[Concentration of tazobactam/piperacillin in the cerebrospinal fluid of patients with Haemophilus influenzae type B meningitis].

While the incidence of Haemophilus influenzae type b (Hib) meningitis is expected to decrease with the widespread use of the Hib vaccine, the resistance of Hib has actually increased. Therefore, selection of the initial antibiotics used for treatment must be performed with resistant bacteria, including beta-lactamase negative ampicillin resistant H. influenzae (BLNAR), in mind. Tazobactam/piperacillin (TAZ/PIPC) has a satisfactory minimum inhibitory concentration (MIC) against BLNAR and is a beta-lactamase inhibitor. Although there is no insurance coverage for its use in patients with meningitis, the penetration of TAZ/PIPC into cerebrospinal fluid (CSF) in animal experiments promises a satisfactory result, and we have been using a combination of ceftriaxone (CTRX) and TAZ/PIPC as an initial treatment and a resistant bacteria countermeasure in patients with Hib meningitis at our hospital since 2008. We examined the concentration of TAZ/PIPC in CSF to further investigate the possibility of using TAZ/PIPC as an antibiotic treatment against bacterial meningitis. In cases treated with a 1: 8 drug formulation of TAZ/PIPC against Hib meningitis at our hospital, we used the remaining portion of a CSF sample collected after the initiation of TAZ/PIPC administration and then measured the concentrations of TAZ and PIPC in the CSF. Six specimens from 5 patients between the ages of 6 and 59 months were examined. The dosage of TAZ/PIPC was 95.7-113.6 mg/kg/dose x 3 times/day, and the CSF concentrations at 0-105 minutes after the completion of the administration were 0.319-1.32 microg/mL for TAZ and 2.54-7.74 microg/mL for PIPC. With the approved dosage, the peak concentration level during the acute period indicated a sufficient CSF concentration level for the antibacterial and beta-lactamase inhibition effects against Hib. As an antibiotic treatment for H. influenzae meningitis, the combined usage of TAZ/PIPC is likely to be effective as a resistant bacteria countermeasure, in addition to third-generation cephem drugs and meropenem.

Therapeutic effect of meropenem on an experimental guinea pig model of meningitis with type b ß-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae.

The purpose of this study was to investigate the relationship between efficacy and percentage of time above the MIC (%T>MIC) in the cerebrospinal fluid (CSF) for different dosing regimens of meropenem against an experimental lethal meningitis model in guinea pigs with type b ß-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (Hib BLNAR). Guinea pigs were intrathecally inoculated with 10(8) CFU/head of Hib BLNAR 8 h before the start of therapy. A single dose of 20, 40, or 80 mg/kg meropenem or multiple doses of 40 mg/kg meropenem were subcutaneously administered. Numbers of bacteria in CSF were counted 8 h after the start of therapy. Meropenem concentration in serum and CSF were determined in infected guinea pigs receiving a single dose of 40 mg/kg. In the single-dose regimen, 40 and 80 mg/kg meropenem significantly reduced the number of bacteria in CSF compared with the control, but 20 mg/kg meropenem did not. The %T>MIC for an 8-h period of 20, 40, and 80 mg/kg meropenem were 41, 52, and 62, respectively. Two and four doses of 40 mg/kg meropenem, for both of which %T>MIC was calculated as 100, had similar efficacy and were significantly superior to a single-dose of 40 mg/kg. In conclusion, meropenem had high efficacy when %T>MIC in the CSF was increased because of the high dose level and shortening of the dosing interval in a guinea pig meningitis model caused by Hib BLNAR, suggesting that high and frequent doses of meropenem are useful for treatment of meningitis with Hib BLNAR.

Direct detection of the multidrug resistance genome of Haemophilus influenzae in cerebrospinal fluid of children: implications for treatment of meningitis.

