ro13-9904 and Meningitis--Pneumococcal

We present the cases of two otherwise healthy adults, one with meningitis and another with a subdural abscess, with both conditions attributable to

Topics: Abscess; Adult; Aged; Ceftriaxone; Humans; Male; Meningitis, Pneumococcal; Streptococcus pneumoniae; Vancomycin

Topics: Amiodarone; Autoimmunity; Blepharoptosis; Ceftriaxone; Cerebrospinal Fluid; Delayed Diagnosis; Dexamethasone; Emergencies; Female; Fever; Heart Valve Prosthesis Implantation; Humans; Hypoxia; Immunocompetence; Magnetic Resonance Imaging; Meningitis, Pneumococcal; Myelitis; Oxygen Inhalation Therapy; Postoperative Complications; Quadriplegia; Spinal Cord; Streptococcus pneumoniae; Tachycardia; Young Adult

We describe unusual delayed recurrent episodes of ischemic stroke in a patient with initial good recovery from pneumococcal meningitis due to progressive arterial stenosis for over 3 months. We postulate that any of the following may have been responsible for his condition: widespread cerebral vasculopathy due to the effects of purulent material bathing the base of the brain, an immune-mediated para-infectious condition, or a rebound effect of the primary inflammatory reaction that was initially suppressed by dexamethasone. This case demonstrates that progressive arterial stenosis can evolve months after bacterial meningitis and should be recognized as a potential vascular complication.

Topics: Acetamides; Brain Damage, Chronic; Brain Ischemia; Ceftriaxone; Community-Acquired Infections; Constriction, Pathologic; Dexamethasone; Disease Progression; Drug Therapy, Combination; Humans; Linezolid; Male; Meningitis, Pneumococcal; Meropenem; Middle Aged; Oxazolidinones; Platelet Aggregation Inhibitors; Prednisolone; Recurrence; Thienamycins

Topics: Adolescent; Ceftriaxone; Child; Clindamycin; Confusion; Drug Therapy, Combination; Humans; Hypertension; Male; Meningism; Meningitis, Pneumococcal; Shock, Septic; Sickle Cell Trait; Sphenoid Sinusitis; Vancomycin

During the past decade antibiotic resistance among Streptococcus pneumoniae isolates has complicated the empiric approach to and treatment of pneumococcal meningitis. Standard empiric therapy for suspected bacterial meningitis for infants and children older than 1 month of age is the combination of cefotaxime or ceftriaxone and vancomycin. Treatment is modified after antimicrobial susceptibilities are available. The optimal treatment of pneumococcal meningitis caused by strains with a cefotaxime/ceftriaxone MIC >2 microg/ml is unknown, although the addition of rifampin to the initial combination is generally recommended. The role of newer agents including quinolones is under investigation. Dexamethasone remains the only adjunctive antiinflammatory therapy to consider. The empiric approach to the child with suspected bacterial meningitis who has received the pneumococcal conjugate vaccine currently remains unchanged.

Topics: Adult; Cefotaxime; Ceftriaxone; Dexamethasone; Drug Resistance; Drug Therapy, Combination; Humans; Infant; Meningitis, Pneumococcal; Streptococcus pneumoniae; Treatment Outcome; Vancomycin

Recent reports have documented the increasing number of pneumococcal isolates that are relatively or completely resistant to penicillin and other antibiotics. This report documents a case in which third-generation cephalosporin failed in the treatment of pneumococcal meningitis and reviews the clinical and microbiological features of the seven similar cases reported to date. In all eight cases, the pneumococci were penicillin resistant. Taken together, these cases suggest that (1) children with intermediately penicillin-resistant pneumococcal meningitis (MIC, 0.1-1.0 micrograms/mL) who are treated with cefotaxime or ceftriaxone should be observed carefully for treatment failure and (2) children with highly penicillin-resistant pneumococcal meningitis (MIC, > or = 2.0 micrograms/mL) are best treated with vancomycin and rifampin until the MICs of cefotaxime and ceftriaxone for the pneumococcus are known.

Topics: Cefotaxime; Ceftriaxone; Drug Resistance, Microbial; Humans; Infant; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Rifampin; Streptococcus pneumoniae; Vancomycin

In many pediatric infectious disease programs, ceftriaxone or cefotaxime is now the preferred drug for bacterial meningitis caused by H. influenzae, meningococci, and pneumococci. Ceftriaxone reaches a high bactericidal titer in the cerebrospinal fluid and persists at the site of infection longer than any other beta-lactam antibiotic. Short-course, once-daily therapy with ceftriaxone requires more study; currently, many pediatricians administer the agent twice daily for suspected or proven meningitis. Given the association of sequelae with prolongation of positive CSF cultures, ceftriaxone's rapid bactericidal activity is an advantage, which may require an adjunctive agent to block the inflammatory response due to antibiotic-induced release of endotoxin and other cell wall components. As empiric therapy, ceftriaxone is effective in infants and children three months to 18 years old. It is not yet recommended in neonates, because of concerns about bilirubin displacement. Thus, infants up to three months of age should receive ampicillin plus cefotaxime. In adults, ceftriaxone is effective therapy for presumed bacterial meningitis but must be combined with ampicillin initially, since L. monocytogenes meningitis cannot be excluded in most cases until CSF culture results are available.

Topics: Adolescent; Adult; Animals; Bacterial Infections; Ceftriaxone; Child; Child, Preschool; Humans; Infant; Meningitis; Meningitis, Haemophilus; Meningitis, Pneumococcal; Middle Aged

Topics: Age Factors; Aminoglycosides; Ampicillin; Anti-Bacterial Agents; Bacteria; Cefotaxime; Ceftriaxone; Cefuroxime; Cerebrospinal Fluid; Child, Preschool; Chloramphenicol; Humans; Infant; Infant, Newborn; Meningitis; Meningitis, Haemophilus; Meningitis, Listeria; Meningitis, Meningococcal; Meningitis, Pneumococcal; Prognosis; Spinal Puncture

Bacterial meningitis is an important cause of morbidity and mortality in developing countries, but the duration of treatment is not well established. We aimed to compare the efficacy of 5 and 10 days of parenteral ceftriaxone for the treatment of bacterial meningitis in children.. We did a multicountry, double-blind, placebo-controlled, randomised equivalence study of 5 versus 10 days of treatment with ceftriaxone in children aged 2 months to 12 years with purulent meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae type B, or Neisseria meningitidis. Our study was done in ten paediatric referral hospitals in Bangladesh, Egypt, Malawi, Pakistan, and Vietnam. We randomly assigned children who were stable after 5 days of treatment, through site-balanced computer-generated allocation lists, to receive a further 5 days of ceftriaxone or placebo. Patients, their guardians, and staff were masked to study-group allocation. Our primary outcomes were bacteriological failure or relapse. Our analysis was per protocol. This study is registered with the International Standard Randomised Controlled Trial Number Register, number ISRCTN38717320.. We included 1004 of 1027 children randomly assigned to study groups in our analyses; 496 received treatment with ceftriaxone for 5 days, and 508 for 10 days. In the 5-day treatment group, two children (one infected with HIV) had a relapse; there were no relapses in the 10-day treatment group and there were no bacteriological failures in either study group. Side-effects of antibiotic treatment were minor and similar in both groups.. In children beyond the neonatal age-group with purulent meningitis caused by S pneumoniae, H influenzae type b, or N meningitidis who are stable by day 5 of ceftriaxone treatment, the antibiotic can be safely discontinued.. United States Agency for International Development.

Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Child, Preschool; Developing Countries; Double-Blind Method; Drug Administration Schedule; Female; Humans; Infant; Male; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Pneumococcal; Neisseria meningitidis; Therapeutic Equivalency; Treatment Outcome

Several studies have evaluated dexamethasone for prevention of hearing loss in childhood bacterial meningitis, but results have varied. We compared dexamethasone and/or glycerol recipients with placebo recipients, and measured hearing at 3 threshold levels.. Children aged 2 months to 16 years with meningitis were treated with ceftriaxone but were double-blindly randomly assigned to receive adjuvant dexamethasone intravenously, glycerol orally, both agents, or neither agent. We used the Glasgow coma scale to grade the presenting status. The end points were the better ear's ability to detect sounds of >40 dB, >or=60 dB, and >or=80 dB, with these thresholds indicating any, moderate-to-severe, or severe impairment, respectively. All tests were interpreted by an external audiologist. Influence of covariates in the treatment groups was examined by binary logistic regression.. Of the 383 children, mostly with meningitis caused by Haemophilus influenzae type b or Streptococcus pneumoniae, 101 received dexamethasone, 95 received dexamethasone and glycerol, 92 received glycerol, and 95 received placebo. Only the presenting condition and young age predicted impairment independently through all threshold levels. Each lowering point in the Glasgow scale increased the risk by 15% to 21% (odds ratio: 1.20, 1.21, and 1.15 [95% confidence interval: 1.06-1.35, 1.07-1.37, and 1.01-1.31]; P = .005, .003, and .039) for any, moderate-to-severe, or severe impairment, respectively. Each increasing month of age decreased the risk by 2% to 6% (P = .0001, .0007, and .041, respectively). Neither dexamethasone nor glycerol prevented hearing loss at these levels regardless of the causative agent or timing of antimicrobial agent.. With bacterial meningitis, the child's presenting status and young age are the most important predictors of hearing impairment. Little relief is obtained from current adjuvant medications.

Topics: Administration, Oral; Adolescent; Audiometry; Ceftriaxone; Child; Child, Preschool; Confidence Intervals; Dexamethasone; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glycerol; Hearing Loss; Humans; Infant; Infusions, Intravenous; Logistic Models; Male; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Pneumococcal; Odds Ratio; Probability; Prospective Studies; Risk Assessment; Severity of Illness Index; Time Factors; Treatment Outcome

Oral glycerol reduces severe neurologic sequelae in childhood bacterial meningitis, but the mechanism awaits elucidation. We conducted a prospective, randomized, double-blind study in which the effects of glycerol and intravenous dexamethasone were compared with placebo recipients in an intensive care setting in India.. Thirty-six children at age 2 months to 12 years with meningitis were treated with ceftriaxone and were randomized to receive also either dexamethasone intravenously, or glycerol orally, or both agents, or neither. The illness was monitored with preset criteria. The primary outcome measures were the changes in plasma osmolality and in urine output.. Nine children received glycerol, 8 dexamethasone, 11 both agents, and 8 only placebo. The leading agents identified were Streptococcus pneumoniae, Haemophilus influenzae type b, and Staphylococcus aureus. Only the glycerol recipients increased plasma osmolality by up to 3% from the mean baseline of 294 mOsm/kg in the glycerol and 295 mOsm/kg in the glycerol-dexamethasone group. This change occurred within 6 hours, the critical period of treatment, and lasted <24 hours. Blood pressure was not affected, nor did urine output increase. The dexamethasone-only and placebo-only recipients showed immediate decrease in serum osmolality.. Because excretion of the cerebrospinal fluid is inversely associated with plasma osmolality, we suggest that the glycerol-induced osmolality increase reduce the volume of cerebrospinal fluid, enhanced water movement back to the plasma by osmosis, increased cerebral blood flow, and thus, improved brain oxygenation.

Topics: Ceftriaxone; Cerebrovascular Circulation; Child; Child, Preschool; Dexamethasone; Double-Blind Method; Female; Glycerol; Humans; Infant; Male; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Pneumococcal; Osmolar Concentration; Staphylococcal Infections

Cefotaxime (CTX) and ceftriaxone (CRO) were compared for cerebrospinal fluid (CSF) penetration and antimicrobial efficacy in cases of bacterial meningitis in children. This was a comparative study of CRO (100mg/kg once daily) and CTX (50 mg/kg 6 hourly) in the treatment of children with bacterial meningitis. The aetiological agents included Streptococcus pneumoniae (SPn), Haemophilus influenzae type b (Hib) and Neisseria meningitidis (NMen). Minimum inhibitory concentrations (MICs) were measured. In 33 patients from whom a second CSF specimen was obtained, CSF was cultured and assayed for antibiotic concentration. Median MICs of CTX and CRO for SPn, Hib and NMen were 0.01 and 0.01 microg/mL, 0.004 and 0.002 microg/mL and 0.008 and 0.004 microg/mL, respectively. All 33 repeat lumbar puncture specimens were sterile. The lowest CSF level recorded (0.45 microg/mL for CTX) was 45 times the MIC (0.01 microg/mL). The highest levels (24-35 microg/mL for CRO) were up to 8750 times the MIC of the patient's causative organism. A wide range of CSF levels for both antibiotics was observed. Levels varied with post-dose interval and duration of illness. On the basis of these findings, clinicians should be reassured that repeat lumbar puncture is not recommended for the causative organisms in this study (i.e., for Hib, NMen and penicillin/cefotaxime/ceftriaxone fully-susceptible SPn).

Topics: Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Female; Haemophilus influenzae type b; Humans; Infant; Infant, Newborn; Male; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal

Thirty-eight patients with streptococcal meningitis, aged 17-75 years, have been identified over a period of 13.5 years. Among these 38 patients, 35 had community-acquired infections, and the other three had nosocomial infections. Twelve of the 38 patients were found to have postneurosurgical forms and 26 to have spontaneous forms. These 38 cases of streptococci included Streptococcus (S.) pneumoniae in 19 cases, viridans group streptococci in 13, non-A, non-B, and non-D streptococci in three, Group D streptococci in one, and Group B streptococci (S. agalactiae) in two. Although one case was found to have penicillin-resistant S. pneumoniae PRSP in 1994, multi-antibiotic resistant strains were rare in this study. Therapeutic outcomes varied according to the different species of streptococci. In this study, the overall mortality rate was 34%. In the multiple logistic regression analysis, only initial consciousness level and the presence of seizure were strongly associated with the mortality rate even after other potentially confounding factors were adjusted for. Early diagnosis and the use of appropriate antibiotics are essential for survival.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Ceftazidime; Ceftriaxone; Chloramphenicol; Community-Acquired Infections; Cross Infection; Drug Therapy, Combination; Female; Humans; Leukocyte Count; Male; Meningitis, Pneumococcal; Middle Aged; Oxacillin; Penicillins; Prognosis; Regression Analysis; Streptococcus; Survival Rate; Treatment Outcome

There are reports of failure of extended-spectrum cephalosporin treatment in pneumococcal meningitis. On the basis of in vitro and animal experimental studies, the addition of vancomycin or rifampin to an extended-spectrum cephalosporin has been recommended for empiric treatment of these patients. Cerebrospinal fluid (CSF) was taken from 31 children with bacterial meningitis randomized to receive ceftriaxone alone (n = 11), ceftriaxone plus rifampin (n = 10), or ceftriaxone plus vancomycin (n = 10). The CSF from children receiving ceftriaxone alone was unable to kill intermediately ceftriaxone-resistant or fully resistant strains when the concentration of ceftriaxone in the CSF was less than 5 micrograms/ml. At higher concentrations bactericidal activity was present. We have shown that vancomycin penetrates reliably into the CSF of children with acute meningitis, which is in contrast to previous studies with adults. The addition of vancomycin or rifampin to ceftriaxone resulted in significantly enhanced CSF bactericidal activity compared with that of ceftriaxone alone against these resistant strains. Our data suggest that the addition of rifampin or vancomycin to ceftriaxone may be useful for the treatment of cephalosporin-resistant pneumococcal meningitis.

Topics: Acute Disease; Anti-Bacterial Agents; Ceftriaxone; Cephalosporin Resistance; Child, Preschool; Dexamethasone; Humans; Infant; Meningitis, Pneumococcal; Rifampin; Serum Bactericidal Test; Streptococcus pneumoniae; Vancomycin

Routine use of steroids as adjunctive treatment of bacterial meningitis remains controversial. We have carried out a prospective, placebo-controlled, double-blind study of dexamethasone in 115 children with acute bacterial meningitis in Switzerland. The patients were randomly assigned to receive either placebo (n = 55) or dexamethasone (n = 60) in addition to optimum antibiotic treatment (100 mg/kg daily ceftriaxone). Dexamethasone therapy (0.4 mg/kg) was started 10 min before the first dose of ceftriaxone and given every 12 h for 2 days. Baseline demographic, clinical, and laboratory features of the two groups were similar. After 24 h treatment meningeal inflammation as shown by cerebrospinal fluid (CSF) glucose concentration was significantly less with dexamethasone than with placebo (mean increase in glucose 63 [76] vs 40 [75]%, p = 0.008). However, other indices of inflammation showed similar changes in both groups. Addition of dexamethasone did not affect the rate at which CSF became sterile. Both groups showed prompt clinical responses and similar frequencies of complications (15 vs 12%). Monitoring for possible adverse effects of dexamethasone revealed no abnormalities. At follow-up examinations 3, 9, and 15 months after hospital discharge, 9 (16%) of 55 placebo recipients and 3 (5%) of 60 dexamethasone recipients had one or more neurological or audiological sequelae (p = 0.066); the relative risk of sequelae was 3.27 (95% CI 0.93-11.47). Our results and those of similarly designed studies lead us to believe that adjunctive dexamethasone therapy improves outcome from bacterial meningitis in infants and children. We recommend its use, preferably in the dose regimen used in this study.

Topics: Adolescent; C-Reactive Protein; Ceftriaxone; Child; Child, Preschool; Dexamethasone; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Hearing Loss, Sensorineural; Humans; Infant; Injections, Intravenous; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Placebos; Prospective Studies; Risk Factors

The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Ceftriaxone; Drug Evaluation; Female; Humans; Infusions, Intravenous; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Vancomycin

To compare ceftriaxone with cefuroxime for the treatment of meningitis, we conducted a study in which 106 children with acute bacterial meningitis were randomly assigned to receive either ceftriaxone (100 mg per kilogram of body weight per day, administered intravenously once daily; n = 53) or cefuroxime (240 mg per kilogram per day, administered intravenously in four equal doses; n = 53). The mean age of the children was 3 years (range, 42 days to 16 years), and the characteristics of the two treatment groups were comparable at admission. Excluded from the study were eight other children who died within 48 hours of admission. After 18 to 36 hours of therapy, cultures of cerebrospinal fluid remained positive for 1 of the 52 children (2 percent) receiving ceftriaxone for whom cultures were available and 6 of 52 (12 percent) receiving cefuroxime (P = 0.11). In both groups the mean duration of antibiotic therapy was 10 days. The clinical responses to therapy were similar in the two treatment groups, and all 106 children were cured. Reversible biliary pseudolithiasis was detected by serial abdominal ultrasonography only in the children treated with ceftriaxone (16 of 35 vs. 0 of 35; P less than 0.001). The treatment of three children was switched from ceftriaxone to alternative antibiotics because these children had upper abdominal pain. Other side effects were infrequent in both groups. At follow-up examination two months later, moderate-to-profound hearing loss was present in two children (4 percent) treated with ceftriaxone and in nine (17 percent) treated with cefuroxime (P = 0.05); other neurologic abnormalities were similar in the two treatment groups. We conclude that ceftriaxone is superior to cefuroxime for the treatment of acute bacterial meningitis in children and that the benefits of milder hearing impairment and more rapid sterilization of the cerebrospinal fluid with ceftriaxone outweigh the problem of reversible biliary pseudolithiasis with this drug.

Topics: Adolescent; Bacterial Infections; Ceftriaxone; Cefuroxime; Cephalosporins; Cerebrospinal Fluid; Child; Child, Preschool; Cholelithiasis; Female; Hearing Loss, Sensorineural; Humans; Infant; Injections, Intravenous; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Multicenter Studies as Topic; Prospective Studies; Random Allocation

In a multicentre study, 220 consecutive cases of bacterial meningitis in children older than 3 months were randomised to treatment with chloramphenicol, ampicillin (initially with chloramphenicol), cefotaxime, or ceftriaxone. The drugs were given in four equal daily doses for 7 days, except ceftriaxone which was given only once daily. 200 cases could be assessed; the causative organisms were Haemophilus influenzae type b (Hib) in 146; meningococci (Mnc) in 32; pneumococci (Pnc) in 13; and other or unknown in 9. In patients with Hib meningitis, sterilisation of the cerebrospinal fluid occurred most rapidly with ceftriaxone. Otherwise, in terms of overall clinical recovery, normalisation of laboratory indices, clinically significant adverse reactions, toxic effects, sequelae, and mortality rate, the treatment groups were very similar. However, there were 4 bacteriological failures, all in the chloramphenicol group. Also, the treatment was extended or changed in more cases in the chloramphenicol group than in the other groups. Chloramphenicol was thus inferior to the other three antimicrobials. Ampicillin is a good and cheap alternative, but there are difficulties with resistance. Easy administration tempts the use of ceftriaxone rather than cefotaxime but it causes diarrhoea. A 7-day course of ampicillin, cefotaxime, or ceftriaxone is sufficient in Hib, Mnc, or Pnc meningitis.

Topics: Adolescent; Ampicillin; Bacterial Infections; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Female; Finland; Follow-Up Studies; Humans; Infant; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Multicenter Studies as Topic; Random Allocation; Recurrence

To assess the comparative efficacy of cefuroxime and ceftriaxone for the treatment of bacterial meningitis, we reviewed the records from four prospective efficacy trials conducted at our institution. One hundred seventy-four infants and children received ceftriaxone and 159 received cefuroxime. The clinical characteristics of the two groups were comparable at admission. After 24 hours of therapy, routine cerebrospinal fluid cultures for all patients treated with ceftriaxone were sterile, whereas 9% of cerebrospinal fluid cultures were positive in cefuroxime-treated patients (p less than 0.001). More cefuroxime-treated patients had abnormal physical examinations at the time of discharge than did ceftriaxone-treated patients (39/159 vs 25/174, p = 0.02). At 6-week and 1-year follow-up examinations, there was no longer a statistically significant difference in the incidence of neurologic abnormalities between the two therapy groups, but the incidence of hearing impairment in one or both ears was higher in the cefuroxime (18%) than in the ceftriaxone (11%) treatment group. Both regimens are efficacious for the treatment of bacterial meningitis, but some patients may not respond as satisfactorily to cefuroxime as to ceftriaxone.

Topics: Adolescent; Ceftriaxone; Cefuroxime; Cephalosporins; Child; Child, Preschool; Clinical Trials as Topic; Female; Follow-Up Studies; Hearing Disorders; Humans; Infant; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Random Allocation; Streptococcal Infections

70 children aged 4 months-12 years, with bacteriologically proven bacterial meningitis were treated with either intramuscular (IM) ceftriaxone (CFT) 100 mg/kg given once daily, or with combined IM ampicillin 160 mg/kg/day and IM chloramphenicol 100 mg/kg/day (AMC) given every 6 h. There were 35 children in each of the treatment groups. The children in both groups were comparable with regard to age, sex, duration of illness, and state of consciousness. 29 children in the CFT group and 26 in the AMC group recovered without any permanent complications or sequelae. Of the 15 children who died 10 (3 in the CFT and 7 in the AMC group) were in deep coma when treatment was started. Intramuscular CFT given once daily proved effective and much easier to administer than our standard hospital therapy with combined AMC given every 6 h IM.

Topics: Ampicillin; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Drug Therapy, Combination; Escherichia coli Infections; Female; Humans; Infant; Injections, Intramuscular; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Time Factors

One hundred patients (71 males and 29 females) with bacterial meningitis were randomly assigned into two therapeutic regimens. Patients in group I were intravenously given ceftriaxone (CRO: Rocephin) to adults and intramuscularly to children once daily in a dose of 100 mg/kg/day. Patients in group II received ampicillin 160 mg/kg/day and chloramphenicol (AMCL) 100 mg/kg/day (i.v. to adults and i.m. to children) every 6 h. No significant difference was observed between the two therapeutic regimens with regard to mortality, time taken to become afebrile, fully alert and sequelae. Seven patients in the CRO group died compared to 10 in the AMCL group. The mean number of days taken to become afebrile were 3.4 and 3.5, and to become fully alert 3.9 and 3.5 for groups I and II, respectively. CRO administered in a single daily dose appears to be as effective as a combination of ampicillin and chloramphenicol given every 6 h in the treatment of acute bacterial meningitis. However, the once daily dose is more appropriate for use especially in areas where nursing care is limited.

Topics: Adolescent; Adult; Ampicillin; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Drug Therapy, Combination; Female; Humans; Infant; Injections, Intramuscular; Injections, Intravenous; Male; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Random Allocation

Thirty patients, 25 males and 5 females, aged 16-30 years (mean 21.8 years) with bacterial meningitis were assigned randomly into one of two therapeutic regimens. Patients in Group I received ceftriaxone 100 mg/kg (max 4 g) intravenously (i.v.) once daily. Those in Group II received ampicillin i.v. 160 mg/kg/day plus chloramphenicol i.v. 100 mg/kg/day every 6 h. Of the 15 patients in Group I, N. meningitidis was isolated from 11 patients and S. pneumoniae from 4; and of the 15 patients in Group II, N. meningitidis was isolated from 10 patients and S. pneumoniae from 5. Response to therapy as measured by mortality, time taken for defervescence and for patients to regain full consciousness were comparable in the two groups. One patient in each group died; both died within 24 h of initiation of therapy. The mean no. of days taken to become afebrile were 3.4 and 3.5 and to regain full consciousness were 3.9 and 3.5 for Groups I and II respectively. Ceftriaxone given i.v. appears to be as effective as a combination of ampicillin and chloramphenicol in the treatment of adult patients with meningitis due to N. meningitidis and S. pneumoniae. However, the once-daily schedule of ceftriaxone is more convenient, saving nursing time and expense.

