1(3%)

Hepatic function Ther Dis Infect abnormal— 1(3%) Table 3 continued Ther Dis Infect References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of therapy dose Regimen events (%) Baert et al. Prospective N = 31 Prevention of PO 6g N = 30 0 (%) 0 (%) [41] randomized infection after 3 g daily before and after Placebo controlled prostate resection procedure for a total of 2 Males 48–83 years doses Follow-up 1 month Ferraro Prospective N = 30 Uncomplicated UTI PO 3g N = 30 GI GI disorders—2 et al. randomized F and M [50 years 3 g once Norfloxacin 400 mg disorders— (7%) [43] controlled 1 (3%) Follow-up 35 days BID 9 7 days Caramalli Prospective N = 20 Complicated and PO N = 76 0 (%) 0 (%) et al. randomized uncomplicated 3 g once Netilmicin 5 mg/kg [45] controlled UTI Follow-up up to IM once (n = 53) M and F [60 years 18 months Amikacin 15 mg/kg IM once (n = 23) Reynaert Prospective N = 16 Uncomplicated UTI PO 3g N = 16 GI GI disorders—1 et al. randomized F 16–75 years 3 g once Norfloxacin 9 3 days disorders— (6%) [42] controlled 1 (6%) Follow-up 5 weeks Table 3 continued References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of dose Regimen events (%) therapy Jardin [55] Prospective N = 144 Uncomplicated PO 3g N = 144 37 (27%) 27 (19%) comparative UTI 3 g once Pipemidic acid Diarrhea—11 (8%) Nausea—16 F 16–75 years Follow-up 28 days Other AE described (11%) as medium and Other AE slight and were described as not specified medium and slight and were not specified Children Principi Prospective N = 71 UTI PO 2g N = 64 4 (6%) 0(%) et al. randomized F and M 2 g once (1 g in children Netilmicin GI disorders—3 [44] controlled 1 month–16 years \1 year) 5 mg/kg IM once (4%) Follow-up 30 days Rash—1 (1.5%) Varese Prospective N = 39 Uncomplicated PO 2 g once 2g N = 35 0 (0%) 0 (0%) [50] randomized UTI Follow-up 30 days Netilmicin 5 mg/kg controlled F and M IM once 6 months–14 years Careddu Prospective N = 24 Recurrent UTI PO 2 g once 2g N = 27 0 (0%) 0 (0%) et al. randomized M(n = 2) and F Follow-up for 1 month Pipemidic acid 400 [49] controlled (n = 22) or 800 mg (for 1–14 years children[25 kg) daily 9 7 days Ther Dis Infect Table 3 continued Ther Dis Infect References Trial type FOM Indication FOM dosing regimen FOM COMP FOM AE COMP AE n (%) N Study population Duration of follow-up total N No of after the start of dose Regimen events (%) therapy Pregnancy Zinner Prospective N = 153 Bacteriuria in PO 3g N = 138 14 (9%) 20 (15%) [36] randomized pregnancy 3 g once Pipemidic Mainly GI Mainly GI controlled F28± 5 years Follow-up 30 days acid 9 7 days disorders disorders No fetal AEs Estebanez Prospective N = 53 Asymptomatic PO 3g N = 56 GI GI disorders—11 et al. [52] randomized bacteriuria in 3 g once AC disorders— (20%) controlled pregnancy 1 (2%) Follow-up 10–14 days, 500/125 mg 9 7 days then until the end of pregnancy Bayrak Prospective N = 44 Asymptomatic PO 3g N = 40 Rash—1 Vaginal et al. [51] randomized bacteriuria in the 3 g once Cefuroxime axetyl (2%) candidiasis—2 controlled second trimester of (5%) Follow-up 1 week 250 mg PO twice pregnancy daily 9 5 days Usta et al. Prospective N = 28 Uncomplicated UTI PO 3g N = 56 7 (25%) 20 (36%) [54] randomized Pregnant F with a 3 g once AC = 27 GI GI disorders—14 controlled mean age of 26 years Follow-up 2 weeks CA = 29 disorders— (25%) 6 (24%) Both drugs 9 5 days Vaginitis—6 Vaginitis—1 (11%) (4%) Infect Dis Ther

comparator arms [10–17]. Seven trials were GI SD (%) CTX

n randomized controlled trials [10, 12–17] and

orally, one was a retrospective study [11]. Fosfomycin follow-up,

PO was used for the treatment of pneumonia

(20%) including ventilator-associated pneumonia [12, COMP AE F-up ventilator-associated 17], primary bacteremia [17], complicated Cefuroxime axetil,

