Intravenous fosfomycin for the treatment of patients with central nervous system infections: evaluation of the published evidence

Figures & data

Table 1. Intravenous fosfomycin for the treatment of patients with CNS infections (prospective and retrospective studies).

Author, country, year [ref.]	Type of study	No of patients (n)	Age	Sex (n)	Relevant Comorbidities and Infections	CNS Infection	Isolated Pathogen (n)
Sicillia et al, Spain, [15]	prospective	12	6 adults/6 children	m (10)/f (2)	deep coma (3), superficial coma(8), general convulsions (6), pneumonia (2)	meningitis	S. pneumoniae
Sicillia et al, Spain, [33]	prospective	12	10 adults/2 children	m (10)/f (2)	deep coma (3), superficial coma (4), general convulsions (6)	meningitis	S. pneumoniae (6), N. meningitidis (4), E. coli (1), H. influenzae(1)
Portier et al, France, [19]	prospective	9	8 adults/1 infant			meningitis	S. aureus (6 total,1 MRSA), S. epidermidis (3 total, 1 MRSE)
Stahl et al, France, [26]	prospective	10	adults	m(5)/f(5)		meningitis	N. meningitidis (6), S. pneumoniae (2), E. cloacae (1) and undetermined (1)
Stahl et al, France, [36]	prospective	16	adults		neurosurgical procedures	meningitis	S. aureus, S. epidermidis, S. pneumoniae, N. meningitidis, H. influenzae,Aeromonas, S. marcescens
Friedrich et al, Germany, [27]	prospective	9	adults			meningitis s/p neurosurgical intervention	S. aureus (6), S. epidermidis (2) S. pneumoniae (1)
May et al, France, [28]	prospective	7			herniated disc, rhinorrhea, enucleation, fracture of the cranial base, derivation, tumor, arachnoid cyst	meningitis s/p trauma or neurosurgical intervention	S. aureus (3), Peptococcus (1)
Portier et al, France, [25]	prospective	32	adults	m (20)/f (12)		meningitis	22 staphylococcal [12 S. aureus (4 MRSA), 11 S. epidermidis (1 MRSE)]/10 enterobacterial
Tritthart et al, Austria. [17]	prospective	31	adults/children			brain (n = 25), spinal (n = 6) abscesses	S. aureus (11), S. epidermidis (5), H.influenzae (4), E.Coli (3), Bacteroides (2)
Trummer et al, Austria, [40]	retrospective	7	adults			post-traumatic brain abscesses or ventricle empyema	CoNegative Staph.(3), 1 S. aureus (1), other (2)
Dihn et al, France, [10]	prospective	7				2 cranial osteitis with cerebral abscess and 5 cerebral derivation shunts infections	KES (1), P. aeruginosa (1), Enterococcus (1), Streptococcus (1), MRSCN (1), E. coli (1), MRSA (1), MSSA (2), H. influenzae (1), polymicrobial (2)
Putensen et al, Germany, [14]	prospective	45	adults			CNS infection, not specified	several Gram-negative and Gram-positive pathogens
Author, country, year [ref.]	Pathogen’s susceptibility	Antibiotics given with fosfomycin (dose/duration when available)	Fosfomycin daily dose	Fosfomycin dosage regimen	Duration of fosfomycin treatment	Clinical outcome	Mirobiological outcome	Adverse events
Sicillia et al, Spain, [15]	fosfomycin, ampicillin, gentamicin	penicillin (5), ampicillin (2) and gentamicin (5)	16 g (adults), 250–750 mg/kg (children)		range 9–17, average 11.2 days	8 cured, 2 cured with sequelae, 2 died	sterilization of CSF
Sicillia et al, Spain, [33]	fosfomycin, penicillin G, ampicillin, chloramphenicol	penicillin G or ampicillin or chloramphenicol	16 g (adults), 200 mg/kg (children)	4 g q 6 h (adults)	range 6-16, average 11 days)	10 cured, 1 cured with sequela, 1 died	11 pts. with sterile CSF, 1 failure (persistent pneumococci in CSF, fatal)
Portier et al, France, [19]		cefotaxime (25 mg/kg, q 6 h)	200 mg/kg	daily dose divided in 4 doses	average 17.6 d	cured	sterilization of CSF
Stahl et al, France, [26]		amoxicillin in 9 pts, cefotaxime in 1 pt	200 mg/kg	daily dose divided in 3 doses	average 12 days	cured	NR
Stahl et al, France, [36]		ceftriaxone	200 mg/kg	daily dose divided in 3 doses		15 cured, 1 relapsed and cured with a second course of the same treatment	sterilization of CSF	none
Friedrich et al, Germany, [27]		none	15 g	5 g q 8 h	10 days	7 cured, 2 died	NR
May et al, France, [28]		ceftriaxone (40 mg/kg/d), metronidazole in one case	200 mg/kg	daily dose divided in 4 doses		6 cured, 1 died	sterilization of CSF
Portier et al, France, [25]		cefotaxime (100 mg/kg/d)	200 mg/kg		average 14.5 days (for staphylococcal infection) 15.9 d (for enterobacterial infection)	17 completely cured, 4 recovered with neurological sequelae, 1 lost of follow-up (staphhylococcal meningitis), 8 cured, 1 died, 1 lost of follow up (enterobacterial)	sterilization of CSF in all cases	intolerance of intravenous infusion, metabolic alcalosis with hypokalemia
Tritthart et al, Austria. [17]		19 pts monotherapy, 4 with moxalactam and 2 with cefoxitin	≤16 g	8 g q 12 h	average 14 days	28 cured, 2 cured with severe neurological sequelae, 1 died	30 with sterile CSF	none
Trummer et al, Austria, [40]		tobramycin and metronidazole in all, 1 plus amoxicillin, 1 plus amphotericin and diflucan	NR	NR	average 25.5 days	2 cured, 2 cured with sequelae, 2 died
Dihn et al, France, [10]		2^nd and 3^rd generation cephalosporins, amoxicillin, carbapenem, glycopeptide, aminoglycoside, pristinamycin	12 or 16 g	4 g q 6 or 8 h	30 ± 32 days	5 cured, 1 died, 1 lost of follow-up	NR	hypovolemia and neutropenia^a
Putensen et al, Germany, [14]		3rd and 4th generation cephalosporins in 77%, carbapenem and metronidazole in 25% and glycopeptide in 10%	≤ 15 g		NR	33 cured	9/11 pts with sterile CSF	hypernatremia, hypokalemia, gastrointestilnal intolerance, pyrexia, hyponatremia