Topics: Adolescent; Adult; Ampicillin; Ceftriaxone; Chloramphenicol; Female; Humans; Male; Meningitis; Meningitis, Meningococcal; Meningitis, Pneumococcal

Ceftriaxone, a new third-generation cephalosporin, appears to be promising for the therapy of acute bacterial meningitis. The 90% MBCs of ceftriaxone against 54 recent cerebrospinal fluid isolates of Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae were less than or equal to 0.06 to 0.25 micrograms/ml. We examined the efficacy and safety of ceftriaxone therapy of meningitis in Bahia, Brazil. The study was conducted in two phases; in phase A, ceftriaxone was coadministered with ampicillin. The mean cerebrospinal fluid concentrations of ceftriaxone 24 h after an intravenous dose of 80 mg/kg were 4.2 and 2.3 micrograms/ml on days 4 to 6 and 10 to 12 of therapy, respectively. These concentrations were 8- to more than 100-fold greater than the 90% MBCs against the relevant pathogens. In phase B, ceftriaxone (administered once daily at a dose of 80 mg/kg after an initial dose of 100 mg/kg) was compared with conventional dosages of ampicillin and chloramphenicol in a prospective randomized trial of 36 children and adults with meningitis. The groups were comparable based on clinical, laboratory, and etiological parameters. Ceftriaxone given once daily produced results equivalent to those obtained with ampicillin plus chloramphenicol, as judged by cure rate, case fatality ratio, resolution with sequelae, type and severity of sequelae, time to sterility of cerebrospinal fluid, and potentially drug-related adverse effects. The cerebrospinal fluid bactericidal titers obtained 16 to 24 h after ceftriaxone dosing were usually 1:512 to greater than 1:2,048 even late in the treatment course, compared with values of 1:8 to 1:32 in patients receiving ampicillin plus chloramphenicol. Ceftriaxone clearly deserves further evaluation for the therapy of meningitis; the optimal dose, dosing frequency (every 12 h or every 24 h), and duration of therapy remain to be determined.

Topics: Ampicillin; Ceftriaxone; Cerebrospinal Fluid; Chloramphenicol; Drug Therapy, Combination; Humans; Klebsiella; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Salmonella

Forty-five children (aged 1 day to 15 years) with bacterial meningitis were randomized to receive either traditional therapy (ampicillin and chloramphenicol or gentamicin, pending sensitivity) or ceftriaxone (100 mg/kg per day in two doses for a minimum of 10 days). The etiological agents involved were similar for the two groups and included Haemophilus influenzae type b, Neisseria meningitidis, Streptococcus pneumoniae, and group B streptococcus. Repeat spinal taps were carried out 24 to 48 h after admission. Organisms were seen on the Gram stain of one patient treated with ceftriaxone, but five patients in the traditional therapy group had organisms present on Gram stain of uncentrifuged spinal fluid or positive cultures of the spinal fluid (or both). Ceftriaxone entered the cerebrospinal fluid well, and the average cerebrospinal fluid bactericidal activity for ceftriaxone 1 h after a dose was at least 60 times greater than for ampicillin or chloramphenicol. In those patients who received treatment for a long enough period of time to permit evaluation, there was one death in each group, both due to S. pneumoniae. The length of fever and complications were similar for the patients in both groups. Ceftriaxone was well tolerated; diarrhea, seen in 5 of the 22 patients who received the drug, was the most commonly encountered adverse effect. It was mild, and in no case was it necessary to discontinue the drug. Ceftriaxone appears in this preliminary study to be a safe and acceptable single agent for the treatment of bacterial meningitis in children.

Topics: Adolescent; Ampicillin; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Female; Gentamicins; Humans; Infant; Infant, Newborn; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Random Allocation

Ceftriaxone is a new cephalosporin with a broad spectrum of antibacterial activity and unique serum and CSF pharmacokinetics. The drug was compared in a randomized fashion with ampicillin and chloramphenicol in the treatment of 19 children with Haemophilus influenzae type b meningitis. Ceftriaxone was also administered non-randomly to six other patients including three children with Gram-negative meningitis. Among the children with H. influenzae meningitis, no deaths were noted and the outcomes of the study and the control groups were similar. Ninety per cent of the isolates of H. influenzae were inhibited by 0.0625, 1 and 1 mg/l of ceftriaxone, ampicillin and chloramphenicol respectively. One child with pneumococcal meningitis and two children with meningococcal meningitis recovered rapidly and without incident during ceftriaxone therapy. Three children with Gram-negative meningitis caused by multiply-drug resistant organisms were bacteriologically cured within five days of the onset of therapy. Persistent pleocytosis and neurological disabilities were noted in two at the conclusion of therapy. Ceftriaxone, as a single agent, was comparable in efficacy with traditional antimicrobial therapy usually employed in childhood meningitis.

Topics: Adolescent; Ampicillin; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Drug Therapy, Combination; Female; Humans; Infant; Male; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Random Allocation

78 patients with bacterial meningitis were evaluated in a prospective, randomised study comparing twice-daily ceftriaxone as single-drug therapy with ampicillin and chloramphenicol given every 6 h. The groups were comparable in age, sex, days of illness before admission, and bacterial colony counts in cerebrospinal fluid (CSF). The pathogens were Haemophilus influenzae type b (54 cases), streptococci (9 cases), meningococci (9 cases), and unknown (6 cases). In 40 CSF specimens obtained 4-12 h after initiation of therapy, cultures were negative in 57% of the ceftriaxone patients and in 42% of the others. The mean falls in the CSF bacterial colony counts were 4.7 and 5.0 log10 colony-forming units/ml, respectively. Mean bactericidal activity in CSF was significantly greater in the ceftriaxone than in the conventional treatment group at the beginning and end of therapy. There were no significant differences in clinical responses or in frequency of complications, except for mild diarrhoea, which occurred in 16 ceftriaxone patients and in 8 in the other group (p less than 0.05).

Topics: Adolescent; Ampicillin; Cefotaxime; Ceftriaxone; Cerebrospinal Fluid; Child; Child, Preschool; Chloramphenicol; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Infant; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Prospective Studies; Random Allocation

Topics: Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Cephalosporins; Humans; Meningitis; Meningitis, Bacterial; Meningitis, Pneumococcal; Microbial Sensitivity Tests

Treatment failure in pneumococcal meningitis due to antibiotic resistance is an increasing clinical challenge and alternatives to antibiotics warrant investigation. Phage-derived endolysins efficiently kill gram-positive bacteria including multi-drug resistant strains, making them attractive therapeutic candidates. The current study assessed the therapeutic potential of the novel endolysin PlyAZ3aT in an infant rat model of ceftriaxone-resistant pneumococcal meningitis.. Efficacy of PlyAZ3aT was assessed in a randomized, blinded and controlled experimental study in infant Wistar rats. Meningitis was induced by intracisternal infection with 5 x 107 CFU/ml of a ceftriaxone-resistant clinical strain of S. pneumoniae, serotype 19A. Seventeen hours post infection (hpi), animals were randomized into 3 treatment groups and received either (i) placebo (phosphate buffered saline [PBS], n = 8), (ii) 50 mg/kg vancomycin (n = 10) or (iii) 400 mg/kg PlyAZ3aT (n = 8) via intraperitoneal injection. Treatments were repeated after 12 h. Survival at 42 hpi was the primary outcome; bacterial loads in cerebrospinal fluid (CSF) and blood were secondary outcomes. Additionally, pharmacokinetics of PlyAZ3aT in serum and CSF was assessed.. PlyAZ3aT did not improve survival compared to PBS, while survival for vancomycin treated animals was 70% which is a significant improvement when compared to PBS or PlyAZ3aT (p<0.05 each). PlyAZ3aT was not able to control the infection, reflected by the inability to reduce bacterial loads in the CSF, whereas Vancomycin sterilized the CSF and within 25 h. Pharmacokinetic studies indicated that PlyAZ3aT did not cross the blood brain barrier (BBB). In support, PlyAZ3aT showed a peak concentration of 785 μg/ml in serum 2 h after intraperitoneal injection but could not be detected in CSF.. In experimental pneumococcal meningitis, PlyAZ3aT failed to cure the infection due to an inability to reach the CSF. Optimization of the galenic formulation e.g. using liposomes might enable crossing of the BBB and improve treatment efficacy.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Endopeptidases; Meningitis, Pneumococcal; Random Allocation; Rats; Rats, Wistar; Streptococcus pneumoniae; Vancomycin

Topics: Animals; Ceftriaxone; Humans; Maraviroc; Meningitis, Pneumococcal; Neuroprotection; Rats; Rats, Wistar; Receptors, CCR5

Topics: Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Cephalosporins; Cohort Studies; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Mitomycin; Monobactams; Penicillin Resistance; Penicillins; Streptococcus pneumoniae

Children with nephrotic syndrome are at increased risk of infections, including bacterial peritonitis, pneumonia, and cellulitis. However, bacterial meningitis, a potentially life-threatening complication, has not been highlighted as an infectious complication of nephrotic syndrome in recent reviews. We report a very subtle and unusual presentation of bacterial meningitis in a child with nephrotic syndrome, which without a high index of suspicion, would have been missed.. A 9-year-old African-American male with a history of steroid-dependent nephrotic syndrome presented to the nephrology clinic for routine follow-up. His medications included mycophenolate mofetil and alternate-day steroids. His only complaint was neck pain and stiffness that the mother attributed to muscle tightness relieved by massage. There was no history of fever, vomiting, headache, photophobia, or altered mental status. On physical examination, he was afebrile (99 °F), but had mild periorbital swelling and edema on lower extremities. He appeared ill and exhibited neck rigidity, and demonstrated reflex knee flexion when the neck was bent. Laboratory evaluation revealed leukocytosis, elevated C-reactive protein, hypoalbuminemia, and proteinuria. Cerebrospinal fluid suggested bacterial meningitis. The patient was treated with ceftriaxone and vancomycin. Both cerebrospinal and blood cultures grew Streptococcus pneumoniae; vancomycin was discontinued. The child completed a 2-week course of ceftriaxone and was discharged home.. A high index of suspicion is necessary in children with nephrotic syndrome treated with corticosteroids, as symptoms may be masked, and thus, a life-threatening disease be missed. Bacterial meningitis should be highlighted as a serious infection complication in children with nephrotic syndrome.

Topics: Ceftriaxone; Child; Humans; Male; Meningitis, Bacterial; Meningitis, Pneumococcal; Nephrotic Syndrome; Vancomycin

Streptococcus pneumoniae causes pneumonia and other invasive diseases, and is a leading cause of mortality in the elderly population. The present study aimed to provide current antimicrobial resistance and epidemiological profiles of S. pneumoniae infections in Taiwan.. A total of 252 nonduplicate S. pneumoniae isolates were collected from patients admitted to 16 hospitals in Taiwan between January 2017 and December 2019, and were analyzed. The minimum inhibitory concentration of antibiotics was determined using the Vitek 2 automated system for antimicrobial susceptibility testing. Furthermore, epidemiological profiles of S. pneumoniae infections were analyzed.. Among the strains analyzed, 88% were recognized as invasive pneumococcal strains. According to the Clinical and Laboratory Standards Institute criteria for non-meningitis, the prevalence of penicillin-non-susceptible S. pneumoniae demonstrated a declining trend from 43.6% in 2017 to 17.2% in 2019. However, the rate of penicillin-non-susceptible S. pneumoniae was 85.7% based on the criteria for meningitis. Furthermore, the prevalence of ceftriaxone-non-susceptible S. pneumoniae was 62.7% based on the criteria for meningitis. Isolates demonstrated higher susceptibility toward doripenem and ertapenem than toward meropenem and imipenem. An increased rate of non-susceptibility toward levofloxacin was observed in southern Taiwan (15.1%) and elderly patients (≥65 years; 11.4%). Most isolates were susceptible to vancomycin and linezolid.. Empirical treatment with ceftriaxone monotherapy for pneumococcal meningitis should be carefully monitored owing to its high non-susceptibility rate. The susceptibility rates of most isolates to penicillin (used for treating non-meningitis pneumococcal diseases), carbapenems (ertapenem and doripenem), respiratory quinolones (moxifloxacin and levofloxacin), vancomycin, and linezolid suggested the potential of these antibiotics in treating pneumococcal diseases in Taiwan.

Topics: Aged; Anti-Bacterial Agents; Ceftriaxone; Doripenem; Drug Resistance, Bacterial; Ertapenem; Humans; Levofloxacin; Linezolid; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillins; Pneumococcal Infections; Streptococcus pneumoniae; Taiwan; Vancomycin

The soft and delicate tissue of the brain, which is the center of our coordination, is protected by its surrounding layers. The disruption of these layers results in complicated situations and serious health problems. The brain has three protective layers of bone or skull tissue, the blood tissue layer, and finally the meningeal layer. The layer of blood tissue contains the blood vessels that are located between the skull and the meningeal membranes. If germs or foreign matter enter the fluid through the blood vessels under any circumstances and cause infection, the bones that protect the meninges will break and cause tissue damage. The present study aimed to assess the histological and immunohistochemical characteristics of the brain of rats that underwent induced acute purulent pneumococcal meningitis after antibiotic therapy with Ceftriaxone. A number of 20 white adult male Wistar rats were assigned to three groups. The first group (n=5) regarded as the control were injected with a saline solution into the subarachnoid space in an equivalent amount. The second and third groups of rats (n=5 and 10, respectively) were infected with acute purulent meningitis by the injection of 10 μl of Streptococcus pneumoniae (S. pneumonia) suspension into the subarachnoid space of the brain using a 23-G needle. The various areas of the brains of rats after meningitis induced by S. pneumoniae were examined after the treatment with Ceftriaxone. The S. pneumoniae culture was injected into the subarachnoid space in the area of the rhomboid fossa. Treatment started 18 h after the injection. On day 10, a repeated puncture was performed with the analysis of cerebrospinal fluid in order to confirm the absence of meningitis; thereafter, the animals were taken out of the experiment. No signs of meningitis were found on histological examination. Mild perivascular and pericellular focal edema were revealed with signs of overload of the lymphatic system in the brain and focal ischemic changes in neurons. The investigation of expression with caspase-3 revealed a positive reaction of individual neurons. A positive reaction with antibodies to NeuN and Doublecortin was detected in most neurons; moreover, Glial fibrillary acidic protein (GFAP)-positive astrocytes and their processes were visualized in all layers of the brain substance. The reaction with neuron-specific enolase (NSE), microtubule-associated protein 2 (MAP-2), CD 31, and CD 34 was negative. Typical structure and pictures

Topics: Animals; Anti-Bacterial Agents; Brain; Ceftriaxone; Male; Meningitis, Pneumococcal; Rats; Rats, Wistar

Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Vancomycin

We report a case of a 62-year-old man treated for

Topics: Ceftriaxone; Cephalosporins; Dexamethasone; Humans; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Penicillin-Binding Proteins; Streptococcus pneumoniae

Mizrahi and colleagues present a well-described case of the emergence of drug resistance in

Topics: Ceftriaxone; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Mutation; Vasculitis, Central Nervous System

To determine the resistance rate of penicillin and ceftriaxone amongst invasive meningitis and nonmeningitis isolates of streptococcus pneumoniae.. The prospective cross-sectional study was conducted from January 2011 to March 2014 at the Clinical Microbiology Laboratory of Aga Khan University, Karachi, and comprised all invasive strains of streptococcus pneumoniae. Penicillin and ceftriaxone susceptibilities were performed and interpreted based on minimum inhibitory concentration breakpoints recommended by Clinical and Laboratory Standards Institute guidelines. Data was analysed using Stata 12.. There were 163 strains isolated from sterile body fluids of 109 patients. Of the total, 46(28%) samples were meningitic while 117(72%) were non-meningitic. Of the meningeal isolates, 12(26%) were resistant to penicillin, while none was resistant to ceftriaxone and vancomycin. None of non meningeal isolates showed resistance to penicillin, ceftriaxone or vancomycin.. There was considerable penicillin resistance among meningeal strains of streptococcus pneumoniae, but here appeared to be no need to add vancomycin for empirical treatment of invasive streptococcus pneumonia infection.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Ceftriaxone; Child; Child, Preschool; Drug Resistance, Bacterial; Emergency Service, Hospital; Female; Humans; Intensive Care Units; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Mortality; Pakistan; Penicillins; Pneumococcal Infections; Risk Factors; Sex Factors; Streptococcus pneumoniae; Vancomycin; Young Adult

A 53-year-old man was referred to our hospital because of fever and disturbed consciousness with a left-sided toothache from 5 days ago. Neurological examinations revealed a low level of consciousness, nuchal rigidity, bilateral mydriasis, and positive Babinski sign. A lumbar puncture yielded clouded fluid with a WBC 22,698/μl (polynuclear cell 98%), 681 mg/dl of protein and 0 mg/dl of glucose. The antigen of Streptococcus pneumoniae in urine and cerebrospinal fluid (CSF) were positive. Streptococcus pneumoniae was isolated from CSF culture. Brain CT on admission showed a communicating hydrocephalus. Diagnosis of pneumococcal meningitis with hydrocephalus was made and we treated with ceftriaxone and dexamethasone. The lumbar drainage placed at L 3/4 level became occluded, thus, extra-ventricular drainage was performed. Intracranial pressure (ICP) was 20 cmH

Topics: Anti-Bacterial Agents; Ceftriaxone; Dexamethasone; Drainage; Humans; Hydrocephalus; Male; Meningitis, Pneumococcal; Middle Aged; Streptococcus pneumoniae; Tomography, X-Ray Computed; Treatment Outcome

Topics: Anti-Bacterial Agents; Ceftriaxone; Heptavalent Pneumococcal Conjugate Vaccine; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillins; Pneumococcal Vaccines; Streptococcus pneumoniae; Vancomycin

The use of empiric vancomycin plus a third-generation cephalosporin for suspected bacterial meningitis has been recommended since 1997. Although the prevalence of ceftriaxone-nonsusceptible pneumococcal meningitis has decreased, vancomycin should still be included as empiric therapy for bacterial meningitis.

Topics: Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Humans; Meningitis, Bacterial; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Streptococcus pneumoniae; Vancomycin

Acute generalized exanthematous pustulosis (AGEP) is seen uncommonly in children and sometimes shows atypical clinical features in this population. Patch testing can be used effectively in children for the confirmation of the culprit drug in cases of multiple drug use. Here, we report a rare, pediatric case of ceftriaxone-induced AGEP confirmed by patch testing with subsequent recurrence of the skin eruption.

Topics: Acute Generalized Exanthematous Pustulosis; Ceftriaxone; Child, Preschool; Drug Hypersensitivity; Humans; Male; Meningitis, Pneumococcal; Methylprednisolone; Patch Tests; Prognosis; Rare Diseases; Recurrence; Risk Assessment; Treatment Outcome

Despite appropriate antibiotic therapy, pneumococcal meningitis (PM) is associated with a case fatality rate of up to 30% in high-income countries. Survivors often suffer from severe lifelong disabilities. An excessive inflammatory reaction drives the pathophysiology, leading to brain damage and neurologic sequelae. We aimed to improve the outcome of experimental PM by simultaneously targeting different pathophysiological mechanisms with combined adjunctive therapies previously shown to be neuroprotective.

Topics: Animals; Astrocytes; Ceftriaxone; Daptomycin; Doxycycline; Hearing Loss; Male; Meningitis, Pneumococcal; Rats; Rats, Wistar; Streptococcus pneumoniae

Pneumococcal meningitis is associated with high risk of neurological sequelae such as cognitive impairment and hearing loss. These sequelae are due to parenchymal brain and inner ear damage primarily induced by the excessive inflammatory reaction in response to bacterial brain invasion. Metformin-a biguanide drug to treat diabetes mellitus type 2-was recently found to suppress neuroinflammation and induce neuroregeneration. This study evaluated the effect of metformin adjunctive to antibiotics on neuroinflammation, brain and inner ear damage, and neurofunctional outcome in experimental pediatric pneumococcal meningitis.. Upon pneumococcal infection, metformin treatment significantly reduced levels of inflammatory cytokines and nitric oxide production in cerebrospinal fluid and in astroglial cell cultures in vitro (p < 0.05). Compared to animals receiving ceftriaxone monotherapy, adjunctive metformin significantly reduced cortical necrosis (p < 0.02) during acute infection and improved median click-induced hearing thresholds (60 dB vs. 100 dB, p < 0.002) 5 weeks after infection. Adjuvant metformin significantly improved pure tone hearing thresholds at all assessed frequencies compared to ceftriaxone monotherapy (p < 0.05) and protected from PM-induced spiral ganglion neuron loss in the inner ear (p < 0.05).. Adjuvant metformin reduces brain injury during pneumococcal meningitis by decreasing the excessive neuroinflammatory response. Furthermore, it protects spiral ganglion neurons in the inner ear and improves hearing impairments after experimental pneumococcal meningitis. These results identify adjuvant metformin as a promising therapeutic option to improve the outcome after pediatric pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Ceftriaxone; Cytokines; Disease Models, Animal; Drug Therapy, Combination; Hearing Loss; Hippocampus; Meningitis, Pneumococcal; Metformin; Neurons; Neuroprotective Agents; Rats; Rats, Wistar; Spiral Ganglion; Treatment Outcome

Pneumococci are the major cause of bacterial meningitis globally. To cause meningitis pneumococci interact with the 2 endothelial receptors, polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1), to penetrate the blood-brain barrier (BBB) and invade the brain.. C57BL/6 mice were infected intravenously with bioluminescent pneumococci, and treated with ceftriaxone (1 hour postinfection) and anti-pIgR and PECAM-1 antibodies (1 or 5 hours postinfection), then monitored for 5 and 10 days. Bacterial brain invasion was analyzed using IVIS imaging and bacterial counts.. Ceftriaxone, given early after pneumococcal challenge, cleared pneumococci from the blood but not from the brain. After combining ceftriaxone with receptor blockade, using anti-pIgR and PECAM-1 antibodies, we found 100% survival after 5 and 10 days of infection, in contrast to 60% for ceftriaxone alone. Combined antibiotic and antibody treatment resulted in no or few viable bacteria in the brain and no microglia activation. Antibodies remained bound to the receptors during the study period. Receptor blockade did not interfere with antibiotic permeability through the BBB.. We suggest that adjunct treatment with pIgR and PECAM-1 antibodies to antibiotics may prevent pneumococcal meningitis development and associated brain damages. However, further evaluations are required.

Topics: Animals; Anti-Bacterial Agents; Antibodies; Bacterial Load; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Intravital Microscopy; Meningitis, Pneumococcal; Mice, Inbred C57BL; Platelet Endothelial Cell Adhesion Molecule-1; Receptors, Polymeric Immunoglobulin; Survival Analysis; Treatment Outcome

Pneumococcal meningitis is one of the most common infectious diseases with a high-mortality rate and long-term neurological sequelae, affecting up to 50% of survivors. Pneumococcal compounds are pro-inflammatory mediators that induce an innate immune response and tryptophan degradation through the kynurenine pathway. Vitamin B6 (vitB6) is an important vitamin which acts as a cofactor at the active sites of enzymes that catalyze a great number of reactions involved in the metabolism of tryptophan through the kynurenine pathway and may thus limit the accumulation of neurotoxic metabolites and preserve the cellular energy status. The aim of this study was to investigate the neuroprotective effect of adjuvant treatment with vitB6 in pneumococcal meningitis.. The effects of vitB6 on the clinical symptoms, the expression of kynureninase (KYN), Kynurenic acid (KYNA), nicotinamide adenine dinucleotide (NAD) and cytokines in brain tissue and memory of infant Wistar rats subjected to pneumococcal meningitis were researched. At the same time, Kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 was applied in order to further investigate the brain protective effect of vitB6 in bacterial meningitis.. Adjuvant therapy of bacterial meningitis with vitB6 could improve the clinical symptoms, learning performance, lead to the maintenance of cellular NAD+ and ATP homeostasis and significantly down-regulate the levels of cytokines in the brain tissue by affecting the KYN pathway.. Adjuvant treatment with vitB6 in pneumococcal meningitis could exert neuroprotective effect via increasing the preservation of cellular energy through affecting the KYN pathway and reducing of the inflammatory response.

Topics: Adjuvants, Immunologic; Adjuvants, Pharmaceutic; Animals; Brain; Ceftriaxone; Cytokines; Kynurenic Acid; Memory; Meningitis, Pneumococcal; Rats, Wistar; Vitamin B 6

Topics: Bone Neoplasms; Ceftriaxone; Child; Female; Femur; Humans; Magnetic Resonance Imaging; Meningitis, Pneumococcal; Osteoma, Osteoid; Radiofrequency Ablation; Sepsis; Tomography, X-Ray Computed

Topics: Anti-Bacterial Agents; Anticoagulants; Ceftriaxone; Cerebrospinal Fluid; Dexamethasone; Diagnostic Techniques, Ophthalmological; Female; Glucocorticoids; Humans; Magnetic Resonance Imaging; Meningitis, Pneumococcal; Middle Aged; Optic Nerve; Sinus Thrombosis, Intracranial; Streptococcus pneumoniae; Tomography, X-Ray Computed; Treatment Outcome; Vision Disorders; Warfarin

Pneumococcal meningitis is associated with high mortality and morbidity rates. Up to 50% of survivors show neurologic sequelae including hearing loss, cognitive impairments and learning disabilities, being particularly detrimental in affected infants and children where adjuvant therapy with dexamethasone has no proven beneficial effect. We evaluated the effect of concomitantly targeting specific pathophysiological mechanisms responsible for brain damage-i.e. matrix-metalloproteinase (MMP) activity and the exacerbated cerebral inflammation provoked through antibiotic-induced bacterial lysis. Here, we combined adjunctive therapies previously shown to be neuroprotective when used as single adjuvant therapies.. Eleven-day-old Wistar rats were infected intracisternally with 6.44 ± 2.17 × 10. We found significantly reduced apoptosis in the hippocampal subgranular zone in infant rats receiving adjuvant Trocade (p < 0.01) or combined adjuvant therapy (p < 0.001). Cortical necrosis was significantly reduced in rats treated with adjuvant daptomycin (p < 0.05) or combined adjuvant therapy (p < 0.05) compared to ceftriaxone monotherapy. Six hours after treatment initiation, CSF cytokine levels were significantly reduced for TNF-α (p < 0.01), IL-1β (p < 0.01), IL-6 (p < 0.001) and IL-10 (p < 0.01) in animals receiving combined adjuvant intervention compared to ceftriaxone monotherapy. Importantly, combined adjuvant therapy significantly improved learning and memory performance in infected animals and reduced hearing loss (77.14 dB vs 60.92 dB, p < 0.05) by preserving low frequency hearing capacity, compared to ceftriaxone monotherapy.. Combined adjuvant therapy with the non-bacteriolytic antibiotic daptomycin and the MMP inhibitor Trocade integrates the neuroprotective effects of both single adjuvants in experimental paediatric pneumococcal meningitis by reducing neuroinflammation and brain damage, thereby improving neurofunctional outcome. This strategy represents a promising therapeutic option to improve the outcome of paediatric patients suffering from pneumococcal meningitis.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Apoptosis; Brain Injuries; Ceftriaxone; Cerebral Cortex; Cytokines; Daptomycin; Disease Models, Animal; Drug Therapy, Combination; Evoked Potentials, Auditory, Brain Stem; Hearing Disorders; Hippocampus; Learning Disabilities; Matrix Metalloproteinase Inhibitors; Matrix Metalloproteinases; Maze Learning; Memory Disorders; Meningitis, Pneumococcal; Rats; Streptococcus pneumoniae

Bacterial meningitis commonly presents with symptoms such as headache, impaired consciousness, neck stiffness, and fever. In most cases, cerebrospinal fluid analysis will yield white cell counts >100/mm. The patient was admitted after being found unconscious on her bed. Upon admittance, she was considered confused, with a temperature of 39.4 °C and slight neutrophilic leukocytosis, but no neck stiffness. A neurological examination revealed bilateral horizontal nystagmus, unstable eye movements, and suspected right-sided gaze paralysis. Cerebrospinal fluid analysis revealed normal parameters, and the microscopy result was negative for bacteria. The most likely diagnosis was considered to be stroke with concomitant infection. However, cerebrospinal fluid and blood cultures subsequently were rapidly positive for pneumococci. Neither immunodeficiency nor blood contamination was considered a likely cause of this discrepancy.. This case emphasizes the need to consider a multidisciplinary approach and empirical meningitis treatment until diagnostic results from microbiological cultures are obtained.