BACKGROUND: Multidrug resistance (MDR), specifically to ampicillin and chloramphenicol, has complicated the treatment of Haemophilus influenzae type b (Hib) meningitis. This is worsened by use of prior antibiotics, which limits identification of the causative agent by culture and increases reliance on antigen detection. OBJECTIVE: We aimed to develop a PCR assay for detecting the family of Haemophilus integrating and conjugative elements (ICEs) represented by ICEHin1056 among antibiotic resistant Hib, and then apply this directly to CSF to diagnose Hib meningitis and predict organism susceptibility, irrespective of culture results. STUDY DESIGN: Primers specific for orf 51 of ICEHin1056 were designed and multiplexed with Bex primers, specific for H. influenzae, and tested on culture positive and negative cases. RESULTS: Of 73 Hib isolates, orf 51 PCR amplicons, predicting the presence of ICEs, were found in all 33 MDR isolates while only in 1 of 33 sensitive strains. The remaining 7 ampicillin susceptible, chloramphenicol and tetracycline resistant strains did not produce a PCR product to orf 51. PCR amplification from CSF specimens of these culture positive cases produced identical results with 100% and 97% positive and negative predictive values, respectively. Multiplex PCR to detect Bex and orf 51 identified another 16 MDR Hib cases among 81 culture-negative CSF samples. CONCLUSIONS: Direct PCR for orf 51 in CSF identified resistance pattern of 51% more Hib strains than culture alone (110 versus 73). The ability to detect MDR, in culture negative Hib meningitis cases has significant implications for better directing antibiotic treatment of meningitis cases and thus for preventing disability and death.

[Studies of treatment for Haemophilus influenzae type b meningitis in children].

We summarize 41 cases of bacterial meningitis in the last 11 years caused by Haemophilus influenzae. All isolates were serotype b strain (Hib). Initial chemotherapy was started with ceftriaxone (CTRX) in 22 cases, ampicillin plus cefotaxime (CTX) in 9, CTRX plus panipenem/betamipron in 5, and CTX in 2. Some 31 cases were treated mainly with CTRX. Although therapeutic antibiotics showed good susceptibility for isolates, 8 complicated cases (19.5%) occurred. Sequalae were observed in 7 (17.1%) but none were fatal. Five strains with elevated MIC of CTX (0.12 to 1 microg/mL) recovered after 2001, and 3 of 5 strains also showed elevated MIC of CTRX (0.12 to 0.5 microg/mL), but all were cured completely with CTRX. At present, no treatment failures due to antibiotic resistance have been observed, and CTRX remains suitable as initial therapy for Hib meningitis. A decline in susceptibility for third-generation cephalosporin against beta-lactamase-nonproducing ampicillin-resistant H. influenzae is emerging, however, so it will be necessary to consider combination therapy with CTRX given the foreseeable trend in MICs.

Genetic and phenotypic characterization of Haemophilus influenzae type b isolated from children with meningitis and their family members in Vietnam.

To investigate Haemophilus influenzae type b (Hib) infection in Vietnamese children under the age of 5 years, cerebrospinal fluid (CSF) samples from patients with meningitis were screened for Hib, and isolates were subjected to evaluation of susceptibility to 12 antibiotics, biotyping, and genotyping with pulsed-field gel electrophoresis (PFGE). The major biotype was type II (68.3%), followed by type I (22.8%). Among 79 Hib isolates, 45 (57%) were beta-lactamase-producing and ampicillin-resistant (44 and 1 isolates produced TEM-1- and ROB-1-type beta-lactamases, respectively), and 34 isolates (43%) were beta-lactamase-nonproducing and ampicillin-sensitive. No beta-lactamase-nonproducing and ampicillin-resistant isolates were found. The PFGE patterns of Hib isolates were highly divergent, but most could be classified into three clusters. We also investigated Hib colonization in household contacts of patients, and found that Hib isolates from the CSF of patients and from nasopharyngeal cavities of household contacts showed the same PFGE patterns. This observation suggested that household contacts of patients are a possible reservoir of Hib.

Long-term outcome for children with bacterial meningitis in rural Papua New Guinea.

This study was undertaken to evaluate the long-term neurological outcome for survivors of bacterial meningitis in rural Papua New Guinea. Children who were discharged from Nonga Base Hospital in Rabaul with a diagnosis of bacterial meningitis between 1992 and 2000 were evaluated in their home villages or on review at hospital. Neurological and developmental complications were documented. The outcomes for 80 of 121 eligible children were determined; eight had died following hospital discharge and 41 were lost to follow-up. Major neurological sequalae were found in 50 (63 per cent) of surviving children, and 27 (34 percent) had multiple severe complications. In rural Papua New Guinea meningitis causes high rates of mortality and severe long-term disability in a high proportion of survivors. High-level resistance to chloramphenicol is likely to be part of the reason for this, but widespread availability of third-generation cephalosporins for the treatment of meningitis, although urgently required, will not overcome the other problems of delayed presentation with established complications. There is a need for the introduction of conjugate Haemophilus influenzae vaccine, and affordable vaccination strategies against Streptococcus pneumoniae. Richer countries could sponsor these vaccines in developing countries, and apply pressure on vaccine producers to lower the costs.

