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

ABSTRACT

Introduction

Central nervous system (CNS) infections have considerable morbidity and mortality. Fosfomycin is a broad spectrum bactericidal antibiotic with favorable pharmacokinetic properties and low toxicity, satisfactory penetration in the cerebrospinal fluid and is authorized for the treatment of bacterial meningitis.

Areas covered

The objective of this analysis was to evaluate the available data regarding the effectiveness and safety of intravenous fosfomycin for the treatment of CNS infections. Thirty-two relevant publications were identified. Data from 224 patients who received intravenous fosfomycin as treatment for CNS infections were evaluated. Overall, 93.8% of patients were cured from the infection. Staphylococcus was the most frequent pathogen; Streptococcus pneumoniae, Neisseria meningitidis, and several other microbial agents, including multi-drug resistant and extensively drug-resistant bacteria, were also implicated. Fosfomycin was given as part of a combination treatment in the vast majority of the patients. The dosage of fosfomycin ranged between 4 g and 24 g per day; a regimen with 14–16 g per day was used in the majority of the cases. Fosfomycin was generally well tolerated.

Expert opinion

The evaluation of the published evidence suggests that fosfomycin may be beneficial in the treatment of patients with CNS infections.

KEYWORDS:

• Fosfomycin
• meningitis
• neurosurgical postoperative infection
• Staphylococcus
• Gram-negative bacteria

1. Introduction

1.1. Central nervous system (CNS) infections

CNS infections, including meningitis, encephalitis, ventriculitis, brain abscesses, and empyema are of great clinical importance and their treatment is challenging. They can be a result of community-acquired infections, or they can develop as post-neurosurgical intervention or post-trauma complications [1].

CNS infections require immediate and well targeted treatment, as neurologic and systematic complications and mortality of these infections are high [2]. Empiric treatment depends on epidemiological factors and antibiotic resistance patterns of the usual pathogens [3]. In some cases, such as subdural empyema and brain abscesses, antibiotic treatment is combined with neurosurgical drainage. The antibiotics of choice vary and most of the times combination therapy is required [1].

1.2. Fosfomycin

Fosfomycin is a low molecular weight antibiotic, with bactericidal activity against a wide variety of Gram-negative and Gram-positive bacteria [4,5]. Fosfomycin is effective against multiple resistant bacteria, both Gram-negative, such as extended-spectrum beta-lactamase-producing (ESBL) and carbapenemase-producing enterobacteria and Gram-positive, including methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE) and penicillin-resistant Streptococcus pneumoniae [6–10].

The use of intravenous fosfomycin has been recently revised, as it has favorable pharmacokinetic characteristics, high tissue penetration, even in deep-seated infections and low toxicity. Fosfomycin’s pharmacokinetic characteristics, together with its extended spectrum antibiotic activity make fosfomycin an attractive choice for the treatment of CNS infections [11]. Fosfomycin can be administered either orally or intravenously. When given orally, the drug is going through acid-catalyzed hydrolysis in the stomach, before reaching the small intestine, where it is being absorbed. The intravenous administration of fosfomycin allows for higher bioavailability when compared to the oral route. It is noteworthy that 90% of the intravenously administered fosfomycin is recovered unchanged in the urine 36–48 h after dosing, whereas only 40-50% of the same dose given orally is excreted in the urine; this is due to incomplete absorption after per os administration.

Fosfomycin’s action is achieved by irreversible inhibition of an early stage of the bacterial cell wall synthesis. It acts by inhibiting the first enzymatic step of the bacterial cell wall synthesis, preventing the division of UDP-GlcNac -3-O- enolpyruvate from UDP-GlcNAc and phosphoenolpyruvate during the first step in peptidoglycan biosynthesis, leading to bacterial cell wall destruction and death. It is active against a wide range of both Gram (+) and Gram (-) bacteria, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Fosfomycin is widely distributed in a variety of tissues, including the cerebrospinal fluid (CSF).

