Application of fosfomycin in CNS infections: effective treatment and excellent tolerability.
16.06.2020
Application of fosfomycin in CNS infections: effective treatment and excellent tolerability.
Pharmacokinetic prerequisites for the use of fosfomycin in the treatment of CNS infections
Currently, there is a sufficient amount of clinical and experimental research aimed at studying the concentrations of fosfomycin in cerebrospinal fluid (CSF) in patients with CNS infections of various etiologies. After intravenous administration, fosfomycin quickly penetrates the blood-brain barrier (BBB) and is detected in the CSF [2]. During inflammation of the meninges, the degree of penetration through the BBB increases. In the acute phase of the infectious process, after infusion of 4 g of fosfomycin, the average concentrations of the drug in serum and CSF were 65.2 mg/L and 10.88 mg/L, respectively, in the remission phase – 83.58 mg/L and 9.63 mg/L, and at the end of treatment – 66.45 mg/L and 4.95 mg/L, respectively [1]. Thus, fosfomycin can be successfully used for the treatment of bacterial meningitis caused by susceptible bacteria such as S. pneumoniae, Staphylococcus spp., and enterobacteria (E. coli). In CSF of adult patients with bacterial meningitis in the acute phase of the disease, fosfomycin concentration was 25.7% of serum concentrations, whereas for penicillin, this figure was 7.9%, and for ampicillin – 15.9% [3]. J. Stahl et al. [4], using a daily dose of 200 mg/kg intravenously for the treatment of meningitis, measured antibiotic concentrations in the CSF two hours after infusion, which were equal to or exceeded 31 mg/L (on the second day of treatment) and 37.2 mg/L (on the fifth day of antibiotic therapy). When comparing fosfomycin concentrations in CSF of neurosurgical patients after infusion of 5 g of the drug, significant differences were found between patients without meningitis (ranging from 6.48 to 8.98 mg/L) and those with meningitis (ranging from 20.28 to 39.8 mg/L) [5]. Similar data were presented by G. Boulard et al. [6], who found stable concentrations in patients with meningitis ranging from 24.5-27.9 mg/L after administering fosfomycin in doses of 12 g/day for adults and 200 mg/kg/day for children.
During inflammation of the meninges, fosfomycin's penetration through the BBB increases by 300 times (normally, 9.24% (at a dose of 5 g) and 13.81% (at a dose of 10 g) of serum concentrations penetrate through the BBB) [7]. According to the results of pharmacokinetic studies of fosfomycin in adult patients with ventriculitis, receiving 8 g intravenously 3 times daily, the areas under the pharmacokinetic curves in serum and CSF were 929 ± 280 mg·h/L and 225 ± 131 mg·h/L, respectively [8]; important parameters of effective antibiotic action, such as t > MIC, were 98%, 92%, and 61% for pathogens with MIC90 of 8, 16, and 32 mg/L, respectively. The authors concluded that all pharmacokinetic prerequisites for recommending fosfomycin at this dose for treating neuroinfection (specifically, post-operative ventriculitis) were found.
Notably, unlike other antibiotics, fosfomycin has good penetration into abscess contents; one study showed that the concentration of the drug in the purulent contents of abscesses reached 32 mg/L, significantly exceeding the MIC for susceptible microorganisms [9].
Fosfomycin in CNS infection treatment regimens
(According to Katerina G Tsegka, Georgios L Voulgaris, Margarita Kyriakidou & Matthew E Falagas. Intravenous Fosfomycin for the Treatment of Patients With Central Nervous System Infections: Evaluation of the Published Evidence. Expert Rev Anti Infect Ther. 2020 May 13;1-12.)
In May 2020, the Expert Review of Anti-infective Therapy published an interesting article that provides a detailed analysis of the use of intravenous fosfomycin for treating CNS infections.