VAP intra-abdominal infection, UTI [17], skin and CA

not applicable, soft tissue infections [17], acute hematogenous

fosfomycin, osteomyelitis in children [11], prevention of NA No of events (%) FOM AE 0 (0%) GI disorders—2 infection after urological surgery [13], FOM

male, prophylaxis of surgical site infection after M

7 days elective total knee arthroplasty [14] and female, 9

F colorectal surgery [10, 15, 16]. Fosfomycin was urinary tract infection, bloodstream infection, administered up to 3 weeks at a dose up to 12 g BSI UTI but the majority of patients in these trials (530/ 10

= 664) received fosfomycin for 1–3 days as comparator, COMP N Regimen Nitrofurantoin N prophylaxis for surgical site infections. lactate dehydrogenase, Parenteral fosfomycin was given in COMP trimethoprim, FOM total dose 3g combination with other antibacterial drugs in LDH 6 comparative trials [10–12, 15–17]; TMP antibacterial drugs that were used in alanine aminotransferase, combination with fosfomycin and those that ALT intravenously, were used as comparators are presented in

IV Table 2. The cumulative rate of AEs was similar

central nervous system, in fosfomycin and comparator arms. The most three times daily, FOM dosing regimen Duration of follow-up after the start of therapy PO 3 g once Follow-up until birth common AEs observed in these trials are CNS TID presented in Table 4. AEs observed in 15 non-comparative trials of intramuscularly, alkaline phosphatase, parenteral fosfomycin [18–32] are presented in IM

ALP Table 5. These trials enrolled 578 patients,

bacteriuria in pregnancy mainly adults. in combination with other Study population Indication antibacterial drugs in 9 trials (Table 5). 13 Asymptomatic Fosfomycin was used at a daily dose of up to = adverse events, N N 24 g for the treatment of various infections

AE including bloodstream, central nervous system surgical site soft tissue infection,

- guanosine triphosphate, infections and ventilator-associated c complicated intra-abdominal infection, SSI pneumonia. The duration of treatment ranged randomized controlled GTP

cIAI from 4 days to 2 months. Prospective

] AEs associated with oral administration of continued 56 fosfomycin are presented in Table 6. The

amoxicillin clavulanate, majority of these trials studied a single dose of The most common AE reported et al. [ Including blinded and open label trials Thoumsin Table 3 a b References Trial type FOM AC pneumonia cotrimoxazole, gastrointestinal, standard deviation, fosfomycin for the treatment of uncomplicated Infect Dis Ther

Table 4 Adverse events associated with parenteral Table 6 Adverse events associated with oral fosfomycin in 8 comparative trials [10–17] administration of fosfomycin in 28 prospective comparative trials [33–59, 71] Adverse event Fosfomycin Comparators N 5 664 N 5 626 Fosfomycin Comparator n (%) n (%) N 5 2743 N 5 2863 n (%) n (%) Death 32 (5%) 34 (5%) Adverse events 219 (8%) 229 (8%) Acute kidney injury 25 (4%) 28 (4%) GI disorders (nausea, 179 (6.5%) 177 (6%) Skin reactions 14 (2%) 17 (3%) vomiting, diarrhea, GI disorders 6 (1%) 16 (3%) abdominal pain) Phlebitis 3 (\1%) 0 Vaginitis 13 (0.5%) 23 (1%) Eosinophilia 2 (\1%) 2 (\1%) Central nervous system 10 (\0.5%) 13 (\0.5%) Abnormal liver tests 6 (1%) 6 (1%) (headache, dizziness) Leucopeniaa 1(\1%) 4 (\1%) Rash 11 (\0.5%) 9 a Leucopenia was deﬁned as a leukocyte count \1G/l on Other (asthenia, dyspnea, 6(\0.5%) 8 (\1%) one trial [11] and not deﬁned in another [15] cough, joint pain) Hepatic function abnormal 0 1 (\1%)