^aData refer to the total study population as no data were reported for the subgroub of patients with neurological infections.

KES: Klebsiella Enterobacter Serratia group, CSF: cerebrospinal fluid, CNS: central nervous system, MRSCN: methicillin-resistant staphylococci coagulase negative, MRSA: methicillin-resistant Staphylococcus aureus, MSSA: methicillin-sensitive Staphylococcus aureus, MRSE: methicillin resistant Staphylococcus epidermidis, NR: not reported, pts: patients, pt: patient, m: male, f: female.

Table 2. Intravenous fosfomycin for the treatment of patients with CNS infections (case series and case reports).

Author, Country, year	No of patients treated with fosfomycin	Age	Sex	Relevant Comorbidities and Infections	CNS Infection	Isolated Pathogen (number of patients)	Pathogen’s resistance
Gimeno et al, Spain, [41]	1	67 years	f	parietal craniectomy	cerebral suppurating infection	E. coli
Boulard et al, France, [43]	5	4 adults/1 child	m		CSF shunt infections	S. epidermidis	penicillin G, oxacillin (4), gentamycin (3), amicacin (1)
Tremeaux, France, [34]	1	69 years	m	trauma	meningitis	S. aureus
Fosse et al, Germany, [44]	1	57 years	f	meningeal hemorrhage, operated for basilar bifurcated aneurysm. Post surgiccal hydrocephalus that required ventriculoperitoneal shunt	meningitis s/p ventriculoperitoneal drain/shunt	Micrococcus luteus
Furuya et al, Japan, [30]	1	80 years	m	uveitis	meningitis	Enterococcus faecium	β-lactams
Sakamoto, Japan, [32]	4	adults		multiple craniotomies, presence of ventricular drainage or ventriculo-peritoneal shunt, and irradiation	meningitis	MRSA	methicillin and cefazolin
Inoue et al, Japan, [21]	1	40 years	m		meningitis	Campylobacter fetus subsp. fetus	ampicillin, piperacillin, cefotaxime, latamoxef
Longuet et al, France, [18]	1	adult			meningitis	penicillin G-resistant pneumococcus
Nusko et al, Germany, [35]	1	24 years	m	granulocytic pleocytosis, presacral phlegmon	meningitis
Silbermann, Netherlands, [22]	1	17 years	m	acute lymphoblastic leukemia, chemotherapy, neutropenia	meningitis	S. epidermidis	penicillin, methicillin, tobramycin and ciprofloxacin
Berner et al, Germany, [42]	1	18 months	m	primitive neuroectodermal tumor in the brainstem and obstructive hydrocephalus	meningitis s/p ventriculoperitoneal drain/shunt	Bacillus cereus	penicillin G and all other beta-lactam antibiotics
Seto, Japan, 1999 [20]	1	69 years	m	MRSA urinary tract infection and bacteremia	meningitis	MRSA
Sonntag, Germany, [37]	1	infant			subdural abscesses	E. coli
Faye et al, France, [24]	1	4 years	f	arthritis	meningitis	N. meningitidis
Hansen et al, Germany, [31]	1	80 years	m	brain atrophy, internal hydrocephalus and relevant cerebral microangiopathy	meningitis	Mycobacterium caprae (post mortem result)
Lee et al, Taiwan, [38]	1	56 years	f	community-acquired left neck abscess and internal jugular vein thrombosis with septicemia	multiple brain abscesses	ESBL-producing K. pneumoniae	ESBL
Mellon et al, France, [29]	1	41 years	m	wound of the scalp in the left parietal region, CSF leakage	meningitis s/p trauma	A. baumannii	piperacillin–tazobactam, cefepim, imipenem-cilastatin, amikacin, and ciprofloxacin
Tseng Yu-Chen, Taiwan, [45]	1	61 years	m	ventriculoperitoneal shunt implanted for hydrocephalus	meningitis	ESBL-producing K. pneumoniae	ESBL
Algubaisi et al, Germany, [39]	1	6 weeks	m	low birth weight	multiple brain abscesses	Citrobacter koseri
Frattari et al, Italy, [23]	1	27 years	m	chronic otitis media, otomastoiditis, right middle-ear and mastoid suppurative infection, without bone fractures. Admitted after a car crash with multiple traumas and respiratory distress	meningitis	(XDR-P. aeruginosa
Sakka et al, Germany, [16]	1	63 years	m	endocarditis (S. aureus), cardiac insufficiency, CHD, renal insufficiency	brain abscess (with bacteremia)	S. aureus