High levels of multiple antibiotic resistance among 938 Haemophilus influenzae type b meningitis isolates from Cuba (1990-2002).

OBJECTIVES: A national surveillance study to determine antimicrobial susceptibility in Haemophilus influenzae type b isolated from cerebrospinal fluid was carried out in Cuba from 1990 to 2002. METHODS: Susceptibility to ampicillin, co-amoxiclav, cefotaxime, ceftriaxone, co-trimoxazole, tetracycline, chloramphenicol and rifampicin was tested by the microdilution method according to the NCCLS guidelines. RESULTS: The 34 participating laboratories recovered 938 consecutive, non-identical isolates. All the isolates were retrieved from children aged <5 years. The mean number of isolates collected by year in the pre-vaccination era (1990-1998) was 93; after vaccination, 57 isolates were reported in 1999, 31 in 2000, four in 2001 and five in 2002. Resistance to ampicillin, co-trimoxazole, tetracycline and chloramphenicol was 46.3% (all beta-lactamase-positive), 51.3%, 33.2% and 44.0%, respectively. Ampicillin-resistant beta-lactamase-negative strains were not detected. All strains were susceptible to co-amoxiclav, cefotaxime, ceftriaxone and rifampicin. Ampicillin resistance was strongly associated with resistance to tetracycline, co-trimoxazole and chloramphenicol (P<0.001). Multidrug resistance was present in 43.8% of isolates. The most prevalent phenotype was resistance to ampicillin/chloramphenicol/tetracycline/co-trimoxazole, which was detected in 29.2% of strains overall. An increase in the prevalence of resistance to these antibiotics was observed from 1990 to 2000 in the range 40.7%-54.8% for ampicillin, 40.1%-51.6% for chloramphenicol, 45.4%-58.1% for co-trimoxazole and 23%-45.2% for tetracycline. CONCLUSIONS: In Cuba, the widespread vaccination against Haemophilus influenzae type b prevented a large number of meningitis cases in children caused by strains resistant to multiple antibiotics.

Cefotaxime use in pediatric infections.

Cefotaxime has been used extensively in many pediatric centers in the United States for the past 10 or more years. Its main usage has been for the treatment of various serious bacterial infections in pediatric patients, primarily meningitis and sepsis. It has also been used to treat intraabdominal, urinary tract, soft tissue, bone, and joint infections. Although there has been a marked reduction in the incidence of invasive Haemophilus influenzae type b infections following the introduction of effective vaccines, cefotaxime remains very useful against the other common pathogens causing serious infections in pediatric patients. The increasing number of pneumococci resistant to penicillin and third-generation cephalosporins has created a new challenge for the management of serious pneumococcal infections. In many institutions, cephalosporins in general have been overused and abused, resulting in the emergence of resistant organisms and an increasing burden on resources. The judicious use of cefotaxime and other cephalosporins should be emphasized.

Development of a protocol for early treatment of endemic meningitis in children in Vanuatu.

Meningitis is endemic in Vanuatu and other Pacific island countries and has a high case fatality rate. The incidence in the southern island of Tanna is especially high. This descriptive study of 64 cases in children (under 15 years) on that island was undertaken over a 21-month period from January 1988 to September 1989. Meningococcus was identified in 23 cases (36%) and Pneumococcus in 12 (19%). The age distribution showed a high rate in under 1 year olds. The symptoms of fever, convulsion and vomiting were most common. Bulging fontanelle (in children under 1 year), neck rigidity, and altered level of consciousness were the most frequent signs. These signs were as frequent in meningococcal as pneumococcal infections and were used to develop a simple protocol for use in primary care. Delay in treatment or referral because of patients seeking traditional medicine is a major problem yet to be overcome. Only a weak association between admissions with meningitis and underweight or crowding was found in this study.

Pharmacokinetics and antibacterial efficacy of cefpirome (HR 810) in experimental Escherichia coli and Haemophilus influenzae type b meningitis.

