fosfomycin and Meningitis--Pneumococcal

To study the in vitro and in vivo efficacy of fosfomycin, alone and in combination with ceftriaxone or vancomycin, against two strains of Streptococcus pneumoniae: HUB 2349 (fosfomycin and ceftriaxone, MICs 16 and 2 mg/L) and ATCC 51916 (MICs 4 and 32 mg/L).. Pharmacokinetics/pharmacodynamics data were collected from the study of eight infected animals after a single intravenous dose of 300 mg/kg of fosfomycin. Time-kill curves were plotted using CSF antibiotic concentrations achievable clinically. In the rabbit model, we studied the efficacy and effects on inflammation of treatment with fosfomycin 1200 mg/kg/day, ceftriaxone 100 mg/kg/day and vancomycin 30 mg/kg/day, over 26 h.. Fosfomycin peak level in serum was 324.48 +/- 102.1 mg/L at 0.5 h; CSF penetration was 49.2%. Time-kill curves showed that fosfomycin was bactericidal against the ATCC 51916 strain and that the addition of fosfomycin to ceftriaxone or vancomycin was synergic against the HUB 2349 strain. Resistance to fosfomycin was detected both when fosfomycin was studied alone and in combination. In the rabbit model, fosfomycin showed bactericidal activity only against the ATCC 51916 strain. Combinations of fosfomycin with ceftriaxone or vancomycin were bactericidal against both strains; they improved efficacy and decreased CSF inflammatory parameters over monotherapies, without showing statistical differences in comparison with the combination of ceftriaxone and vancomycin.. Fosfomycin in combination with ceftriaxone or vancomycin appeared to be effective for the treatment of experimental cephalosporin-resistant pneumococcal meningitis. These combinations are possible alternatives in cases of allergy or intolerance to first-line drugs or in rare meningitis caused by highly cephalosporin-resistant pneumococci.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporin Resistance; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Fosfomycin; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae; Vancomycin

In 1999, in Rhône-Alpes region, in a survey of resistance to antibiotics of Streptococcus pneumoniae, 35 cases of meningitis were observed. A retrospectic questionnary was sent to each participant. MICs to Penicillin, Amoxicillin and Cefotaxime were determined with ATB-PNEUMO gallery or E-test and by disk diffusion for the other antibiotics. The results were interpreted according to the recommendations of the CA-SFM. Mean age was 38.1 years (range : 1 month -78 years) and sex-ratio 2/5. Eight patients had previously received antibiotics, 22 patients had risk factors and 23 were transferred in intensive care unit. The patients received C3G + glycopeptide in 15 of 16 children and in 13/19 adults according to the consensus recommendations. Diagnostic was made on the direct examination of CSF in 83%, and blood cultures was positive in 74.3% of cases. The percentage of PRP was 48.6% with 17.1% of intermediate-amoxicilline and 14.3% intermediate-cefotaxime strains. Resistance to trimethoprim-sulfamethoxazole was 45.7%, to chloramphenicol 30% and to fosfomycin 6.9%. All the strains were susceptible to rifampicin and vancomycin. Among the 17 PRP strains, 7 were belonging to serotype 6 (6 in children). The clinical outcome was fatal in 7 male cases (20%), without risk factors in 3 children and 6 of 7 strains were susceptible to penicillin. Six patients (17%) had auditive and/or neurologic sequellaes. This study shows that nearly 50% of strains isolated in meningitis, in Rhône-Alpes region, were not susceptible to penicillin, and confirms the frequency of sequellaes while the mortality is not related with the resistance of strains to the antibiotics.

Topics: Adolescent; Adult; Aged; Amoxicillin; Cefotaxime; Child; Child, Preschool; Chloramphenicol; Drug Resistance, Microbial; Female; Fosfomycin; France; Humans; Infant; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Penicillins; Retrospective Studies; Rifampin; Surveys and Questionnaires; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Topics: Cefotaxime; Fosfomycin; Meningitis, Pneumococcal

Fosfomycin is an antibacterial substance of low molecular weight and negligible binding to plasma proteins exhibiting in-vitro activity against most pathogens involved in bacterial meningitis including pneumococci. Due to these properties the drug has been recommended for therapy of central nervous system (CNS) infections. For this reason, fosfomycin at doses of 10, 40, 80 and 160 mg/kg/h iv, was investigated in the rabbit model of pneumococcal meningitis. Bacterial counts in cerebrospinal fluid (CSF) before, and 2, 5 and 8 h after initiation of therapy were quantitated by plating on blood agar. Fosfomycin concentrations in serum and CSF were determined by the agar well diffusion method. The MIC and MBC of fosfomycin for the Streptococcus pneumoniae type 3 strain used was 4 and 32 mg/L, respectively. The MIC of ceftriaxone was 0.016 mg/L. In vitro, both drugs showed an additive effect (fractional inhibitory concentration index = 0.75). In vivo at each dose tested, fosfomycin was less active than ceftriaxone (means +/- S.D.): delta log cfu/mL/h at 10 mg/kg/h + 0.130 +/- 0.062 (n = 2), at 40 mg/kg/h -0.217 +/- 0.185 (n = 3), at 80 mg/kg/h -0.270 +/- 0.121 (n = 3), at 160 mg/kg/h -0.331 +/- 0.118 (n = 3) vs -0.647 +/- 0.193 at 10 mg/kg/h ceftriaxone (n = 3). CSF penetration of fosfomycin as estimated by the CSF-to-serum concentration ratio at 8 h was 0.55 +/- 0.22 (n = 11). For bactericidal activity CSF concentrations of at least ten times the MIC were necessary. Coadministration of both drugs (1 mg/kg/h ceftriaxone + 40 mg/kg/h fosfomycin) tended to be more active than either drug alone (in-vivo drug interaction = 1.3). In conclusion, fosfomycin at very high doses reduced bacterial counts in CSF. However, fosfomycin CSF concentrations usually observed in patients with meningitis receiving fosfomycin were not bactericidal in this model. At all doses tested the bactericidal rate was lower than that of ceftriaxone. Fosfomycin is therefore unsuitable as a single agent, but may be used as a reserve antibiotic in combination with a newer cephalosporin for pneumococcal meningitis unresponsive to conventional therapy.

