Concentrations of fosfomycin in the cerebrospinal fluid of neurointensive care patients with ventriculostomy-associated ventriculitis.

OBJECTIVE: The present study was performed to test the ability of fosfomycin to penetrate into the CSF of neurointensive care patients with ventriculostomy-associated ventriculitis. PATIENTS AND METHODS: Six patients requiring neurointensive care monitoring, including extraventricular drainage due to secondary obstructive hydrocephalus, were enrolled into the study. All patients received 8 g of fosfomycin intravenously three times a day over a period of at least 5 days. Concentrations of fosfomycin in the CSF and plasma were measured after single-dose administration and at steady state. RESULTS: Mean values of the fosfomycin area under the time-concentration curves for the dosing interval of 8 h (AUC(8)) were 929 +/- 280 and 225 +/- 131 mg.h/L for plasma and CSF after single-dose administration, respectively (P < 0.03). The ratios of the AUC(8) for CSF to the AUC(8) for plasma were 0.23 +/- 0.07 after a single dose and 0.27 +/- 0.08 following multiple doses (P > 0.05, not significant). Additional in vitro experiments have shown that fosfomycin exerts non-concentration-dependent microbial growth inhibition. At steady state, the time above MIC (t > MIC) values were 98%, 92% and 61% for pathogens with MIC values of 8, 16 and 32 mg/L, respectively. CONCLUSION: The present pharmacokinetic study indicates that 8 g of fosfomycin three times per day should provide sufficient antimicrobial concentrations in the CSF for the overall treatment period. Thus, the co-administration of fosfomycin could be useful for the treatment of ventriculitis caused by susceptible pathogens.

Determination of fosfomycin in biological fluids by capillary electrophoresis.

A capillary electrophoresis method was developed for the determination of the antibiotic fosfomycin in serum, cerebrospinal fluid and aqueous humor. The technique uses indirect UV detection and the working buffer includes an organic cation to improve fosfomycin mobility. The electrophoretic time of migration is less than 7 min in both fluids. The limit of quantification is 2.5 and 1 microgram/ml in serum and aqueous fluids, respectively (signal-to-noise ratio = 3). The method was validated in serum and water over the concentration range 2.5-200 micrograms/ml. The calibration graph for serum was linear with a correlation coefficient r = 0.999. At a fosfomycin concentration of 2.5 micrograms/ml in serum, the intra- and inter-day precisions (coefficients of variation) were 5 and 5.2%, respectively. The mean recovery in serum was 94.5% (S.D. = 2.4%).

[Treatment with a cefotaxime-fosfomycin combination of staphylococcal or enterobacterial meningitis in adults]. / Traitement par l'association céfotaxime-fosfomycine des méningites de l'adulte à staphylocoques ou à entérobactéries.

Thirty-two patients were included in this trial: 22 with staphylococcal meningitis (including 5 methicillin-resistant) and 10 with enterobacterial meningitis. Mean duration of treatment was 14.5 and 15.9 days respectively. The combination was synergistic in vitro against 10 of the 12 strains of Staphylococcus and 5 of the 6 strains of Enterobacteriaceae studied. Bacteriological sterilization occurred in all cases which could be evaluated, and clinical recovery was obtained in 95.2% of patients with staphylococcal meningitis (4 unrelated deaths) and 100% of patients with enterobacterial meningitis (2 deaths). Bactericidal power of the cerebro-spinal fluid, often less than 1/8, was not correlated with effectiveness against Staphylococci. Mean CSF concentrations of cefotaxime, desacetylcefotaxime and fosfomycin on the 2nd and 15th days of treatment were 4, 3.5 and 39.8 mg/l and 2.2, 2.1 and 28.0 mg/l, respectively. Clinical and biological acceptability was satisfactory. There were three cases of superinfection or colonization, by Pseudomonas and Enterobacter.

Penetration of fosfomycin into cerebrospinal fluid across non-inflamed and inflamed meninges.

