Onset of Hemophilus influenzae type-b meningitis during cefaclor therapy for preseptal cellulitis

Second generation cephalosporins are frequently used for the treatment of bacteremic Hemophilus influenzae type b infections. "Breakthrough" meningitis during cefamandole therapy has documented the need for adequate cerebrospinal fluid penetration by these antibiotics if they are to be used in the therapy of Hemophilus infections. A child with H. influenzae type b preseptal cellulitis is reported who initially responded to treatment with intravenous cefuroxime and oral cefaclor. However, while still receiving cefaclor, the child was readmitted with H. influenzae meningitis. Microtiter broth dilution susceptibility testing performed during the second admission showed the isolate to be relatively resistant to cefuroxime (minimum bactericidal concentration [MBC] = 4 micrograms/ml) and resistant to cefaclor (MBC greater than 16 micrograms/ml). This experience documents the need to monitor the clinical response closely during therapy of H. influenzae bacteremic infections with these second generation cephalosporin treatment regimens. In addition, attention should be paid to minimum inhibitory concentrations of these cephalosporins, since variations in H. influenzae type b susceptibility to these agents may limit their efficacy.     

Moxalactam therapy of Haemophilus influenzae type b meningitis in children

Thirty-four children with Haemophilus influenzae type b meningitis were given prospectively either moxalactam (200 mg/kg/day) or ampicillin (400 mg/kg/day) plus chloramphenicol (75 mg/kg/day). One patient in each group died. The mean duration of fever, clinical response, sequential cerebrospinal fluid findings, and incidence of neurologic sequelae were similar between groups. Moxalactam cerebrospinal fluid bioactivity was significantly greater than that of ampicillin or chloramphenicol throughout therapy. Neutropenia, liver enzyme abnormalities, and diarrhea were not significantly different. In eight of 11 patients given moxalactam (versus one of 14 controls) there was complete elimination of gram-negative aerobic flora in the stools by day 10 (P = 0.002); however, none acquired Clostridium difficile. Moxalactam in effective therapy for H. influenzae type b meningitis.     

Subdural effusion and its relationship with neurologic sequelae of bacterial meningitis in infancy: a prospective study

One hundred thirteen infants, aged 1 to 18 months, were screened systematically and serially using transillumination for the presence of subdural effusion during acute bacterial meningitis due to Haemophilus influenzae type b, Streptococcus pneumoniae, or Neisseria meningitidis. Effusion developed in 44 (39%) of the patients during the course of treatment. Young age, rapid onset of illness, low peripheral white blood cell count, and high cerebrospinal fluid levels of protein and bacterial antigen were associated with a higher likelihood of developing effusion. Although patients with effusion were more likely to have neurologic abnormalities both at the time of admission and at completion of therapy, and were more likely to have seizures during the course of treatment, there was no greater incidence of seizures, hearing loss, neurologic deficits, or developmental delay on longterm follow-up (median follow-up interval 5.5 years) in patients with effusion. Specific invasive therapy is not indicated in infants with meningitis and subdural effusion who are otherwise improving.     

Excretion of Haemophilus influenzae type b polysaccharide antigen in urine of healthy nasopharyngeal carriers

We measured concentrations of Haemophilus influenzae type b (Hib) polysaccharide antigen by ELISA in urine samples from 81 healthy North American children with positive or negative throat cultures for Hib, to investigate the possibility that asymptomatic carriers may have antigenuria. For comparison, we determined the concentrations of Hib polysaccharide antigen in urine samples from 56 patients with proven Haemophilus disease, including 13 children with lower respiratory infections who resided in developing countries. Among the healthy children, antigen was detected in the urine of seven of 19 (37%) carriers of Hib compared with one of 62 (2%) children with negative throat cultures (p less than 0.001). Among the patients with invasive Haemophilus infections, 93% had antigen detected. Although there was overlap in the concentrations of antigen in the positive urines from the asymptomatic carriers and those of the ill patients, the concentrations of the ill patients were higher than those of the carriers. The respective geometric means of the positive patients were: American patients with meningitis, 42.5 ng/mL (range 1.7-9800 ng/mL); American patients with infections not involving the CNS, 5.8 ng/mL (range: 1.0-96 ng/mL); patients from developing countries with lower respiratory infections, 29.6 ng/mL (range: 0.9-5290), and American asymptomatic carriers, 1.9 ng/mL (range: 0.6-16.7 ng/mL). Thus, antigenuria is present in a high proportion of healthy children with positive throat cultures for Hib, and the antigen concentrations of the carriers overlap those of ill patients. These results suggest that either mucosal colonization itself is sufficient to produce antigen-uria, or asymptomatic carriers may be experiencing asymptomatic invasive Hib infection.     

