Intravenous fosfomycin for the treatment of patients with bone and joint infections: a review

Figures & data

Table 1. Published evidence on the use of intravenous fosfomycin for the treatment of patients with bone and joint infections

Author, country, year [ref]	Type of study	No. of patients (n) that received intravenous fosfomycin	Age	Pediatric/Adult	Indication (s)	Isolated pathogens (numbe of patients)	Fosfomycin as first-/second-line line treatment	Antibiotics given with fosfomycin (number of patients)	Fosfomycin daily dose	Fosfomycin dosage regimen	Duration of fosfomycin treatment	Clincal outcome	Adverse events (number of patients)
Badelon et al, France, 1988 [39]	prospective	14	12 days – 13 years (mean: 3.3 y)	pediatric	osteomyelitis arthritis	S. aureus and H. influenzae (42% of cases)	first-line	cefotaxime	100 mg/kg	100 mg/kg in three doses	15 days	14/14 cured	NA
Corti et al, Switzerland, 2003 [26]	case-control	60	Group 1: fosfomycin alone: mean 7 y (0.08–15 y) Group 2: fosfomycin in combination: mean 6 years (0.08–15.5 y)	pediatric	acute hematogenous osteomyelitis, without primary surgery	Group 1: S. aureus (4), CoNegative Staph.(3) Group 2: S. aureus (11), CoNegative Staph. (3), S. pyogenes (2), S. pneumonia (1)	first-line	Group 1: 23 patients received fosfomycin alone Group 2: 47 patients received fosfomycin with other antimicrobials (flucloxacillin (38) amoxicillin (2), amoxicillin/clavulanic acid (4), clindamycin (2), gentamycin (1))	200 mg/kg	NA	Group 1: 2.5 weeks Group 2: 3.1 weeks	60/60 cured	Group 1: diarrhea (1) Group 2: fosfomycin with flucloxacillin 10 exanthema (10), diarrhea (1), leukopenia (1)
Dinh A et al, France, 2012 [5]	prospective	32	NA	NA	bone and joint infections	MRCNS (10) KES (7) E. coli (6) P. aeruginosa(5) MRSA (4) Streptococcus spp.(3) MSSA (3) A. viridans (1) Proteus (1) Citrobacter (1) Enterococcus (1), polymicrobial infection (6)	first-line	glycopeptide (10) third generation cephalosporin (9) carbapenem (8) fluoroquinolone (4) methicillin (2) rifampicin (3) metronidazole, cefepime, colistin (1)	12–16 gr	4 gr x 3–4 times/day	49.3 + 40 days mean 54 days	19/32: favorable outcome, 4/32 unfavorable, 1/32: early death, 8/32: lost on follow-up	NA
Fitoussi, F et al, France, 2007 [27]	retrospective	18	9 month – 14 years (mean 6.5 y)	pediatric	hematogenous wrist osteomyelitis	MSSA (7), MRSA (1)	first-line	cefotaxime (7 days) IV, followed by oral antibiotics (18)	NA	NA	7 days IV and 6 weeks in total	15/18 cured 3/18 radiologic abnormalities of the wrist	NA
Gouyon JB et al, France, 1985 [28]	case series	2	newborns	pediatric	osteomyelitis	Staphylococcus spp. (2)		cefotaxime (2)	50 mg/kg	NA	mean 12.7 days, (9–14 days)	2/2 cured	hypernatremia (2)