Cefpirome (HR 810) is a new cephalosporin related to cefotaxime that has potent bactericidal activity against a broad spectrum of gram-negative and gram-positive organisms. The pharmacokinetics and bacteriological efficacy of cefpirome administered as a single intravenous dose were assessed in rabbits with experimental Haemophilus influenzae type b and Escherichia coli K1 meningitis. The mean penetrations into the cerebrospinal fluid (CSF) in relation to the amount of drug in serum of animals infected with H. influenzae and E. coli were 25 and 54%, respectively. The median CSF bactericidal titers were 1:128 against both organisms at 1 h of uninfected animals, the mean penetration was 4.5%. There was a significant reduction in the concentrations of bacteria in CSFs of both groups of animals treated with cefpirome compared with that in untreated groups. Mortality was also significantly lower in treated animals than it was in untreated animals. Intravenous administration of dexamethasone before the cefpirome dose did not compromise penetration, bactericidal titers, or antibacterial activity of cefpirome in CSF.

Use of third-generation cephalosporins. Hemophilus influenzae.

Meningitis constitutes the major infection associated with H. influenzae. Caution must be used when selecting antibiotic treatment based on MIC data, alone, because bacterial levels in the cerebrospinal fluid are higher than those in the blood, on which MICs are calculated. Certain third-generation cephalosporins are effective in producing maximum killing of H. influenzae in the CSF. This strong bactericidal activity may actually prove to be detrimental, however, by augmenting the inflammatory response, and thus contributing to the complications and the sequelae of meningitis. The addition of an agent to block the exaggerated response may be possible.

Pharmacokinetics and bacteriological efficacy of ticarcillin-clavulanic acid (timentin) in experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis.

The pharmacokinetics and bacteriological efficacy of ticarcillin and clavulanic acid administered individually or in combination were assessed in rabbits with experimental Escherichia coli K-1 and Haemophilus influenzae type b meningitis. The mean penetrations into the cerebrospinal fluid (CSF) of infected animals after a single dose of ticarcillin-clavulanic acid were approximately 11 and 28% for ticarcillin and clavulanic acid, respectively. In continuous-infusion experiments, the mean penetrations into CSF were 14.6 and 35% for ticarcillin and clavulanic acid, respectively, in rabbits with E. coli meningitis and 6.1 and 24%, respectively, in rabbits with H. influenzae meningitis. In animals that received a continuous infusion of the two drugs alone or in combination, the median CSF bactericidal titers for E. coli were less than 1:2, less than 1:2, and 1:2 for ticarcillin, clavulanic acid, and ticarcillin-clavulanic acid, respectively, and for H. influenzae the titers were less than 1:2, less than 1:2, and 1:4, respectively. The addition of clavulanic acid potentiated significantly the bacteriological efficacy of ticarcillin in reducing the number of bacteria in CSF of infected rabbits. Additional studies in animals and humans are required before recommendations can be made regarding the use of ticarcillin-clavulanic acid for treatment of meningitis.

Limitations of animal models in predicting beta-lactam efficacy for endocarditis and meningitis.

Animal models are important in predicting the efficacy in humans of antimicrobial agents for various disease conditions, including endocarditis and meningitis. Screening models are useful in assessing antibiotic effectiveness and toxicity; their advantages include simplicity, a reproducible course of infection, a well-defined therapeutic end point, and low cost. However, the inoculum size, the virulence of the organism, and the production of beta-lactamases can have important effects on outcome and must be considered in the interpretation of data obtained from such models. Discriminative models are those designed to mimic human disease as closely as possible with respect to infectious inoculum, host response, and course of disease. Each drug's pharmacokinetics must be carefully documented before being extrapolated to humans. Rigid criteria must be established to minimize misinterpretation of results from animal studies before conclusions from in vivo animal models are applied to human disease.

Comparative evaluation of aztreonam in therapy for experimental bacterial meningitis and cerebritis.