Cefoperazone pharmacokinetics in acute childhood meningitis

We studied the serum pharmacokinetics and cerebrospinal fluid concentrations of cefoperazone in 15 children with acute meningitis. Mean cefoperazone concentrations of 117 micrograms/ml in the serum and 3.8 micrograms/ml in the cerebrospinal fluid were noted 2 hours after a single 100 mg/kg dose. Following multiple 50 or 100 mg/kg doses, the mean peak serum cefoperazone concentrations were 232 and 498 micrograms/ml, respectively, with an overall mean elimination phase half-life of 2.12 hours. The data best fit a linear, two-compartment model. Cerebrospinal fluid concentrations 1.5 to 2.5 hours after the end of cefoperazone infusions ranged from 1.4 to 19.2 micrograms/ml for all doses and states of illness. This represented 1.2% to 6.4% of simultaneous serum values. The cerebrospinal fluid inhibitory titer was greater than or equal to 1:16 in 17 of 18 specimens tested against a strain of Haemophilus influenzae type b resistant to both chloramphenicol and ampicillin. In the doses given, cefoperazone produces adequate cerebrospinal fluid concentrations and bioactivity to treat the common bacterial forms of acute meningitis in infants and children.     

Latex agglutination: an appropriate technology for the diagnosis of bacterial meningitis in developing countries

We evaluated prospectively the utility of a latex agglutination technique for the diagnosis of Haemophilus influenzae type b meningitis in a paediatric ward in India. Eight of 44 children had H. influenzae grown from cerebrospinal fluid. These proven cases plus four additional cases of H. influenzae meningitis were detected by the latex agglutination test. There were no cross reactions with other organisms. The high degree of sensitivity and specificity, combined with the speed and simplicity of this technique make it an appropriate method for developing countries.     

Severity and frequency of sequelae of bacterial meningitis in Alaska Native infants. Correlation with a scoring system for severity of sequelae.

OBJECTIVES--To (1) determine the frequency and severity of sequelae of Haemophilus influenzae type b and Streptococcus pneumoniae meningitis in Alaska Native children, (2) compare morbidity and mortality of H influenzae b and S pneumoniae meningitis, and (3) evaluate the applicability of the Herson-Todd prognostic score (HTPS) to both H influenzae b and S pneumoniae meningitis in this population. DESIGN--A retrospective study of all cases of H influenzae b and S pneumoniae meningitis in Alaska Native children younger than age 5 years. Data on meningitis sequelae, obtained from medical charts and records of the Infant Learning Program, were collected, and incidence of sequelae tabulated. Data obtained on admission to the hospital were used to calculate HTPS. SETTING--Indian Health Service facility for the Yukon-Kuskokwin Delta region of southwest Alaska. STUDY SUBJECTS--51 of 63 Alaska Native children with H influenzae b meningitis and 13 of the same 63 Alaska Native children with S pneumoniae meningitis occurring between 1980 and 1988. One child was infected with both organisms, producing a total of 64 cases for study. SELECTION PROCEDURES--Cases were identified by surveillance for these diseases between January 1, 1980, and December 31, 1988, maintained by the Arctic Investigations Program, Centers for Disease Control. MEASUREMENTS AND RESULTS--Sequelae of bacterial meningitis caused by H influenzae b were equal to or exceeded rates of sequelae described in other children in the United States. After H influenzae b meningitis, motor abnormalities (29%) and hydrocephalus (7%) occurred two to four times more often in Alaska Native children than in children in other parts of the United States. Differences in severity of H influenzae b sequelae could not be accounted for by microbiologic markers of the H influenzae b strain, including ampicillin sensitivity, biotype, outer membrane protein type, or electropherotype. Numbers of cases of S pneumoniae meningitis were too small for statistically valid comparison, but sequelae of S pneumoniae meningitis occurred in roughly equal proportion as sequelae of H influenzae b meningitis. The HTPS was applied to Alaska Native children with H influenzae b meningitis and was found to be very accurate in predicting children with major sequelae. Analysis of the prognostic factors used in deriving the HTPS revealed a unique set of predictors for sequelae in Alaska Native children: seizures at admission, glucose levels in cerebrospinal fluid of less than 1.1 mmol/L; and male gender, with a significant predictive interaction between male gender and age less than 6 months at admission. CONCLUSIONS--Alaska Native children suffer greater neurologic morbidity as a result of H influenzae b meningitis than do their non-Native counterparts. The HTPS was a good predictor of major sequelae in Alaska Native children with H influenzae b or S pneumoniae meningitis and could be useful in determining which patients need referral to a tertiary care center.     