CNS infections are a group of pathologies characterized by particularly severe clinical courses, where, without appropriate treatment, the mortality rate and incidence of disabling consequences are high. Undoubtedly, CNS infections, depending on their etiology and pathogenesis, require a comprehensive therapeutic approach, with antimicrobial chemotherapy playing a crucial role.
The authors of the article analyzed 32 publications in medical journals related to the use of fosfomycin for treating CNS infections from 1977 to 2019. Eleven articles provided data from prospective studies, and one from a retrospective study. Fosfomycin was used in 224 patients for the treatment of various CNS infections: 123 had bacterial meningitis (including post-traumatic, after neurosurgical interventions, and as a complication of ENT pathology), 39 had brain abscesses, 12 had infections related to ventriculoperitoneal shunts, 3 had brain ventriculitis, 1 had a post-traumatic infectious complication due to aspergilloma, and 46 had unspecified CNS infections.
Microbiological diagnostic data are of interest: Staphylococcus [Staphylococcus aureus, Staphylococcus epidermidis], including MRSA (n = 12) and MRSE (n = 2), were identified in 73 patients; 22 cases were associated with Streptococcus pneumoniae, 12 cases with Neisseria meningitidis, 7 with Escherichia coli, 6 with Haemophilus influenzae, 2 with Bacteroides, 2 with Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases, and 2 with Acinetobacter baumannii. Other identified pathogens included Bacillus cereus, Campylobacter fetus subsp., Citrobacter koseri, XDR Pseudomonas aeruginosa strains (XDR-PA), Aspergillus fumigatus, Enterococcus raffinosus, and Serratia marcescens.
Fosfomycin was used as a first-line treatment in 164 patients, while in other cases, the drug or its combinations with antibiotics from other groups were prescribed after one or more unsuccessful courses of antibiotic therapy.
In monotherapy, fosfomycin was used in 29 patients, while the remaining 195 patients received fosfomycin in combination with other antibiotics. The most commonly used combinations included third- and fourth-generation cephalosporins (with cefotaxime being the most frequent), carbapenems, metronidazole, glycopeptides, and amoxicillin. The advantages of fosfomycin combinations with other antibiotics are evident: fosfomycin has been shown to exhibit synergistic and additive effects, especially in combinations with drugs whose antimicrobial action is also related to the disruption of bacterial cell structural component synthesis.
Fosfomycin dosages were calculated based on body weight (200 mg/kg per day for adults, divided into 3 or 4 doses; for children, doses varied from 100 to 750 mg/kg per day), or fixed doses of 14 to 16 g per day, divided into 3 doses. In some cases, the daily dose was increased to 24 g per day. Various administration regimens were applied, but intravenous infusion was used for high-dose therapy.
The duration of fosfomycin therapy varied from 6 days to 2 months, depending on the severity of the infection.
The most common adverse reactions to fosfomycin were electrolyte disturbances, including hypernatremia, hyponatremia, and hypokalemia with or without metabolic alkalosis.
The clinical effectiveness of fosfomycin in treating CNS infections was high. Among 208 patients for whom disease outcomes were available for evaluation, 195 (93.8%) achieved complete resolution of their CNS infections. Of these, 183 showed no recurrence or neurological consequences; 11 patients had various neurological sequelae, and 1 experienced a recurrence, requiring a repeat course of antibiotic therapy with the same antimicrobial agents. Thirteen patients from the 224 evaluated died, of which 3 deaths were not related to CNS infection, and in 1 case, M. tuberculosis was detected postmortem in the CSF. In 3 other cases, clinical outcomes could not be assessed.
The microbiological effectiveness was evaluated in 142 patients. CSF sterilization was achieved in 138 (97.2%) of them. In one case, microbiological effectiveness was assessed based on eradication of the pathogen from the blood. In the remaining cases, pathogen persistence in the CSF was noted, leading to an unfavorable disease outcome (death).
In conclusion:
References:
1. Drobnic L., Quiles, M., Rodriguez A. A study of the levels of fosfomycin in the cerebrospinal fluid in adult meningitis. Chemotherapy 1977; 23 (Suppl. 1): 180-188.