Topics: Aged; Anti-Bacterial Agents; Ceftriaxone; Consciousness Disorders; Dexamethasone; Diagnosis, Differential; Female; Humans; Meningitis, Pneumococcal; Penicillin G; Stroke; Treatment Outcome

Topics: Ceftriaxone; Dexamethasone; Drug Resistance, Bacterial; Humans; Intensive Care Units; Male; Meningitis, Pneumococcal; Meropenem; Middle Aged; Molecular Typing; Moxifloxacin; Republic of Belarus; Streptococcus pneumoniae; Treatment Outcome

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies.. We investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2. MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity.. MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis.

Topics: Aged; Animals; Anti-Bacterial Agents; Antibodies; Ceftriaxone; Cohort Studies; Cytokines; Disease Models, Animal; Female; Freund's Adjuvant; Gene Expression Regulation; Glasgow Outcome Scale; Humans; Male; Mannose-Binding Protein-Associated Serine Proteases; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Time Factors

Topics: Anti-Bacterial Agents; Brain; Ceftriaxone; Female; Humans; Infant; Magnetic Resonance Imaging; Meningitis, Pneumococcal; Pneumococcal Vaccines; Serogroup; Vaccines, Conjugate

Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n = 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P = 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children.

Topics: Adjuvants, Pharmaceutic; Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Apoptosis; Ceftriaxone; Cell Proliferation; Dexamethasone; Hippocampus; Meningitis, Pneumococcal; Rats; Rats, Wistar; Regeneration; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Ceftriaxone; Emergency Service, Hospital; Female; Fever; Humans; Infant; Lethargy; Male; Meningitis, Pneumococcal; Pneumococcal Vaccines; Seizures; Serotyping; Sinus Thrombosis, Intracranial; Streptococcus pneumoniae; Stroke; Treatment Outcome; Vancomycin

Acute bacterial meningitis is still a life threatening disease.. We performed a retrospective observational study on the clinical characteristics of consecutively admitted patients with acute pneumococcal meningitis in a single tertiary care center in central Europe (from 2003 until 2015). Data were compared with a previously published historical group of 87 patients treated for pneumococcal meningitis at the same hospital (from 1984 until 2002).. Fifty-five consecutive patients with microbiologically proven pneumococcal meningitis were included. Most striking, mortality was down to 5.5 %, which was significantly lower than in the historical group where 24.1 % of the patients did not survive. Intracranial complications during the course of the disease were common and affected half of the patients. Unlike in the historic group, most of the intracranial complications (except ischemic stroke) were no longer associated with a low Glasgow Outcome Score at discharge.. The drastic reduction of mortality proves there have been important advances in the treatment of pneumococcal meningitis. Nevertheless, the fact that only 44.2 % of survivors had a full recovery indicates that the search for new adjunctive treatment options must be ongoing.

Topics: Adult; Aged; Anti-Bacterial Agents; Ceftriaxone; Dexamethasone; Female; Germany; Humans; Male; Meningitis, Pneumococcal; Middle Aged; Retrospective Studies; Steroids; Streptococcus pneumoniae

Despite the development of new antibiotic agents, mortality of pneumococcal meningitis remains high. In addition, meningitis results in severe long-term morbidity, most prominently cognitive deficits. Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation and differentiation of hematopoietic progenitor cells and increases the number of circulating neutrophil granulocytes. This study investigated the effect of adjuvant G-CSF treatment on cognitive function after pneumococcal meningitis. C57BL/6 mice were infected by subarachnoid injection of Streptococcus pneumoniae serotype 3 and treated with ceftriaxone and G-CSF subcutaneously or ceftriaxone alone for 5 days. Clinical scores, motor performance, and mortality during bacterial meningitis were unaffected by adjuvant G-CSF treatment. No effect of G-CSF treatment on production of proinflammatory cytokines or activation of microglia or astrocytes was observed. The G-CSF treatment did, however, result in hippocampal neurogenesis and improved spatial learning performance 6 weeks after meningitis. These results suggest that G-CSF might offer a new adjuvant therapeutic approach in bacterial meningitis to reduce long-term cognitive deficits.

Topics: Adult Stem Cells; Animals; Anti-Bacterial Agents; Ceftriaxone; Cell Differentiation; Cognition Disorders; Cytokines; Disease Models, Animal; Granulocyte Colony-Stimulating Factor; Hippocampus; Male; Maze Learning; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Motor Activity; Neurogenesis; Phosphorylation; Streptococcus pneumoniae; Time Factors

Neutrophilic inflammation often persists for days despite effective antibiotic treatment and contributes to brain damage in bacterial meningitis. We propose here that myeloid-related protein 14 (MRP14), an abundant cytosolic protein in myeloid cells, acts as an endogenous danger signal, driving inflammation and aggravating tissue injury.. The release pattern of MRP14 was analyzed in human and murine cerebrospinal fluid (CSF), as well as in isolated neutrophils. Its functional role was assessed in a mouse meningitis model, using MRP14-deficient mice.. We detected large quantities of MRP14 in CSF specimens from patients and mice with pneumococcal meningitis. Immunohistochemical analyses and a cell-depletion approach indicated neutrophils as the major source of MRP14. In a meningitis model, MRP14-deficient mice showed a better resolution of inflammation during antibiotic therapy, which was accompanied by reduced disease severity. Intrathecal administration of MRP14 before infection reverted the phenotype of MRP14-deficient mice back to wild type. Moreover, intrathecal injection of MRP14 alone was sufficient to induce meningitis in a Toll-like receptor 4 (TLR4)-CXCL2-dependent manner. Finally, treatment with the MRP14 antagonist paquinimod reduced inflammation and disease severity significantly, reaching levels comparable to those achieved after genetic depletion of MRP14.. The present study implicates MRP14 as an essential propagator of inflammation and potential therapeutic target in pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; ATP-Binding Cassette Transporters; Calgranulin B; Case-Control Studies; Ceftriaxone; Chemokine CXCL2; Humans; Male; Meningitis, Pneumococcal; Mice, Inbred C57BL; Mice, Knockout

High mortality and morbidity rates are observed in patients with bacterial meningitis (BM) and urge for new adjuvant treatments in addition to standard antibiotic therapies. In BM the hippocampal dentate gyrus is injured by apoptosis while in cortical areas ischemic necrosis occurs. Experimental therapies aimed at reducing the inflammatory response and brain damage have successfully been evaluated in animal models of BM. Fluoxetine (FLX) is an anti-depressant of the selective serotonin reuptake inhibitors (SSRI) and was previously shown to be neuroprotective in vitro and in vivo. We therefore assessed the neuroprotective effect of FLX in experimental pneumococcal meningitis.. Infant rats were infected intracisternally with live Streptococcus pneumoniae. Intraperitoneal treatment with FLX (10mgkg(-1)d(-1)) or an equal volume of NaCl was initiated 15min later. 18, 27, and 42h after infection, the animals were clinically (weight, clinical score, mortality) evaluated and subject to a cisternal puncture and inflammatory parameters (i.e., cyto-/chemokines, myeloperoxidase activity, matrix metalloproteinase concentrations) were measured in cerebrospinal fluid (CSF) samples. At 42h after infection, animals were sacrificed and the brains collected for histomorphometrical analysis of brain damage.. A significant lower number of animals treated with FLX showed relevant hippocampal apoptosis when compared to littermates (9/19 animals vs 18/23, P=0.038). A trend for less damage in cortical areas was observed in FLX-treated animals compared to controls (13/19 vs 13/23, P=ns). Clinical and inflammatory parameters were not affected by FLX treatment.. A significant neuroprotective effect of FLX on the hippocampus was observed in acute pneumococcal meningitis in infant rats.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Antidepressive Agents, Second-Generation; Apoptosis; Brain Injuries; Ceftriaxone; Cytokines; Disease Models, Animal; Fluoxetine; Granulocyte Colony-Stimulating Factor; Hippocampus; Interleukin-3; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Meningitis, Pneumococcal; Rats; Recombinant Fusion Proteins; Streptococcus pneumoniae

Topics: Adult; Anti-Bacterial Agents; Brain Edema; Ceftriaxone; Humans; Magnetic Resonance Imaging; Male; Meningitis, Pneumococcal; Otitis Media; Pneumococcal Infections

Hospital-based surveillance for pneumococcal meningitis has been conducted since January 1996 in the city of Salvador, Brazil. The purpose of this study was to describe the temporal evolution of Penicillin Non-Susceptible Streptococcus pneumoniae (PNSSP) in regards to serotype distributions and clonal diversity recovered from meningitis cases over 17 years.. Broth microdilution was used to identify pneumococcal isolates that were PNSSP (Minimum Inhibitory Concentration > 0.12 μg/ml). The annual incidence rate of meningitis cases was calculated. Serotyping was defined using multiplex polymerase chain reaction assays and quellung reaction. Genetic diversity of PNSSP isolates was assessed using both pulsed-field gel electrophoresis (PFGE) and Multilocus Sequence Typing (MLST) analyses.. A total of 854 cerebrospinal fluid (CSF) culture pneumococcal isolates were tested by broth microdilution method and serotyped. A total of 173 (20.3%) were penicillin non-susceptible (PNSSP) (Minimum Inhibitory concentration ≥ 0.12 μg/ml). The annual incidence of meningitis cases declined from 1.65/100,000 population (1996) to 0.2/100,000 population in 2012 and the rate due to PNSSP declined 82% over the 17-years of surveillance. PNSSP isolates were restricted to 13 serotypes, being the most common ones serotypes 14 (45.1%; 78/173), 23 F (19.1%; 33/173), 6B (14.4%; 25/173), 19 F (9.2%; 16/173) and 19A (5.2%; 9/173). Among the PNSSP isolates, 94% had serotypes represented in the 10-valent conjugate vaccine (PCV10). The predominant serotype 14 clonal groups were identified as PFGE group A/multilocus sequence type 66 (ST66) [35.3% (61/173)] and PFGE group GK/ST156 [4.6% (8/173)], the latter one associated with high level resistance to penicillin and ceftriaxone.. Our results show sustained reductions in pneumococcal meningitis cases in the Metropolitan region of Salvador from 1996 to 2012. This might reflect a beneficial impact of conjugate vaccines. Continued surveillance and further studies need to be conducted to better understanding on PCV10 vaccine impact.

Topics: Antigenic Variation; Bacterial Typing Techniques; Brazil; Ceftriaxone; Child; Child, Preschool; Female; Genetic Variation; Humans; Incidence; Infant; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Multiplex Polymerase Chain Reaction; Penicillin G; Penicillin Resistance; Pneumococcal Vaccines; Serotyping; Streptococcus pneumoniae; Time Factors; Vaccines, Conjugate

A 67-year-old man was transported to our hospital and diagnosed with pneumococcal meningitis. We immediately administered ceftriaxone and vancomycin according to the guidelines, but did not administer dexamethasone to him because he had been previously administered antibiotics. His left eye became complicated by endogenous endophthalmitis on the next day, which resulted in blindness, although his meningitis rapidly ameliorated. In comparison to other patients who have been reported to recover from complications with endophthalmitis after the combination therapy of antibiotics, corticosteroids and vitreous surgery, we consider that this patient's poor visual outcome may have been caused by severe inflammation or the breakdown of the blood ocular barrier due to the action of S. pneumoniae. Corticosteroids may be able to successfully treat such inflammation or disruption of the blood ocular barrier.

Topics: Aged; Anti-Bacterial Agents; Blindness; Blood-Retinal Barrier; Ceftriaxone; Drug Therapy, Combination; Endophthalmitis; Eye Infections, Bacterial; Humans; Male; Meningitis, Pneumococcal; Streptococcus pneumoniae; Vancomycin

Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Ear, Inner; Follow-Up Studies; Hearing Loss; Humans; Male; Meningitis, Pneumococcal; Paraparesis; Recurrence; Tomography, X-Ray Computed; Treatment Outcome

The aim of this study was to delineate mortality indicators in pneumococcal meningitis with special emphasis on therapeutic implications.. This retrospective, multicenter cohort study involved a 15-year period (1998-2012). Culture-positive cases (n=306) were included solely from 38 centers.. Fifty-eight patients received ceftriaxone plus vancomycin empirically. The rest were given a third-generation cephalosporin alone. Overall, 246 (79.1%) isolates were found to be penicillin-susceptible, 38 (12.2%) strains were penicillin-resistant, and 22 (7.1%) were oxacillin-resistant (without further minimum inhibitory concentration testing for penicillin). Being a critical case (odds ratio (OR) 7.089, 95% confidence interval (CI) 3.230-15.557) and age over 50 years (OR 3.908, 95% CI 1.820-8.390) were independent predictors of mortality, while infection with a penicillin-susceptible isolate (OR 0.441, 95% CI 0.195-0.996) was found to be protective. Empirical vancomycin use did not provide significant benefit (OR 2.159, 95% CI 0.949-4.912).. Ceftriaxone alone is not adequate in the management of pneumococcal meningitis due to penicillin-resistant pneumococci, which is a major concern worldwide. Although vancomycin showed a trend towards improving the prognosis of pneumococcal meningitis, significant correlation in statistical terms could not be established in this study. Thus, further studies are needed for the optimization of pneumococcal meningitis treatment.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Cohort Studies; Drug Therapy, Combination; Female; Humans; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Penicillin Resistance; Penicillins; Retrospective Studies; Treatment Outcome; Turkey; Vancomycin; Young Adult

Pneumococcal meningitis often results in death or neurological sequelae, but the underlying pathogenetic mechanisms remain poorly understood. In C57BL/6J mice subjected to intracerebroventricular (icv) challenge with Streptococcus pneumoniae, the chemokine CCL2 and cytokines interferon-γ, interleukin (IL)-1β, IL-6 and tumour necrosis factor were prominently expressed in the brain during the acute phase of the disease. The upregulation of these immune mediators was markedly diminished in IL-18-deficient mice. Uninfected IL-18(-/-) mice exhibited decreases in anxiety phenotype and licking behaviour, and an increase in behavioural habituation, in an automated monitoring system (the IntelliCage). Without antibiotic intervention, a majority of IL-18(+/+) mice developed irreversible disease after icv S. pneumoniae but this was significantly improved by deleting IL-18 gene function. IL-18(+/+) mice cured of pneumococcal meningitis with four doses of ceftriaxone, initiated at 20 h post-inoculation, showed enduring sequelae. These included abnormal behavioural phenotypes featuring diurnal hypoactivity and nocturnal hyperactivity, light phobia and disrupted cognitive function. While the hyperactive phenotype was absent in the corresponding IL-18(-/-) survivors, cognitive impairments and behavioural deficits were still present. Overall, the results suggest that the high levels of cytokines and/or chemokines released after pneumococcal challenge provoked a series of pathological events, ultimately causing acute death. Furthermore, since only a subset of behavioural phenotypes were ameliorated in the pneumococcus-infected IL-18(-/-) mice, the pathological pathways causing mortality may be, at least in part, distinct from those leading to long-term neurological sequelae.

Topics: Animals; Anti-Bacterial Agents; Anxiety; Ceftriaxone; Chemokines; Circadian Rhythm; Cognition Disorders; Cytokines; Disease Models, Animal; Disease Progression; Drinking Behavior; Exploratory Behavior; Female; Habituation, Psychophysiologic; Interleukin-18; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Photic Stimulation

Bacterial meningitis is a life-threatening disease. The incidence of meningitis is about 2.6-6 cases per 100.000 adults per year in developed countries. The most common causative microorganisms are Sreptococcus pneumoniae and Neisseria meningitidis. A 33-year-old multigravida, at 24 week of gestation was admitted to the hospital because of ear pain, haedache, fever and confusion. Lumbal puncture was performed and cerebrospinal fluid analysis showed signs of bacterial meningitis. Latex agglutination test was positive for S. pneumoniae, Gram-positive diplococci have seen under microscope and later cultivation verified S. pneumoniae as the causative agent. After ceftriaxon, dexamethasone administration and treatment in intensive care unit, left side mastoidectomy was performed since cranial computed tomography showed acut exacerbation of chronic mastoiditis on the left side. After extubation, mobilisation and 14 days antibiotic treatment the patient, who had residual hearing loss on the left side, was discharged from the hospital. During the treatment the foetal parameters were normal. The patient at 39 week of gestation gave birth to a healthy infant. Forty-eight case reports have been published in this topic around the world until April, 2012. The most common causative agents were S. pneumoniae and Listeria monocytogenes. Because of the little amount of data, it is hard to appreciate the actual incidence and prognosis of this life-threatening illness both for mother and infant. As far as we know this is the first published case report of meningitis during pregnancy in Hungary. By this article we would like to draw attention to the importance of teamwork, of prevention of brain abscess formation and of the removal of the infection's focus.

Topics: Adult; Anti-Bacterial Agents; Anti-Inflammatory Agents; Ceftriaxone; Dexamethasone; Drug Therapy, Combination; Female; Humans; Hungary; Latex Fixation Tests; Mastoid; Meningitis, Pneumococcal; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Spinal Puncture; Streptococcus pneumoniae; Treatment Outcome

It is important to monitor β-lactam antimicrobial nonsusceptibility trends for Streptococcus pneumoniae to inform empirical treatment guidelines. In this study, we describe penicillin and ceftriaxone susceptibility trends using national laboratory-based pneumococcal surveillance data from 2003 to 2010. A sentinel enhanced-site patient subset (2009 to 2010) contributed to the risk factor and mortality analyses. We included 9,218 invasive pneumococcal disease (IPD) cases for trend analyses and 2,854 IPD cases for risk factor and mortality analyses. Overall, we detected no significant changes in penicillin (patients <5 years of age, P = 0.50; patients ≥ 5 years of age, P = 0.05) or ceftriaxone nonsusceptibility rates (patients <5 years of age, P = 0.21; patients ≥ 5 years of age, P = 0.60). Factors associated with ceftriaxone nonsusceptibility on multivariate analysis were an age of <5 years (<1 year of age: adjusted odds ratio [aOR], 2.87; 95% confidence interval [CI], 1.70 to 4.86; 1 to 4 years of age: aOR, 2.58; 95% CI, 1.53 to 4.35, versus 25 to 44 years of age), province (Gauteng [aOR, 2.46; 95% CI, 1.26 to 4.84], and Northern Cape [aOR, 4.52; 95% CI, 1.95 to 10.52] versus KwaZulu-Natal), β-lactam use within 24 h preceding admission (aOR, 2.52; 95% CI, 1.41 to 4.53), and 13-valent vaccine serotypes (aOR, 51.64; 95% CI, 7.18 to 371.71). Among patients ≥ 5 years of age with meningitis who were treated according to current guidelines, HIV-infected patients (aOR, 2.94; 95% CI, 1.32 to 6.54) and patients infected with ceftriaxone-nonsusceptible isolates (aOR, 3.17; 95% CI, 1.27 to 7.89) had increased mortality rates. Among children <5 years of age with meningitis, mortality was increased in HIV-infected patients (aOR, 3.04; 95% CI, 1.40 to 6.56) but not in those with ceftriaxone-nonsusceptible isolates. Penicillin and ceftriaxone nonsusceptibility remained stable over the study period. Ceftriaxone nonsusceptibility was associated with increased mortality among patients ≥5 years of age with meningitis. The introduction of a pneumococcal conjugate vaccine may reduce ceftriaxone-nonsusceptible meningitis.

Topics: Adolescent; Adult; Age Factors; Aged; Anti-Bacterial Agents; Ceftriaxone; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Humans; Infant; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Penicillins; Pneumococcal Infections; Public Health Surveillance; Risk Factors; South Africa; Streptococcus pneumoniae; Young Adult

Pneumococci are one of the most common causes of bacterial meningitis in children. It's also responsible for the other invasive pneumococcal diseases (IPD) including bacteremia and pneumonia worldwide. Unvaccinated children are more prone to IPD. Although IPD tend to have a higher prevalence under 2 years of age and in children with primary/secondary immunodeficiencies, and various predisposing factors, older age groups with no underlying diseases also experience IPD. In this report, a pediatric case diagnosed with meningitis due to Streptococcus pneumoniae serotype 35F with no underlying condition and no history of pneumococcal vaccination was presented. An 11-year-old male patient was admitted to the hospital with the complaints of high (39.4°C) fever, headache, vomiting and sleepiness. On the basis of findings from physical examination and laboratory results, the patient was prediagnosed as bacterial meningitis and empirical ceftriaxone and vancomycin therapy was initiated. The cerebrospinal fluid culture of the patient yielded penicillin-susceptible pneumococci and the isolate was identified as serotype 35F by quellung reaction. Vancomycin treatment discontinued depending on the culture result, and the patient fully recovered with 14-days of ceftriaxone therapy without any complications during his follow-ups. Although effective antibiotics are available for IPD, vaccination is indispensable considering the high mortality rates. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) which are currently included in the vaccine, were the most common serotypes related to IPD globally. After mass infant vaccination has been introduced, invasive pneumococcal diseases due to the vaccine serotypes have tended to decrease in both vaccinated young children and non-vaccinated age groups due to herd immunity. Nevertheless, non-vaccine serotypes (NVTs) have emerged as the agents of IPD as a result of serotype replacement. 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in April, 2011 nationwide in our country. This case report was about a patient who had developed meningitis after the introduction of PCV13. There has been no data evaluating the pneumococcal serotype distribution after PCV13 in our country yet. On February, 2013, the Advisory Committee on Immunization Practices (ACIP) recommended routine use of PCV13 for children aged 6-18 years with underlying disease conditions. However, there is no recommendation for children with no underlying diseases in

Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Humans; Male; Meningitis, Pneumococcal; Pneumococcal Vaccines; Serotyping; Streptococcus pneumoniae

Pneumococcal meningitis is a lethal form of bacterial infection in the central nervous system that often causes lifelong neurological sequelae, despite therapeutic advances. The contemporary view is that the inflammatory response to infection contributes to the functional disabilities among survivors of this disease. We previously have established a mouse model of neurobehavioural deficits, using an automated IntelliCage™ system that revealed long-term behavioural and cognitive deficits in C57BL/6J female mice cured of meningitis by ceftriaxone treatment. We now have investigated the roles of two kynurenine pathway enzymes, indoleamine dioxygenase-1 (IDO1) and tryptophan dioxygenase-2 (TDO2), in the pathomechanisms of pneumococcal meningitis. Since tryptophan metabolism has long been implicated in behavioural and cognitive modulation through the production of neuroactive compounds, we hypothesised that preventing the actions of these enzymes through gene knockout would be beneficial in mice subjected to pneumococcal infection. We found no significant effect of IDO1 or TDO2 on mortality. Post-meningitic wild-type mice showed long-term diurnal hypoactivity and nocturnal hyperactivity when they were exposed to an Intellicage adaptation test throughout both the light and dark phases. These changes were not apparent in IDO1(-/-) survivors, but were present in the TDO2(-/-) survivors. Both IDO1(-/-) and TDO2(-/-) survivors were not protected against developing long-term cognitive deficits as measured in IntelliCage-based patrolling or reversal tasks. Collectively, these observations suggest (i) involvement of the kynurenine pathway in causing some behavioural sequelae of pneumococcal meningitis and (ii) that this pathway might operate synergistically with, or independently of, other pathways to cause other aspects of neurological sequelae.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cognition; Disease Models, Animal; Female; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Motor Activity; Neuropsychological Tests; Tryptophan

Pneumococcal meningitis is associated with neurologic sequelae, such as learning and memory impairment. Most recently, a nonbacteriolytic antibiotic has been investigated to minimise the inflammatory host response and prevent cognitive damage. In this study, we compared daptomycin (DPTO) or ceftriaxone (CFX) treatment on the inflammatory parameters and on the blood-brain barrier (BBB) integrity in experimental pneumococcal meningitis. In the first experiment, the animals received 10 µl of a Streptococcus pneumoniae suspension or artificial cerebrospinal fluid by intracerebroventricular (i.c.v.) and were treated with CFX or DPTO at 18 h post-infection. The animals were euthanised at 18, 20, 24, 36 and 40 h post-infection. In the hippocampus, brain-derived neurotrophic factor (BDNF), tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and IL-10 levels were not different between treatment groups; however, IL-4 and cytokine-induced neutrophil chemoattractant 1 (CINC-1) levels decreased in the CFX group. In the frontal cortex, TNF-α, IL- 4, IL-6, IL-10 and BDNF levels were not different between treatment groups. Only CINC-1 levels decreased at 40 h postinfection with CFX treatment. In the second experiment, the animals received DPTO or CFX for 7 days and were euthanised 10 days after pneumococcal meningitis induction. TNF-α, IL-6, IL-10, CINC-1 and BDNF levels were not different between treatment groups in the hippocampus; however, IL-4 levels decreased in CFX group. In the third experiment, the animals received 10 µl of an S. pneumoniae suspension or artificial CSF by i.c.v. and were treated with a single dose of CFX or DTPO antibiotic; assessment of the BBB breakdown showed that both antibiotics prevented the BBB disruption. Both treatments equally protected the BBB integrity, and there were no significant difference in cytokine production.