The permeability of cerebrospinal fluid is increased when the meninges are inflamed, thus the concentration of fosfomycin in the CSF can increase by nearly threefold in the case of meningitis [12]. In suppurative lesions, it is reported that repeated doses of fosfomycin can yield a concentration of 32 mg/L of fosfomycin in the abscess, despite the increased inter-individual variability in the pharmacokinetic of fosfomycin in the abscess fluid [13]. Given the above, fosfomycin has the bactericidal spectrum and pharmacokinetic characteristics needed, in order to be considered as an effective option for the treatment of CNS infections.

1.3. Objective

The objective of this article was to explore and evaluate the existing evidence on whether the use of intravenous fosfomycin is an effective choice for the treatment of CNS infections.

2. Literature search

A search in PubMed was performed, looking for literature focusing on the use of fosfomycin for the treatment of CNS infections. Terms used for this search included fosfomycin and CNS infection (or meningitis or CSF shunt infection or CNS abscesses). Papers published from 1977 to 2019 and referring only to human data were included in the analysis. Data from published papers, including prospective and retrospective studies, case series, and case reports that referred to the effectiveness and safety of intravenous fosfomycin in the treatment of CNS infections, were analyzed.

We collected information regarding the number and the demographic data of patients treated with fosfomycin, the therapeutic indication for which each patient received fosfomycin, whether this was a first- or second-line antibiotic, which antibiotic was given as combination therapy and what was the dosage and the duration of treatment with fosfomycin. Additionally, data concerning the clinical and microbiological outcome of the treatment with intravenous fosfomycin, as well as the possible adverse events related to it, were analyzed and are presented in this paper.

3. Available published evidence

3.1. Relevant studies

Our search yielded 32 relevant publications, examining cases of CNS infections, treated with intravenous fosfomycin, published from 1977 to May 2019 [14,15]. They consist of 11 prospective studies and one retrospective study (Table 1), as well as 3 case series and 17 case reports (Table 2). Data from a subgroup analysis of NIS-FOM study were also included in this article [16]. According to data presented in the abovementioned publications, a total of 224 patients received intravenous fosfomycin as a treatment for CNS infections. The majority of them were adults, but there are also data on children and infants. Specifically, there are data on 11 children and 4 infants (below 1 year of age). There is also one paper referring to a range of ages starting from 2 years to 69 years, but not specifying the number of children studied in the analysis [17].

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.

Data regarding the use of intravenous fosfomycin as first- or second-line treatment, in combination regimen or as monotherapy, the type of CNS infection treated and the clinical and microbiological outcomes, are presented in summary, in Table 3.

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.

3.2. Types of CNS infection

Out of the total 224 patients studied, 123 patients presented with meningitis of various etiologies (post traumatic, post neurosurgical intervention, complication of infections in adjacent body sites) [15,18–36]. Thirty-nine patients were treated for CNS (brain or spinal) abscesses [10,17,37–40]. Twelve patients were treated for CSF shunt infections, three were treated for ventricle empyema, one patient was treated for post-traumatic CNS infection, which postmortem was proved to be aspergilloma and 46 patients were diagnosed with CNS infection not clearly specified in the analysis [10,14,40–44].

3.3. Pathogens

In more than 73 patients, the microbial agent that was isolated was Staphylococcus [Staphylococcus aureus, Staphylococcus epidermidis, including MRSA (n = 12) and MRSE (n = 2)]. The rest of the pathogens isolated are analyzed as follows: 22 cases of Streptococcus pneumoniae meningitis, 12 cases of Neisseria meningitidis, 7 cases of Escherichia coli, 6 cases of Haemophilus influenzae, 2 cases of Bacteroides, 2 ESBL Klebsiella pneumoniae, 2 cases of Acinetobacter baumannii. In addition, several other microorganisms were reported in case reports, including Bacillus cereus, Campylobacter fetus subsp., Citrobacter koseri, extensively drug resistant Pseudomonas aeruginosa (XDR-PA), Aspergillus fumigatus, Enterococcus raffinosus, Serratia marcescens. There were some cases of meningitis, in which the pathogen was not isolated.