2. Gallego A., Marin B., Rodriguez A. Farmacodinamia de lafosfomicina I. Estudios en animales. Actas XII Reunion Soc Esp Ciene Fisiol, Santiago de Compostela 1970; 225-228.
3. Sicilia T, Estevez E., Rodriguez A. Fosfomycin penetration into the cerebrospinal fluid of patients with bacterial meningitis. Chemotherapy 1981; 27: 405-413.
4. Stahl J.P., Croize J., Bru J.P. et al. Diffusion de lafosfomycine dans le liquide cephalo-rachidien au cours des meningites purulentes. Presse Med 1984; 13: 2693-2695.
5. Friedrich H., Engel E., Potel J. Fosfomycin levels in the cerebrospinal fluid of patients with and without meningitis. Immun Infekt 1987; 15: 98-102.
6. Boulard G., Quentin C., Scontrini G., Dautheribes M,. Pouguet P, Sabathie M. Traitement des ventriculites a Staphylococcus epidermidis sur materielpar l’association fosfomycine-aminoside. Evolution des taux ventriculaires de fosfomycine. Pathol Biol Paris 1983; 31: 525-527.
7. Kuhnen E., Pfeifer G., Frenkel C. Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges. Infection 1987; 15: 422- 424.
8. Pfausler B., Spiss H., Dittrich P., Zeitlinger M., Schmutzhard E., Joukhadar C. Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis. J Antimicrob Chemother. 2004 May;53(5):848-52.
9. Sauermann R, Karch R, Langenberger H, et al. Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles. Antimicrob Agents Chemother. 2005 Nov;49(11):4448–4454.
Currently, there is a sufficient amount of clinical and experimental research aimed at studying the concentrations of fosfomycin in cerebrospinal fluid (CSF) in patients with CNS infections of various etiologies. After intravenous administration, fosfomycin quickly penetrates the blood-brain barrier (BBB) and is detected in the CSF [2]. During inflammation of the meninges, the degree of penetration through the BBB increases. In the acute phase of the infectious process, after infusion of 4 g of fosfomycin, the average concentrations of the drug in serum and CSF were 65.2 mg/L and 10.88 mg/L, respectively, in the remission phase – 83.58 mg/L and 9.63 mg/L, and at the end of treatment – 66.45 mg/L and 4.95 mg/L, respectively [1]. Thus, fosfomycin can be successfully used for the treatment of bacterial meningitis caused by susceptible bacteria such as S. pneumoniae, Staphylococcus spp., and enterobacteria (E. coli). In CSF of adult patients with bacterial meningitis in the acute phase of the disease, fosfomycin concentration was 25.7% of serum concentrations, whereas for penicillin, this figure was 7.9%, and for ampicillin – 15.9% [3]. J. Stahl et al. [4], using a daily dose of 200 mg/kg intravenously for the treatment of meningitis, measured antibiotic concentrations in the CSF two hours after infusion, which were equal to or exceeded 31 mg/L (on the second day of treatment) and 37.2 mg/L (on the fifth day of antibiotic therapy). When comparing fosfomycin concentrations in CSF of neurosurgical patients after infusion of 5 g of the drug, significant differences were found between patients without meningitis (ranging from 6.48 to 8.98 mg/L) and those with meningitis (ranging from 20.28 to 39.8 mg/L) [5]. Similar data were presented by G. Boulard et al. [6], who found stable concentrations in patients with meningitis ranging from 24.5-27.9 mg/L after administering fosfomycin in doses of 12 g/day for adults and 200 mg/kg/day for children.