Table 5 Adverse events associated with parenteral UTIs. In two trials of prophylaxis of recurrent administration of fosfomycin in 15 non-comparative UTI, fosfomycin was administered for trials [18–32] 3–6 months [33, 34]. The most frequently Adverse event Fosfomycin reported adverse reactions (8%) were N 5 578 gastrointestinal disorders. More details are n (%) provided in Table 6. Hypokalemia 28 (5%) One placebo-controlled trial for prophylaxis Transaminase elevation 10 (2%) of recurrent uncomplicated UTI evaluated safety of a prolonged exposure to oral GI disorders 12 (2%) fosfomycin [33]. The trial compared 166 Rash 11(2%) females treated with 3 g of oral fosfomycin Peripheral phlebitis 7 (1%) every 10 days for 6 months with 155 subjects Deaths 5 (1%) treated with placebo. After a follow-up of Sodium overload and heart failure 5 (1%) 360 days including 6 interim evaluations there were 2 (1%) AEs (rash and mild dyspnea) in the Neutropenia (not defined) 5 (1%) treatment arm as compared with 4 events in the Injection site pain 4 (1%) placebo arm. Hematology and chemistry Thrombocytopenia 4 (1%) laboratory parameters at the end of the study Renal toxicity 3 (\1%) did not show any significant difference between Heart failure 2 (\1%) the two arms. Trials conducted in pediatric population Hypertension 2 (\1%) included 3 retrospective trials of parenteral Infect Dis Ther fosfomycin (n = 118) [11, 25, 29] and 3 The report notes that side effects were prospective randomized trials of oral observed in 17% of patients and included fosfomycin (n = 134) [44, 49, 50]. In trials of aspartate aminotransferase and parenteral fosfomycin, the drug was given up to glutamic-pyruvate transaminase elevations 4 weeks for the treatment of acute (although infrequent), pain at the injection hematogenous osteomyelitis, bacteremia, and site, gastrointestinal disorders, palpitations, lung infection. Oral fosfomycin was and rash. administered as a single time dose for the Mayama et al. analyzed postmarketing treatment of UTI. There were also several experience with oral fosfomycin in Japan by studies of parenteral [18, 24, 26–28] and oral reviewing clinical records of 35,481 patients who [28, 59, 60] fosfomycin that included children were prescribed fosfomycin calcium capsules in that did not present safety data in children 1981–1986 [63]. The overall incidence of side separately. Four pediatric trials were effects was 3.5%. The incidence of side effects was comparative [11, 44, 49, 50]. Overall, no higher at a daily dose [3 g and was not specific safety issues related to the use of dependent on the duration of administration. fosfomycin in children were identified. The most common side effects were related to Five trials of a total of 291 patients reported gastrointestinal disorders (2.7%), hepatobiliary on the use of fosfomycin in pregnancy for the disorders (0.2%), and skin disorders (0.2%). treatment of asymptomatic bacteriuria [36, 51, There was one case of thrombocytopenia and 52, 54, 56]. One of these trials in 153 patients one case of anemia. specifically indicated that no serious fetal AEs There have been a few reports of liver were observed [36]. toxicity associated with fosfomycin [64, 65]. Our review of the literature also identified An acute painful hepatomegaly, transaminase several reviews reporting on the efficacy and elevation and a hyperechogenic liver on safety of fosfomycin. A meta-analysis of 27 ultrasound were reported in a 30-year-old randomized controlled trials compared female with cystic fibrosis and normal baseline fosfomycin (n = 2188) with other antibacterial liver function tests and liver ultrasound [64]. drugs (n = 2052) for the treatment of cystitis The liver abnormalities reoccurred three times [61]. The authors reported that fosfomycin had during repeated courses of IV fosfomycin for a comparable safety profile with the evaluated Pseudomonas aeruginosa bronchitis. Laboratory comparators in non-pregnant women, mixed and ultrasound abnormalities resolved every and pediatric populations, and was associated time after discontinuation of fosfomycin. with fewer AEs in pregnant women [61]. Another report of fosfomycin-induced liver Information on the efficacy and safety of injury described a 50-year-old male with no fosfomycin was provided by the Japan Research underlying liver diseases who developed mixed Committee of Fosfomycin in a report evaluating hepatocellular and cholestatic liver injury 1191 and 503 patients who received oral and IV 3 days after being started on fosfomycin (route fosfomycin, respectively [62]. For the oral is not reported) [65]. His alanine formulation, AEs were observed in 122 of 1191 aminotransferase peaked at 12.8 times the cases (10%) and included mainly upper limit of normal and total bilirubin gastrointestinal disturbances. increased to 42 lmol/L (normal range Infect Dis Ther