3.4. Fosfomycin in first-line treatment

One hundred and sixty-four out of the 224 patients (73.3%) received fosfomycin as first-line treatment. Out of them, 29 patients were reportedly treated with fosfomycin as monotherapy, while the rest 135 received fosfomycin in combination with other antibiotics.

3.5. Combination regimens

From the patients included in this article and for whom there are available data on the combination regimen, the vast majority received combination of fosfomycin with cephalosporins. Specifically, 44 patients received fosfomycin with cefotaxime. In 45 patients, the combination therapy included third and fourth generation cephalosporins, carbapenem, metronidazole, and glycopeptide. In 12 patients, fosfomycin was combined with amoxicillin, in 7 with metronidazole and tobramycin (one in addition to amoxicillin and one plus amphotericin and diflucan), and in 7 with ceftriaxone. Seven more patients received fosfomycin in combination with gentamicin, five with penicillin, four with meropenem, one of them plus amikacin. Four patients were treated with fosfomycin and vancomycin. In four cases, fosfomycin was combined with moxalactam, whereas in two cases with ampicillin, and two other with cefoxitin.

Some more combinations of fosfomycin with other antibiotics for the treatment of CNS infections result from single cases, such as one patient who received fosfomycin with streptomycin, one other with ampicillin/sulbactam and rifampicin and one with high-dose ceftolozane-tazobacam and rifampicin. Finally, one patient was treated with fosfomycin plus imipenem/cilastatin and minocycline.

3.6. Fosfomycin dosage

Fosfomycin was given either in a body weight-based dose or as a standard dose. Weight-based dose was calculated for adults as 200 mg/kg/day, given in three or four doses per day. In studies concerning children, the dose was calculated based on the body weight ranging from 100 to 750 mg/kg/day.

In the majority of the cases though, the dose of fosfomycin was independent of the body weight; it ranged from 4 g/day to 24 g/day. Most of the patients studied in this analysis, received a standard dose of 14–16 g of fosfomycin per day, divided in several dose interval schedules. In some cases, it was specified that fosfomycin was administered in continuous intravenous infusion [15,19,25,26,34]. The duration of the treatment with fosfomycin was variable, ranging from 6 days to 2 months.

3.7. Adverse events

Data on adverse events of fosfomycin within this analysis result from three prospective studies and one case report [10,14,25,45]. Electrolytes’ disturbances were the most common adverse events, including hypernatremia, hyponatremia, and hypokalemia with and without metabolic alkalosis. In several studies included in this article, no adverse events were reported or data are not available [17,22,29,38,45].

3.8. Clinical outcomes

Out of 208 patients in total for whom there are available data on the clinical outcome, 195 (93.8%) had complete resolution of the CNS infection. From them, 183 (93.8%) patients (87.9% of the total number of 208 evaluated patients) had no neurological sequelae or recurrence of the CNS infection; 11 had neurological sequelae. One patient relapsed and was cured with a second course of the same treatment. Three patients had insufficient follow up. Thirteen patients died. However, in three cases, the reason of death was not related to the CNS infection. More in specific, one patient died 1-month post therapy, due to recurrent meningeal hemorrhage; in another case, the patient was transferred to a rehabilitation center, where fosfomycin was discontinued and the patient died suddenly due to acute myocardial infarction, 15 days later. Finally, one other patient died 15 days after treatment completion due to septic shock [19,31,44]. There is missing data regarding the clinical outcome on 13 out of the total 224 patients who were treated with intravenous fosfomycin.