Serum and cerebrospinal fluid (CSF) concentrations of fosfomycin were evaluated in 45 patients. Mean serum concentration was 260.1 mg/l at 15 min postinfusion in 35 patients receiving a 5 g bolus dose, and 440 mg/l in five patients receiving a 10 g bolus dose. Mean distribution volume was 18.5 l (5 g dose), the total clearance was 118.8 ml/min, half-life was nearly 2 h, and the determined AUC were 420.95 mg/l.h (5 g dose) and 423.57 mg/l.h (10 g dose). The average peaks at 360 min in CSF reached 11.6 mg/l (5 g dose) and 17.7 mg/l (10 g dose). The CSF/serum ratio was 9.24% (5 g dose), and 13.81% (10 g dose). The CSF levels were not below 30 mg/l from the second day on in patients receiving 3 X 5 g fosfomycin per day. Meningeal inflammation increased the CSF concentrations from 30 mg/l at 6 h up to 150 mg/l at 120 h in the saturation phase, e. g., up to 300% more in comparison to non-inflamed meninges.

[Fosfomycin levels in the cerebrospinal fluid of patients with and without meningitis]. / Fosfomycinspiegel im Liquor bei Patienten mit und ohne Meningitis.

18 neurosurgical patients were given 15 g fosfomycin at 8-hour intervals. Simultaneously serum and cerebrospinal fluid (CSF) concentrations were determined periodically over 8 hrs. In patients with noninflamed meninges the CSF-concentrations ranged between 6.48 and 8.98 micrograms/ml. In patients with meningitis the CSF-levels amounted to 20.28 and 39.80 micrograms/ml. For perioperative short-time prophylaxis and postoperative infections in neurosurgical patients therapeutically relevant fosfomycin levels against Staph. aureus und Staph. epidermidis can be achieved.

[Treatment of neurosurgical bacterial meningitis using the combination of ceftriaxone-fosfomycin]. / Traitement des méningites bactériennes neurochirurgicales par l'association ceftriaxone-fosfomycine.

16 patients with bacterial meningitis following a neurosurgical procedure were given a combination of ceftriaxone and fosfomycin. 8 microorganism were isolated: 2 Staphylococcus epidermidis, 1 Staphylococcus aureus, 1 Neisseria meningitidis, 1 Streptococcus pneumoniae, 1 Haemophilus influenzae, 1 Serratia marcescens and 1 Aeromonas hydrophila. No pathogen was identified in the remaining cases. All of the isolated strains were susceptible to both antibiotics. In vitro, neither synergy nor antagonism were observed between the two antimicrobial agents. The acute infectious episode resolved in all patients. One relapse only was observed, in a patient with meningitis related to a ventricular shunt, and successfully treated by the same therapeutic schedule associated with removal of the tubing. Lastly, CSF concentrations of both antibiotics were assayed and found to be comparable with those reported by most author.

Pharmacokinetic aspects of cerebrospinal fluid penetration of fosfomycin.

Even today antibiotic therapy of postoperative or posttraumatic meningitis remains a problem. In patients in a neurosurgical intensive care unit, nosocomial microorganisms with high resistance are mainly found. There are no antibiotics available which have simultaneously a good efficacy on the higher resistant nosocomial microorganisms and a good penetration through the blood-brain or blood-cerebrospinal fluid barrier. We analysed the cerebrospinal fluid (CSF) penetration of fosfomycin carrying out the investigations in patients in whom a CSF drainage was required for a neurosurgical indication. The blood-brain barrier was considered to be largely intact (total CSF protein and cell counts with in the normal range). Five or 10 g fosfomycin were administered to adults in 30 min infusions. After administration of 5 g, the CSF concentration formed a plateau between 8.6 and 9.9 micrograms/ml 3 to 6 h after the infusion. Increasing the dose infused (10 g) markedly shortened the latency period between reaching a sufficient concentration of fosfomycin in the CSF. With repeated doses of fosfomycin (3 X 5 g/day) the concentration in the CSF did not fall below the therapeutic level. Even in the presence of an intact blood-brain barrier, fosfomycin in our investigation showed a satisfactory penetration into the CSF. This is attributable to the favourable physicochemical state of fosfomycin (relative molecular mass 182).

Bactericidal activity of cefotaxime and fosfomycin in cerebrospinal fluid during the treatment of rabbit meningitis experimentally induced by methicillin-resistant Staphylococcus aureus.