During inflammation of the meninges, fosfomycin's penetration through the BBB increases by 300 times (normally, 9.24% (at a dose of 5 g) and 13.81% (at a dose of 10 g) of serum concentrations penetrate through the BBB) [7]. According to the results of pharmacokinetic studies of fosfomycin in adult patients with ventriculitis, receiving 8 g intravenously 3 times daily, the areas under the pharmacokinetic curves in serum and CSF were 929 ± 280 mg·h/L and 225 ± 131 mg·h/L, respectively [8]; important parameters of effective antibiotic action, such as t > MIC, were 98%, 92%, and 61% for pathogens with MIC90 of 8, 16, and 32 mg/L, respectively. The authors concluded that all pharmacokinetic prerequisites for recommending fosfomycin at this dose for treating neuroinfection (specifically, post-operative ventriculitis) were found.
Notably, unlike other antibiotics, fosfomycin has good penetration into abscess contents; one study showed that the concentration of the drug in the purulent contents of abscesses reached 32 mg/L, significantly exceeding the MIC for susceptible microorganisms [9].
Fosfomycin in CNS infection treatment regimens
(According to Katerina G Tsegka, Georgios L Voulgaris, Margarita Kyriakidou & Matthew E Falagas. Intravenous Fosfomycin for the Treatment of Patients With Central Nervous System Infections: Evaluation of the Published Evidence. Expert Rev Anti Infect Ther. 2020 May 13;1-12.)
In May 2020, the Expert Review of Anti-infective Therapy published an interesting article that provides a detailed analysis of the use of intravenous fosfomycin for treating CNS infections.
CNS infections are a group of pathologies characterized by particularly severe clinical courses, where, without appropriate treatment, the mortality rate and incidence of disabling consequences are high. Undoubtedly, CNS infections, depending on their etiology and pathogenesis, require a comprehensive therapeutic approach, with antimicrobial chemotherapy playing a crucial role.
The authors of the article analyzed 32 publications in medical journals related to the use of fosfomycin for treating CNS infections from 1977 to 2019. Eleven articles provided data from prospective studies, and one from a retrospective study. Fosfomycin was used in 224 patients for the treatment of various CNS infections: 123 had bacterial meningitis (including post-traumatic, after neurosurgical interventions, and as a complication of ENT pathology), 39 had brain abscesses, 12 had infections related to ventriculoperitoneal shunts, 3 had brain ventriculitis, 1 had a post-traumatic infectious complication due to aspergilloma, and 46 had unspecified CNS infections.
Microbiological diagnostic data are of interest: Staphylococcus [Staphylococcus aureus, Staphylococcus epidermidis], including MRSA (n = 12) and MRSE (n = 2), were identified in 73 patients; 22 cases were associated with Streptococcus pneumoniae, 12 cases with Neisseria meningitidis, 7 with Escherichia coli, 6 with Haemophilus influenzae, 2 with Bacteroides, 2 with Klebsiella pneumoniae strains producing extended-spectrum beta-lactamases, and 2 with Acinetobacter baumannii. Other identified pathogens included Bacillus cereus, Campylobacter fetus subsp., Citrobacter koseri, XDR Pseudomonas aeruginosa strains (XDR-PA), Aspergillus fumigatus, Enterococcus raffinosus, and Serratia marcescens.
Fosfomycin was used as a first-line treatment in 164 patients, while in other cases, the drug or its combinations with antibiotics from other groups were prescribed after one or more unsuccessful courses of antibiotic therapy.
In monotherapy, fosfomycin was used in 29 patients, while the remaining 195 patients received fosfomycin in combination with other antibiotics. The most commonly used combinations included third- and fourth-generation cephalosporins (with cefotaxime being the most frequent), carbapenems, metronidazole, glycopeptides, and amoxicillin. The advantages of fosfomycin combinations with other antibiotics are evident: fosfomycin has been shown to exhibit synergistic and additive effects, especially in combinations with drugs whose antimicrobial action is also related to the disruption of bacterial cell structural component synthesis.