3.9. Microbiological outcomes

Data regarding the microbiological outcome are reported in 142 patients. Sterilization of the CSF was achieved in 138 (97.2%) of these cases. In one case, the microbiological outcome was expressed by sterilization of blood cultures [38]. In another patient, there was failure in eradicating the infection (persistent pneumococci in CSF) and subsequently, the patient died [33]. In a different case, CSF analysis grew M. tuberculosis complex post mortem [31]. For the rest of the patients included in the analysis, there are no data available, regarding the microbiological outcome.

4. Evaluation of the published evidence

The high proportion of clinical success (93.8%) in the cases presented above suggests that fosfomycin is an effective choice when treating patients with CNS infections. Thirteen deaths were recorded in this analysis and there is not always clear correlation of death with failure of treatment of the CNS infection. Fosfomycin in its intravenous form is officially indicated for bacterial meningitis, but it is also recommended by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and the German Neurological Society (DGN) guidelines for the treatment of bacterial meningitis due to MSSA, MRSA and Pseudomonas aeruginosa (DGN) and brain abscess (DGN) [16,46–49].

In the United States, fosfomycin is only approved for oral administration for the treatment of uncomplicated urinary tract infections though intravenous fosfomycin currently undergoes registration process, whereas in many other countries (including Spain, France, Germany, the United Kingdom, the Netherlands, Austria, and Greece) both oral and intravenous formulations are available.

Fosfomycin has the ability to highly penetrate into many tissues, including the cerebrospinal fluid, thus leading to increased distribution to the CNS [50]. However, its permeability into the abscess cavity is highly variable [13]. The available data suggest that fosfomycin is penetrating CSF, especially when the meninges are inflamed and it is effective against both meningitis and CNS abscesses.

In addition, fosfomycin has been shown to have excellent bactericidal activity against a range of gram-positive and gram-negative organisms, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) pathogens [51].

This contributes to the good clinical outcomes in the studies presented in this review, even though the pathogens isolated were of various characteristics and levels of antimicrobial resistance. Most of the cases were due to staphylococcal infections, including MRSA and MRSE, indicating that pathogen’s resistance pattern might not be the dominant driver for fosfomycin use. Streptococcus pneumoniae was another common cause of meningitis. Fosfomycin was also active against less common causes of CNS infections, for example, ESBL-Klebsiella pneumoniae, Acinetobacter baumannii and extensively drug resistant Pseudomonas aeruginosa (XDR-PA).

An interesting finding is that in most of the cases studied (73.3%), fosfomycin was a first-line antibiotic for the treatment of the CNS infections. This reflects the fact that most of these cases arise from prospective studies, where the administration of fosfomycin for the treatment of CNS infections was part of the study design, as well as the fact that the pathogen isolated from the CNS was susceptible to fosfomycin. Another explanation for the frequent use of fosfomycin as combination partner in first-line treatment might be a pharmacokinetic limitation of standard antibiotics to achieve sufficient drug levels in the CNS [52–54].

In 195 (87%) of the patients, fosfomycin was given in combination with other antibiotics, in several cases with more than two. Most clinicians use fosfomycin in combination with other antimicrobial agents in the treatment of patients with severe infections to avoid selecting resistant mutations. In a recent review, it is reported that resistance emerged during fosfomycin monotherapy ranged from <3% to 17.9% [55]. This matches the frequency of emergence of resistance reported for other antibiotic classes (i.e. penicillins, carbapenems, or aminoglycosides) as well as those reported in another relevant review [56–58].

The use of fosfomycin in combination with other antibiotics is supported in several in-vitro studies, especially against MDR organisms. Several combinations have been tested for in-vitro synergy against Gram-positive cocci (fosfomycin-linezolid for MRSA, fosfomycin-amoxicillin, and fosfomycin-daptomycin for VRE), MDR Neisseria gonorrhea (fosfomycin-ceftriaxone) and Gram-negative bacilli (fosfomycin-imipenem for MDR Pseudomonas aeruginosa), fosfomycin-colistin for XDR Acinetobacter baumanii [11,59–63]. Another study evaluated double-drug combinations of fosfomycin with imipenem, meropenem, doripenem, colistin, netilmicin, and tigecycline for in vitro synergy against MDR Klebsiella pneumoniae, Escerichia coli, and Pseudomonas aeruginosa clinical isolates [64].

