Table 2.

Adverse events associated with parenteral use of fosfomycin in individual trials

References	Trial design	FOM N	Patients’ gender and age Indication	FOM dosing regimen	FOM total dose	COMP N Regimen	FOM AE No of events (%)	COMP AE n (%)
Andaker et al. [15]	Prospective randomized controlleda	N = 259	F and M; mean age 67 years Prophylaxis of infection after colorectal surgery	FOM IV 8 g + metronidazole 1 g once and FOM 8 g 8 h later	16 g	N = 258 Doxycycline + metronidazole once	5% (12/259) Death 2% (5/259) Urticaria/purpura 1% (3/259) Nausea 1% (3/259) Thrombophlebitis 0.5% (1/259)	4% (11/258) Death 2% (5/259) Urticaria 1% (2/258) Nausea 0.5% (1/258) Leucopenia 0.5% (1/258) Vaginitis 0.5% (1/258) Pulmonary edema 0.5% (1/258)
Ishizaka et al. [13]	Prospective randomized controlled	N = 101	F and M >20 years Prevention of infection after urological surgery	FOM IV 2 g once + 2 g twice daily × 3 days Follow-up 14 days	14 g	N = 101 Cefotiam × 4 days	3 (3%) Eosinophilia—2 (2%) Elevated LDH—1 (1%)	6 (6%) Eosinophilia—2 (2%) Elevated LDH—1 (1%) Elevated GTP—1 (1%) GI disorders—2 (2%)
Nohr et al. [10]	Prospective randomized controlled	N = 84	F and M 24–90 years Prophylaxis of infection after colorectal surgery	FOM IV 8 g + metronidazole 1 g once	8 g	N = 88 Bacitracin + neomycin × 2 days + metronidazole and ampicillin once	2 (2%) Rash—1 (1%) GI disorders—1 (1%)	7 (8%) Rash—1 (1%) GI disorders—6 (7%)
Chareancholvanich [14]	Prospective randomized controlled	N = 56	F and M 57–86 years Prevention of surgical infection after elective total knee arthroplasty	FOM IV 2 g 12 h apart Follow-up 6 months	4 g	N = 56 Cefuroxime, 3 g total divided in 3 doses q 8 h	0% (0/56)	0% (0/56)
Sirijatuphat and Thamlikitkul [17]	Prospective randomized controlled	N = 47	F and M 31–96 years Treatment of carbapenem-resistant Acinetobacter baumannii infection including pneumonia (79%), primary bacteremia, UTI, cIAI, SSI	FOM IV 4 g every 12 h plus colistin at 5 mg of colistin base activity/kg × median duration 12 days (range 3–14)	56–168 g	N = 47 Colistin at 5 mg of colistin base activity/kg × median duration 12 days (range 3–56)	28-days all cause mortality 46.8% AKI- 53.4% Abnormal liver tests 12.8%	28-days all cause mortality 57.4% AKI—59.6% Abnormal liver tests 12.8%
Lindhagen et al. [16]	Prospective randomized controlled	N = 30	Prophylaxis of infection after elective colorectal surgery	FOM 2 g + metronidazole 0.5 g Q6 h × 3 days for the total dose of FOM of 32 g and metronidazole of 8 g	32 g	N = 28 Cephalotin + metronidazole × 3 days for the total dose of cephalotin of 32 g and metronidazole of 8 g	0% (0/30)	0% (0/28)
Nissen et al. [12]	Prospective randomized controlled	N = 17	F and M ≥ 18 years of age Mean age 57 years Pneumonia requiring mechanical ventilation in 22 out 32 patients	FOM IV 4 g every 8 h + AMP 1 g q 6 h Mean treatment duration 5.5 days	About 180 g	N = 15 Gentamicin 80 mg every 8 h + AMP 1 g q 6 h	Peripheral phlebitis—2 (12%) “mild transient” AST elevation—1 (6%)	0
Pontiki et al. [31]	Prospective non-comparative	N = 66	F and M 56.7 ± 17.2 years (age ± SD) Infections due to resistant pathogens including primary bacteremia (n = 18), VAP (n = 14), CR-BSI (n = 7), cIAI, UTI, meningitis.	FOM IV + colisitin (n = 32), tigecycline (n = 19), gentamicin (n = 15), meropenem (n = 12), and piperacillin-tazobactam (n = 4) for median duration of 14 days (IQR 8–17 days) at a median dose 24 g/day (IQR 16–24 g/day)	About 336 g	NA	Hypokalemia 10 (15.2%) Renal toxicity 3 (4.5%) Thrombocytopenia 4 (6%) Diarrhea 2 (3%) Rash 1 (1.5%) Neutropenia 1 (1.5%)	NA
Meissner et al. [20]	Prospective non-comparative	N = 60	F and M 17–78 years Chronic post-traumatic osteomyelitis	FOM IV 10 g once, then 5 g 3 times daily Mean duration 13.9 days (5–28)	50–420 g	NA	Peripheral phlebitis—7 (12%) GI disorders—4 (7%) Exanthema—2 (3%)	NA
Stengel et al. [21]	Prospective non-comparative	N = 52	F and M ≥18 years; mean age 63 years DFI with high risk of major amputation	FOM IV 8-24 g × 14 days (range 3–40) in combination with carbapenems and other β-lactams, quinolones, clindamycin	Varied	NA	Nausea and rash—4 (8%)	NA
Rio et al. [32]	Prospective non-comparative	N = 16	Rescue therapy for MRSA bacteremia or infective endocarditis (n = 12)	FOM IV 2 g every 6 h plus imipenem 1 g every 6 h Median duration 28 days (range 4–75)	48–900 g	NA	Deaths—5 (31%); 1 death due to sodium overload, hypernatremia and acute renal failure was considered FOM related Leucopenia—1 Sodium overload—3	NA