Topics: Animals; Anti-Bacterial Agents; Blood-Brain Barrier; Brain-Derived Neurotrophic Factor; Ceftriaxone; Cytokines; Daptomycin; Disease Models, Animal; Dose-Response Relationship, Drug; Hippocampus; Male; Meningitis, Pneumococcal; Rats; Rats, Wistar; Streptococcus pneumoniae; Time Factors

Bacterial complications, particularly skin superinfections, are common during chickenpox. However, reports of acute bacterial meningitis associated with chickenpox are unusual and amount to only a very few observations. For the most part, they are caused by Neisseria meningitidis or Streptococcus pyogenes. We report an infrequent occurrence of pneumococcal meningitis 2 days after the onset of a chickenpox rash in a 7-year-old previously healthy boy. Based on data from the literature, we attempt to understand the possible mechanisms resulting in bacterial complications, particularly meningitis, during chickenpox and to determine the means to prevent it.

Topics: Brain; Ceftriaxone; Chickenpox; Child; Coinfection; Diagnosis, Differential; Humans; Male; Meninges; Meningitis, Pneumococcal; Tomography, X-Ray Computed

Topics: Anti-Bacterial Agents; Blood; Ceftriaxone; Cerebrospinal Fluid; Female; Humans; Meningitis, Pneumococcal; Microscopy; Middle Aged; Streptococcus pneumoniae; Treatment Outcome

Evidence has demonstrated that matrix metalloproteinases (MMPs) contribute to the pathophysiology of bacterial meningitis; therefore, MMP inhibitors may be a neuroprotective treatment for brain injury caused by meningitis because of their antiinflammatory effects. The objective of this study was to evaluate the effect of the MMP inhibitor GM6001 in a rat model of S. pneumoniae meningitis. For these experiments, 7-day-old Sprague-Dawley rats were randomly divided into an uninfected group, meningitis group, antibiotic group and GM6001+antibiotic group. Uninfected animals were sham infected with sterile saline. Rats in the other three groups were inoculated with S. pneumoniae and left untreated, treated with ceftriaxone, or treated with ceftriaxone combined with GM6001. Rats in the meningitis group were severely ill, and MMP-9 was significantly up-regulated. The change in brain water content was consistent with the MMP-9 level. A significant loss of neurons and impaired learning function were observed in the meningitis group. Treatment with the antibiotic and GM6001 significantly down-regulated the level of MMP-9, decreased the brain water content, attenuated neuronal injury and improved learning. Conclusions: GM6001 protected the brain from damage caused by S. pneumoniae, and this effect may occur via downregulating MMP-9 and decreasing brain water content.

Topics: Analysis of Variance; Animals; Animals, Newborn; Anti-Bacterial Agents; Brain Edema; Ceftriaxone; Dipeptides; Disease Models, Animal; Gelatinases; Gene Expression Regulation; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Maze Learning; Meningitis, Pneumococcal; Rats; Rats, Sprague-Dawley; Spatial Learning; Spatial Memory

To determine the common aetiolog of acute bacterial meningitis in children and their antibiotic susceptibility pattern.. A retrospective study with a review of cerebrospinal fluid culture reports of paediatric patients aged 0-15 years, suspected of acute meningitis in the Medical Microbiology Department of Aminu Kano Teaching Hospital, Kano, Nigeria from October 2006 to October 2009 from October 2006 to October 2009.. A positive culture bacterial isolation rate of 3.3% (n=50/1500) with prevalence of Streptococcus pneumoniae (24%), Neisseria meningitidis (22%), Escherichia coli (16%), Haemophilus influenzae (14%), Group B streptococci (8%) and Enterococci (8%) which were susceptible to ceftriaxone (96%), cefotaxime (95%) and ciprofloxacin (93%) across the bacterial isolates. Neonates were 55% (n=6.8/12.4) most at risk.. Neonates are the most at risk of acute bacterial meningitis. In the absence of antibiotic susceptibility report, ceftriaxone should be considered as a first choice reliable antibiotic for empirical treatment of meningitis in children, in this environment.

Topics: Adolescent; Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Cerebrospinal Fluid; Child; Child, Preschool; Ciprofloxacin; Enterococcus; Escherichia coli; Haemophilus influenzae; Humans; Infant; Infant, Newborn; Meningitis, Bacterial; Meningitis, Escherichia coli; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Nigeria; Retrospective Studies; Streptococcus agalactiae; Tertiary Care Centers

Despite antibiotic therapy, acute and long-term complications are still frequent in pneumococcal meningitis. One important trigger of these complications is oxidative stress, and adjunctive antioxidant treatment with N-acetyl-l-cysteine was suggested to be protective in experimental pneumococcal meningitis. However, studies of effects on neurological long-term sequelae are limited. Here, we investigated the impact of adjunctive N-acetyl-l-cysteine on long-term neurological deficits in a mouse model of meningitis. C57BL/6 mice were intracisternally infected with Streptococcus pneumoniae. Eighteen hours after infection, mice were treated with a combination of ceftriaxone and placebo or ceftriaxone and N-acetyl-l-cysteine, respectively. Two weeks after infection, neurologic deficits were assessed using a clinical score, an open field test (explorative activity), a t-maze test (memory function), and auditory brain stem responses (hearing loss). Furthermore, cochlear histomorphological correlates of hearing loss were assessed. Adjunctive N-acetyl-l-cysteine reduced hearing loss after pneumococcal meningitis, but the effect was minor. There was no significant benefit of adjunctive N-acetyl-l-cysteine treatment in regard to other long-term complications of pneumococcal meningitis. Cochlear morphological correlates of meningitis-associated hearing loss were not reduced by adjunctive N-acetyl-l-cysteine. In conclusion, adjunctive therapy with N-acetyl-l-cysteine at a dosage of 300 mg/kg of body weight intraperitoneally for 4 days reduced hearing loss but not other neurologic deficits after pneumococcal meningitis in mice. These results make a clinical therapeutic benefit of N-acetyl-l-cysteine in the treatment of patients with pneumococcal meningitis questionable.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Ceftriaxone; Cochlea; Disease Models, Animal; Hearing Loss; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL

Topics: Adult; Anti-Bacterial Agents; Brain Ischemia; Ceftriaxone; Dexamethasone; Exotropia; Glucocorticoids; Headache; Humans; Magnetic Resonance Imaging; Male; Meningitis, Pneumococcal; Myoclonus

Following the introduction of a heptavalent pneumococcal conjugate vaccine (PCV7) in the Netherlands in 2006, the incidence of invasive pneumococcal disease (IPD) declined significantly. Since then a shift towards non-vaccine serotype IPD has been noted.. We present the case of multidrug resistant non-vaccine serotype 19A pneumococcal meningitis in a 5-month-old boy. He was admitted to our Paediatric Intensive Care Unit (PICU) with seizures and septic shock. A barbiturate-induced coma was eventually required to control the seizures; shock was combated with intravenous fluids and inotropes. He received a 6-week course of ceftriaxone and vancomycin. At follow-up, one year after discharge, he had unilateral deafness and minor developmental delay.. Worldwide, pneumococcal serotype 19A is now the most common cause of IPD in children, with an increasing incidence of multidrug resistant strains. This trend has not yet been observed in the Netherlands. This case demonstrates that even following the introduction of PCV7 pneumococcal meningitis can still occur. Prompt recognition of the symptoms is still essential.

Topics: Anti-Bacterial Agents; Ceftriaxone; Drug Resistance, Multiple, Bacterial; Heptavalent Pneumococcal Conjugate Vaccine; Humans; Infant; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Pneumococcal Vaccines; Serotyping; Streptococcus pneumoniae; Vancomycin

The role of adjunctive corticosteroids remains controversial in meningitis by penicillin-resistant pneumococci. We determined the effect of adjunctive corticosteroids in adults with pneumococcal meningitis in a region with a high rate of penicillin resistance. A multicenter, retrospective cohort study was conducted between 1998 and 2008 in Korea. The mortality and neurological sequelae were evaluated. Among 93 patients with pneumococcal meningitis, adequate adjunctive corticosteroids were given in 45.2%. The penicillin resistance rate was 60.0%, and 42.1% were nonsusceptible to ceftriaxone. The 30-day mortality rates in the group receiving adequate corticosteroid therapy, the group in which corticosteroid was not given, and that inadequately given were 24.3, 31.6, and 27.3%, respectively, and there was no difference between the groups. The rates of development of neurological sequelae were 34.3, 33.3, and 43.5%, respectively. Multivariate analysis showed that adequate corticosteroids did not reduce mortality (HR 0.773, 95% CI 0.293-2.040) and neurologic sequelae (HR 0.604, CI 0.262-1.393). Propensity-adjusted analysis showed that adjunctive corticosteroid was not associated with time to death (HR 0.949, CI 0.374-2.408), however, a decreasing tendency was shown in neurologic sequelae in the adequate corticosteroid group (HR 0.479, CI 0.207-1.110). In conclusion, adjunctive corticosteroids did not affect mortality in adults with pneumococcal meningitis in a region with high rates of resistance to penicillin and ceftriaxone; however, the patients receiving adequate corticosteroid therapy tended to develop neurologic sequelae less frequently.

Topics: Adrenal Cortex Hormones; Adult; Aged; Anti-Bacterial Agents; Ceftriaxone; Cohort Studies; Female; Humans; Kaplan-Meier Estimate; Male; Meningitis, Pneumococcal; Middle Aged; Penicillin Resistance; Penicillins; Retrospective Studies; Streptococcus pneumoniae; Survival Rate; Time Factors; Treatment Outcome

Exacerbation of cerebrospinal fluid (CSF) inflammation in response to bacteriolysis by beta-lactam antibiotics contributes to brain damage and neurological sequelae in bacterial meningitis. Daptomycin, a nonlytic antibiotic acting on Gram-positive bacteria, lessens inflammation and brain injury compared to ceftriaxone. With a view to a clinical application for pediatric bacterial meningitis, we investigated the effect of combining daptomycin or rifampin with ceftriaxone in an infant rat pneumococcal meningitis model. Eleven-day-old Wistar rats with pneumococcal meningitis were randomized to treatment starting at 18 h after infection with (i) ceftriaxone (100 mg/kg of body weight, subcutaneously [s.c.], twice a day [b.i.d.]), (ii) daptomycin (10 mg/kg, s.c., daily) followed 15 min later by ceftriaxone, or (iii) rifampin (20 mg/kg, intraperitoneally [i.p.], b.i.d.) followed 15 min later by ceftriaxone. CSF was sampled at 6 and 22 h after the initiation of therapy and was assessed for concentrations of defined chemokines and cytokines. Brain damage was quantified by histomorphometry at 40 h after infection and hearing loss was assessed at 3 weeks after infection. Daptomycin plus ceftriaxone versus ceftriaxone significantly (P < 0.04) lowered CSF concentrations of monocyte chemoattractant protein 1 (MCP-1), MIP-1α, and interleukin 6 (IL-6) at 6 h and MIP-1α, IL-6, and IL-10 at 22 h after initiation of therapy, led to significantly (P < 0.01) less apoptosis, and significantly (P < 0.01) improved hearing capacity. While rifampin plus ceftriaxone versus ceftriaxone also led to lower CSF inflammation (P < 0.02 for IL-6 at 6 h), it had no significant effect on apoptosis and hearing capacity. Adjuvant daptomycin could therefore offer added benefits for the treatment of pediatric pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Brain Damage, Chronic; Ceftriaxone; Chemokines; Cytokines; Daptomycin; Drug Administration Schedule; Drug Therapy, Combination; Hearing Loss; Inflammation; Meningitis, Pneumococcal; Random Allocation; Rats; Rats, Wistar; Rifampin

Neuronal injury in pneumococcal meningitis is a consequence of microglial activation and direct toxicity by bacterial products and systemic inflammation.. The treatment effect of the TEPC-15 antibody recognizing teichoic and lipoteichoic acids was investigated in murine microglial cells and in a rabbit model of pneumococcal meningitis.. In vitro, the TEPC-15 antibody recognizing teichoic and lipoteichoic acids increased Streptococcus pneumoniae phagocytosis by murine microglial cells. In rabbit ceftriaxone-treated S. pneumoniae meningitis, intracisternal TEPC-15 reduced the density of apoptotic neurons in the hippocampal dentate gyrus (116 ± 70 vs. 221 ± 132/mm(2); p = 0.03). Cerebrospinal fluid inflammatory parameters (protein, lactate, leukocytes, prostaglandins) were not reduced in TEPC-15-treated rabbits.. Intracisternal treatment with the TEPC-15 antibody reduced neuronal damage probably by promoting rapid phagocytosis of bacterial products.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Monoclonal; Ceftriaxone; Cells, Cultured; Dentate Gyrus; Disease Models, Animal; Lactic Acid; Leukocytes; Lipopolysaccharides; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Microglia; Phagocytosis; Prostaglandins; Proteins; Rabbits; Streptococcus pneumoniae; Teichoic Acids

Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons.. Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology.. The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone.. Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Astrocytes; Brain-Derived Neurotrophic Factor; Ceftriaxone; Cerebral Cortex; Cochlea; Dexamethasone; Disease Models, Animal; Hearing Loss; Hippocampus; Humans; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Neurons; Neurotrophin 3; Placebos; Receptors, Nerve Growth Factor; Spiral Ganglion

Topics: Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid; Delayed Diagnosis; False Negative Reactions; Female; Glasgow Coma Scale; Humans; Meningitis, Pneumococcal; Middle Aged; Spinal Puncture; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Child, Preschool; Drug Administration Schedule; Humans; Infant; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Pneumococcal; Neisseria meningitidis; Treatment Outcome

A 62-year-old man with adenocarcinoma underwent complete resection with a right upper lobectomy and en-bloc resection of the chest wall, with metallic clips applied to the vertebral nerve roots. A sudden deterioration in neurological status occurred due to pneumocephalus and ascending bacterial meningitis resulting from a subarachnoid-pleural fistula. The neurological status normalized after thoracoplasty and ceftriaxone treatment.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Anti-Bacterial Agents; Brain Diseases; Ceftriaxone; Fistula; Humans; Iatrogenic Disease; Lung Neoplasms; Male; Meningitis, Pneumococcal; Middle Aged; Pleural Diseases; Pneumocephalus; Pneumonectomy; Reoperation; Respiratory Tract Fistula; Streptococcus pneumoniae; Subarachnoid Space; Thoracoplasty; Tomography, X-Ray Computed; Treatment Outcome

Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1beta (IL-1beta), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1alpha) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid; Daptomycin; Disease Models, Animal; Humans; Inflammation; Meningitis, Pneumococcal; Rats; Rats, Wistar; Treatment Outcome

Bacterial meningitis in children causes high rates of mortality and morbidity. In a recent clinical trial, oral glycerol significantly reduced severe neurological sequelae in paediatric meningitis caused by Haemophilus influenzae type b, and a tendency towards a benefit of adjunctive glycerol was seen in pneumococcal meningitis.. Here we examined the effects of glycerol in pneumococcal meningitis of infant rats and adult mice. All animals received ceftriaxone, and glycerol or placebo. Brain damage, hearing loss, and inflammatory parameters were assessed.. Clinically and by histopathology, animals treated with glycerol or placebo did not differ. While both groups showed equally high levels of matrix metalloproteinase-9 at 24 h after infection, a significant difference in favour of glycerol was observed at 40 h after infection. However, this difference in matrix metalloproteinase-9 in late disease did not result in an improvement of histopathologic parameters.. No benefit of adjunctive glycerol was found in these models of pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Enzyme Inhibitors; Glycerol; Humans; Matrix Metalloproteinase 9; Meningitis, Pneumococcal; Mice; Placebos; Rats; Treatment Outcome

Topics: Adult; Algorithms; Ampicillin; Ceftriaxone; Child; Community-Acquired Infections; Dexamethasone; Diagnosis, Differential; Drug Therapy, Combination; Emergencies; Humans; Meningitis, Bacterial; Meningitis, Listeria; Meningitis, Meningococcal; Meningitis, Pneumococcal; Neurologic Examination

Streptococcus pneumoniae is now the predominant pathogen causing meningitis. The resistance of S. pneumoniae to penicillin and third-generation cephalosporins has grown steadily.. To assess the antibiotic susceptibility of S. pneumoniae isolated from the cerebrospinal fluid of children with meningitis, and determine the antibiotic regimen appropriate for suspected bacterial meningitis in Israel.. The study group included 31 children with 35 episodes of meningitis hospitalized from 1998 to 2006. S. pneumoniae isolates from the cerebrospinal fluid were tested for susceptibility to penicillin and ceftriaxone.. Of the 35 isolates, 17 (48.6%) showed resistance to penicillin (minimum inhibitory concentration > or = 0.12 microg/ml). Only 3 isolates (8.6%) showed intermediate resistance to ceftriaxone (> or = 0.5 and < (2 microg/ml), and none showed complete resistance (MIC > or = 2 microg/ml). The rates of antibiotic resistance were higher in children who were treated with antibiotics prior to admission (penicillin 88.9% vs. 34.6%, P = 0.007; ceftriaxone 22.2% vs. 3.8%, P = 0.156).. The rate of penicillin resistance is high in children with S. pneumoniae meningitis in Israel, especially in those treated with oral antibiotics prior to admission. Resistance to ceftriaxone is infrequent though not negligible. On the basis of these findings, current recommendations to empirically treat all children with suspected bacterial meningitis with ceftriaxone in addition to vancomycin until the bacterial susceptibility results become available are justified also in Israel.

Topics: Anti-Bacterial Agents; Ceftriaxone; Cephalosporin Resistance; Child; Child, Preschool; Drug Resistance, Bacterial; Female; Hospitals; Humans; Infant; Israel; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Streptococcus pneumoniae; Treatment Outcome

A case of Streptococcus pneumoniae meningitis in a possibly immune-compromised child with a ventriculoatrial shunt is described. The infection was successfully eradicated by treatment with intravenous ceftriaxone and rifampicin, without removal of the shunt.

Topics: Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid Shunts; Drug Therapy, Combination; Female; Humans; Infant; Meningitis, Pneumococcal; Pneumonia, Pneumococcal; Prosthesis-Related Infections; Rifampin

Meropenem is a broad-spectrum carbapenem antibiotic that is highly active against the pathogens causing meningitis. The aims of this study was to determine the efficacies of meropenem alone and combined with rifampin against two Streptococcus pneumoniae strains with different susceptibility to beta-lactams using the guinea pig meningitis model and compare them with the standard ceftriaxone plus vancomycin therapy. All treatments except rifampin were bactericidal from 6 h. The addition of rifampin did not improve the activity of meropenem alone. Our results provide good evidence of the efficacy of meropenem in the treatment of penicillin- and cephalosporin-susceptible and -resistant pneumococcal meningitis similar to that of ceftriaxone plus vancomycin, suggesting that meropenem might be a good option in the management of this infection.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Female; Guinea Pigs; Humans; Meningitis, Pneumococcal; Meropenem; Microbial Viability; Rifampin; Streptococcus pneumoniae; Thienamycins; Time Factors; Treatment Outcome; Vancomycin

In bacterial meningitis, severe systemic and local inflammation causes long-term impairment and death of affected patients. The current antibiotic therapy relies on cell wall-active beta-lactam antibiotics, which rapidly sterilize the cerebrospinal fluid (CSF). However, beta-lactams inhibit cell wall synthesis, induce bacteriolysis, and thereby evoke a sudden release of high amounts of toxic and proinflammatory bacterial products. Because tissue damage in bacterial meningitis is the result of bacterial toxins and the inflammatory host response, any reduction of free bacterial compounds promises to prevent neuronal damage.. In vitro experiments and randomized prospective animal study.. University research laboratories.. Streptococcus pneumoniae broth cultures and New Zealand White rabbits.. We evaluated a concept to improve bacterial meningitis therapy in which a short-term pretreatment with the protein synthesis-inhibiting antibiotic rifampicin precedes the standard antibiotic therapy with ceftriaxone. First, logarithmically growing pneumococcal cultures were subdivided and exposed to different antibiotics. Then, rabbits suffering from pneumococcal meningitis were randomized to receive rifampicin pretreatment or ceftriaxone alone.. In pneumococcal cultures, quantitative immunoblotting and real-time polymerase chain reaction revealed a reduced release of pneumolysin and bacterial DNA by rifampicin pretreatment for 30 minutes in comparison with ceftriaxone treatment alone. In vivo, a 1-hour rifampicin pretreatment reduced the release of bacterial products and attenuated the inflammatory host response, as demonstrated by decreased CSF levels of prostaglandin E2 and total protein and increased glucose CSF/plasma ratios. Rifampicin pretreatment reduced infection-associated neuronal apoptotic cell loss compared with ceftriaxone-treated controls.. A short-term pretreatment with rifampicin reduced the beta-lactam-induced release of deleterious bacterial products, attenuated inflammation, and thereby decreased neuronal cell loss in experimental bacterial meningitis. This concept has the potential to reduce inflammation-associated neuronal injury in bacterial meningitis and should be evaluated in a clinical trial.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Ceftriaxone; Cell Culture Techniques; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Meningitis, Pneumococcal; Neurons; Rabbits; Rifampin

To examine the routes, dynamics and correlates of cochlear inflammation in meningitis to provide information on the pathogenesis of the associated hearing loss and indications for rational pharmacotherapeutical intervention.. A well-established rat model of Streptococcus pneumoniae meningitis was employed.. Eight rats were inoculated intrathecally and not treated, whereas 26 were inoculated and treated with ceftriaxone. Six rats were sham-inoculated, making a total of 40 rats. The rats were sacrificed when reaching terminal illness or after 7 days, followed by light microscopy. Routes of cochlear inflammatory infiltration were examined. The volume fraction of inflammatory infiltration was estimated and correlated to bacterial and leukocyte counts in cerebrospinal fluid (CSF) and blood.. The perilymphatic space was infiltrated with inflammatory cells via cochlear aqueduct, whereas the endolymphatic space was infiltrated from the spiral ligament. Rosenthal's canal was infiltrated through osseous spiral lamina canaliculi. In the untreated group, the degree of inflammation correlated with time of death, whereas antibiotic treatment reversed this development. Perilymphatic inflammation correlated significantly with the CSF leukocyte count, whereas endolymphatic inflammation correlated with spiral ligament inflammation.. Meningogenic inflammation of the rat cochlea occurs via the cochlear aqueduct and the spiral ligament capillary bed. The spiral ganglion is infiltrated through the osseous spiral lamina. The degree of inflammation correlates positively with time of death in untreated meningitis, whereas antibiotic treatment leads to subsiding infiltration during recovery.

Topics: Animals; Biopsy, Needle; Ceftriaxone; Cerebrospinal Fluid; Cochlear Diseases; Disease Models, Animal; Immunohistochemistry; Inflammation; Leukocyte Count; Male; Meningitis, Pneumococcal; Microscopy, Electron; Random Allocation; Rats; Rats, Wistar; Sensitivity and Specificity

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Drug Administration Schedule; Drug Therapy, Combination; Humans; Meningitis, Pneumococcal; Rabbits; Rifampin

No recent publications are available about pneumococcal meningitis in Hungarian children. The aim of this study was to collect data of epidemiological, clinical and prognostic features of pneumococcal meningitis in children treated at Szent László Hospital, Budapest, Hungary.. We conducted a retrospective review of medical charts and follow-up records of patients aged 1 to 18 years admitted to our Pediatric and Pediatric Intensive Care Units due to pneumococcal meningitis between 1st Jan 1998 and 30th Jun 2007.. 31 children with 34 cases of pneumococcal meningitis were admitted to our hospital in the study period. Two children developed recurrent illness. The mean age was 6 years, 26% were under 1 year of age. The mean duration of hospital stay was 21 days, 97% required intensive care. Frequent clinical symptoms were fever (100%), nuchal rigidity and vomiting (78%), altered mental status (71%), Kernig's and Brudzinski's signs (58%) and seizures (41%). Otitis media, sinusitis, mastoiditis were present in 44%, 58%, 41%, respectively. Subdural effusion, parenchymal cerebral lesion and sinus thrombosis were documented in 5, 3 and 2 cases, respectively. One third of the patients received ceftriaxon, two thirds were administered ceftriaxon and vancomycin. Adjunctive therapy with dexamethasone was given to 91% of the children. 70% of patients required mechanical ventilation. 9 patients (25%) required endoscopic sinus surgery. In 13 cases (38%) mastoidectomy, in 5 children (15%) neurosurgery was performed. The case fatality rate was 23.5%. 8 (23.5%) patients had mild or moderate, 1 child (3%) developed severe neurological sequelae.. Pneumococcal meningitis in children remains a source of substantial morbidity and mortality in childhood. The long hospital stay, the frequent need for intensive care and severe neurologic sequelae emphasize the importance of early diagnosis, early treatment and prevention with pneumococcal conjugate vaccines.

Topics: Adolescent; Anti-Bacterial Agents; Ataxia; Ceftriaxone; Child; Child, Preschool; Female; Follow-Up Studies; Hospital Departments; Humans; Hungary; Infant; Infant, Newborn; Intellectual Disability; Intensive Care Units, Pediatric; Length of Stay; Male; Medical Records; Meningitis, Pneumococcal; Muscle Hypotonia; Pneumococcal Vaccines; Recurrence; Respiration, Artificial; Retrospective Studies; Urinary Bladder, Neurogenic; Vaccines, Conjugate; Vancomycin

The prevalence of penicillin-resistant Streptococcus pneumoniae (PRSP) meningitis has increased worldwide, particularly in East Asia and the United States. We recently experienced a case of PRSP meningitis that developed during frontofacial distraction. The patient was a 7-year-old girl with Crouzon disease who was treated by frontofacial monobloc/Le Fort IV minus glabellar osteotomy with quadruple internal distraction devices. Penicillin-resistant Streptococcus pneumoniae meningitis was diagnosed after surgery and treated successfully with meropenem (a carbapenem) at 120 mg kg d every 8 hours, ceftriaxone (a third-generation cephalosporin) at 100 mg kg d every 12 hours, and vancomycin (a glycopeptide) at 45 mg kg d every 6 hours. This case indicates that severe and fatal bacterial meningitis may occur as a postoperative complication due to multidrug-resistant bacteria indigenous to the nasal cavity after simultaneous osteotomy of the cranium and facial bone in intracraniofacial surgery, such as that for syndromic craniosynostosis and hypertelorbitism. In such cases, preventive strategies should include preoperative administration of pneumococcal vaccine, preoperative screening of nasal bacterial flora by nasal culture test, and prior administration of a carbapenem with good cerebrospinal fluid transfer or a third- or fourth-generation cephem covering PRSP. Postoperatively, suspected meningitis may be treated with a combination of the 3 drugs used in our case, in parallel with emergency cephalic contrast computed tomography and culture tests of blood and cerebrospinal fluid. Our experience suggests that these measures will facilitate a successful outcome in frontofacial distraction osteogenesis.