The clinical use of fosfomycin in combination with other antibiotics has also been evaluated for several types of infections. In a preliminary prospective evaluation, fosfomycin as an adjunct therapy of life-threatening infections caused by carbapenem-resistant Klebsiella pneumoniae showed that all 11 studied patients had good bacteriological and clinical outcome of infection. The partner agents of fosfomycin in that study were colistin, gentamicin, and piperacillin-tazobactam [9]. Data on combination regimens of intravenous fosfomycin are also provided by another study, in which 16 adult patients with complicated MRSA bacteremia or endocarditis requiring rescue therapy were studied. Treatment with fosfomycin plus imipenem was initiated after failure of other antibiotics. Blood cultures were negative 72 h after the first dose of the combination in all cases. The success rate was 69%, and only 1 of 5 deaths was related to the MRSA infection [65].

Data from this analysis show that there is no consensus on the dose of fosfomycin required for the treatment of CNS infections. The daily dose of fosfomycin is usually determined based on the indication, severity and site of the infection, susceptibility of the pathogen(s) to fosfomycin and the renal function. In children, it is also determined by age and body weight. There are data suggesting that 24 g of fosfomycin per day, administered in three doses, provide a steady-state concentration of 16 mg/L in the cerebrospinal fluid for more than 90% of the time interval between doses [50]. Most of the patients in this evaluation of the published evidence received a divided daily dose of more than 14 g of fosfomycin. This is in keeping with more recent studies in which the fosfomycin dose ranged between 12 and 24 g/day, divided in three or four doses [16,66,67]. The use of weight-based dose regimen was an alternative approach, calculating the dose as 200 mg/kg/day for adult patients. It is emphasized that the licensed dosage recommendation for bacterial meningitis is 16 to 24 g of fosfomycin per day [49]. The duration of treatment was also variable, depending on the severity of the infection, the clinical status and response of the patient.

Fosfomycin is generally well tolerated, with the most common adverse event being mild gastrointestinal distress. Safety data from the evaluated studies were similar to relevant published data. The results of the current analysis suggest that electrolytes’ disturbance was the most common adverse event reported, during the treatment with intravenous fosfomycin. This is in accordance with a study reporting that the most common adverse events during intravenous treatment with fosfomycin were hypernatremia (14.8%) and hypokalemia (6.2%) [14]. A causal relationship to fosfomycin was suspected in 10.5% of patients with hypernatremia and 2.4% of those with hypokalemia.

Several limitations should be taken into consideration before interpreting the data provided by the studies included in this analysis. The number of patients who received fosfomycin for the treatment of CNS infections is considerable; however more clinical data are appreciated to further substantiate the evidence for effectiveness and safety of fosfomycin for the treatment of CNS infections.

Additionally, information from case reports and case series presented in this paper may represent successful cases and not failures of treatment, a fact that is frequently described as publication bias. In addition, data evaluated in this article come from prospective descriptive studies, retrospective studies, case series, and case reports. Another important limitation when evaluating the available data is the heterogeneity of data with respect to clinical efficacy endpoints together with the fact that studies from previous decades reported on significantly different pathogens and dosage regimens of fosfomycin (mostly lower dosages) and often used IV fosfomycin in monotherapy than current studies.

The lack of well designed, randomized controlled trials limits the rigorousness of the information regarding the use of fosfomycin for the treatment of CNS infections. However, conducting randomized controlled trials in this small and clinically heterogeneous entity would be difficult with constraints to study design and time.