\26 lmol/L). Liver function tests normalized associated with either oral or parenteral 1 week after the withdrawal of the drug. administration of fosfomycin were found by There have been four case reports of literature search. Considering more than anaphylaxis associated with fosfomycin 40-year experience with the drug, administration [66–68]. All reported cases were fosfomycin-associated aplastic anemia seems associated with oral formulations of fosfomycin to be a rare event. and occurred within minutes to an hour after With regard to liver toxicities, we did not see fosfomycin intake. an imbalance between fosfomycin- and comparator-treated patients in the DISCUSSION comparative trials. However, several cases of liver toxicities associated with fosfomycin have Fosfomycin has been in clinical use for about been reported and monitoring of liver functions 25 years and its safety profile has been in patients receiving parenteral fosfomycin previously described [6, 61, 69]. Our review when the drug is administered for several days did not identify new safety concerns related to may be warranted. fosfomycin. The most frequent AEs associated The rates of hypersensitivity reactions were with parenteral administration of fosfomycin also comparable in fosfomycin- and included rash, peripheral phlebitis, comparator-treated patients in comparative hypokalemia, and gastrointestinal disorders. trials and also four cases of anaphylactic Gastrointestinal disorders were the most reactions associated with fosfomycin have common AEs associated with oral been reported. Of note, the package insert for administration. oral fosfomycin lists the AEs of aplastic anemia, While the initial results of data mining for all angioedema, cholestatic jaundice, and hepatic reports of AEs associated with fosfomycin in the necrosis in the Adverse Reactions/ FAERS database revealed a higher than expected Postmarketing Experience section [1]. frequency of reports of agranulocytosis, liver Important safety consideration for parenteral injury, severe skin reactions, and fosfomycin is its high sodium content which pseudomembranous colitis, subsequent may result in sodium overload and heart failure searches for adverse reactions implicating [23, 70]. Thus, each gram of fosfomycin fosfomycin as the primary suspect as well as contains 14.35 mEq (330 mg) of sodium. the literature review did not suggest an Considering that an average dose of association of the drug with these AEs. Serious fosfomycin is about 12 g, the sodium load AEs of cytopenias, liver toxicities, and associated with its use may be significant, hypersensitivity reactions were not more especially for patients with underlying heart frequent in fosfomycin-treated patients in failure. In comparison, piperacillin and comparative trials and were not common in tazobactam, the antibacterial drug that is non-comparative trials. considered to have high sodium content A separate search and detailed analysis of all contains 2.36 mEq (54.28 mg) of sodium per FAERS reports of cytopenia identified one case gram of piperacillin. A pooled analysis of that met pre-defined criteria of aplastic anemia comparative trials in our review did not that was associated with the use of oral demonstrate a higher rate of heart failure in fosfomycin. No cases of aplastic anemia fosfomycin-treated patients. However, a Infect Dis Ther publication that specifically addressed AEs Limitations of the literature review are associated with IV fosfomycin reported that related to a small number of randomized 6% of patients experienced cardiovascular AEs comparative prospective trials for parenteral related due to sodium overload [23]. fosfomycin and that in 5 out of 7 of these Hypokalemia was the most common AE in trials the drug was given for up to 3 days for this study (26%). Another publication reports prophylaxis of surgical site infection [10, on the case of fosfomycin-associated heart 13–16]. Only 64 patients were treated with failure that promptly resolved after the fosfomycin in randomized prospective discontinuation of the drug [70]. comparative trials [12, 17]. Another Although, fosfomycin was suspected to be comparative trial was retrospective and the cause of fetal toxicities in 7 cases in the enrolled 70 patients in the fosfomycin arm [11]. FAERS database, the data mining search demonstrated EB05 scores of 1–2 for these CONCLUSION types of AEs, indicating an overall expected frequency of reporting of this adverse reaction. In conclusion, no new safety concerns related to Our review of the literature also did not identify fosfomycin have been identified by this review. cases of fetal toxicities. Of note, oral fosfomycin In comparative trials serious AEs such as is labeled as pregnancy category B. cytopenia, anaphylaxis, and liver toxicities Our analyses have several limitations. FAERS were not more common in fosfomycin-treated contains spontaneously submitted data on AEs patients as compared with those treated with by the public and reporting biases such as comparator. The most frequently reported AEs under- and over-reporting of drug events can associated with parenteral administration of occur. Because of the spontaneous nature of fosfomycin were rash, peripheral phlebitis, reporting, the results of this analysis should not hypokalemia, and gastrointestinal disorders. be interpreted as a formal comparison of High sodium content of parenteral fosfomycin treatment groups or of their relative risks and should be taken into consideration in treating does not allow one to determine adverse event patients with underlying heart disease. An incidence rates. important limitation of the available safety The effects of concomitant illnesses or data regarding the parenteral formulation of therapy cannot be fully controlled in this fosfomycin is that only in a very small number data mining analysis. Other factors such as of randomized comparative trials was parenteral the length of time of marketing, drug usage, fosfomycin administered for a duration that and changes in coding practices over time would be expected in the treatment of the should also be considered when interpreting majority of infections. Oral formulations of these data mining results. Given the fosfomycin were mostly associated with limitations inherent in the FAERS data, the gastrointestinal disturbances. high scores do not prove causality or an increased relative risk of the drug–AE in all patients exposed to fosfomycin. Another ACKNOWLEDGMENTS limitation of the FAERS search is that only 5 reports with parenteral administration of No funding or sponsorship was received for this fosfomycin were retrieved. study or publication of this article. All named Infect Dis Ther