Topics: Animals; Anti-Bacterial Agents; Blood Bactericidal Activity; Cerebrospinal Fluid; Disease Models, Animal; Dose-Response Relationship, Drug; Fosfomycin; Glucose-6-Phosphate; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcal Infections; Streptococcus pneumoniae

In the years 1970 to 1979 312 patients with purulent meningitis were treated at the University of Innsbruck, Department of Pediatrics. The overall fatality rate was 16%, the majority of fatal cases were due to gram negative organisms before 1977. The mortality rate of meningococcal meningitis due to H. influenzae was 5.6 and 1.6%, respectively and compares very well to reports in the literature. 12% of children are severely handicapped. Hearing impairment is the most frequent cause of retardation with 6.8%. We compared therapeutic results of two different treatment regimen in our clinic with the therapeutic results in other centers reported in the literature. The combination of ampicillin and chloramphenicol was superior to other treatment modalities particularly ampicillin monotherapy in H. influenzae meningitis and meningitis due to unknown organisms. Theoretical reservations against this combination have been eliminated by the proof of the bactericidal action of chloramphenicol against the most common meningeal pathogens and the synergistic action with beta lactam antibiotics. In pneumococcal meningitis the administration of high doses of Na-Penicillin G as i. v. bolus proved to be connected with unexpected complications and fatalities. The administration of 25000-40000 E Na Penicillin G as an i. v. infusion over 1 hour 4--6 times daily was a less hazardous yet effective therapy. Unsatisfying results in the treatment of gram negative meningitis in neonates prompted the investigation of a new compound fosfomycin for this indication. In vitro investigation of the antimicrobial activity against 68 meningeal pathogens and investigation of this drug in a lapine model showed encouraging results. In the last years a limited clinical trial in severely affected newborn infants was done with promising therapeutic efficacy. A larger scale investigation of this drug is now proceeding in form of a National cooperative Study of gram negative meningitis in Austria. Besides an effective antimicrobial treatment particular attention has to be paid to an adequate fluid and electrolyte replacement. Symptomatic therapy of complications e. g. seizures as well as continuous close monitoring of all vital signs is mandatory for optimal therapeutic success. Subdural effusions have been observed infrequently and only diagnostic subdural punctures have been performed.

Topics: Ampicillin; Child; Child, Preschool; Chloramphenicol; Cortisone; Electrolytes; Fluid Therapy; Fosfomycin; Humans; Infant; Meningitis; Meningitis, Haemophilus; Meningitis, Pneumococcal; Penicillin G; Prognosis; Shock, Septic

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.

Topics: Aged; Anti-Bacterial Agents; Child, Preschool; Drug Interactions; Female; Fosfomycin; Humans; Infant; Male; Meningitis; Meningitis, Meningococcal; Meningitis, Pneumococcal; Middle Aged; Neisseria meningitidis; Streptococcus pneumoniae

A study has been made of 12 patients with pneumococcal meningitis with ages ranging from 12 months to 59 years. In all cases pneumococcus was isolated in the cerebrospinal fluid (CSF). Seventeen pneumococci were studied for their sensitivity to fosfomycin, ampicillin and gentamicin, including their MIC. All were sensitive to fosfomycin and ampicillin and 7 to gentamicin. On the other hand there has also been made a study of the interaction between fosfomycin plus ampicillin and fosfomycin plus gentamicin. The concentration of antibiotics in plasma and CSF had been determined. The association of fosfomycin to penicillin or ampicillin was also studied in some cases, depending on whether the patient was younger or older than 2 years, and in other cases, the association of fosfomycin with gentamicin. The concentrations of antibiotics in the CSF varied according to the stage of evolution of the meningitis. As regards clinical results, 10 cures and 2 failures have been obtained. The pneumococcus was eradicated from the CSF in all cases, including the two failures, in the control carried out 2-3 days after beginning of treatment, the rest of the analytical data of the CSF became normal within 5 and 17 days treatment.

Topics: Adult; Ampicillin; Cerebrospinal Fluid; Child; Drug Interactions; Drug Therapy, Combination; Female; Fosfomycin; Gentamicins; Humans; Infant; Male; Meningitis, Pneumococcal; Middle Aged; Penicillin Resistance; Streptococcus pneumoniae