Guggenbichler JP et al, Germany-Austria, 1989 [29]	case series	36	children	pediatric	acute hematogenous osteomyelitis	S. aureus (16) H. influenzae (2) Salmonella (1) Enterobacter (1) S. pneumomiae (1) unknown (15)		cefamandole IV (36) for 10–14 days, (followed by oral clindamycin for 3–6 weeks)	250 mg/kg	250 mg/kg in three doses	10–14 days	34/36 cured	neutropenia (1)
Hernandesz-Casado V, Spain, 1977 [30]	case series	2	adults	adults	osteomyelitis	S. aureus (2)	first-line	none	12 g/day IV 4 g/day IM 4 g/day PER OS	NA	1 pt (3 days IV, 6 days IM and 14 days per os) 2nd pt (2 days IV, 10 days IM and 20 days per os)	2/2 cured	NA
Meissner A et al, Germany, 1989 [32]	prospective	60	17–76 years (mean 37.4 y)	adults	chronic posttraumatic osteomyelitis	S. aureus (34) CoNegative Staph. (15) S. agalacticae (4) E. faecalis (4) P. aeruginosa (10) P. vulgaris (2) P. maltophila (2) and others (1 each)	second-line	NA	10 g loading dose (5 g in 5 cases) before surgery and then 15 g/day	10 g loading dose (5 g in 5 cases) before surgery and then 3 × 5 g/day	5–28 days (mean 13.9 days)	29/60 very good 2/60 good 8/60 satisfactory 14/60 relapse of osteomyelitis 7/60 lost to follow-up	allergic exanthema (2) mild gastrointenstinal disorders (4) phlebitis (7)
Portier, H et al, France, 1984 [34]	prospective	10	2.5 months −69 years (7 adults 3 children)	both	bone and joint infections (4 post- traumatic, 2 post – surgery, 2 osteo-arthritis, 1 post- osteosynthesis and 1 osteomyelitis)	S. aureus (10) (2 MRSA, 8 penicillinase +), 2 were mulitinfections: 1 S aureus penicillinase +, Bacteroides, 1 MRSA with group D Streptococcus alcaligenes)		cefotaxime (10)	50 mg/kg	50 mg/kg in three doses	11–21 days (mean 16.5 days)	9/10 cured, 1/10 relapsed	Treatment was discontinued in 3 cases, because of neutropenia and hyperpyrexia, neutropenia (1200/mm^3) at day 21, increase of alanine-aspartate transaminase at day 15. Cefotaxime was incriminated in these adverse effects since they were reversible after its discontinuation.
Reinehr T et al, Holland, 2000 [35]	case series	11	mean 11 years	pediatric	chronic osteomyelitis	not reported		combination with penicillin (11), followed by oral clindamycin for 3 months	200 mg/kg	NA	mean 21 days	5/5 cured in group A 5/6 cured in group B – 1/6 relapsed 11 months later, but recovered after another course of antibiotics	NA
Nakamura et al, Japan, 2020 [33]	case report	1	84 years	adult	vertebral osteomyelitis L2-3 and a psoas abscess	MRSA (1)	second-line – previous treatments: 2 weeks of vancomycin, 2 weeks of daptomycin and 4 weeks of high dose vancomycin with abscess drainge	imipenem/cilastatin (1)	4g	NA	4 weeks	1/1 improvement of the abscess-almost disappeared, CRP within normal range	NA
Lee WS et al, Taiwan, 2016 [31]	case report	1	85 years	adult	osteomyelitis and discitis L4-5, epidural abscess	MRSA (1)	second-line- previously received ertapenem/vancomycin. Empirical for 4 days: cefoperazone/sulbactam	teicoplanin (1)	24 g	4 gr q 6 h	5 weeks	1/1 cured	NA