Portier et al. [18]	Prospective non-comparative	N = 16	8 days–73 years (five children aged 8 days 14 years) Meningitis (3); bone and joint infections (6); persistent bacteremia (7)	IV 50 mg/kg 3–4 times daily for 11–21 days in combination with cefotaxime 25 mg/kg 3–4 times daily	About 115–295 g	NA	Neutropenia—3 (19%) (not specified) AST increase—1 (6%) (not specified)	NA
Mirakhur et al. [19]	Prospective non-comparative	N = 15	F and M mean age 23 years (18–37) Pulmonary exacerbations of Pseudomonas aeruginosa infection in patient with cystic fibrosis	FOM IV 5 g three times daily Mean course length 16.6 days (7–36); mean 2 courses per patient (range 1–3), FOM given in combination with 1–2 other intravenous antibacterial drugs	Varied	NA	Nausea—1 (7%)	NA
Michalopoulos et al. [22]	Prospective non-comparative	N = 11	Adults Carbapenem-resistant Klebsiella pneumoniae infections: VAP, BSI, UTI, and wound infection	FOM IV 2–4 g every 6 h × 14 ± 5.6 days in combination with colistin, gentamicin, or piperacillin/tazobactam	72–320 g	NA	0 (0%)	NA
Hernandez Casado [26]	Retrospective non-comparative	N = 99	M and F 7–74 years (No. of children is not reported) At risk of bone fracture infection or established osteomyelitis	N = 39 IV 8–16 g × 4 days, then IM 2–8 g × 2–6 days, then PO 2–4 g × 2–6 days N = 60 IM or PO, doses are not specified	Varied	NA	Rash—1 (1%)	NA
Florent et al. [23]	Retrospective non-comparative	N = 72	M and F 55 ± 19 years Infections of bone and joint (n = 33); CNS (n = 11); ear and sinus (n = 9); UTI (n = 9); bacteremia (n = 5); SSTI (n = 4); pneumonia (n = 1)	FOM IV 12 g a day in 86% of cases with a median duration of 11 days; co-administered with another antibacterial in all cases	About 132 g	NA	27 (38%) Hypokalemia—19 (26%) Injection site pain—3 (4%) Heart failure—2 (3%) Hypertension—2 (3%) ALT elevated—1 (1.4%)	NA
Gallardo et al. [28]	Retrospective non-comparative	N = 33	M and F 10–79 years cIAI (n = 29) SSI (n = 4e)	IM/IV 4–6 daily × 5 days in the cIAI (n = 29) group and IM 3–6 daily (n = 4) in the SSI group	IM/IV 18–30 g	Historical control; but no safety data are reported for the control	Petechial rash—1 (3%)	Not reported
Ruiz Garcia et al. [30]	Retrospective non-comparative	N = 31	Females 16–39 years Endometritis	FOM IM 4 g/day (N = 29) FOM IV 8–12 g/day (N = 2) for 7 days	28–84 g	NA	0	NA
Hutzler et al. [24]	Retrospective non-comparative	N = 30	M and F 4–77 years UTI (n = 13), pneumonia (n = 14), osteomyelitis (n = 2), septicemia (n = 1)	IM or PO 2–8 g daily (100–230 mg/kg/day) divided in 4 doses given every 6 h × 5–58 days	20–200 g	NA	Pain at the injection site 1 (3%) Transaminase elevation—2 (7%) Eosinophilia—1 (3%)	NA
Menendez et al. [27]	Retrospective non-comparative	N = 27	M and F 11–80 years Pneumonia and bronchitis	Parenterally N = 19 PO N = 8 (calcum salt) 4–12 g daily for 1–2 weeks;	28–168 g	NA	Rash—1 (4%) Diarrhea—1 (4%)	NA
Children
Corti et al. [11]	Retrospective comparative	N = 70 FOM (23) FOM+(47)b	Children <16 years of age acute hematogenous osteomyelitis	IV 200 mg/kg daily Mean duration 2.5–3 weeks	Varied	N = 33 Flucloxacillin, amoxicillin, amoxicillin/clavulanic acid, clindamycin	FOM Exanthema—0 Diarrhea—1 (4%) Leucopenia —0c FOM+ Exanthema—10 (21%) Diarrhea—1 (2%) Leucopenia—1 (2%)	Exanthema—14 (42%) Diarrhea—7 (21%) Leucopenia—3 (9%)c
Baquero et al. [29]	Retrospective non-comparative	N = 26 (number of treatments in 24 patients)	F and M Serratia marcescens bacteremia Children; 22 out of 24 were <1 year including 11 <1 month	IV 75 mg/kg every 6 h for 2–4 weeks, FOM alone (n = 6), in combination with gentamicin (n = 18) and carbenicillin (2)f	Varied	NA	0—“no significant side effects”	NA
Llorens et al. [25]	Retrospective non-comparative	N = 24	Children of 11 months to 12 years Pneumonia, empyema, bronchitis	200 mg/kg/day given in 4 injections every 6 h; IV—10, IM—14; co-administered with ampicillin in 1 case Duration 4–23 days	Varied	NA	Transient “slight” transaminase elevation—6 (25%)—resolved without stopping FOM Nicolau syndrome—1 (4%)d	NA

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 γ-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

^aIncluding blinded and open label trials

^bFOM+ fosfomycin was combined with flucloxacillin (38), amoxicillin (2), amoxicillin/clavulanic acid (4), clindamycin (2), and with gentamicin (1)

^cLeucopenia was defined as a leukocyte count <1G/l

^dNicolau syndrome—necrosis of the skin and underlying tissues at the site on intramuscular injection

^eAdditional 21 patients received FOM orally

^fPatients could receive more than one course of treatment