5. Expert opinion

When it comes to evaluating the outcomes, data studied in this analysis are supporting the consideration of intravenous fosfomycin for the treatment of patients with CNS infections, such as meningitis, brain or spinal abscesses, ventriculitis or CSF shunt infections, especially when used in combination with other antibiotics. The wide spectrum of bactericidal activity, the high penetration into the CNS and the low toxicity of fosfomycin, makes it a good choice for the treatment of meningitis or CNS abscesses. CSF sterilization was achieved in 97.2% of the cases with available relevant data supporting fosfomycin’s bactericidal activity that is particularly desired in immune-privileged organ systems like the CNS [68,69]. The complete recovery of 93.8% of patients who received fosfomycin for the treatment of CNS infections suggests that fosfomycin may be a valuable therapeutic option against these infections.

Given the high morbidity and mortality of various types of CNS infections, the promising evaluated data on the effectiveness and safety of intravenous fosfomycin for this indication suggests that further research efforts are warranted. In addition, clinicians who use intravenous fosfomycin for patients with CNS infections are encouraged to publish their relevant experience.

The evolving problem with MDR Gram (-) bacterial infections, unfortunately, does not spare patients with CNS infections. Thus, clinicians may take into consideration the use of intravenous fosfomycin for patients with such infections, especially when they are due to MDR Enterobacteriaceae, such as Klebsiella pneumaniae and Escherichia coli for which isolates, fosfomycin has been shown to have excellent in vitro antibacterial activity.

Future research on the field should clarify the comparative effectiveness and safety of combination antimicrobial regimens including intravenous fosfomycin versus treatment with monotherapy. Additionally, future research data will help specify whether fosfomycin can be useful when used as part of the first-line antibiotic treatment, or whether it should be kept as a second-line choice for the treatment of CNS infections, when the initial regimen fails to be effective. Also, future research efforts should further elucidate the therapeutic role of intravenous fosfomycin for patients with CNS infections due to specific microbial etiologies, given the increasing trends in clinical therapeutics for pathogen driven treatment of patients with infectious diseases based on modern molecular diagnostic methods. Finally, there is need for data coming from published clinical experience regarding the optimal daily dose of intravenous fosfomycin for the treatment of patients with various types of CNS infections.

Given the increasing need for alternative choices for the effective treatment of CNS infections, the use of intravenous fosfomycin is expected to play a crucial role in this field. Intravenous fosfomycin is safe, effective and has the required PK/PD properties and antibacterial spectrum that make it an attractive choice for the treatment of CNS infections.

Article highlights

• CNS infections are characterized by increased morbidity and mortality. Their treatment is challenging and frequently requires the administration of combination of antibiotics.

• Fosfomycin is a broad spectrum bactericidal antibiotic, effective against both many Gram-positive and Gram-negative pathogens, including MDR and XDR isolates. Its mechanism of action is unique and its PK/PD properties allow for sufficient distribution into the CNS, thus making it an attractive therapeutic choice for CNS infections.

• In this article, data on the use of intravenous fosfomycin for the treatment of CNS infections are presented and evaluated. Data derived from 32 papers and a total of 224 patients were included in the analysis.

• Intravenous fosfomycin was administered as part of a combination therapy in 87% of the patients.

• The most commonly used dose of intravenous fosfomycin was 14-16 g per day. Regimens of 24 g of intravenous fosfomycin per day were also used.

• From the available data, 97.2% of the patients had sterilization of the cerebrospinal fluid (CSF).

• 93.8% of the patients were cured (88.5% were completely cured, whereas another 5.3% of the patients were cured, but had neurological sequelae).

• 6.2% of the studied patients died.

• Intravenous fosfomycin, used as part of an antibiotic combination regimen for the treatment of CNS infections, is safe and effective and can be considered as a therapeutic option of these infections.

Declaration of interest

ME Falagas participated in advisory boards of AstraZeneca, InfectoPharm, Tetraphase, Shionogi, and Xellia; received lecture honoraria from Cipla, Merck, and Pfizer; and received research support from Shionogi, Tetraphase, Helperby, and Xellia. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by InfectoPharm Arzneimittel und Consilium GmbH.