Stengel et al, Germany-Austria, 2005 [36]	prospective	52	mean 63 years	adult	diabetic foot osteomyelitis-limb-threatening	S. aureus (24), Streptococcus spp. (14), Proteus spp. (13), Enterococcus spp. (7), Pseudomonas spp. (4), E. coli (3), Citrobacter freundii (3), Others 4 (1 case of Klebsiella, Bacteroides, Enterobacter, and Serratia spp. each)	second-line. Twenty-two participants had unsuccessfully been pretreated with different antibiotic drugs for an average of two weeks. Most often used agents were clindamycin, ciprofloxacin, and amoxicillin (in fixed combination with a beta-lactamase inhibitor).	meropenem (14) amoxicillin + clavulanic acid (12) clindamycin (10) ciprofloxacin (10) ceftriaxone (4) imipenem (2) others (5)	8 to 24 g (mean daily dose 14.9 ± 4.9 g)	NA	14.4 + 8.3 days, (3–40 days)	affected limbs could be salvaged in 48 of 52 patients (92.3%)- 4 major amputations	mild nausea and rash (4)
Luengo et al, Spain, 2018 [42]	case report	1	79	adult	total femoral replacement infection	S. epidermidis	second-line plus multiple surgeries	daptomycin (1)	8 g	2 gr x 4/d	42 days	1/1 wound healed succesfully	none
Gillard et al, France, 2005 [41]	retrospective	3	mean 57.6 years	adult	pyogenic discitis	negative cultures before treatment	first-line followed by other oral treatment combination	fluoroquinolone (2) third generation cephalosporin (1)	NA	NA	mean 18.3 days of IV fosfomycin (then other antibiotic oral treatment for 2–2.5 months in total)	3/3 cured	NA
Baron et al, France, 1986 [37]	retrospective	20	NA	NA	acute osteomyelitis (n = 12), osteoarthritis (n = 8)	Staphylococcus spp. (20)	first-line	oxacillin (17), pefloxacin (2), aminoglycoside (1)	200 mg/kg	q 6 or 8 h	NA	10/20 cured, 9 improved, needed surgical interventions, 1/20 failed-amputation	NA
Stockl et al, Germany/Austria, 2005 [38]	prospective	40	14–80 years (median 60 years)	NA	spondylodiscitis (vertebral osteomyelitis)	S. aureus (21) Streptococcus spp (3) E. coli (3) S. epidermidis (2) Salmonella (1) Enterococcus spp. (1)	56% second line treatment	second generation cephalosporins (22) beta-lactams (5) clindamycin (7) rifampicin (6) vancomycin (3) metronidazole (1)	8–24 g	4 g q 12 h (n = 19) 4 g q 8 h (n = 4) 8 g q 12 h (n = 11) 8 g q 8 h (n = 5)	3–89 days (mean 24 days)	30/40 cured 5/40 improved-needed surgical interventions 5/40 failure	flush (1) taste disorder (1)
Baron et al, France, 2019 [40]	case report	1	43 years	adult	septicpseudoarthrosis	Carbapenemase-producing Klebsiella pneumoniae	NA	colistin IV, doxycycline PO	12 g	4 g q 8 h	3 months	cured	none
Narayanasamy et al, Australia 2020 [43]	case report	1	75 years	adult	internal fixation infection	carbapenemase-producing extensively drug-resistant Pseudomonas aeruginosa	second-line	colistin	3 g PO for 3 days and 16 g IV	4 g q 6 h	82 days	cured	renal impairment due to colistin