	1	75 years	f	bacterial meningoencephalitis, cerebellar infarction, severe CAP, septic shock, renal failure, arterial hypertension, obesity, COPD/athma	postsurgical bacterial meningitis	S. aureus, K. oxytoca
	1	78 years	m	wound infection, subarachnodial and intracerebral bleeding, arterial hypertension	postsurgical bacterial meningitis	MSSA
	1	55 years	m	intracranial abscess, endocarditis, alcohol abuse, arterial hypertension	brain abscess	MSSA
	1	61 years	m	HCV infection, prostehtic valve, bactereamia, BJI, endocarditis, intraspinal abscess, spondylodiszitis, acute hepatic failure	intraspinal abscess, spondylodiscitis	S. aureus
	1	65 years	m	leptomeningitis, spinal abscess, severe SSTI, BJI	meningitis	NR
	1	74 years	m	renal failure, cancer, CHD, endocarditis	brain abscess	S. aureus
	1	20 years	m	open fracure os occipitale	brain abscess, cerebellar granuloma (MRSA)	MRSA
	1	74 years	f	dysarthria, arterial hypertension, cerebral insult	intracranial abscess	S. epidermidis
	1	77 years	f	autoimmune disorder, hemiparesis, obesity	meningitis (suspected)	NR
	1	52 years	m	diabetes mellitus, skull fracture, epidural hematoma, obesity, cholangitis	extradural emphyema	CoNS, A. baumannii
	1	54 years	m	diabetes mellitus, autoimmune disorder, polymyositis w. vasculitis, arterial hypertension, obesity	sepsis after epidural abscess	S. aureus
	1	78 years	m	COPD/asthma, hypertension	brain abscess	Enterococcus raffinosus, S. marcescens
	1	79 years	m	cerebral edema, decubitus sacralis, arterial hypertension	bacterial meningitis	Bacillus spp.
Author, Country, year	Pathogen’s susceptibility	Treatment prior to fosfomycin initiation (dose and duration when available)	Antibiotics given with fosfomycin (dose/dura tion when available)	Fosfomycin daily dose	Clinical outcome	Mirobiological outcome	Adverse events	Follow up
Gimeno et al, Spain, [41]	cephalothin, ampicillin, kanamycin, neomycin, tobramycin, fosfomycin	cephalothin	none	16 g	cured	NR
Boulard et al, France, [43]	fosfomycin, streptomycin, gentamycin (2) and amicacin (4)	none	amikacin (2), gentamicin (2) and streptomycin (1)	12 g (adults), 200 mg/kg (child)	cured	NR
Tremeaux, France, [34]		penicillin G (300,000 U/kg), followed by oxacillin/gentamicin	cefotaxime (100 mg/kg q day)	200 mg/kg	cured	NR		4 months later, no signs of complication
Fosse et al, Germany, [44]	benzylpenicillin, amoxicillin, chloramphenicol and fosfomycin.	none	amoxicillin (8 g q 6 h)	24 g	cured-died due to hemorrhage recurrence, one month post discharge	sterilization of CSF
Furuya et al, Japan, [30]	rifampicin, fosfomycin, ofloxacin	latamoxef, ampicillin, clindamycin	rifampicin and ofloxacin	4 g	cured	sterilization of CSF
Sakamoto, Japan, [32]		none	minocycline and cefmetazole	NR	cured	sterilization of CSF
Inoue et al, Japan, [21]	imipenem/cilastatin, minocycline, kanamycin, gentamicin, erythromycin, ofloxacin, chloraphenicole, fosfomycin	none	imipenem/cilastatin (1 g/d), minocycline (200 mg/d)	4 g	cured	sterilization of CSF
Longuet et al, France, [18]		amoxicillin, third generation cephalosporins	vancomycin		cured	NR
Nusko et al, Germany, [35]		none	doxycycline (200 mg/d), netilmicin (400 mg/d) and ofloxacin (200 mg/d)	5 g	cured	NR
Silbermann, Netherlands, [22]	erythromycin, clindamycin, rifampicin, fusidic acid and vancomycin	vancomycin, fusidic acid, penicillin	vancomycin	16 g	cured	sterilization of CSF	none
Berner et al, Germany, [42]	fosfomycin and vancomycin	vancomycin	vancomycin		cured	sterilization of CSF		without complications
Seto, Japan, 1999 [20]	arbekacin, vancomycin and clindamycin	arbekacin and vancomycin	vancomycin	4 g	cured	NR
Sonntag, Germany, [37]		ampicillin, cefotaxime and gentamycin	amikacin and meropenem	NR	cured	NR		at 6.5 months- healthy
Faye et al, France, [24]		cefotaxime (200 mg/kg/d, 7 days)	cefotaxime (100 mg/kg/d)	100 mg/kg	cured	NR		6 weeks of amoxicillin/clavulanic acid per os. 19 months follow up no signs of recurrence