Topics: Anti-Bacterial Agents; Ceftriaxone; Child; Craniofacial Dysostosis; Drug Combinations; Female; Follow-Up Studies; Frontal Bone; Humans; Meningitis, Pneumococcal; Meropenem; Osteogenesis, Distraction; Osteotomy; Osteotomy, Le Fort; Penicillin Resistance; Streptococcus pneumoniae; Surgical Wound Infection; Thienamycins; Tomography, X-Ray Computed; Treatment Outcome; Vancomycin

Topics: Adult; Anesthesia, Spinal; Bacteremia; Ceftriaxone; Cerebrospinal Fluid; Consciousness Disorders; Dexamethasone; Equipment Contamination; Foot; Humans; Male; Meningitis, Pneumococcal; Needles; Neuroma; Penicillin Resistance; Peripheral Nervous System Neoplasms; Postoperative Complications; Punctures; Streptococcus pneumoniae; Vancomycin; Wound Infection

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [(3)H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.

Topics: Animals; Anti-Bacterial Agents; Bacteriolysis; Ceftriaxone; Cell Wall; Cerebrospinal Fluid; Choline; Daptomycin; Disease Models, Animal; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Treatment Outcome; Tritium

Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 x 10(4) +/- 0.5 x 10(4) CFU of Streptococcus pneumoniae serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.]; n = 55) or daptomycin (50 mg/kg s.c.; n = 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log(10) 3.6 +/- 1.0 and log(10) 6.3 +/- 1.4 CFU/ml, respectively; P < 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (P < 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively; P < 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Brain Injuries; Ceftriaxone; Cerebral Cortex; Cerebrospinal Fluid; Daptomycin; Disease Models, Animal; Humans; Inflammation; Meningitis, Pneumococcal; Random Allocation; Rats; Treatment Outcome

Streptococcus (S.) pneumoniae meningitis has a high lethality despite antibiotic treatment. Inflammation is a major pathogenetic factor, which is unresponsive to antibiotics. Therefore adjunctive therapies with antiinflammatory compounds have been developed. TNF484 is a TNF-alpha converting enzyme (TACE) inhibitor and has been found efficacious in experimental meningitis. Toll-like receptor 2 (TLR2) contributes to host response in pneumococcal meningitis by enhancing bacterial clearing and downmodulating inflammation. In this study, TNF484 was applied in mice, which lacked TLR2 and exhibited a strong meningeal inflammation.. 103 CFU S. pneumoniae serotype 3 was inoculated subarachnoidally into C57BL/6 wild type (wt) mice or TLR2-/-, CD14-/- and CD14-/-/TLR2-/- mice. Severity of disease and survival was followed over 9 days. Response to antibiotics (80 mg/kg ceftriaxone i.p. for 5 days) and/or TACE inhibitor treatment (1 mg/kg s.c. twice daily for 4 days) was evaluated. Animals were sacrificed after 12, 24, and 48 h for analysis of bacterial load in cerebrospinal fluid (CSF) and brain and for TNF and leukocyte measurements in CSF.. TLR2-/- mice were significantly sicker than the other mouse strains 24 h after infection. All knockout mice showed higher disease severity after 48 h and died earlier than wt mice. TNF release into CSF was significantly more elevated in TLR2-/- than in the other strains after 24 h. Brain bacterial numbers were significantly higher in all knockout than wt mice after 24 h. Modulation of outcome by antibiotic and TACE inhibitor treatment was evaluated. With antibiotic therapy all wt, CD14-/- and TLR2-/-/CD14-/- mice, but only 79% of TLR2-/- mice, were rescued. TACE inhibitor treatment alone did not rescue, but prolonged survival in wt mice, and in TLR2-/- and CD14-/- mice to the values observed in untreated wt mice. By combined antibiotic and TACE inhibitor treatment 95% of TLR2-/- mice were rescued.. During pneumococcal meningitis strong inflammation in TLR2-deficiency was associated with incomplete responsiveness to antibiotics and complete response to combined antibiotic and TACE inhibitor treatment. TACE inhibitor treatment offers a promising adjuvant therapeutic strategy in pneumococcal meningitis.

Topics: ADAM Proteins; ADAM17 Protein; Animals; Anti-Bacterial Agents; Ceftriaxone; Chemotherapy, Adjuvant; Female; Hydroxamic Acids; Lipopolysaccharide Receptors; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Pneumococcal Infections; Streptococcus pneumoniae; Toll-Like Receptor 2; Tumor Necrosis Factor-alpha

Although the disposition of ceftriaxone and cefepime in the cerebrospinal fluid (CSF) has been described, the ability of these agents to achieve critical pharmacodynamic targets against Streptococcus pneumoniae in CSF has not been reported. Plasma and CSF pharmacokinetic data were obtained from hospital patients with external ventricular drains and receiving ceftriaxone or cefepime. Concentration-time profiles in plasma and CSF were modeled using a 3-compartment model with 0-order infusion and 1st-order elimination and transfer. The model parameters were identified with population pharmacokinetic analysis (Big Non-Parametric Adaptive Grid with adaptive gamma). A Monte Carlo Simulation (9999 subjects) estimated the probability of target attainment (PTA) for total drug CSF concentrations at 50% and 100% T>MIC for ceftriaxone 2G IV Q12H and cefepime 2G IV Q8H. The S. pneumoniae bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program (USA) provided the distribution of contemporary (2003-2004) MICs. Post-Bayesian measures of bias and precision, observed-predicted plots, and R2 values were highly acceptable for both drugs. The probabilities of achieving 50% and 100% T>MIC in the CSF for ceftriaxone were 76% and 65%, respectively. For cefepime, the PTA at 50% and 100% T>MIC in the CSF were 91.8% and 82%, respectively. The CSF pharmacodynamics against S. pneumoniae for cefepime were superior to that of ceftriaxone. The implications of these findings need to be reexamined in the clinical setting.

Topics: Anti-Bacterial Agents; Blood Chemical Analysis; Cefepime; Ceftriaxone; Cephalosporins; Cerebrospinal Fluid; Female; Humans; Male; Meningitis, Pneumococcal; Middle Aged; Monte Carlo Method; Streptococcus pneumoniae

In the African meningitis belt, reported case-fatality ratio (CFR) for meningitis are usually calculated on the basis of presumed cases. We reviewed 3509 presumed cases of bacterial meningitis reported in Niger for which a cerebrospinal fluid (CSF) sample had been tested later at the reference laboratory. The main aetiologies were Neisseria meningitidis (1496 cases), Streptococcus pneumoniae (303 cases) and Haemophilus influenzae (105 cases). The CFR of meningococcal meningitis was lower for serogroup A (5.5%) than for serogroups X (12%) and W135 (12.7%). With a CFR of 49.8%, pneumococcal meningitis, albeit representing only 20.7% of confirmed cases, accounted for 50% of the deaths. The disease burden of pneumococcal meningitis must be better taken into consideration in the future. As most treatments are presumptive, there is a urgent need for an easy-to-administer, cheap first-line treatment effective on N. meningitidis as well as on S. pneumoniae and H. influenzae that would replace the single-dose oily chloramphenicol treatment which is the most frequent treatment administered today, independent of microbial aetiology and season. The development of diagnostic tools really suitable for remote health facilities also is an urgent challenge.

Topics: Adolescent; Amoxicillin; Ampicillin; Anti-Bacterial Agents; Ceftriaxone; Child; Child, Preschool; Chloramphenicol; Haemophilus influenzae; Humans; Infant; Infant, Newborn; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Neisseria meningitidis; Niger; Streptococcus pneumoniae; Survival Rate

In this study, we investigated cytokine expression during experimental pneumococcal meningitis. Mice were intracisternally infected with Streptococcus pneumoniae and treated with ceftriaxone starting at 24 h after infection. At different time points before and after antibiotic therapy, the cytokine expression pattern was determined in mouse brains using protein arrays. Underlining the power of this method, the meningitis-relevant cytokines interleukin-1beta (IL-1beta), IL-6, KC, macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractant protein-1 (MCP-1/CCL2) were markedly elevated in infected animals. Newly identified proteins during the acute stage of the disease (until 30 h after infection) included lymphotactin (XCL-1), MIP-1gamma (CCL9) and MCP-5 (CCL12), cytokine responsive gene- 2 (CRG-2/CXCL10) and CXCL16, and insulin-like growth factor binding protein 3 (IGFBP3). During later stages, an induction of T-cell activation-3 (TCA-3/CCL1), platelet factor-4 (PF-4/CXCL4) and stromal derived factor-1alpha (SDF-1alpha/CXCL13), and IL-4 was observed. The validity of this method was supported by an additional ELISA analysis of the expression profile of CXCL16 and IGFBP3, which was identical to that observed by protein array. In conclusion, the use of protein array technology led to an extension of the current picture of protein expression in pneumococcal meningitis. Most important, new factors that might play a role in pneumococcal meningitis were identified.

Topics: Animals; Anti-Bacterial Agents; Brain; Ceftriaxone; Chemokine CXCL10; Chemokine CXCL13; Chemokines, C; Chemokines, CC; Chemokines, CXC; Cytokines; Disease Models, Animal; Interleukin-4; Macrophage Inflammatory Proteins; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Monocyte Chemoattractant Proteins; Monokines; Platelet Factor 4; Protein Array Analysis; Streptococcus pneumoniae; Time Factors

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

This study evaluated the role of linezolid in the treatment of patients suffering from pneumococcal meningitis. Treatment included ceftriaxone (4000 mg every 24 h), linezolid (600 mg every 12 h) and dexamethasone (8 mg every 6 h). Linezolid was withdrawn if a penicillin-susceptible isolate of Streptococcus pneumoniae was identified. Of 16 patients studied, seven were infected with penicillin-non-susceptible isolates of S. pneumoniae, two died, and three reported sequelae. No toxicity was reported. It was concluded that linezolid can be used for the treatment of pneumococcal meningitis, as an alternative to vancomycin or rifampicin, in regimens including a third-generation cephalosporin.

Topics: Acetamides; Adult; Aged; Ceftriaxone; Drug Therapy, Combination; Female; Humans; Linezolid; Male; Meningitis, Pneumococcal; Middle Aged; Oxazolidinones; Penicillin Resistance; Penicillins; Streptococcus pneumoniae; Treatment Outcome

Experts recommend that children with suspected pneumococcal meningitis should empirically receive combination therapy with vancomycin plus either ceftriaxone or cefotaxime. The relationship between timing of the first dose of vancomycin relative to other antibiotics and outcome in these children, however, has not been addressed.. Medical records of children with pneumococcal meningitis at a single institution from 1991-2001 were retrospectively reviewed. Vancomycin start time was defined as the number of hours from initiation of cefotaxime or ceftriaxone therapy until the administration of vancomycin therapy. Outcome variables were death, sensorineural hearing loss, and other neurologic deficits at discharge. Associations between independent variables and outcome variables were assessed in univariate and multiple logistic regression analyses.. Of 114 subjects, 109 received empiric vancomycin therapy in combination with cefotaxime or ceftriaxone. Ten subjects (9%) died, whereas 37 (55%) of 67 survivors who underwent audiometry had documented hearing loss, and 14 (13%) of 104 survivors were discharged with other neurologic deficits. Subjects with hearing loss had a significantly shorter median vancomycin start time than did those with normal hearing (<1 vs 4 hours). Vancomycin start time was not significantly associated with death or other neurologic deficits in univariate or multivariate analyses. Multiple logistic regression revealed that hearing loss was independently associated with vancomycin start time <2 hours, blood leukocyte count <15000/microL, and cerebrospinal fluid glucose concentration <30 mg/dL.. Early empiric vancomycin therapy was not clinically beneficial in children with pneumococcal meningitis but was associated with a substantially increased risk of hearing loss. It may be prudent to consider delaying the first dose of vancomycin therapy until > or =2 hours after the first dose of parenteral cephalosporin in children beginning therapy for suspected or confirmed pneumococcal meningitis.

Topics: Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Drug Therapy, Combination; Female; Hearing Loss, Sensorineural; Humans; Infant; Male; Meningitis, Pneumococcal; Survival Rate; Vancomycin

Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 microM in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Brain; Ceftriaxone; Cochlea; Doxycycline; Female; Injections, Subcutaneous; Meningitis, Pneumococcal; Rats; Rats, Wistar; Tumor Necrosis Factor-alpha

Bacteraemia concomitant with meningitis has been shown to greatly affect outcome. Consequently, the efficacy of serotype-specific anti-pneumococcal antiserum (APAS) was investigated in a rat model of pneumococcal meningitis.. Rats were infected with Streptococcus pneumoniae serotype 3. All rats received ceftriaxone starting 26 h post-infection. APAS was administered either at the time of infection or 26 h post-infection and effects were compared with rats treated with antibiotics only.. A significant clinical benefit was found when APAS was given at the time of infection whereas no effect was found when administered 26 h after infection. This work indicates that the clinical value of using APAS in pneumococcal meningitis may be limited.

Topics: Animals; Anti-Bacterial Agents; Antibodies, Bacterial; Bacterial Capsules; Ceftriaxone; Disease Models, Animal; Drug Therapy, Combination; Immunization, Passive; Meningitis, Pneumococcal; Motor Activity; Rats; Rats, Wistar; Streptococcus pneumoniae; Survival Analysis; Time Factors

The aim of the study was to determine the efficacy of teicoplanin, alone and in combination with ceftriaxone, in a rabbit model of cephalosporin-resistant pneumococcal meningitis, and to assess the effect of concomitant therapy with dexamethasone.. In vitro killing curves of teicoplanin, with and without ceftriaxone, were performed. Groups of eight animals per treatment were inoculated with a cephalosporin-resistant pneumococcal strain (penicillin MIC, 4 mg/L; ceftriaxone MIC, 2 mg/L; teicoplanin MIC, 0.03 mg/L) and treated over a 26 h period. Teicoplanin was administered at a dose of 15 mg/kg, alone and in combination with ceftriaxone at 100 mg/kg with or without dexamethasone at 0.25 mg/kg. CSF samples were collected at different time-points, and bacterial titres, white blood cell counts, lactate and protein concentrations and bacteriostatic/bactericidal titres were determined. Blood and CSF teicoplanin pharmacokinetic and pharmacodynamic parameters were determined.. Teicoplanin alone promoted a decrease in bacterial counts at 6 h of -2.66 log cfu/mL and was bactericidal at 24 h, without therapeutic failures. Similar good results were obtained when dexamethasone was used simultaneously, in spite of the penetration of teicoplanin into the CSF being significantly reduced, from 2.31% to 0.71%. Teicoplanin and ceftriaxone combinations were synergic in vitro, but not in the meningitis model.. Teicoplanin alone was very effective in this model of cephalosporin-resistant pneumococcal meningitis. The use of concomitant dexamethasone resulted in lower CSF teicoplanin levels, but not in therapeutic failures. The combination of teicoplanin plus ceftriaxone and dexamethasone might be a good alternative for the empirical therapy of pneumococcal meningitis. Additional data should confirm our experiments, in advance of clinical trials to assess efficacy in humans.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Ceftriaxone; Cephalosporin Resistance; Colony Count, Microbial; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae; Teicoplanin

Topics: Acute Disease; Ceftriaxone; Child; Diagnosis, Differential; Female; Follow-Up Studies; Frontal Bone; Frontal Sinus; Humans; Meningitis, Pneumococcal; Radiography; Skull Base; Skull Fractures; Treatment Outcome

Rheumatoid arthritis is a severe deforming chronic disease which has major implications for mortality and quality of life. Agents with anti-tumour necrosis factor alpha (TNFalpha) activity are a new modality of therapy, which can significantly reduce the acute inflammation in this condition. However, TNFalpha is a cytokine involved in initiating the protective immune response; consequently, patients receiving this therapy are at increased risk of infection. Etanercept is a recombinant form of the p75 TNF receptor (TNF-RII) dimerised by fusion with a portion of the human IgG1 Fc tail with anti-TNFalpha activity. We report the first case of a patient with rheumatoid arthritis who developed pneumococcal meningitis whilst on etanercept, suggesting a possible association between etanercept and this severe life threatening infection.

Topics: Antirheumatic Agents; Ceftriaxone; Ciprofloxacin; Disease Susceptibility; Etanercept; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Infusions, Intravenous; Meningitis, Pneumococcal; Middle Aged; Otitis Media; Receptors, Tumor Necrosis Factor; Streptococcus pneumoniae; Treatment Outcome

Rifampin, a protein synthesis inhibitor, reduced mortality in a mouse model of meningitis compared to bacteriolytic cephalosporin standard therapy. To assess whether moxifloxacin (known to cause a less rapid bacteriolysis than cephalosporins) can similarly reduce mortality, mice infected with Streptococcus pneumoniae by deep intracerebral injection were treated subcutaneously with either 200 mg/kg of moxifloxacin or ceftriaxone every 8 hours for 5 days (n = 49 each). They were then observed for an additional 8 days. Overall mortalities were 35 and 29 in moxifloxacin- and ceftriaxone-treated mice, respectively (p = 0.29). Kaplan-Meier survival analysis also revealed no statistically significant differences (p = 0.32). Moxifloxacin failed to reduce mortality compared to cephalosporin standard therapy.

Topics: Animals; Anti-Bacterial Agents; Aza Compounds; Ceftriaxone; Disease Models, Animal; Drug Administration Schedule; Fluoroquinolones; Injections, Subcutaneous; Male; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Moxifloxacin; Quinolines; Treatment Outcome

The aim of the study was to assess the in vitro and in vivo efficacy of ceftriaxone, vancomycin and rifampicin alone and combined against Streptococcus pneumoniae ATCC 51916 (MIC of ceftriaxone: 32 mg/L).. In vitro killing curves were performed with clinically achievable CSF antibiotic concentrations. In the rabbit model of pneumococcal meningitis, we studied the efficacy of and effects on inflammation of treatment with ceftriaxone 100 mg/kg/day, vancomycin 30 mg/kg/day and rifampicin 15 mg/kg/day, alone and combined, over a 26 h period.. Time-kill curves showed that vancomycin was bactericidal, and ceftriaxone and rifampicin produced a bacteriostatic effect. An additive effect was observed when combinations of ceftriaxone plus vancomycin were studied at subinhibitory concentrations. Emergence of resistance to rifampicin was detected both when rifampicin was studied alone and when combined with ceftriaxone or vancomycin. In the rabbit meningitis model, ceftriaxone was bacteriostatic, whereas rifampicin and vancomycin were bactericidal at 24 h. Although not synergistic, the combinations of ceftriaxone plus vancomycin or rifampicin, and vancomycin plus rifampicin, improved the efficacy of any antibiotic tested alone--all combinations were bactericidal from 6 h--and significantly decreased inflammatory parameters in CSF compared with control and ceftriaxone groups.. Ceftriaxone plus vancomycin, and vancomycin plus rifampicin appeared to be effective in the therapy of experimental pneumococcal meningitis caused by highly cephalosporin-resistant strains such as ATCC 51916. Our results provide an experimental basis for using these combinations as empirical therapy for pneumococcal meningitis, regardless of the degree of cephalosporin resistance of the causative strain.

Topics: Animals; Ceftriaxone; Cephalosporin Resistance; Cerebrospinal Fluid; Colony Count, Microbial; Disease Models, Animal; Drug Combinations; Drug Interactions; Drug Resistance, Bacterial; Female; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Rifampin; Streptococcus pneumoniae; Vancomycin

Angio-oedema may be hereditary or acquired and is characterised by episodes of potentially life threatening localised tissue oedema and swelling resulting from deficiency of compliment pathway C1 esterase inhibitor. Acquired angio-oedema is about ten times less frequent than the hereditary type and has been associated with immune-deficiency disorders, malignancies and exposure to specific medications and food substances. We present a case of seven year old, human immune-deficiency virus positive girl, who developed gross swelling of the tongue and neck while on treatment for pneumococcal meningitis with ceftriaxone. Difficulties in arriving at a definitive diagnosis of angio-oedema in a resource poor country are discussed and alternative diagnostic options proposed.

Topics: AIDS-Related Opportunistic Infections; Angioedema; Anti-Bacterial Agents; Ceftriaxone; Child; Fatal Outcome; Female; HIV Infections; Humans; Meningitis, Pneumococcal

Ceftriaxone acted synergistically with levofloxacin in time-killing assays in vitro over 8 h against two penicillin-resistant pneumococcal strains (WB4 and KR4; MIC of penicillin: 4 mg/L). Synergy was confirmed with the chequerboard method, showing FIC indices of 0.25. In the experimental rabbit meningitis model, ceftriaxone (1x 125 mg/kg) was slightly less bactericidal (-0.30 Deltalog(10) cfu/mL(.)h) compared with levofloxacin (-0.45 Deltalog(10) cfu/mL(.)h) against the penicillin-resistant strain WB4. The combination therapy (levofloxacin and ceftriaxone) was significantly superior (-0.64 Deltalog(10) cfu/mL(.)h) to either monotherapy. In cycling experiments in vitro, the addition of ceftriaxone at a sub-MIC concentration (1/16 MIC) reduced levofloxacin-induced resistance in the two strains KR4 and WB4. After 12 cycles with levofloxacin monotherapy, the MIC increased 64-fold in both strains versus a 16-fold increase with the combination (levofloxacin + ceftriaxone 1/16 MIC). In both strains, levofloxacin-induced resistance was confirmed by mutations detected in the genes parC and gyrA, encoding for subunits of topoisomerase IV and gyrase, respectively. The addition of ceftriaxone suppressed mutations in parC but led to a new mutation in parE in both strains.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; DNA Topoisomerase IV; DNA, Bacterial; Drug Resistance, Bacterial; Drug Synergism; Levofloxacin; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Ofloxacin; Penicillin Resistance; Rabbits; Reverse Transcriptase Polymerase Chain Reaction; Streptococcus pneumoniae

To evaluate the therapeutic efficacy of ceftriaxone + vancomycin + rifampicin (CVR) in the treatment of pneumococcal meningitis caused by a multidrug-resistant strain, single-drug regimens (ceftriaxone 100 mg/kg, rifampicin 15 mg/kg, or vancomycin 20 mg/kg), double-drug regimens (ceftriaxone + vancomycin [CV] and ceftriaxone + rifampicin [CR]) and a triple-drug combination (CVR) with or without dexamethasone were compared in a rabbit meningitis model. Meningitis was induced by a highly penicillin-resistant (MIC 2 mg/l) and ceftriaxone-resistant (MIC 4 mg/l) pneumococcal strain. Final therapeutic efficacy was evaluated by the bacterial concentration at 24 h, and the bacterial killing rate was also evaluated. All combination regimens were superior to ceftriaxone or vancomycin single-drug regimens with regard to sterilisation of CSF and bacterial killing rate. Rifampicin was as effective as combination regimens. Regardless of dexamethasone, therapeutic efficacy of CVR and CR were superior to that of CV. CVR showed comparable therapeutic efficacy to CR. Data suggested that CVR would not have additional therapeutic benefit over CR during the initial 24 h of treatment.

Topics: Animals; Ceftriaxone; Colony Count, Microbial; Dexamethasone; Drug Evaluation, Preclinical; Drug Therapy, Combination; Meningitis, Pneumococcal; Rabbits; Rifampin; Streptococcus pneumoniae; Vancomycin

Tumor necrosis factor-alpha (TNF-alpha) is critically involved in inflammation and may participate in hippocampal injury in bacterial meningitis. In a mouse model of ceftriaxone-treated pneumococcal meningitis, spatial memory and motor performance of TNF-alpha-deficient (n = 57) and control mice (n = 55) were investigated. After infection, therapy was initiated with ceftriaxone (100 mg/kg twice daily for 5 days). Sixty-three percent TNF-alpha-deficient mice and 40% control animals died within 6 days (Fisher's exact test: P = 0.02). TNF-alpha-deficient mice surviving pneumococcal meningitis took substantially longer to reach the hidden platform than controls, and the distance of swim tracks was longer (P = 0.02). The swim speed in both groups was similar (P = 0.59). The proliferation of dentate granule cells was lower in TNF-alpha-deficient than in wild-type mice (P = 0.03). In pneumococcal meningitis, TNF-alpha deficiency caused increased mortality and stronger deficits in spatial memory possibly due to impaired neurogenesis.

Topics: Animals; Ceftriaxone; Hippocampus; Maze Learning; Memory Disorders; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Psychomotor Performance; Tumor Necrosis Factor-alpha

Topics: Aged; Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Meningitis, Pneumococcal; Pneumocephalus; Streptococcus pneumoniae; Treatment Outcome

In animal models of Streptococcus pneumoniae meningitis, rifampin is neuroprotective in comparison to ceftriaxone. So far it is not clear whether this can be generalized for other protein synthesis-inhibiting antimicrobial agents. We examined the effects of the bactericidal protein synthesis-inhibiting clindamycin (n = 12) on the release of proinflammatory bacterial components, the formation of neurotoxic compounds and neuronal injury compared with the standard therapy with ceftriaxone (n = 12) in a rabbit model of pneumococcal meningitis. Analysis of the CSF and histological evaluation were combined with microdialysis from the hippocampal formation and the neocortex. Compared with ceftriaxone, clindamycin reduced the release of lipoteichoic acids from the bacteria (p = 0.004) into the CSF and the CSF leucocyte count (p = 0.011). This led to lower extracellular concentrations of hydroxyl radicals (p = 0.034) and glutamate (p = 0.016) in the hippocampal formation and a subsequent reduction of extracellular glycerol levels (p = 0.018) and neuronal apoptosis in the dentate gyrus (p = 0.008). The present data document beneficial effects of clindamycin compared with ceftriaxone on various parameters linked with the pathophysiology of pneumococcal meningitis and development of neuronal injury. This study suggests neuroprotection to be a group effect of bactericidal protein synthesis-inhibiting antimicrobial agents compared with the standard therapy with beta-lactam antibiotics in meningitis.