Abbreviations: IV: intravenous, IM: intramuscular, PO: per os, MRSA: methicillin resistant Staphylococcus aureus, MSSA: methicillin susceptible Staphylococcus aureus, MRCNS: methicillin resistant coagulase negative Staphylococcus, KES: Klebsiella-Enterobacter-Serratia, NA: not applicable

Badelon O, Bingen E, Sauzeau C, et al. [Choice of first-line antibiotic therapy in the treatment of bone and joint infections in children]. Pathol Biol. 1988;36(5 Pt 2):746–749.

 PubMedGoogle Scholar

Corti N, Sennhauser FH, Stauffer UG, et al. Fosfomycin for the initial treatment of acute haematogenous osteomyelitis. Arch Dis Child. 2003;88(6):512–516.

 PubMed Web of Science ®Google Scholar

Dinh A, Salomon J, Bru JP, et al. Fosfomycin: efficacy against infections caused by multidrug-resistant bacteria. Scand J Infect Dis. 2012;44(3):182–189.

 PubMed Web of Science ®Google Scholar

Fitoussi F, Litzelmann E, Ilharreborde B, et al. Hematogenous osteomyelitis of the wrist in children. J Pediatr Orthop. 2007;27(7):810–813.

 PubMed Web of Science ®Google Scholar

Gouyon JB, Duez JM, Portier H, et al. [Fosfomycin-cefotaxime combination in severe staphylococcal infections in newborn infants]. Presse Med. 1985;14(42):2135–2138.

 PubMed Web of Science ®Google Scholar

Guggenbichler JP, Bonatti H, Rottensteiner F. [Resistance of staphylococci to intracellular killing by macrophages–a new pathophysiologic concept of acute hematogenous osteomyelitis in childhood and its therapeutic consequences]. Padiatr Padol. 1989;24(1):21–32.

 PubMedGoogle Scholar

Hernandez Casado V. Fosfomycin in a traumatological department. Chemotherapy. 1977;23(Suppl 1):403–410.

 PubMedGoogle Scholar

Meissner A, Haag R, Rahmanzadeh R. Adjuvant fosfomycin medication in chronic osteomyelitis. Infection. 1989;17(3):146–151.

 PubMed Web of Science ®Google Scholar

Portier H, Tremeaux JC, Chavanet P, et al. Treatment of severe staphylococcal infections with cefotaxime and fosfomycin in combination. J Antimicrob Chemother. 1984;14(Suppl B):277–284.

 PubMedGoogle Scholar

Reinehr T, Burk G, Michel E, et al. Chronic osteomyelitis in childhood: is surgery always indicated? Infection. 2000;28(5):282–286.

 PubMed Web of Science ®Google Scholar

Nakamura I, Yamaguchi T, Aoki K, et al. Imipenem plus fosfomycin as salvage therapy for vertebral osteomyelitis. Antimicrob Agents Chemother. 2020;65(1):1.

 Web of Science ®Google Scholar

Lee WS, Chen YC, Chen HP, et al. Vertebral osteomyelitis caused by vancomycin-tolerant methicillin-resistant staphylococcus aureus bacteremia: experience with teicoplanin plus fosfomycin combination therapy. J Microbiol Immunol Infect. 2016;49(4):600–603.

 PubMedGoogle Scholar

Stengel D, Gorzer E, Schintler M, et al. Second-line treatment of limb-threatening diabetic foot infections with intravenous fosfomycin. J Chemother. 2005;17(5):527–535.

 PubMed Web of Science ®Google Scholar

Luengo G, Lora-Tamayo J, Paredes D, et al. Daptomycin plus fosfomycin as salvage therapy in a difficult-to-treat total femoral replacement infection. J Bone Jt Infect. 2018;3(4):207–211.

 PubMedGoogle Scholar

Gillard J, Boutoille D, Varin S, et al. Suspected disk space infection with negative microbiological tests-report of eight cases and comparison with documented pyogenic discitis. Joint Bone Spine. 2005;72(2):156–162.

 PubMed Web of Science ®Google Scholar

Baron D, Desjars P, Touze M, et al. Clinical study on combined therapy with fosfomycin for staphylococcal lnfections. (Ed.^(Eds) (Service d’Urgence and Service de Reanimation Medicale H6tel-Oieu, Nantes, France, 1987)

 Google Scholar

Stöckl B, Schmutzhard E. Antimikrobielle therapie der spondylodiszitis - überlegungen zur optimierung. Chemother J. 2005;14:11–15.

 Google Scholar

Baron SA, Cassir N, Mekideche T, et al. Successful treatment and digestive decolonisation of a patient with osteitis caused by a carbapenemase-producing Klebsiella pneumoniae isolate harbouring both NDM-1 and OXA-48 enzymes. J Glob Antimicrob Resist. 2019;18:225–229.

 PubMed Web of Science ®Google Scholar

Narayanasamy S, Nation RL, Mahony AA, et al. Cure of limb-threatening XDR pseudomonas aeruginosa infection: combining genome sequencing, therapeutic drug level monitoring, and surgical debridement .Open Forum Infect Dis. 2020;8(1):ofaa572.

 PubMed Web of Science ®Google Scholar