The purpose of this study was to evaluate the therapeutic effect of cefotaxime (CTX) and fosfomycin (FOS), alone or in combination, in an experimental meningitis, with cerebrospinal fluid (CSF) concentrations of the two antibiotics reproducing those obtained in human CSF during bacterial meningitis. With a dose of 50 mg/kg of CTX and 100 mg/kg of FOS injected i.v. (CTX over 0.5 h and FOS over 3 h), CSF concentrations were comparable to those observed in man. In a series of five rabbits per treatment group, the bacterial population was counted before and after treatment (two doses with a six-hour interval) with CTX, FOS or CTX + FOS (CTX over 0.5 h before the end of FOS infusion). By the 12th hour of treatment, the percentage of bacteria surviving in CSF compared to the initial population was 4.35% for CTX, 0.20% for FOS and 0.19% for CTX + FOS. Thus, it seemed that CTX + FOS was not more active than FOS alone. In another series of four rabbits per group, the bactericidal effect was followed at T0, T6, T12, T24 and T48 after treatment (two doses with a six-hour with a six-hour interval). With CTX, a variable drop in bacterial count from one rabbit to the other occurred during the first 12 h, and then a bacteriostasis followed. With FOS, a quick bactericidal effect was observed during the first 12 h, becoming slower during the following 36 h (0.03% of bacteria surviving at the 48th hour). With CTX and FOS in combination, a quick bactericidal effect was achieved, remaining steady over a 48-hour period (0.001% of bacteria surviving at the 48th hour).

[Diffusion of fosfomycin into the cerebrospinal fluid in purulent meningitis]. / Diffusion de la fosfomycine dans le liquide céphalo-rachidien au cours des méningites purulentes.

Cerebrospinal fluid levels of fosfomycin were measured in 10 patients with bacterial meningitis. Fosfomycin 200 mg/kg/day was administered in three 4-hour intravenous infusions. The antibiotic was associated with amoxicillin in 9 patients and with cefotaxime in one. Cerebrospinal fluid was obtained on the 2nd and 5th days of treatment, 2 hours after the end of the infusion. The mean CSF fosfomycin levels were 31 mg/l on the 2nd day and 37.2 mg/l on the 5th day. These levels were higher than the MIC 90 for most bacteria encountered in meningitis. Fosfomycin could be used to treat some cases of bacterial meningitis, but always in association with another antibiotic.

[Cerebrospinal fluid diffusion kinetics of cefotaxime and fosfomycin in Staphylococcus aureus meningitis with otorrhea]. / Etude de la cinétique de diffusion dans le liquide céphalo-rachidien du céfotaxime et de la fosfomycine au cours d'une méningite à staphylocoque doré avec otorrhée.

A case of post-traumatic meningitis with otorrhea due to Staphylococcus aureus was successfully treated with a cefotaxim-fosfomycin (CTX-FOS) combination. Serial samples of CSF leaking from the ear showed that maximal concentrations of CTX and FOS, 3.24 mg/l and 19.10 mg/l respectively, occurred one hour after the infusion of both antibiotics was terminated. For desacetyl-cefotaxim (D-CTX), maximal concentration (1.24 mg/l) occurred two hours later. These findings suggest that lumber puncture to control maximal penetration of CTX and FOS into CSF should be done one hour after infusion of both antibiotics.

[Treatment of ventriculitis caused by Staphylococcus epidermidis on equipment with the combination of fosfomycin and an aminoglycoside. Course of ventricular levels of fosfomycin]. / Traitement des ventriculites à Staphylococcus epidermidis sur matériel par l'association fosfomycine-aminoside. Evolution des taux ventriculaires de fosfomycine.

Five patients (4 adults and 1 child) with cerebrospinal fluid shunt infections caused by Staphylococcus epidermidis were successfully treated by fosfomycin combined with an aminoglycoside. Fosfomycin was given intravenously over 4 hours 3 times a day. The antibiotic dose was 12 g/day for adults and 200 mg/kg/day for the child. In 3 patients with an external CSF drainage system, serum and ventricular fluid samples were obtained before and after one infusion during 10 days. The serum concentrations varied greatly (48,12 +/- 31,47 and 115,07 +/- 46,5 micrograms/ml. However the drug levels in ventricular fluid were constant and similar for the 3 patients (24,48 +/- 10,28 à 27,87 +/- 8,58 micrograms/ml), well above the MICS (1 and 2 micrograms/ml).

[Transfer of fosfomycin into the cerebrospinal fluid].