Topics: Animals; Anti-Bacterial Agents; Body Temperature; Brain; Ceftriaxone; Cell Line, Tumor; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Clindamycin; Colony Count, Microbial; Glutamic Acid; Glycerol; Humans; Lactic Acid; Leukocyte Count; Lipid Peroxidation; Lipopolysaccharides; Male; Meningitis, Pneumococcal; Microdialysis; Neuroprotective Agents; Rabbits; Teichoic Acids; Tyrosine

Rifampin (RIF) releases smaller quantities of lipoteichoic acids (LTAs) from Streptococcus pneumoniae than ceftriaxone (CRO). Due to the rapid development of resistance, RIF cannot be used as a single agent for therapy of bacterial meningitis. For this reason, we compared the effect of treatment with RIF followed by treatment with CRO (RIF-CRO) or the effect of treatment with clindamycin (CLI) followed by treatment with CRO (CLI-CRO) to that of CRO alone on the concentrations of LTAs and teichoic acids in vitro. The effects of RIF-CRO on LTA concentrations in cerebrospinal fluid (CSF) and on neuronal injury were investigated in a rabbit model of S. pneumoniae meningitis. In vitro, bacterial titers were effectively reduced by CRO, RIF-CRO, and CLI-CRO when each drug was used at 10 micro g/ml. The levels of release of LTAs after the initiation of therapy were lower in RIF-CRO- and CLI-CRO-treated cultures than in cultures treated with CRO alone (P < 0.05 from 3 to 12 h after initiation of treatment). Similarly, in rabbits, the increase in the amount of LTAs in CSF was lower in RIF-CRO-treated animals than in CRO-treated animals (P = 0.02). The density of dentate apoptotic granular cells was lower after RIF-CRO therapy than after CRO therapy (medians, 58.4 and 145.6/mm(2), respectively; 25th quartiles, 36.3 and 81.7/mm(2), respectively; 75th quartiles, 100.7 and 152.3/mm(2), respectively; P = 0.03). Therefore, initiation of therapy with a protein synthesis-inhibiting antibacterial and continuation of therapy with a combination that includes a beta-lactam may be a strategy to decrease neuronal injury in bacterial meningitis.

Topics: Animals; Ceftriaxone; Drug Therapy, Combination; Lipopolysaccharides; Meningitis, Pneumococcal; Neurons; Rabbits; Rifampin; Teichoic Acids

Using a rabbit model of meningitis, we sought to determine the efficacy of LY333328, a semisynthetic glycopeptide, in the treatment of cephalosporin-resistant pneumococcal meningitis. LY333328 was administered at a dose of 10 mg/kg of body weight/day, alone and in combination with ceftriaxone at 100 mg/kg/day with or without dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with LY333328 with or without dexamethasone and LY333328-ceftriaxone with or without dexamethasone. Rabbits were inoculated with a cephalosporin-resistant pneumococcal strain (ceftriaxone MIC, 2 microg/ml; penicillin MIC, 4 microg/ml; LY333328 MIC, 0.008 microg/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the lactic acid concentration, the CSF LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro, LY333328 was highly bactericidal and its use in combination with ceftriaxone at one-half the MIC was synergistic. In the rabbit model, LY333328 alone was an excellent treatment for cephalosporin-resistant pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of LY333328 in combination with ceftriaxone improved the activity of LY333328, but no synergistic effect was observed. The combination of LY333328 with dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of LY333328 with ceftriaxone and dexamethasone was effective, without therapeutic failures.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Ceftriaxone; Cephalosporin Resistance; Colony Count, Microbial; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Female; Glycopeptides; Lactic Acid; Leukocyte Count; Lipoglycopeptides; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae

The penetration of ertapenem, a new carbapenem with a long half-life, reached 7.1 and 2.4% into inflamed and noninflamed meninges, respectively. Ertapenem had excellent antibacterial activity in the treatment of experimental meningitis due to penicillin-sensitive and -resistant pneumococci, leading to a decrease of 0.69 +/- 0.17 and 0.59 +/- 0.22 log(10) CFU/ml x h, respectively, in the viable cell counts in the cerebrospinal fluid. The efficacy of ertapenem was comparable to that of standard regimens (ceftriaxone monotherapy against the penicillin-sensitive strain and ceftriaxone combined with vancomycin against the penicillin-resistant strain). In vitro, ertapenem in concentrations above the MIC was highly bactericidal against both strains. Even against a penicillin- and quinolone-resistant mutant, ertapenem had similar bactericidal activity in vitro.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; Ceftriaxone; Disease Models, Animal; Ertapenem; Lactams; Meningitis, Pneumococcal; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Vancomycin

Streptococcus pneumoniae is one of the leading causes of acute bacterial meningitis and the emergence of antibiotic resistant pneumococci is an increasing problem worldwide. In this report, a 22-years-old woman was presented with pneumococcal meningitis occurring twice in a 5 months period. After the first meningitis attack, the patient had been vaccinated by 23-valent polysaccharide vaccine but the illness has relapsed. Although S. pneumoniae which was isolated from the patient has been found intermediate resistant to penicillin and susceptible to ceftriaxone by E-test, the patient could be treated only with meropenem. The case has been presented and discussed for ceftriaxone failure in spite of in-vitro susceptibility. On the other hand, this case indicated that vaccination might fail to prevent recurrence.

Topics: Adult; Anti-Bacterial Agents; Ceftriaxone; Female; Humans; Immunotherapy, Active; Meningitis, Pneumococcal; Meropenem; Penicillins; Pneumococcal Vaccines; Secondary Prevention; Streptococcus pneumoniae; Thienamycins

Pneumolysin, a virulence factor of Streptococcus pneumoniae with cytotoxic and proinflammatory activities, occurs at concentrations from 0.85 to 180 ng/ml in cerebrospinal fluid (CSF) of meningitis patients. In pneumococcal cultures and in a rabbit meningitis model, the concentrations of pneumolysin in supernatant and CSF were lower after addition of nonbacteriolytic bactericidal antibiotics (rifampin and clindamycin) than after incubation with ceftriaxone.

Topics: Adult; Aged; Animals; Anti-Bacterial Agents; Bacterial Proteins; Ceftriaxone; Cephalosporins; Child, Preschool; Colony Count, Microbial; Culture Media; Depression, Chemical; Electrophoresis, Polyacrylamide Gel; Female; Humans; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Middle Aged; Rabbits; Streptococcus pneumoniae; Streptolysins

Hearing loss is the most frequent long-term complication of pneumococcal meningitis, affecting up to 40% of survivors. Unfortunately, adjuvant therapy with dexamethasone has failed to satisfactorily reduce its incidence. Therefore, we evaluated the use of antioxidants for the adjunctive therapy of meningitis-associated deafness. Eighteen hours after intracisternal injection of 7.5 x 10(5) colony-forming units of Streptococcus pneumoniae, rats were treated systemically either with ceftriaxone and the antioxidants and peroxynitrite scavengers Mn(III)tetrakis(4-benzoic acid)-porphyrin (MnTBAP) or N-acetyl-L-cysteine (NAC) or placebo (1 ml phosphate-buffered saline) for 4 days. Hearing was assessed by auditory brainstem response audiometry. Adjunctive antioxidant therapy significantly reduced the long-term hearing loss (14 days after infection) for square wave impulses (mean hearing loss +/- SD: ceftriaxone and placebo, 45+/-26 dB; ceftriaxone and MnTBAP, 9+/-23 dB; ceftriaxone and NAC, 19+/-30 dB) as well as 1 kHz (ceftriaxone and placebo, 28+/-19 dB; ceftriaxone and MnTBAP, 10+/-16 dB; ceftriaxone and NAC, 10+/-17 dB), and 10 kHz tone bursts (ceftriaxone and placebo, 62+/-27 dB; ceftriaxone and MnTBAP, 16+/-13 dB; ceftriaxone and NAC, 25+/-26 dB). Furthermore, both antioxidants attenuated the morphological correlates of meningogenic hearing loss, namely, long-term blood-labyrinth barrier disruption, spiral ganglion neuronal loss, and fibrous obliteration of the perilymphatic spaces. Adjuvant antioxidant therapy is highly otoprotective in meningitis and therefore is a promising future treatment option.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Antioxidants; Audiometry; Ceftriaxone; Cell Count; Cochlea; Disease Models, Animal; Drug Interactions; Evans Blue; Evoked Potentials, Auditory, Brain Stem; Hearing Loss; Labyrinthitis; Male; Meningitis, Pneumococcal; Metalloporphyrins; Peroxynitrous Acid; Rats; Rats, Wistar; Spiral Ganglion; Time Factors

Although more and more new potent antibiotics have been used, mortality and neurologic deficits still occur frequently following bacterial meningitis in children. In this article, the expression of brain-derived neurotrophic factor messenger ribonucleic acid (RNA) and its production in the brains of rats were investigated during the course of experimental bacterial meningitis and after treatment with an antibiotic plus dexamethasone. In the brains of Streptococcus pneumoniae-inoculated rats, brain-derived neurotrophic factor (BDNF) messenger RNA was obviously up-regulated after inoculation for 24 hours (P < .01) and then declined but was still greater than that in the brains of control rats after inoculation for 5 days (P < .05). The expression of brain-derived neurotrophic factor in the brains of infected rats treated by antibiotic was dose dependent, down-regulated, and almost undetectable (P < .01) but up-regulated after treatment with an antibiotic plus dexamethasone (P < .01). However, the expression of brain-derived neurotrophic factor messenger RNA did not change in control rats treated with an antibiotic. Brain-derived neurotrophic factor protein showed similar changes, except it declined to normal levels 5 days after inoculation. Brain-derived neurotrophic factor messenger RNA and its production were observed in some infiltrating inflammatory cells in the brain of infected rats. The results of our studies support the hypothesis that brain-derived neurotrophic factor might play a neuroprotective role in brain damage during bacterial meningitis, and the expression of brain-derived neurotrophic factor messenger RNA and its production might be inhibited after treatment with antibiotics. The findings suggest that both eradicating the bacterial pathogen with antibiotics and adjuvant administering of brain-derived neurotrophic factor might be more beneficial to prevent brain damage.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Brain; Brain Damage, Chronic; Brain-Derived Neurotrophic Factor; Ceftriaxone; Dexamethasone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Gene Expression; Injections, Subcutaneous; Meningitis, Pneumococcal; Rats; Rats, Sprague-Dawley; RNA, Messenger

We evaluated the effect of different peroxynitrite scavengers for adjunctive therapy of experimental bacterial meningitis. Twenty hours after intracisternal injection of Streptococcus pneumoniae, rats were treated with ceftriaxone [100 mg/kg intraperitoneal (i.p.)] and either urate (300 mg/kg i.p.), Mn(III)tetrakis(4-benzoic acid)porphyrin (MnTBAP, 15 mg/kg i.p.), ascorbate (100 mg/kg i.p.), or urate (300 mg/kg i.p.) + ascorbate (100 mg/kg i.p.). Six hours after initiation of treatment, the cerebrospinal fluid (CSF) pleocytosis was significantly (p<0.05) reduced by urate (8697 +/- 1526 cells/microl) and MnTBAP (8542 +/- 4059 cells/microl) vs. ceftriaxone alone (15,793 +/- 3202 cells/microl). Brain concentrations of proinflammatory cytokines [interleukin-1beta (IL-beta), interleukin-6 (IL-6), and macrophage inflammatory protein-2 (MIP-2)] were also reduced by urate and MnTBAP. The intracranial hypertension was significantly reduced by MnTBAP (14.0 +/- 5.4 mm Hg), but not by urate (25.5 +/- 7.1 mm Hg) vs. ceftriaxone alone (22.5 +/- 5.9 mm Hg). Ascorbate alone had no effect on CSF pleocytosis (15,775 +/- 7058 cells/microl), intracranial pressure (25.6 +/- 8.8 mm Hg), and brain cytokine concentrations. However, the combination of urate and ascorbate was as effective as MnTBAP (CSF pleocytosis: 5392 +/- 4232 cells/microl, intracranial pressure: 13.3 +/- 6.9 mm Hg).

Topics: Animals; Brain Chemistry; Ceftriaxone; Cephalosporins; Chemokine CXCL2; Chemokines; Cytokines; Free Radical Scavengers; Indicators and Reagents; Interleukin-1; Interleukin-6; Male; Meningitis, Pneumococcal; Monokines; Peroxynitrous Acid; Rats; Rats, Wistar

We present the case of a patient seen in the Emergency Department (ED) at the height of enteroviral meningitis season with the chief complaint of the worst headache of his life. He was subsequently found to have pneumococcal meningitis as the result of an encephalocele located within the left ethmoid sinus. The key features of the patient's past medical history, the steps to diagnosis, and a discussion of this exceedingly rare entity are detailed.

Topics: Anti-Bacterial Agents; Ceftriaxone; Emergency Service, Hospital; Encephalocele; Ethmoid Bone; Ethmoid Sinus; Humans; Male; Meningitis, Pneumococcal; Meningocele; Middle Aged; Tomography, X-Ray Computed

Topics: Ceftriaxone; Child; Chloramphenicol; Egypt; Female; Hearing Loss, Sensorineural; Humans; Meningitis, Pneumococcal; Penicillins; Recurrence; Streptococcus pneumoniae

T-3811ME (BMS-284756) is a new des-F(6)-quinolone with high levels of activity against gram-positive bacteria, including penicillin-resistant Streptococcus pneumoniae (PRSP) strains. T-3811, the free base of T-3811ME, exhibited potent activity against 28 clinical strains of PRSP isolated clinically (MIC at which 90% of the isolates tested are inhibited, 0.0625 microg/ml). After the intravenous dosing of T-3811ME (20 mg/kg of body weight as T-3811) in rabbits with meningitis caused by PRSP, the area under the concentration-time curve (AUC) of T-3811 in cerebrospinal fluid (CSF) was 5.79 microg. h/ml and was 4.5-fold higher than that of T-3811in the CSF of rabbits without meningitis. In addition, the AUC/MIC for T-3811ME (20 mg/kg as T-3811) in CSF was 185, which was 4.3-fold higher than that for ceftriaxone (administered intravenously at 100 mg/kg). After the administration of any dose of T-3811ME (5, 10, and 20 mg/kg as T-3811), the viable cell counts in CSF decreased in a dose-dependent manner. In particular, after dosing of 20 mg/kg (as T-3811), the viable cell counts in CSF were significantly less than those in the nontreated group (P < 0.01). By histopathological evaluation, 6 h after the administration of T-3811ME (20 mg/kg as T-3811), the thickening of the cerebral meninx and the infiltration of neutrophils into the cerebral meninx were less severe in the treated group than in the nontreated group. T-3811ME (BMS-284756) may be expected to be evaluated for the management of meningitis caused by highly penicillin-resistant pneumococci.

Topics: Animals; Anti-Infective Agents; Brain; Ceftriaxone; Cephalosporins; Fluoroquinolones; Indoles; Injections, Intravenous; Isoindoles; Male; Meningitis, Pneumococcal; Penicillin Resistance; Quinolones; Rabbits; Streptococcus pneumoniae

Topics: Adult; Anti-Bacterial Agents; Ceftriaxone; Clarithromycin; Female; Humans; Meningitis, Pneumococcal; Otitis Media; Pneumococcal Infections; Streptococcal Infections; Streptococcus pneumoniae

The course of bacterial titers, meningeal inflammation, behavioral abnormalities, and neuronal damage was studied in a mouse model of Streptococcus pneumoniae meningitis. At 24 h after injection of 10(4) colony-forming units (CFU) S. pneumoniae into the right forebrain, infected mice became severely lethargic. Bacterial titers in cerebrospinal fluid and cerebellum rose to 10(9) CFU/ml, with strong granulocyte invasion into the meninges and neuronal necroses in the neocortex, striatum and hippocampal formation. Meningeal inflammation and neuronal damage in intercellular cell adhesion molecule-1- and macrophage colony-stimulating factor-deficient mice was similar to that in wild-type littermates. Untreated, the infection was fatal. Wild-type mice treated earlier than 24 h after infection with ceftriaxone (2 mg every 12 h for 3 days) survived without apparent behavioral abnormalities. Delay of treatment beyond 30 h led to the death of more than 50% of the infected mice. This mouse model is suitable for therapeutic studies and for the investigation of inflammation in knockout mice. The neuronal damage resembles morphological abnormalities observed in humans.

Topics: Animals; Body Weight; Brain; Ceftriaxone; Cephalosporins; Disease Models, Animal; Glial Fibrillary Acidic Protein; Gliosis; Hyaluronan Receptors; Immunohistochemistry; Intercellular Adhesion Molecule-1; Leukocyte Count; Leukocytes; Macrophage Colony-Stimulating Factor; Macrophage-1 Antigen; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Mice, Knockout; Streptococcus pneumoniae; Survival Rate; Treatment Outcome

BMS-284756 is a novel des-fluoro(6) quinolone with a broad antimicrobial activity, including Streptococcus pneumoniae. The purpose of this study was to evaluate the pharmacodynamic profile and effectiveness of BMS-284756 for therapy of experimental meningitis caused by penicillin- and cephalosporin-resistant S. pneumoniae (CRSP). Meningitis was induced in rabbits by intracisternal inoculation of CRSP. BMS-284756 was given intravenously 16 h after intracisternal inoculation in single doses of 2.5 (n = 5 animals), 5 (n = 6), 10 (n = 6), 20 (n = 8), and 30 mg/kg (n = 6), in two doses of 10 mg/kg each separated by 5 h (n = 4), and as a 20-mg/kg dose followed 5 h later by 10 mg/kg (n = 5). The MICs and MBCs of BMS-284756, ceftriaxone, and vancomycin were 0.06 and 0.06, 4 and 4, and 0.25 and 0.25 microg/ml, respectively. After single doses of 10, 20, and 30 mg/kg, the maximum concentrations in cerebrospinal fluid (CSF) (mean +/- standard deviation) were 0.32 +/- 0.12, 0.81 +/- 0.38, and 1.08 +/- 0.43 microg/ml, respectively; the elimination half-life in CSF was 4.5 to 6.3 h. The CSF bacterial killing rates (BKR) at 5 h of the single-dose regimens of 10, 20 and 30 mg/kg were -0.84 +/- 0.48, -1.09 +/- 0.32, and -1.35 +/- 0.05 Deltalog(10) CFU/ml/h. The BKR(0-5) of the divided regimens (10 mg/kg twice and 20 mg/kg followed by 10 mg/kg) was -0.82 +/- 0.52 and -1.24 +/- 0.34 Deltalog(10) CFU/ml/h, respectively. The BKR(0-5) of the combined therapy with vancomycin and ceftriaxone was -1.09 +/- 0.39 Deltalog(10) CFU/ml/h. The penetration of BMS-284756 into purulent CSF relative to plasma was 14 to 25%. The bactericidal effect of BMS-284756 in CSF was concentration dependent. BMS-284756 at 30 mg/kg as a single or divided dose was as effective as standard therapy with vancomycin and ceftriaxone.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Ceftriaxone; Cephalosporin Resistance; Fluoroquinolones; Indoles; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Quinolones; Rabbits; Vancomycin

Despite the lack of evidence defining a time interval during which cerebrospinal fluid (CSF) culture yield will not be affected by previous antibiotic therapy, recent publications cite a "minimum window" of 2 to 3 hours for recovery of bacterial pathogens after parenteral antibiotic administration. We conducted a retrospective review of children with bacterial meningitis to describe the rate at which parenteral antibiotic pretreatment sterilizes CSF cultures.. The medical records of pediatric patients who were discharged from a tertiary children's hospital during a 5-year period with the final diagnosis of bacterial meningitis or suspected bacterial meningitis were reviewed. The decay in yield of CSF cultures over time was evaluated in patients with lumbar punctures (LP) delayed until after initiation of parenteral antibiotics and in patients with serial LPs before and after initiation of parenteral antibiotics.. The pathogens that infected the 128 study patients were Streptococcus pneumoniae (49), Neisseria meningitidis (37), group B Streptococcus (21), Haemophilus influenzae (8), other organisms (11), and undetermined (3). Thirty-nine patients (30%) had first LPs after initiation of parenteral antibiotics, and 55 (43%) had serial LPs before and after initiation of parenteral antibiotics. After >/=50 mg/kg of a third-generation cephalosporin, 3 of 9 LPs in meningococcal meningitis were sterile within 1 hour, occurring as early as 15 minutes, and all were sterile by 2 hours. With pneumococcal disease, the first negative CSF culture occurred at 4.3 hours, with 5 of 7 cultures negative from 4 to 10 hours after initiation of parenteral antibiotics. Reduced susceptibility to beta-lactam antibiotics occurred in 11 of 46 pneumococcal isolates. Group B streptococcal cultures were positive through the first 8 hours after parenteral antibiotics. Blood cultures were positive in 74% of cases without pretreatment and in 57% to 68% of cases with negative CSF cultures.. The temptation to initiate antimicrobial therapy may override the principle of obtaining adequate pretreatment culture material. The present study demonstrates that CSF sterilization may occur more rapidly after initiation of parenteral antibiotics than previously suggested, with complete sterilization of meningococcus within 2 hours and the beginning of sterilization of pneumococcus by 4 hours into therapy. Lack of adequate culture material may result in inability to tailor therapy to antimicrobial susceptibility or in unnecessarily prolonged treatment if the clinical presentation and laboratory data cannot exclude the possibility of bacterial meningitis.

Topics: Adolescent; Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Confidence Intervals; Female; Humans; Infant; Infant, Newborn; Male; Meningitis, Bacterial; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Patient Selection; Spinal Puncture; Time Factors

Increased total CSF lactate is an important indicator differentiating bacterial from aseptic meningitis. Bacteria can produce D- and L-lactate; mammalian cells produce only L-lactate. We measured D- and L-lactate production of Streptococcus pneumoniae, Staphylococcus aureus, Neisseria meningitidis and Escherichia coli in vitro, of S. pneumoniae and E. coli in rabbit experimental meningitis and of various common pathogens in CSF from patients with bacterial meningitis. Despite marked in vitro production of D-lactate by S. aureus (maximum: 4.59 mmol/l; i.e. 34.9% of total lactate), N. meningitidis (4.62 mmol/l; i.e. 98.1%) and E. coli (3.14 mmol/l; i.e. 97.2%), minimal amounts were measured in human S. aureus (0.38 mmol/l; i.e. 1.3% of total lactate) or N. meningitidis (0.28 mmol/l; i.e. 3.9%) and experimental E. coli meningitis (0.75 mmol/l; i.e. 4.4%). In only 9 of 54 human CSF samples did D-lactate exceed 0.15 mmol/l. S. pneumoniae did not produce significant amounts of D-lactate in vitro (maximum: 0.55 mmol/l; i.e. 2.7% of total lactate), in experimental meningitis (0.18 mmol/l; i.e. 3%) or in human cases of meningitis (0.28 mmol/l; i.e. 1.9%). In conclusion, increased total CSF lactate in meningitis consists mainly of L-lactate and originates predominantly from host cells. CSF D-lactate is of limited diagnostic value.

Topics: Animals; Bacteria; Ceftriaxone; Humans; Lactic Acid; Meningitis, Bacterial; Meningitis, Pneumococcal; Rabbits; Species Specificity; Streptococcus pneumoniae

Cefepime, a broad-spectrum, fourth-generation cephalosporin, showed excellent CSF penetration with levels ranging between 10 and 16 mg/L after two intravenous injections (100 mg/kg). The bactericidal activity of cefepime (-0.60 +/- 0.28 Deltalog(10) cfu/mL/h) was superior to that of ceftriaxone (-0.34 +/- 0.23 Deltalog(10) cfu/mL/h, P < 0.05) and vancomycin (-0.39 +/- 0.19 Deltalog(10) cfu/mL/h, P < 0.05) in the treatment of rabbits with meningitis caused by an isolate highly resistant to penicillin (MIC of penicillin G: 4 mg/L). The addition of vancomycin to both cephalosporins did not significantly increase the killing rate compared with monotherapies (P > 0.05). Similar results were obtained in time-killing experiments in vitro.

Topics: Animals; Anti-Bacterial Agents; Cefepime; Ceftriaxone; Cephalosporins; Drug Evaluation, Preclinical; Drug Therapy, Combination; Meningitis, Pneumococcal; Penicillin Resistance; Rabbits; Vancomycin

In a rabbit model of Streptococcus pneumoniae meningitis, 5 mg of gemifloxacin mesylate (SB-265805) per kg/h reduced the bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as 10 mg of ceftriaxone per kg/h (Deltalog CFU/ml/h +/- standard deviation [SD], -0.25 +/- 0.09 versus -0.38 +/- 0.11; serum and CSF concentrations of gemifloxacin were 2.1 +/- 1.4 mg/liter and 0.59 +/- 0.38 mg/liter, respectively, at 24 h). Coadministration of 1 mg of dexamethasone per kg did not affect gemifloxacin serum and CSF levels (2.7 +/- 1.4 mg/liter and 0.75 +/- 0.34 mg/liter, respectively, at 24 h) or activity (Deltalog CFU/ml/h +/- SD, -0.26 +/- 0.11).