Fosfomycin dosages were calculated based on body weight (200 mg/kg per day for adults, divided into 3 or 4 doses; for children, doses varied from 100 to 750 mg/kg per day), or fixed doses of 14 to 16 g per day, divided into 3 doses. In some cases, the daily dose was increased to 24 g per day. Various administration regimens were applied, but intravenous infusion was used for high-dose therapy.
The duration of fosfomycin therapy varied from 6 days to 2 months, depending on the severity of the infection.
The most common adverse reactions to fosfomycin were electrolyte disturbances, including hypernatremia, hyponatremia, and hypokalemia with or without metabolic alkalosis.
The clinical effectiveness of fosfomycin in treating CNS infections was high. Among 208 patients for whom disease outcomes were available for evaluation, 195 (93.8%) achieved complete resolution of their CNS infections. Of these, 183 showed no recurrence or neurological consequences; 11 patients had various neurological sequelae, and 1 experienced a recurrence, requiring a repeat course of antibiotic therapy with the same antimicrobial agents. Thirteen patients from the 224 evaluated died, of which 3 deaths were not related to CNS infection, and in 1 case, M. tuberculosis was detected postmortem in the CSF. In 3 other cases, clinical outcomes could not be assessed.
The microbiological effectiveness was evaluated in 142 patients. CSF sterilization was achieved in 138 (97.2%) of them. In one case, microbiological effectiveness was assessed based on eradication of the pathogen from the blood. In the remaining cases, pathogen persistence in the CSF was noted, leading to an unfavorable disease outcome (death).
In conclusion:
Fosfomycin is a bactericidal broad-spectrum antibiotic effective against many Gram-positive and Gram-negative pathogens, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) isolates. Its mechanism of action is unique, and its pharmacokinetics show sufficient distribution in the CNS, making it an attractive therapeutic choice for treating CNS infections.- Fosfomycin for intravenous use should preferably be used in combination therapy for CNS infections.
- The most commonly used dose of fosfomycin for intravenous administration in CNS infections is 14-16 g per day. In some cases, the daily dose can be increased to 24 g.
- Fosfomycin for intravenous use is a safe and effective drug and may be recommended for the treatment of bacterial CNS infections in combination with other antibiotics.
References:
1. Drobnic L., Quiles, M., Rodriguez A. A study of the levels of fosfomycin in the cerebrospinal fluid in adult meningitis. Chemotherapy 1977; 23 (Suppl. 1): 180-188.
2. Gallego A., Marin B., Rodriguez A. Farmacodinamia de lafosfomicina I. Estudios en animales. Actas XII Reunion Soc Esp Ciene Fisiol, Santiago de Compostela 1970; 225-228.
3. Sicilia T, Estevez E., Rodriguez A. Fosfomycin penetration into the cerebrospinal fluid of patients with bacterial meningitis. Chemotherapy 1981; 27: 405-413.
4. Stahl J.P., Croize J., Bru J.P. et al. Diffusion de lafosfomycine dans le liquide cephalo-rachidien au cours des meningites purulentes. Presse Med 1984; 13: 2693-2695.
5. Friedrich H., Engel E., Potel J. Fosfomycin levels in the cerebrospinal fluid of patients with and without meningitis. Immun Infekt 1987; 15: 98-102.
6. Boulard G., Quentin C., Scontrini G., Dautheribes M,. Pouguet P, Sabathie M. Traitement des ventriculites a Staphylococcus epidermidis sur materielpar l’association fosfomycine-aminoside. Evolution des taux ventriculaires de fosfomycine. Pathol Biol Paris 1983; 31: 525-527.
7. Kuhnen E., Pfeifer G., Frenkel C. Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges. Infection 1987; 15: 422- 424.
8. Pfausler B., Spiss H., Dittrich P., Zeitlinger M., Schmutzhard E., Joukhadar C. Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis. J Antimicrob Chemother. 2004 May;53(5):848-52.
9. Sauermann R, Karch R, Langenberger H, et al. Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles. Antimicrob Agents Chemother. 2005 Nov;49(11):4448–4454.