Aztreonam (SQ 26,776), a new monocyclic beta-lactam agent, was compared with several frequently used antibiotics in therapy for three types of experimental meningitis in rabbits and for experimental Escherichia coli cerebritis in rats. Aztreonam was highly active against common gram-negative meningeal pathogens in vitro (all minimal bactericidal concentrations less than or equal to 0.125 microgram/ml), including ampicillin-sensitive and ampicillin-resistant strains of Haemophilus influenzae, E. coli, and meningococci. In both rabbits and rats, serum concentrations of all antibiotics evaluated closely approximated concentrations found in humans receiving standard parenteral regimens. The percent penetration of aztreonam into purulent rabbit cerebrospinal fluid was 23%. In experimental meningitis, aztreonam was more rapidly bactericidal than ampicillin in meningitis due to ampicillin-sensitive H. influenzae, than ampicillin or chloramphenicol in meningitis due to ampicillin-resistant H. influenzae, and than gentamicin in meningitis due to E. coli. Aztreonam also reduced concentrations of E. coli in rat brain as rapidly as did gentamicin during therapy for experimental cerebritis, the early stage of brain abscess formation.

Prospective comparative trial of ceftriaxone vs. conventional therapy for treatment of bacterial meningitis in children.

Fifty children with bacterial meningitis were prospectively evaluated in a randomized comparative trial of twice daily ceftriaxone with conventional ampicillin and chloramphenicol therapy. The groups were comparable in age, sex, days of illness before admission, severity of illness at admission, etiology and admission cerebrospinal fluid (CSF) parameters and bacterial colony counts. The pathogens were Haemophilus influenzae type b (34 beta-lactamase-negative, 8 beta-lactamase-positive); Streptococcus pneumoniae (4); Neisseria meningitidis (3); and Streptococcus agalactiae (1). Initial CSF colony counts ranged from 2.5 X 10(2) to 1 X 10(10) colony-forming units/ml. In 44 children a lumbar puncture was repeated 10.5 to 18 hours after starting treatment; 16 of 24 (67%) ceftriaxone patients and 12 of 20 (60%) conventional therapy patients had sterile cultures. The reduction in the CSF bacterial colony counts (6.3 log10 colony-forming units/ml) was similar in both groups. Ceftriaxone CSF levels ranged from 1.0 to 8.0 micrograms/ml, representing a mean CSF penetration of 11.3% (range, 3.0 to 24.5%) of the simultaneous serum concentration. The median ceftriaxone bactericidal titer in CSF was 1:1024 compared with 1:4 achieved with conventional therapy. There were no significant differences in clinical responses or in frequency of complications, except for diarrhea which occurred in 59% of the ceftriaxone group and in 22% of the other (P less than 0.01). Despite one H. influenzae type b relapse occurring in the ceftriaxone group, ceftriaxone appears to be safe and as effective as conventional therapy for bacterial meningitis in children older than 2 months of age.

Aztreonam therapy in experimental meningitis due to Haemophilus influenzae type b and Escherichia coli K1.

The penetration of aztreonam into cerebrospinal fluid was 7 to 15% and 9 to 25%, respectively, in experimental Haemophilus influenzae type b and Escherichia coli K1 meningitis. Aztreonam was effective in reducing the number of organisms in cerebrospinal fluid after single-dose and continuous infusion administration, and the median bactericidal titers in cerebrospinal fluid were 1:32 against both meningeal pathogens.

Evaluation of ceftazidime, ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis.

In an infant rat model of Haemophilus influenzae, type b meningitis, where treatment was given 24 and 48 h after infection, the dose of ceftazidime required to eradicate the infection from the CSF of half the animals (CD50) ranged from less than 0.15-1.5 mg/kg/dose. The accompanying blood infections were marginally less responsive to therapy with CD50 values ranging from 0.5-3.9 mg/kg/dose. Comparable data for ampicillin were 12.5-40 mg/kg/dose and 20- greater than 200 mg/kg/dose for the CSF and blood infections while those for chloramphenicol were 18- greater than 100 mg/kg/dose and 22- greater than 100 mg/kg/dose for the CSF and blood infections respectively. Investigation of the relative rates of kill in vivo showed that all three drugs rapidly reduced the bacterial numbers to minimal levels. However, whereas ceftazidime completely eradicated the infection, chloramphenicol, and to a lesser extent, ampicillin-treated rats experienced substantial relapsing. Ceftazidime penetrated into the CSF of infected and uninfected rats slightly better than ampicillin--7.3% compared to 4.0% of the corresponding blood levels respectively. These results indicate that ceftazidime is significantly more active in the infant rat model of H. influenzae, type b meningitis than ampicillin or chloramphenicol.

Comparison of the efficacy and safety of ceftriaxone to ampicillin/chloramphenicol in the treatment of childhood meningitis.

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.