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Cerebrospinal Fluid; Disease Models, Animal; Fluoroquinolones; Gemifloxacin; Hippocampus; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Naphthyridines; Neurons; Rabbits; Streptococcus pneumoniae

The treatment of meningitis caused by strains of Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins is an increasingly frequent and difficult problem. In this study a rabbit model of meningitis was used to determine the efficacy of ceftriaxone at different dosages, and to establish the effect of the addition of dexamethasone to the chemotherapeutic regimen. Groups of eight rabbits were inoculated with 10(6) cfu/mL of a cephalosporin- resistant strain of S. pneumoniae (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours after inoculation, ceftriaxone (50 or 100 mg/kg/day) with or without dexamethasone (0. 25 mg/kg/ day) was administered for a period of 48 h. The ceftriaxone dose of 50 mg/kg/day was not fully effective in this model (therapeutic failure rate 28%). With a dose of 100 mg/kg/day there were no therapeutic failures and all CSF cultures were below the level of detection at 48 h. CSF ceftriaxone concentrations, area under the time-concentration curve and time above the MIC were not significantly different with or without dexamethasone. However, concomitant use of dexamethasone resulted in higher CSF bacterial counts and a higher number of therapeutic failures (57% with the 50 mg/kg/day dose and 28% with the 100 mg/kg/day dose). Increasing doses of ceftriaxone might be an effective mode of therapy for meningitis caused by S. pneumoniae with MIC

Topics: Animals; Anti-Inflammatory Agents; Area Under Curve; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Dexamethasone; Drug Therapy, Combination; Female; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae

The therapeutic efficacy of clinafloxacin, a fluoroquinolone in clinical trials, was compared with that of ciprofloxacin and ceftriaxone in a novel pneumococcal meningitis mouse model. Mice were challenged by the intracerebral ventricular route with 50 IL of a lethal bacterial suspension and treated subcutaneously 2 h later. Both penicillin-susceptible and multidrug-resistant pneumococcal strains were used for evaluation. Survival percentages were calculated as the median curative dose (CD50) using log-probit statistical methods. Ceftriaxone was the most active agent against the penicillin-susceptible strain (CD50 = 2 mg/kg), but showed a 30-fold decrease in potency against the resistant strain. Clinafloxacin was equally effective against both strains, and proved to be the most active agent against the penicillin-resistant pneumococcus.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Ciprofloxacin; Female; Fluoroquinolones; Meningitis, Pneumococcal; Mice; Microbial Sensitivity Tests; Models, Biological; Streptococcus pneumoniae

Bacterial compounds induce the production of reactive oxygen species (ROS) in meningitis. Rifampin releases smaller quantities of proinflammatory compounds from Streptococcus pneumoniae than do beta-lactam antibiotics. Therefore, rabbits infected intracisternally with S. pneumoniae were treated intravenously either with rifampin 5 mg/kg/h or ceftriaxone 10 mg/kg/h (n=9 each). Before initiation of antibiotic treatment, a strong positive correlation between ROS production of cerebrospinal fluid (CSF) phagocyte populations and bacterial CSF titers was observed (granulocytes: rs=.90, P<.0001; monocytes: rs=.81, P<.0001). CSF leukocytes from rifampin-treated rabbits produced less ROS (monocytes at 2 h after initiation of treatment: P=.045; at 5 h: P=.014; granulocytes at 5 h: P=.036) than did leukocytes from animals receiving ceftriaxone. The CSF malondialdehyde concentrations and the density of apoptotic neurons in the dentate gyrus were lower in rifampin- than in ceftriaxone-treated animals (P=.002 and.005). The use of rifampin to reduce the release of ROS and to decrease secondary brain injury appears promising.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Ceftriaxone; Cerebrospinal Fluid; Hippocampus; Meningitis, Pneumococcal; N-Formylmethionine Leucyl-Phenylalanine; Neurons; Phagocytes; Rabbits; Reactive Oxygen Species; Rifampin

The bactericidal activities of monotherapy with trovafloxacin (-0.37 +/- 0.15 Delta log(10) CFU/ml. h), vancomycin (-0.32 +/- 0.12 Delta log(10) CFU/ml. h), and ceftriaxone (-0.36 +/- 0.19 Delta log(10) CFU/ml. h) for the treatment of experimental meningitis in rabbits due to a clinical penicillin-resistant pneumococcal strain (MIC, 4 mg/liter) were similar. The combination of ceftriaxone with trovafloxacin considerably improved the killing rates (-0.67 +/- 0.16 Delta log(10) CFU/ml. h) and was slightly superior to ceftriaxone with vancomycin (killing rate, -0.53 +/- 0. 22 Delta log(10) CFU/ml. h), the regimen most commonly used in clinical practice. In vitro, synergy was demonstrated between ceftriaxone and trovafloxacin by the checkerboard method (fractional inhibitory concentration index, 0.5) and by time-killing assays over 8 h.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Naphthyridines; Penicillin Resistance; Pneumococcal Infections; Rabbits; Streptococcus pneumoniae

Topics: Adolescent; Cefotaxime; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Cerebrospinal Fluid; Child; Child, Preschool; Female; Humans; Infant; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Retrospective Studies; Streptococcus pneumoniae; Treatment Outcome

Topics: Adolescent; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Drug Resistance, Multiple; Humans; India; Infant; Meningitis, Pneumococcal; Penicillin Resistance

Compared with beta-lactam antibiotics, rifampin releases smaller quantities of proinflammatory cell wall products from Streptococcus pneumoniae in vitro. Mice infected intracerebrally with S. pneumoniae were treated subcutaneously with 2-mg doses of rifampin or ceftriaxone (n=43 each) every 12 h for 3 days and then observed for another 3 days. Rifampin reduced overall mortality from 49% to 26% (P=.04). Kaplan-Meyer analysis revealed a substantial reduction of mortality during the first 24 h in mice receiving rifampin (difference in survival time: P=.007). Eight h after receiving a single 2-mg dose of rifampin or ceftriaxone, rifampin-treated mice had lower serum and cerebrospinal fluid concentrations of lipoteichoic and teichoic acids than did ceftriaxone-treated mice (median serum level: <0.5 vs. 27.0 ng/mL, P=.02; median cerebrospinal fluid level of pooled specimens: 97.5 vs. 206.0 ng/mL). Thus, the use of rifampin appears promising for reducing the release of proinflammatory bacterial components and decreasing early mortality in bacterial meningitis.

Topics: Animals; Ceftriaxone; Inflammation Mediators; Meningitis, Pneumococcal; Mice; Mice, Inbred C57BL; Probability; Rifampin

The inflammatory response following initiation of antibiotic therapy and parameters of neuronal damage were compared during intravenous treatment with quinupristin/dalfopristin (100 mg/kg as either a short or a continuous infusion) and ceftriaxone (10 mg/kg/h) in a rabbit model of Streptococcus pneumoniae meningitis. With both modes of administration, quinupristin/dalfopristin was less bactericidal than ceftriaxone. However, the concentration of proinflammatory cell wall components (lipoteichoic acid (LTA) and teichoic acid (TA)) and the activity of tumour necrosis factor (TNF) in cerebrospinal fluid (CSF) were significantly lower in the two quinupristin/dalfopristin groups than in ceftriaxone-treated rabbits. The median LTA/TA concentrations (25th/75th percentiles) were as follows: (i) 14 h after infection: 133 (72/155) ng/mL for continuous infusion of quinupristin/dalfopristin and 193 (91/308) ng/mL for short duration infusion, compared with 455 (274/2042) ng/mL for ceftriaxone (P = 0.002 and 0.02 respectively); (ii) 17 h after infection: 116 (60/368) ng/mL for continuous infusion of quinupristin/dalfopristin and 117 (41/247) ng/mL for short duration infusion, compared with 694 (156/2173) ng/mL for ceftriaxone (P = 0.04 and 0.03 respectively). Fourteen hours after infection the median TNF activity (25th/75th percentiles) was 0.2 (0.1/1.9) U/mL for continuous infusion of quinupristin/dalfopristin and 0.1 (0.01/3.5) U/mL for short duration infusion, compared with 30 (4.6/180) U/mL for ceftriaxone (P = 0.02 for each comparison); 17 h after infection the TNF activity was 2.8 (0.2/11) U/mL (continuous infusion of quinupristin/dalfopristin) and 0.1 (0.04/6.1) U/mL (short duration infusion), compared with 48.6 (18/169) U/mL for ceftriaxone (P = 0.002 and 0.001). The concentration of neuron-specific enolase (NSE) 24 h after infection was significantly lower in animals treated with quinupristin/dalfopristin: 4.6 (3.3/5.7) microg/L (continuous infusion) and 3.6 (2.9/4.7) microg/L (short duration infusion) than in those treated with ceftriaxone (17.7 (8.8/78.2) microg/L) (P = 0.03 and 0.009 respectively). In conclusion, antibiotic treatment with quinupristin/dalfopristin attenuated the inflammatory response within the subarachnoid space after initiation of antibiotic therapy. The concentration of NSE in the CSF, taken as a measure of neuronal damage, was lower in quinupristin/dalfopristin-treated rabbits than in ceftriaxone-treated rabbits.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid Proteins; Disease Models, Animal; Inflammation; Lactic Acid; Lipopolysaccharides; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Neurons; Phosphopyruvate Hydratase; Rabbits; Streptococcus pneumoniae; Subarachnoid Space; Teichoic Acids; Tumor Necrosis Factor-alpha; Virginiamycin

Minimum inhibitory concentrations of penicillin, ceftriaxone, ciprofloxacin, and moxifloxacin (BAY 12-8039), a new 8-methoxyquinolone, were determined for 60 cerebrospinal fluid isolates of Streptococcus pneumoniae collected during January 1997-April 1998 at Italian medical centres. Three reference isolates with predetermined MIC values (two penicillin- and multidrug-resistant isolates, one uniformly susceptible to all antibiotics) were also tested with the same antibiotics. The MIC90 of penicillin was < or = 0.03 mg/L (range < or = 0.03-2 mg/L), of ceftriaxone 0.06 mg/L (range < or = 0.03-0.5 mg/L), of ciprofloxacin 2 mg/L (range 0.5-8 mg/L) and of moxifloxacin 0.06 mg/L (range 0.03-0.12 mg/L). Moxifloxacin was effective against all the penicillin-resistant isolates tested, with an MIC of 0.06 mg/L. Moxifloxacin was 32-fold more active than ciprofloxacin and was not affected by penicillin and cephalosporin resistance. These results indicate that moxifloxacin could be useful for the treatment of both penicillin-sensitive and -resistant S. pneumoniae meningitis.

Topics: Anti-Bacterial Agents; Aza Compounds; Ceftriaxone; Ciprofloxacin; Fluoroquinolones; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Moxifloxacin; Penicillins; Pneumococcal Infections; Quinolines; Streptococcus pneumoniae

In the rabbit model of Streptococcus pneumoniae meningitis, treatment with rifabutin, quinupristin-dalfopristin, moxifloxacin and trovafloxacin led to smaller increases of the CSF concentrations of the pro-inflammatory cell wall components lipoteichoic and teichoic acids (LTA and TA) than did treatment with ceftriaxone. Low doses of moxifloxacin were associated with higher LTA and TA concentrations in CSF than were high doses.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Ceftriaxone; Cephalosporins; Disease Models, Animal; Fluoroquinolones; Immunoenzyme Techniques; Lipopolysaccharides; Meningitis, Pneumococcal; Moxifloxacin; Naphthyridines; Polysaccharides, Bacterial; Quinolines; Rabbits; Reference Values; Rifabutin; Teichoic Acids; Virginiamycin

Topics: Aged; Ceftriaxone; Cross Infection; Drug Therapy, Combination; Female; Herpes Simplex; Herpesvirus 1, Human; Humans; Meningitis, Pneumococcal; Meningoencephalitis; Vancomycin

In a rabbit model of meningitis caused by a pneumococcus highly resistant to penicillin (MIC, 4 microg/ml), meropenem, a broad-spectrum carbapenem, was bactericidal (-0.48+/-0.14 deltalog10 cfu/ml h) and slightly superior to ceftriaxone (-0.34+/-0.23 deltalog10 cfu/ml x h) and vancomycin (-0.39+/-0.19 deltalog10 cfu/ml x h). Although the combination of vancomycin with ceftriaxone was significantly more active than ceftriaxone alone (-0.55+/-0.19 deltalog10 cfu/ml x h), only an insignificant gain was observed by the addition of vancomycin to meropenem (-0.55+/-0.28 deltalog10 cfu/ml x h).

Topics: Animals; Ceftriaxone; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Drug Therapy, Combination; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Thienamycins; Vancomycin

The activities of meropenem, imipenem, ceftriaxone, and vancomycin were evaluated against 80 penicillin-susceptible and -resistant Streptococcus pneumoniae strains. Meropenem, imipenem, ceftriaxone, and vancomycin MICs at which 90% of the isolates are inhibited were 0.5, 0.25, 1, and 0.25 microg/ml, respectively. Against penicillin-resistant strains, the best killing activity at cerebrospinal fluid concentrations was obtained with imipenem and ceftriaxone-vancomycin. However, while the killing activity of imipenem was significantly greater than that of meropenem, no significant difference was observed between the activities of meropenem and ceftriaxone-vancomycin.

Topics: Anti-Bacterial Agents; Carbapenems; Ceftriaxone; Cephalosporins; Child; Drug Therapy, Combination; Humans; Imipenem; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Streptococcus pneumoniae; Thienamycins; Vancomycin

Moxifloxacin is a new 8-methoxyquinolone with high activity against gram-positive bacteria, including penicillin-resistant pneumococci. In an experimental meningitis model, we studied the pharmacokinetics of moxifloxacin in infected and uninfected rabbits and evaluated the antibiotic efficacies of moxifloxacin, ceftriaxone, and vancomycin against a penicillin-resistant Streptococcus pneumoniae strain (penicillin, ceftriaxone, vancomycin, and moxifloxacin MICs were 1, 0.5, 0.5, and 0.125 microgram/ml, respectively). Moxifloxacin entered cerebrospinal fluid (CSF) readily, with peak values within 15 to 30 min after bolus intravenous infusion and with a mean percent penetration into normal and purulent CSF of approximately 50 and 80%, respectively. The bactericidal effect of moxifloxacin was concentration dependent, and regrowth was seen only when the concentration of moxifloxacin in CSF was below the minimal bactericidal concentration. All antibiotic-treated groups (moxifloxacin given in two doses of 40 mg/kg of body weight, moxifloxacin in two 20-mg/kg doses, ceftriaxone in one 125-mg/kg dose, and vancomycin in two 20-mg/kg doses) had significantly higher reductions in CSF bacterial concentration than the untreated group (P < 0.05). Moxifloxacin was as effective as vancomycin and ceftriaxone in reducing bacterial counts at all time points tested (3, 5, 10, and 24 h). Moreover, moxifloxacin given in two 40-mg/kg doses resulted in a significantly higher reduction in CSF bacterial concentration (in log10 CFU per milliliter) than vancomycin within 3 h after the start of antibiotic treatment (3.49 [2.94 to 4.78] versus 2.50 [0.30 to 3.05]; P < 0.05). These results indicate that moxifloxacin could be useful in the treatment of meningitis, including penicillin-resistant pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Aza Compounds; Ceftriaxone; Cephalosporins; Drug Evaluation; Fluoroquinolones; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Moxifloxacin; Penicillin Resistance; Protein Binding; Quinolines; Quinolones; Rabbits; Streptococcus pneumoniae; Time Factors; Vancomycin

To evaluate the antibiotic susceptibility of Streptococcus pneumoniae isolates obtained from the blood and cerebrospinal fluid of children with meningitis. To describe and compare the clinical and microbiological characteristics, treatment, and outcome of children with meningitis caused by S pneumoniae based on antimicrobial susceptibility of isolates and the administration of dexamethasone.. Children with pneumococcal meningitis were identified from among a group of patients with systemic infections caused by S pneumoniae who were enrolled prospectively in the United States Pediatric Multicenter Pneumococcal Surveillance Study at eight children's hospitals in the United States. From September 1, 1993 to August 31, 1996, 180 children with 181 episodes of pneumococcal meningitis were identified and data were collected by retrospective chart review.. Clinical and laboratory characteristics were assessed. All pneumococcal isolates were serotyped and antibiotic susceptibilities for penicillin and ceftriaxone were determined. Clinical presentation, hospital course, and outcome parameters at discharge were compared between children infected with penicillin-susceptible isolates and those with nonsusceptible isolates and for children who did and did not receive dexamethasone.. Fourteen (7.7%) of 180 children died; none of the fatalities were because of a documented failure of treatment caused by a resistant strain. Only 1 child, who had mastoiditis and a lymphangioma, experienced a bacteriologic failure with a penicillin-resistant (minimum inhibitory concentration = 2 microgram/mL) organism. Of the 166 surviving children, 41 (25%) developed neurologic sequelae (motor deficits) and 48 (32%) of 151 children had unilateral (n = 26) or bilateral (n = 22) moderate to severe hearing loss at discharge. Overall, 12.7% and 6.6% of the pneumococcal isolates were intermediate and resistant to penicillin and 4.4% and 2.8% were intermediate and resistant to ceftriaxone, respectively. Clinical presentation, cerebrospinal fluid indices on admission, and hospital course, morbidity, and mortality rates were similar for patients infected with penicillin- or ceftriaxone-susceptible versus nonsusceptible organisms. However, the relatively small numbers of nonsusceptible isolates and the inclusion of vancomycin in the treatment regimen for the majority of the patients limit the power of this study to detect significant differences in outcome between patients infected with susceptible and nonsusceptible isolates. Nonetheless, our results show that the nonsusceptible organisms do not seem to be intrinsically more virulent. Forty children (22%) received dexamethasone (>/=8 doses) initiated before or within 1 hour after the first dose of antibiotics. The incidence of any moderate or severe hearing loss was significantly higher in the dexamethasone group (46%) compared with children not receiving any dexamethasone (23%). The incidence of any neurologic deficits, including hearing loss, also was significantly higher in the dexamethasone group (55% vs 33%). However, children in the dexamethasone group more frequently required intubation and mechanical ventilation and had lower initial concentration of glucose in the cerebrospinal fluid than children who did not receive any dexamethasone. When we controlled for the confounding factor, severity of illness (intubation), the incidence of any deafness and of any neurologic sequelae, including deafness, were no longer significantly different between children who did or did not receive dexamethasone.. Children with pneumococcal meningitis caused by penicillin- or ceftriaxone-nonsusceptible organisms and those infected by susceptible strains had similar clinical presentation and outcome. The use of dexamethasone was not associated with a beneficial effect in this retrospective and nonrandomized study. (ABSTRACT TRUNCATED)

Topics: Adolescent; Ceftriaxone; Cephalosporin Resistance; Child; Child, Preschool; Deafness; Dexamethasone; Female; Humans; Incidence; Infant; Infant, Newborn; Male; Meningitis, Pneumococcal; Penicillin Resistance; Population Surveillance; Prospective Studies; Retrospective Studies; Serotyping; Streptococcus pneumoniae; Treatment Outcome; United States

Topics: Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Drug Prescriptions; Drug Resistance, Microbial; Drug Therapy, Combination; Empiricism; Humans; Meningitis, Pneumococcal; Vancomycin

Gelatinolytic activity of matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-2, was studied by quantitative zymography in a rabbit model of bacterial meningitis during 24 h after inoculation with Streptococcus pneumoniae. In cerebrospinal fluid (CSF), MMP-2 was constitutively present and its level did not change during the experiment. In contrast, MMP-9, hardly detectable in CSF of healthy animals, increased dramatically. The increase of MMP-9 was correlated with both, an increase of CSF cell count and of total protein concentration. Intrathecal production of MMP-9 and MMP-2 was demonstrated by zymography of equal amounts of total protein from CSF and serum. Homogenates, prepared from various cortical regions of infected rabbits did not show increase of MMP activities. On the other hand, leucocytes isolated from CSF expressed high levels of MMP-9 suggesting a significant contribution of these cells to the elevation of MMP-9 activity in this body fluid.

Topics: Animals; Ceftriaxone; Cerebral Cortex; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Collagenases; Colony Count, Microbial; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Gelatinases; Leukocytes; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Meningitis, Pneumococcal; Metalloendopeptidases; Rabbits; Time Factors

The fluoroquinolone trovafloxacin was bactericidal (0.47 +/- 0.23 delta log10 CFU/ml x h after 10 mg/kg of body weight and 0.78 +/- 0.15 delta log10 CFU/ml x h after 30 mg/kg) in the treatment of experimental meningitis caused by a highly penicillin-resistant (MIC and minimum bactericidal concentration = 4 and 4 microg/ml) strain of Streptococcus pneumoniae. Combinations with ampicillin and rifampin were indifferent compared to single drugs.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Ceftriaxone; Fluoroquinolones; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Naphthyridines; Penicillin Resistance; Rabbits; Rifampin; Streptococcus pneumoniae

Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Ceftriaxone; Drug Resistance, Microbial; Drug Therapy, Combination; Humans; Infant; Injections, Intravenous; Male; Meningitis, Pneumococcal; Steroids

This study evaluates the ability of the new fluoroquinolone trovafloxacin to attenuate the inflammatory burst known to occur after initiation of antibiotic treatment in pneumococcal meningitis. After exposure to trovafloxacin or ceftriaxone for 3 h in vitro, Streptococcus pneumoniae was injected intracisternally (i.c.) into rabbits every 3 h over 9 h (n = 6 for each antibiotic). Ceftriaxone-treated S. pneumoniae induced consistently higher CSF leucocyte counts (median 2568/microL versus 543/microL at 6 h; P = 0.03; 4560/microL versus 2207/microL at 18 h; P = 0.03) than trovafloxacin-treated bacteria. Meningitis induced in rabbits by i.c. injection of live S. pneumoniae was treated with equal doses of trovafloxacin or ceftriaxone i.v. (ten per group). The bactericidal rates of both antibacterial agents in CSF were almost identical. In comparison with ceftriaxone, trovafloxacin resulted in lower tumour necrosis factor (TNF) and interleukin 1beta (IL-1beta) CSF levels 2 h after the initiation of treatment (TNF levels, median 26 U/mL versus 141 U/mL; P = 0.02; IL-1beta levels 455 pg/mL versus 1399 pg/mL; P = 0.02). Twelve hours after initiation of therapy, however, TNF and IL-1beta were higher in trovafloxacin-treated animals (TNF, 61 U/mL versus 7 U/mL; P = 0.001; IL-1beta, 4320 pg/mL versus 427 pg/mL; P = 0.006). The increase in CSF lactate was less during trovafloxacin therapy than with ceftriaxone (median: 2.0 mmol/L versus 4.0 mmol/L; P = 0.03). In conclusion, S. pneumoniae treated in vitro with trovafloxacin induced less CSF leucocytosis than ceftriaxone-treated S. pneumoniae. After i.c. inoculation of live S. pneumoniae, trovafloxacin therapy delayed, but did not inhibit, the release of the proinflammatory cytokines TNF and IL-1beta, probably by slowing the liberation of bacterial cell wall components into the subarachnoid space.

Topics: Adult; Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporins; Disease Models, Animal; Fluoroquinolones; Humans; Injections, Intravenous; Interleukin-1; Lactic Acid; Meningitis, Pneumococcal; Naphthyridines; Rabbits; Streptococcus pneumoniae; Tumor Necrosis Factor-alpha

Adequate concentrations of beta-lactam antibiotics in cerebrospinal fluid (CSF) are difficult to achieve for meningitis caused by drug-resistant Streptococcus pneumoniae. Ceftriaxone in dosages of 150 or 400 mg/kg of body weight per day, given in one or two doses, was used for the treatment of experimental highly cephalosporin-resistant (MIC and MBC, 4 microg/ml) pneumococcal meningitis. The bacterial killing rate (delta log10 CFU per milliliter per hour) and pharmacokinetic indices, including percentage of time the antibiotic concentration exceeded the MBC during a 24-h period (T>MBC), CSF peak concentration above the MBC, and area under the concentration-time curve from 0 to 24 h above MBC, were measured and correlated. By multiple stepwise regression, only T>MBC independently predicted the bacterial killing rate. There was a direct linear correlation between T>MBC in CSF and the bacterial killing rate during the first 24 h of therapy (r = 0.87; P = 0.004). Sterilization of CSF was achieved only when the T>MBC was 95 to 100%. In the first 24 h, the 200-mg/kg/12-h regimen, compared with the 400-mg/kg/24-h regimen, was associated with a greater T>MBC (87% +/- 10% versus 60% +/- 22%; P = 0.03) and greater bacterial killing rate (0.2 +/- 0.04 versus 0.13 +/- 0.07; P = 0.003), confirming that ceftriaxone exhibits time-dependent bactericidal activity. After 24 h, the T>MBC and the CSF sterilization rates were similar whether ceftriaxone was given once or twice daily.

Topics: Animals; Area Under Curve; Ceftriaxone; Cephalosporins; Drug Resistance, Microbial; Half-Life; Male; Meningitis, Pneumococcal; Rabbits; Streptococcus pneumoniae

In-vitro susceptibility of 299 Neisseria meningitidis and 157 Streptococcus pneumoniae strains from meningitis patients in The Netherlands in 1993 and 1994 to meropenem was determined using the Etest. Susceptibility to penicillin, ceftriaxone, and chloramphenicol was also determined. Rifampicin susceptibility was additionally tested for N. meningitidis. Of the meningococci, 4.3% were of intermediate resistance to penicillin and 0.3% were resistant to rifampicin. One pneumococcal isolate (0.6%) was of intermediate resistance to penicillin. All strains were susceptible to meropenem. We conclude that meropenem is in vitro highly active against N. meningitidis and S. pneumoniae.

Topics: Anti-Bacterial Agents; Ceftriaxone; Chloramphenicol; Humans; Meningitis, Meningococcal; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Neisseria meningitidis; Netherlands; Penicillins; Streptococcus pneumoniae; Thienamycins

Typical features of pneumococcal meningitis have been demonstrated in rats inoculated with Streptococcus pneumoniae. HU-211, a novel noncompetitive N-methyl-D-aspartate antagonist recently demonstrated to inhibit tumor necrosis factor-alpha production under various conditions, improves recovery in some experimental models of brain injury. The present study tested the efficacy of HU-211 in combination with antimicrobial therapy in reducing brain damage in experimental pneumococcal meningitis. S. pneumoniae-infected rats were treated with saline alone, ceftriaxone alone, or with combination of ceftriaxone and HU-211 18 h after inoculation of the bacteria. Brain edema and blood-brain barrier impairment 48 h after infection were significantly (P<.05) reduced suggest that HU-211 when given concomitantly with antibiotics attenuates brain damage in the rat model of pneumococcal meningitis.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Ceftriaxone; Disease Models, Animal; Dronabinol; Drug Therapy, Combination; Male; Meningitis, Pneumococcal; Neuroprotective Agents; Rats; Tumor Necrosis Factor-alpha

Since a significant proportion of Streptococcus pneumoniae strains is now resistant to penicillin and sometimes to third-generation cephalosporin, it is necessary to reevaluate the initial therapy of bacterial meningitis proposed before identification of the organism and its susceptibility pattern.. From 1 January 1992 to 31 March 1994, nine children with acute S pneumoniae meningitis were treated with ceftriaxone plus aminoglycoside as conventional initial therapy. Eight children were less than 1 year-old (five from 3 to 6 months). Five S pneumoniae strains were penicillin-resistant; four had a ceftriaxone minimal inhibitory concentration (MIC) of 0.047 to 0.094 mg/L and one of 1.5 mg/L. Ceftriaxone was given intravenously at doses of 50 mg/kg twice a day to patients less than 12 months old and 100 mg/kg once a day to patients older than 12 months. Intravenous amikacin (7.5 mg/kg twice daily) or netilmicin (3 mg/kg twice daily) were administered in combination. Dexomethasone was given to all children as adjunctive therapy. Follow-up lumbar puncture was performed after 24 to 36 hours of treatment.. For each of the nine patients, cerebrospinal fluid was sterile with normal glucose level. After 2 or 4 days, initial therapy had been modified according to antibiogram and MIC. Monotherapy with ceftriaxone was continued in five children. Rifampicin was associated with initial bitherapy in one case. In two other patients, initial empiric therapy was stopped and changed to chloramphenicol.. No case of bacteriological failure was noted in our patients but evolution of epidemiology and emergence of decreased penicillin sensibility in S pneumoniae strains (55% in our study) suggests that a third antibiotic (vancocin or rifampicin) should be associated with the standard first-line drug when S pneumoniae is suspected.