Hansen et al, Germany, [31]		ceftriaxone and ampicillin (22d) then meropenem plus ampicillin and rifampicin (450 mg i.v./day), isoniazid (300 mg p.o./day), pyrazinamide (3 g p.o. 2 times/week) and ciprofloxacin (500 mg p.o./day).	meropenem plus ampicillin	9 g	died due to myocardial infarction, 2 weeks after transfer to a rehabilitation facility	post mortem growth of M. tuberculosis complex		died 2 weeks post discharge (transferred to rehabilitation center)
Lee et al, Taiwan, [38]	fosfomycin, meropenem	ceftazidime (2 g q 8 h) and metronidazole (500 mg q 6 h, 2 days), followed by ceftriaxone (2 g q 12 h) and amikacin (375 mg q 12 h for 2 more days). Then, meropenem monotherapy (10 g q 8 h, 7 days)	meropenem (10 g q 8 h)	12 g	cured	sterilization of blood cultures	none	1 month post discharge brain MRI: resolution of abscesses
Mellon et al, France, [29]	rifampicin, colistin, and fosfomycin	piperacillin/tazobactam (4 g q 8 h), for elbow’s infection	ampicillin/sulbactam (3/1.5 g q 4 h for 21 d) and rifampicin (600 mg q 6 h for 11 d)	16 g	cured	sterilization of CSF	none
Tseng Yu-Chen, Taiwan, [45]	carbapenems, fosfomycin	imipenem/cilastatin (500 mg q 6 h)	meropenem (1 g q 8 h)	24 g	cured	sterilization of CSF	hypernatremia	2 months later, no signs of infection
Algubaisi et al, Germany, [39]	fosfomycin	ampicillin, gentamicin and cefotaxime	meropenem (120 mg/kg/d)	120 mg/kg	cured	NR		at the age of 2 years, mild speech delay
Frattari et al, Italy, [23]	colistin, ceftolozane-tazobactam	amikacin and cefazolin, piperacillin-tazobactam and linezolid, high-dose meropenem and colistin intravenously and nebulized (given for respiratory infection and sepsis).	ceftolozane -tazobactam (3 g/q 8 h for 14 d), rifampicin (600 mg/q 12 h)	16 g	cured	sterilization of CSF
Sakka et al, Germany, [16]		cefazolin (6 g/d for 2 days), flucloxacillin (8 g/d for 1 day) imipenem/cilastin (1 g/d for one day), vancomycin (1 g/d, for 42 days), gentamicin (0.32 g/d, for 5 days)	vancomycin (1 g/d)	15 g	cured	NR		no relapse
		ciprofloxacin (0.4 g/d, 1 day), vancomycin (6 g/d, 11 days), rifampicin (1.2 g/d, 6 days), ceftriaxone 2 g/d, 5 days), clindamycin (1.8 g/d, 5 days)	vancomycin (0.5 g/d), meropenem (6 g/d), ceftazidim (6 g/d)	15 g	cured	NR		no relapse
		piperacillin/tazobactam (13.5 g/d, 4 days), vancomycin (2 g/d, 4 days), flucloxacillin (3 g/d, 3 days)	flucloxacillin (12 g/d)	15 g	cured	NR
		amoxicillin (21 days), moxifloxacin (21 days), vancomycin (2 g/d, 5 days), ceftriaxone (4 g/d, 5 days), metronidazole (2 g/d, 5 days)	flucloxacillin (12 g/d)	15 g	died	NR		no relapse
		gentamicin (0.24 g/d, 16 days), flucloxacillin (8 g/d, 2 days), rifampicin (0.6 g/d, 2 days), erythromycin (0.28 g/d, for 12 days)	meropenem (6 g/d), cephazolin (6 g/d), gentamicin (0.24 g/d), erythromycin (0.28 g/d)	8 g	cured	NR
		meropenem (3 g/d, 15 days)	erythromycin (0.21 g/d), meropenem (3 g/d),	12 g	died	NR		no relapse
		gentamycin (0,24 g/d, 14 days), flucloxacillin (6 g/d, 16 days)	meropenem (3 g/d), fluconazole (0.2 g/d), rifampicin (0.6 g/d), flucloxacillin (6 g/d), vancomycin	9 g	died	NR
		vancomycin (2 g/d, 15 days), metronidazole (1.5 g/d, 15 days), ceftazidime (8 g/d, 15 days)	vancomycin (2 g/d), metronidazole (1.5 g/d)	15 g	cured	NR		no relapse
		none	ceftazidim (2 g/d), metronidazole (0.5 g/d), vancomycin (2 g/d)	15 g	cured	NR
		none	ceftriaxon (2 g/d), vancomycin (1 g/d for 1 day), vancomycin (2 g/d for 4 days)	15 g	cured	NR
		imipenem (1 g/d, 1 day)	imipenem/cilastin, flucloxacillin	15 g		NR
		none	rifampicin (0.6 g/d), ceftazidim (2 g/d), metronidazole (0.5 g/d), vancomycin (2 g/d), ciprofloxacin (0.4 g/d), flucloxacillin (2 g/d)	15 g	cured	NR
		erythromycin (0.125 g/d, 4 days)	vancomycin (2 g/d), ceftriaxone (2 g/d), rifampicin (0.6 g/d)	15 g	cured	NR
		rifampicin (0.6 g/d, 5 days), vancomycin (2.5 g/d, 12 days), ceftriaxone (2 g/d, 5 days)	rifampicin (0.6 g/d), vancomycin (2 g/d), ceftriaxone (2 g/d)	15 g	cured	NR