authors meet the International Committee of susceptibility of Gram-negative nonurinary Medical Journal Editors (ICMJE) criteria for bacteria to fosfomycin and other antimicrobials. Future Microbiol. 2010;5(6):961–70. authorship for this manuscript, take responsibility for the integrity of the work as a 5. Perdigaõ-Neto LV, Oliveira MS, Rizek CF, Carrilho CM, Costa SF, Levin AS. Susceptibility of whole, and have given final approval for the multiresistant gram-negative bacteria to version to be published. fosfomycin and performance of different susceptibility testing methods. Antimicrob Agents Chemother. 2014;58(3):1763–7 Disclosures. D Iarikov, R. Wassel, J. Farley 6. Falagas ME, Giannopoulou KP, Kokolakis GN, and S. Nambiar have no disclosures to declare. Rafailidis PI. Fosfomycin: use beyond urinary tract and gastrointestinal infections. Clin Infect Dis. 2008;46(7):1069–77. Compliance with ethics guidelines. This article is based on previously conducted 7. Szarfman A, Machado SG, O’Neill RT. Use of screening algorithms and computer systems to studies and does not involve any new studies efficiently signal higher-than-expected of human or animal subjects performed by any combinations of drugs and events in the US FDA’s spontaneous reports database. Drug Saf. of the authors. No identifiable patient data were 2002;25(6):381–92. provided or accessed. 8. Medical Dictionary for Regulatory Activities Maintenance and Support Services Organization Open Access. This article is distributed [online]. http://www.meddramsso.com/. Accessed under the terms of the Creative Commons March 7, 2011.

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