After the fosfomycin (FOM) infusion, its levels in serum and cerebrospinal fluid (CSF) were repeatedly measured in 8 cases without meningitis. 1. The peak concentration of FOM in CSF was 15.5 micrograms/ml with the average of 10.3 micrograms/ml and was reached at 240 minutes with the average of 210 minutes after the infusion. The biological half life time of FOM in CSF was 2 to 6.5 hours. 2. The peak concentration in CSF was compared with it in serum. The average ratio was 4.3 per cent. Each area under the curve (AUC) of FOM concentration in CSF and serum was calculated and average of their ratio was 9.0 per cent. 3. In a case with middle cerebral artery aneurysm, FOM transferred into CSF with ease. The lowest diffusion into the CSF was shown in 2 cases of meningioma. In 3 cases of hypertensive intracerebral hemorrhage with intraventricular perforation, FOM moderately transferred into CSF.

Fosfomycin penetration into the cerebrospinal fluid of patients with bacterial meningitis.

A comparative study was made of the penetration of fosfomycin, penicillin G, ampicillin and chloramphenicol into the cerebrospinal fluid of patients with meningitis treated with combinations of fosfomycin and one of the other three antibiotics. Minimal inhibitory concentrations and in vitro interaction of these antibiotics against Streptococcus pneumoniae and Neisseria meningitidis strains were determined. 90-96.5% of these strains were sensitive to penicillin G, 95-96.5% to ampicillin, 85-100% to chloramphenicol and 90-100% to fosfomycin. Fosfomycin shows a more marked synergism with penicillin G or ampicillin than with chloramphenicol against both bacterial species. The percentages of penetration into the cerebrospinal fluid were: chloramphenicol, 32%; fosfomycin, 25.7%; ampicillin, 15.9%, and penicillin G, 7.9%. The clinical results show that the combination of fosfomycin + penicillin G or fosfomycin + ampicillin can be an alternative in the treatment of meningitis produced by moderately susceptible strains of S. pneumoniae and N. meningitidis to penicillin G and ampicillin.

A study of the levels of fosfomycin in the cerebrospinal fluid in adult meningitis.

In order to determine the liquor concentration of fosfomycin, we chose 27 patients who were suffering from meningitis with different etiology. According to route, type of administration and doses employed, we classified the patients into five groups. Blood samples were taken from the patients 1 h after concluding the administration of the antibiotic and 2 h after the CSF sample. The concentration of fosfomycin in the serum and the CSF were then determined in the laboratory. In order to evaluate the results we divided our cases into three groups according to the state of their meningeal inflammation. In the first group of patients with active meningitis, we obtained an average concentration of fosfomycin in the serum of 65.20 mug/ml and in the CSF of 10.88 mug/ml. In the second group of patients with meningitis in the remission stage, the concentration of fosfomycin in the serum was 83.58 mug/ml and in the CSF it was 9.63 mug/ml. In the third group of patients with their meningitis cured, the concentration of fosfomycin in the serum was 66.45 mug/ml and in the CSF it was 4.95 mug/ml. On the basis of the concentrations obtained and with regard to the sensitivity in vitro, we concluded that fosfomycin can be useful in the treatment of meningitis caused by Pneumococcus, Staphylococcus, E. coli and other gram-negative bacilli.

The passage of fosfomycin into the cerebrospinal fluid in children's meningitis.

This report deals with the results of a study that was made on the passage of fosfomycin into the CSF in 22 children with meningitis (11 parotideal meningitis and 11 meningococcal meningitis). The plasma and liquor levels of fosfomycin were determined in the acute phase of the illness and after the normalization of the CSF, with the object of studying the passage of the antibiotic through the blood-brain barrier in the presence and absence of meningeal inflammation. A greater permeability of the meninges was found to exist when they were in an inflammatory state and there seems to be a certain accumulative effect in the CSF when the fosfomycin is administered by intravenous perfusion. The concentrations that were obtained in the CSF were not high enough to justify the exclusive use of fosfomycin in the treatment of meningitis. Nevertheless, considering its wide antibacterial spectrum, its MIC against different microbial species and its lack of toxicity, we believe that fosfomycin can be of use when associated with other antibiotics in the treatment of meningitis caused by S. aureus, D. pneumoniae, H. influenzae, E. coli, P. mirabilis and S. marcescens.