Topics: Adolescent; Amikacin; Anti-Bacterial Agents; Ceftriaxone; Cephalosporins; Drug Therapy, Combination; Female; Gentamicins; Humans; Infant; Male; Meningitis, Pneumococcal; Netilmicin; Penicillin Resistance; Probability; Retrospective Studies

CP-99,219 is a new fluoroquinolone that has excellent activity against gram-positive organisms including penicillin- and cephalosporin-resistant Streptococcus pneumoniae strains. In our well-established rabbit model of meningitis, we conducted experiments to determine the concentrations of CP-99,219 in cerebrospinal fluid (CSF) after intravenous administration and its ability to eradicate two penicillin-resistant pneumococcal isolates. The peak and trough concentrations of CP-99,219 in the CSF were from 19 to 25% of the concentrations simultaneously obtained in serum and were unaffected by concomitant dexamethasone administration. Compared with untreated (control) animals, three doses of CP-99,219 given 5 h apart significantly reduced the bacterial count in CSF by 5 to 6 log10 CFU at 10 h. Although 47% of the dexamethasone-treated animals and 18% of those not given the steroid had positive cultures at 24 h (14 h after administration of the last antibiotic dose), the mean bacterial counts did not change from those observed at 10 h. Additionally, only results for animals infected with one of the two pneumococcal strains appeared to be affected by concomitant dexamethasone therapy.

Topics: Animals; Anti-Infective Agents; Ceftriaxone; Cephalosporin Resistance; Colony Count, Microbial; Dexamethasone; Drug Evaluation; Drug Therapy, Combination; Fluoroquinolones; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Naphthyridines; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Vancomycin

Bacterial meningitis, particularly that resulting from Streptococcus pneumoniae, is a common cause of acquired profound sensorineural deafness in children. The pathogenesis of meningogenic hearing loss has been investigated in an experimental rabbit model. In this study significant deafness was documented within the first 15 hours of infection. Initiation of antibiotic therapy at this time diminished the severity of hearing loss in most animals. The addition of dexamethasone to antibiotic therapy prevented the development of profound deafness. These results suggest this model will be useful in developing antiinflammatory strategies to improve the outcome of bacterial meningitis.

Topics: Animals; Ceftriaxone; Dexamethasone; Disease Models, Animal; Drug Therapy, Combination; Evoked Potentials, Auditory; Female; Hearing Loss, Sensorineural; Linear Models; Meningitis, Pneumococcal; Rabbits

Using a rabbit model of meningitis, we sought to determine whether concomitant use of dexamethasone affects the penetration and efficacy of ceftriaxone or vancomycin in cerebrospinal fluid. Rabbits were inoculated with a penicillin-sensitive strain of Streptococcus pneumoniae and treated with ceftriaxone or vancomycin with or without dexamethasone. In the ceftriaxone-treated groups, no statistically significant differences were seen between the group treated with dexamethasone and that without dexamethasone; however, in the vancomycin-treated groups we found statistically significant lower cerebrospinal fluid vancomycin levels at 2 h in the dexamethasone-treated rabbits and differences in bacterial killing.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents; Ceftriaxone; Cephalosporins; Dexamethasone; Drug Synergism; Female; Meningitis, Pneumococcal; Rabbits; Vancomycin

An in vitro pharmacodynamic model was used to determine the killing kinetics of cefpirome against 20 Streptococcus pneumoniae strains (penicillin G MICs, > 0.125 to 2 micrograms/ml) isolated from patients with meningitis. The concentration of cefpirome was adjusted dynamically to simulate the median concentration profile obtained in the cerebrospinal fluid of adults after the infusion of a single dose of 2 g. The cefpirome MIC at which 90% of isolates are inhibited was 0.5 microgram/ml. Bactericidal activity was observed at 6 h, with mean killing of 3.51 +/- 0.34 log10 CFU/ml for all strains for which the cefpirome MIC was < 0.5 microgram/ml. In contrast, for strains for which the cefpirome MIC was > or = 0.5 microgram/ml, killing was significantly less (P < 0.05), with a mean reduction of only 2.86 +/- 0.57 log10 CFU/ml.

Topics: Adult; Cefpirome; Ceftriaxone; Cephalosporins; Humans; Meningitis, Pneumococcal; Penicillin Resistance; Penicillins; Streptococcus pneumoniae

Due to a worldwide increasing number of cephalosporin resistant Streptococcus (S) pneumoniae strains, it appears necessary to modify the current treatment of pneumococcal meningitis. The authors recommend an initial antimicrobial regimen associating cefotaxime or ceftriaxone to vancomycin in any case of bacterial meningitis in which S pneumoniae appears to be involved (Gram positive cocci on direct examination of the CSF and/or presence of soluble bacterial antigen). There is also a need for a reappraisal of the duration of the treatment which, in any case, should not be shorter than 10 days. In the case of meningitis due to a penicillin resistant S pneumoniae, lumbar puncture must be repeated until sterilisation of the CSF.

Topics: Cefotaxime; Ceftriaxone; Drug Therapy, Combination; Humans; Infant; Meningitis, Pneumococcal; Vancomycin

Rifampin at a maximally effective dose was less active than ceftriaxone (both drugs at 10 mg/kg of body weight.h) in a rabbit model of pneumococcal meningitis (delta log10 CFU/ml.h, -0.40 +/- 0.13 versus -0.77 +/- 0.18; P < 0.01). The bactericidal activity of rifampin decreased at concentrations in cerebrospinal fluid greater than those that are clinically achievable, and use of rifampin in combination with ofloxacin had no synergistic or additive effect.

Topics: Animals; Ceftriaxone; Drug Synergism; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Rifampin; Serum Bactericidal Test; Streptococcus pneumoniae

Children with meningitis due to Streptococcus pneumoniae isolates that are relatively or fully resistant to penicillin and have decreased susceptibility to broad-spectrum cephalosporins (MIC, > or = 2.0 micrograms/ml) who have failed treatment with broad-spectrum cephalosporins have been reported. The National Committee for Clinical Laboratory Standards has newly revised guidelines indicating that S. pneumoniae isolates associated with meningitis for which the MICs are > or = 0.5 micrograms/ml should be considered resistant to broad-spectrum cephalosporins. This recommendation is not clearly based on data related to clinical outcome and may be too conservative. We present data on five children who had S. pneumoniae meningitis due to isolates that were relatively or fully resistant to penicillin (MIC range, 0.125 to 4.0 micrograms/ml) and had cefotaxime or ceftriaxone MICs of 0.50 to 2.0 micrograms/ml. Their clinical courses and outcomes were comparable to those of five children with S. pneumoniae meningitis due to strains that were relatively or fully resistant to penicillin and were inhibited by cefotaxime at concentrations of < or = 0.25 micrograms/ml, as well as to those of 25 patients with S. pneumoniae meningitis due to penicillin-susceptible isolates identified during the same period. Children with meningitis due to S. pneumoniae with cefotaxime or ceftriaxone MICs of < or = 1.0 micrograms/ml may be adequately treated with these antibiotics. Further clinical data are required before solid recommendations can be made regarding cephalosporin breakpoints for S. pneumoniae.

Topics: Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Cephalosporins; Child; Child, Preschool; Drug Resistance, Microbial; Humans; Infant; Leukocyte Count; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Retrospective Studies; Streptococcus pneumoniae; Treatment Outcome

Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin- and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of approximately 10(4) CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.

Topics: Animals; Ceftriaxone; Cerebrospinal Fluid; Cyclosporine; Dexamethasone; Drug Resistance, Microbial; Drug Therapy, Combination; Male; Meningitis, Pneumococcal; Penicillins; Rabbits; Rifampin; Vancomycin

The most appropriate therapy for meningitis caused by Streptococcus pneumoniae strains resistant to the extended-spectrum cephalosporins is unknown. We evaluated ceftriaxone, vancomycin, and rifampin alone and in different combinations and meropenem, cefpirome, and clinafloxacin alone in the rabbit meningitis model. Meningitis was induced in rabbits by intracisternal inoculation of one of two pneumococcal strains isolated from infants with meningitis (ceftriaxone MICs, 4 and 1 microgram/ml, respectively). Two doses, 5 h apart, of each antibiotic were given intravenously (except that ceftriaxone was given as one dose). Cerebrospinal fluid bacterial concentrations were measured at 0, 5, 10, and 24 h after therapy was started. Clinafloxacin was the most active single agent against both strains. Against the more resistant strain, ceftriaxone or meropenem alone was ineffective. The combination of vancomycin and ceftriaxone was synergistic, suggesting that this combination might be effective for initial empiric therapy of pneumococcal meningitis until results of susceptibility studies are available.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Cefpirome; Ceftriaxone; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fluoroquinolones; Male; Meningitis, Pneumococcal; Meropenem; Microbial Sensitivity Tests; Penicillin Resistance; Quinolones; Rabbits; Rifampin; Thienamycins; Vancomycin

Topics: Animals; Ceftriaxone; Clarithromycin; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Rabbits; Streptococcus pneumoniae

Kirby-Bauer disk susceptibility tests with five standard cephalosporin disks were performed on 23 penicillin-resistant Streptococcus pneumoniae isolates for which ceftriaxone MICs were 0.125 to 4 micrograms/ml. Cefuroxime disk inhibition zone diameters distinguished clearly isolates for which ceftriaxone MICs were > or = 2 micrograms/ml from more susceptible strains, whereas cephalothin, ceftizoxime, cefotaxime, and ceftriaxone disks distinguished these isolates less clearly than the cefuroxime disk did.

Topics: Ceftriaxone; Cefuroxime; Cephalosporins; Child; Drug Resistance, Microbial; Evaluation Studies as Topic; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Streptococcus pneumoniae

Topics: Ceftriaxone; Cerebrospinal Fluid; Drug Resistance, Microbial; Female; Humans; Infant; Injections, Intramuscular; Meningitis, Pneumococcal; Microbial Sensitivity Tests

The following article describes a girl with right upper quadrant abdominal colic following Ceftriaxon therapy for purulent meningitis. Ultrasound made it possible to demonstrate sludge-balls, floating in the gallbladder, a follow up examination was normal. Moreover the features of gallbladder precipitations following Ceftriaxon therapy will be described, and the clinical consequences will be discussed.

Topics: Ceftriaxone; Child; Cholelithiasis; Colic; Female; Gallbladder Diseases; Humans; Infusions, Intravenous; Meningitis, Pneumococcal; Ultrasonography

Topics: Ceftriaxone; Child, Preschool; Drug Resistance, Microbial; Humans; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Streptococcus pneumoniae

Topics: Ceftriaxone; Chloramphenicol; Humans; Infant; Male; Meningitis, Pneumococcal; Penicillin Resistance; Recurrence

A total of 33 patients with bacterial meningitis were treated with single daily doses of ceftriaxone (CTR 100 mg/kg/day i.v.) for a median duration of 13 days. Pathogens isolated by culture and/or determined by latex agglutination were 15 Haemophilus influenzae b, 7 Neisseria meningitidis, 2 Streptococcus pneumoniae, 1 group B streptococcus, 2 Streptococcus viridans and 2 Staphylococcus epidermidis. In 4 cases a diagnosis of purulent meningitis could only be made by means of the inflammatory liquor parameters. All cerebrospinal fluid (CSF) drug levels even at the end of the dosing interval were at least 10-fold higher than the MICs of the respective bacterial isolates. The average penetration of CTR into the CSF was 6.6%. Within 12-46 h after the first dose, control spinal taps were performed. Cultures were sterile in all cases. Side effects encountered were diarrhea, exanthema, neutropenia and transient elevation of glutamic oxaloacetic transaminase, but none caused a change of therapy. One patient developed a biliary concrement. No patient died; 5 patients had prolonged fever (greater than 5 days), and 2 were left with persistent hearing deficiencies. CTR can be recommended as a safe and effective antibiotic agent for once daily treatment of bacterial meningitis in children.

Topics: Adolescent; Ceftriaxone; Child; Child, Preschool; Female; Half-Life; Humans; Infant; Injections, Intravenous; Latex Fixation Tests; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Time Factors

FCE 22101 is a new penem antibiotic with a spectrum of activity suggesting a possible role in the empirical treatment of meningitis. It appears to achieve a mean reduction in bacterial titre in CSF comparable with currently accepted agents for both pneumococcal and Escherichia coli meningitis. Its efficacy may, however, be variable. It does not achieve CSF level/MIC ratios as favourable as imipenem for the pathogens studied. Further studies are necessary to determine its role, if any, in this disease.

Topics: Animals; Anti-Bacterial Agents; Blood Bactericidal Activity; Carbapenems; Ceftriaxone; Escherichia coli Infections; Imipenem; Meningitis; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillins; Rabbits

Ceftriaxone, a cephalosporin with an extended half-life and excellent antibacterial activity was used to treat bacterial meningitis, given as a single daily intravenous dose of 100 mg/kg on day one, followed by 80 mg/kg daily. A total of 22 patients were treated, of whom 14 had Haemophilus influenzae type b, five had Streptococcus pneumoniae and three Neisseria meningitidis isolated from their CSF. The CSF of all patients became sterile within 24-48 h. The CSF ceftriaxone concentrations 24 h after dosing were 10 to 100-fold higher than the MIC of the pathogenic bacteria early in therapy, and five to 50-fold higher at the end of therapy. Side effects encountered included mild diarrhoea (32%), thrombocytosis (77%) and neutropenia (9%), but none caused therapy to be stopped. Ceftriaxone is a safe and effective antibiotic for the treatment of bacterial meningitis when administered once daily.

Topics: Adolescent; Ceftriaxone; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal

The authors carried out this work with the purpose both of verifying the present importance of penicillin G for the treatment of pneumococcal meningitis and of comparing it with the clinical effectiveness of other medicines presently available for the same purpose. They have studied 27 patients with clinical and laboratory diagnosis of pneumococcal meningitis and which were admitted in the "Serviço de Infecto-Contagiosos" of Santa Maria Hospital, Lisbon, for the period from 1.1.81 until 31.05.86. Of these patients 18 were males and 9 females, ranging from 8 to 80 years old. All of them were treated exclusively with penicillin G, the medium dose being 400,000 IU/kg per day and for a medium period of 15 days. The final results accounted for: 23 patients healed (85.2%), 2 decreased (7.4%) and the remaining 2 (7.4%) with neurological sequels by the time of discharge from the hospital. These, in our opinion, are values for the minimum equivalent to those in other series of the same pathology and under treatment by the different medicines presently available in alternative. Bearing in mind these results and considering it is more expensive to use these new antibiotics, the authors think they may state that penicillin G keeps ahead for the treatment of pneumococcal meningitis, except for cases of hypersensitivity to this medicine or penicillin-resistance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cefotaxime; Ceftazidime; Ceftriaxone; Child; Costs and Cost Analysis; Female; Humans; Male; Meningitis, Pneumococcal; Middle Aged; Penicillin G

Topics: Ceftriaxone; Child; Escherichia coli Infections; Humans; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal

The authors tested cephalosporin antibiotic of the 3rd generation--Ceftriaxon--in treatment of bacterial meningitis. After studying the infiltration of the antibiotic into the cerebrospinal fluid in 13 patients with parotitic meningoencephalitis, the authors treated 15 patients with bacterial meningitis. Ceftriaxon has been applied in 100 mg/kg in two doses i.v. The research antibiotic levels in cerebrospinal fluid varied from 10 to 30% of sera levels and were much higher than MIC for pathogens isolated from liquor. The treatment effects were very good the dropping of temperature followed on the 3-4 day, the 5-6, day under 100/3. The side effects showed a short time increasing of transaminases and diarrhoea. After completing the treatment normalisation occurred quickly. Other side effects have not occurred. The authors can state, Ceftriaxon in treatment of bacterial meningitis is a highly effective antibiotic.

Topics: Adolescent; Adult; Ceftriaxone; Child; Child, Preschool; Humans; Infant; Meningitis, Meningococcal; Meningitis, Pneumococcal; Middle Aged; Parotitis

Topics: Aged; Ceftriaxone; Female; Humans; Injections, Spinal; Medication Errors; Meningitis, Pneumococcal

The pharmacokinetics and bacteriological efficacies of penicillin G, ceftriaxone, vancomycin, and imipenem were determined in rabbits with experimental meningitis caused by Streptococcus pneumoniae strains with different penicillin susceptibilities. Drug dosages were adjusted to attain peak concentrations in serum that were similar to those observed in infants and children. In animals infected with a penicillin-susceptible (MBC, 0.008 micrograms/ml) pneumococcus, penicillin G and ceftriaxone reduced the number of organisms in cerebrospinal fluid (CSF) by greater than or equal to 4.14 log10 CFU/ml after single doses and after 9-h continuous infusions. A single large dose (50 mg/kg) of penicillin G was comparatively ineffective (-2.15 log10 CFU/ml) against a relatively penicillin-resistant (MBC, 0.5 micrograms/ml) strain, whereas ceftriaxone therapy resulted in a 3.66- and 4.77-log10 CFU/ml reduction after single doses and 9-h continuous infusions, respectively. In animals in which meningitis was caused by a penicillin-resistant (MBC, 8.0 micrograms/ml) pneumococcus, a single dose of penicillin (50 or 150 mg/kg) or of ceftriaxone failed to lower the number of organisms in CSF. Vancomycin and imipenem reduced the counts in CSF by at least 2.19 and 4.10 log10 CFU/ml after single doses and 9-h infusions, respectively. In all experiments, a bactericidal titer of greater than or equal to 1:8 in CSF was necessary to achieve a maximal bacteriological effect.

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Ceftriaxone; Kinetics; Male; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin G; Penicillin Resistance; Penicillins; Rabbits; Streptococcus pneumoniae; Vancomycin

In order to define the characteristics of the antibacterial activity of beta-lactam antibiotics in the treatment of bacterial meningitis, the relationship between cerebrospinal fluid (CSF) drug concentrations and the rate of bacterial killing was investigated for penicillin G and four new cephalosporins in an animal model of meningitis due to Streptococcus pneumoniae. All five drugs showed a significant correlation between increasing drug concentrations in CSF and increasing bactericidal rates. Minimal activity was observed in CSF at drug concentrations of approximately the broth minimal bactericidal concentration (MBC). Maximal activity occurred with CSF concentrations 10-30 times higher. In vitro tests did not reproduce the unique correlation of increasing drug concentrations and killing activity found in vivo. When evaluating new beta-lactam antibiotics for the treatment of bacterial meningitis, it is reasonable to establish a minimum standard of CSF drug concentrations of greater than or equal to 30 times the MBC against the infecting organism.

Topics: Animals; Anti-Bacterial Agents; Cefmenoxime; Cefotaxime; Ceftriaxone; Meningitis, Pneumococcal; Moxalactam; Penicillin G; Rabbits; Streptococcus pneumoniae

The pharmacokinetics of ceftriaxone were studied in five infants (7 to 15 months old) and five young children (24 to 70 months old). Both groups received a single 50-mg/kg dose in an intravenous infusion over 5 min. No major pharmacokinetic differences were observed between the two populations. The total (bound plus unbound) plasma concentration-versus-time data could be described in each case by a biexponential equation. Changes in renal clearance indicated time- and dose- dependent pharmacokinetic behavior. The fraction excreted unchanged in the urine (fu) and the biological half-life (t 1/2 (beta)) were, however, dose independent. The average values were 47% for fu (0 to 12 h) and 6.5 for T 1/2 (beta). Weight-corrected total systemic clearance was C1TS = 0.71 ml/min per kg; volume of distribution was VD (beta) = 394 mg/kg. The data support intravenous administration of 50 mg of ceftriaxone per kg of body weight every 12 h in assessing its activity against Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis in postneonatal-stage pediatric patients.

Topics: Cefotaxime; Ceftriaxone; Child, Preschool; Female; Half-Life; Humans; Infant; Infusions, Parenteral; Kinetics; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Protein Binding; Serum Albumin

The pharmacokinetics and bacteriological efficacy of cefoperazone, cefuroxime, ceftriaxone, and moxalactam were evaluated in the experimental rabbit meningitis model of Haemophilus influenzae type b or Streptococcus pneumoniae infection. The cerebrospinal fluid penetration of these beta-lactam antibiotics was from 3 to 14% and was greater in Haemophilus-infected that in pneumococcus-infected animals. With the exception of moxalactam, the antibacterial activity in cerebrospinal fluid and change in concentration of bacteria during therapy with the test drugs were comparable to those of penicillin G in pneumococcal infection. In animals infected with H. influenzae, cefoperazone, moxalactam, and ceftriaxone were as effective as chloramphenicol in reducing the bacterial counts in cerebrospinal fluid. Moxalactam and ceftriaxone produced the largest cerebrospinal fluid bactericidal titers against this beta-lactamase-producing strain of Haemophilus. On the basis of these data, it was concluded that ceftriaxone and cefoperazone were effective against both pathogens in this meningitis model, whereas moxalactam was effective against only Haemophilus, and cefuroxime was effective against only S. pneumoniae.

Topics: Animals; Cefoperazone; Cefotaxime; Ceftriaxone; Cefuroxime; Cephalosporins; Cephamycins; Dose-Response Relationship, Drug; Infusions, Parenteral; Kinetics; Male; Meningitis, Haemophilus; Meningitis, Pneumococcal; Moxalactam; Rabbits; Streptococcus pneumoniae

Ceftriaxone is a wide-spectrum-third generation cephalosporin characterized by outstandingly high efficacy as well as pharmokinetic properties making it suitable for administration in a single daily injection. Ceftriaxone has been found to be useful for treatment of the very severe infectious pathology in countries where hygiene and medical superstructures are still rudimentary. Eighteen of 20 patients with purulent meningitis (13 to Neisseria meningitidis A, 3 to Streptoc. pneumoniae, 1 to Listeria and 3 aseptic) recovered (there being 2 deaths at the 36th hour) after a mean 6 days of hospitalization. Despite the very delicate patient condition, recovery was seen in all 11 cases of very grave bronchopneumopathy, generally due to Streptoc, pneumonia. A dose of 2 g/day in 1 or 2 IV injections is sufficient in the adult, 0.50 g in a single dose being injected to infants weighing less than 10 kg, Meningitis required 4 to 7 days treatment (9 days in a case of Listeria) while the treatment period was longer for respiratory infections. Seven patients had been refractory to treatment with beta-lactamines and/or aminosides, and no adverse drug reactions were noted.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Bronchopneumonia; Cefotaxime; Ceftriaxone; Child; Child, Preschool; Female; Hospitals, University; Humans; Infant; Injections; Male; Meningitis; Meningitis, Meningococcal; Meningitis, Pneumococcal; Middle Aged; Niger

Single-dose pharmacokinetics of ceftriaxone were determined in 19 patients with proven bacterial meningitis. The dosage was 50 mg of ceftriaxone per kg. The plasma concentration time curve declined in a biexponential manner. The mean peak plasma concentration was 207 micrograms/ml, and the elimination half-life was 4 h. In 12 patients, multiple-dose pharmacokinetics were determined after a loading dose of 75 mg of ceftriaxone per kg, followed by 50-mg/kg doses every 8 h in 5 patients or every 12 h in 7 patients. The mean peak plasma concentration was 230 micrograms/ml after the first dose and 263 micrograms/ml after the last dose. Of 12 patients, 5 had trough values that were larger after multiple doses than after a single dose. Mean penetration of ceftriaxone into cerebrospinal fluid was 3.1%. The median cerebrospinal fluid bactericidal titer against the patients pathogens was greater than 1:1,024 and less than 1:2,048. The drug was well tolerated without adverse effects.

Topics: Bacteria; Cefotaxime; Ceftriaxone; Child, Preschool; Female; Humans; Infant; Kinetics; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Meningococcal; Meningitis, Pneumococcal; Microbial Sensitivity Tests

In 21 of the 24 cases the diagnosis of purulent meningitis was confirmed by culturing the causal agent and/or by immunological diagnosis. The daily dosage of Rocephin ranged between 15 and 200 mg/kg administered in 2 i.m. injections. A cure was achieved in cases of meningococcal meningitis (1 case with sequelae: blindness in one eye), in 5 out of 6 cases of Haemophilus influenzae meningitis (1 case with severe neuropsychiatric sequelae), in 3 out of 9 cases of pneumococcal meningitis and in 2 out of 4 cases of enterobacterial meningitis. The tolerance was generally excellent. Sterilisation of the cerebrospinal fluid (CSF) was achieved in all 20 cases of meningitis confirmed by culture. The MIC levels are lower than the lowest CSF peak for Rocephin found in this study. The unusual pharmacological behavior of Rocephin makes it possible to achieve and to maintain for a long time highly satisfactory concentration levels in the CSF. These properties of Rocephin should lift the long-standing objections to the use of cephalosporins for the treatment of purulent meningitis.

Topics: Adolescent; Adult; Ceftriaxone; Cephalosporins; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Male; Meningitis; Meningitis, Haemophilus; Meningitis, Pneumococcal