BJI: bone and joint infections, CAP: community-acquired pneumonia, CHD: coronary heart disease, CNS: central nervous system, COPD: chronic obstructive pulmonary disease, CSF: cerebrospinal fluid, ESBL: Extended Spectrum Beta-Lactamase, f: female, m: male, MSSA: methicillin-sensitive Staphylococcus aureus, NR: not reported, spp: species, SSTI: skin and soft tissue infections, XDR: Extensively drug-resistant.

Table 3. Data on the use of fosfomycin as first- or second-line treatment, combination treatment or monotherapy, the types of central nervous system infections treated and the clinical and microbiological outcome.

	Number of patients	Percentage (%)
First/second line treatment
Fosfomycin as first-line treatment	164	73.3%
Fosfomycin as second-line treatment	15	6.7%
Not specified	45	20%
Combination treatment	195	87%
Monotherapy	29	13%
Type of CNS infection
Meningitis	123	54.9%
Brain abscess	33	14.7%
Spinal abscess	6	2.7%
Ventricle empyema	3	1.3%
CSF shunt infection	12	5.4%
Not specified/other	47	21%
Clinical outcome
Cure	184	88.5%
Cure with neurological sequelae	11	5.3%
Death	13	6.2%
Microbiological outcome
Sterilization of CSF	138	97.2%
Failure of sterilization of CSF	2	1.4%
Sterilization of blood cultures	1	0.7%
Post- mortem growth of MTBC	1	0.7%

CSF: cerebrospinal fluid, CNS: central nervous system, MTBC: Mycobacterium tuberculosis cοmplex.

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