Value of antigen quantitation in Haemophilus influenzae type b meningitis

We studied Haemophilus influenzae type b meningitis in 68 patients to evaluate whether quantitative determination of PRP in body fluids obtained at admission or measurement of the duration of its presence helped identify patients at risk for complications. Geometric mean admission PRP concentrations in CSF, blood, and urine increased with severity of disease, but individual values varied greatly. Measurements of the duration of antigenemia and antigenuria also varied widely and were best predicted by the admission or peak PRP concentration. The mean duration of both antigenemia and antigenuria increased with severity of disease. In contrast, the elimination half-life of PRP did not differ significantly with severity of hospital course, peak PRP concentration in blood or urine, or patient age. Clearance from CSF could not be accurately assessed, but PRP was detectable in only six of 41 patients in whom spinal fluid was obtained after the eighth day of hospitalization; all had complicated courses. Although latex particle agglutination assay is a valuable aid in rapid diagnosis of invasive Hib infections, the predictive value of antigen quantitation at admission and the determination of its duration in body fluids is limited by the wide range of observed values.     

Cefuroxime in bacterial meningitis.

In order to find an alternative antimicrobial treatment for childhood bacterial meningitis 30 infants and children with meningitis, due to Haemophilus influenzae (n = 13), Neisseria meningitis (n = 9), Streptococcus pneumoniae (n = 5), or meningitis of unknown aetiology (n = 3), were treated with cefuroxime, 200 mg/kg a day, as the only antibiotic. Prompt clinical and bacteriological responses were noted and every patient was cured. Cefuroxime concentrations in cerebrospinal fluid ranged from 1.1 to 18.8 (mean 7.0) mg/l at the beginning and from 0.5 to 4.1 (mean 1.6) mg/l at the end of treatment. Three infants developed symptomatic sterile subdural effusions which were managed by repeated subdural aspirations while still on antibiotics. Cefuroxime concentrations in the subdural fluid ranged from 17.4 to 32.4 mg/l. At follow-up 2 patients had moderate unilateral hearing loss and one had mild ataxia. We conclude that cefuroxime is effective and safe for the treatment of childhood bacterial meningitis caused by any of these common organisms.     

Comparison of three latex agglutination kits and counterimmunoelectrophoresis for the detection of bacterial antigens in a pediatric population

Three commercial latex agglutination kits (Bactigen, Wampole Laboratories, Cranbury, NJ; Directigen, Hynson, Westcott & Dunning, Baltimore, MD; Wellcogen, Wellcome Diagnostics, Dartford, England) used for the detection of bacterial polysaccharide antigens (Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis) were compared with counterimmunoelectrophoresis and Gram stain for the identification of systemic bacterial disease in children. Urine and (when available) cerebrospinal fluid specimens were saved for all patients. Positive blood or cerebrospinal fluid culture isolates included 36 with H. influenzae type b, 11 with S. pneumoniae, 3 with N. meningitidis and 6 with other organisms. All latex kits performed similarly for the detection of H. influenzae type b antigen with a sensitivity range of 91 to 100%. The four methods performed poorly for the detection of S. pneumoniae (23 to 50%) and N. meningitidis (0%) antigen. Gram stain of cerebrospinal fluid appeared to be equally sensitive to the antigen detection methods for patients with meningitis. The false positive rates for the latex kits and counterimmunoelectrophoresis ranged from 2.8 to 9.2%, with Wellcogen having the lowest rates. The false negative rates ranged from 6.5% to 12% with Directigen having the lowest rate.     

Etiology of meningitis among patients admitted to a tertiary referral hospital in Botswana

This retrospective review evaluated records of cerebrospinal fluid samples between 2000 and 2008 at Princess Marina Hospital in Gaborone, Botswana. Of the 7501 cerebrospinal fluid samples reviewed, Streptococcus pneumoniae (n = 125) and Haemophilus influenzae (n = 60) were the most common bacteria cultured. There were also 1018 cryptococcal and 44 tuberculous meningitis cases. Antimicrobial susceptibilities are described. Public health interventions could decrease the burden of meningitis in Botswana.     

Simultaneous recovery of bacterial and viral pathogens from cerebrospinal fluid

Mixed bacterial infection in meningitis is well-documented, but there have been few previous reports of mixed viral-bacterial meningitis. A retrospective analysis of the bacterial and viral cerebrospinal fluid (CSF) cultures from a 1-year period in a 315-bed children's hospital revealed 5 patients with mixed viral-bacterial meningitis among 276 patients with viral and/or bacterial culture-positive meningitis. These 5 accounted for 2.8% of the patients with positive CSF viral cultures and 4.8% of those with positive CSF bacterial cultures. All of the viruses were identified as enteroviruses, and the bacteria were Group B Streptococcus, Group D Salmonella, Streptococcus pneumoniae, Haemophilus influenzae type b and Staphylococcus aureus. The ages of the patients ranged from 10 days to 22 years. The clinical course of each of the illnesses was typical of bacterial meningitis. This relatively high frequency of mixed viral-bacterial meningitis could affect the utility of rapid viral diagnostic tests for CSF viruses.     

Septic arthritis in childhood. A 13-year review

Medical records of 111 children discharged with the diagnosis of septic arthritis from 1973 through 1985 were examined; 122 infected joints were identified. Bacteria were isolated from joint fluid of 75 patients and from blood, cerebrospinal fluid, cervix, bone, or wounds of 16. No agent was isolated from 20 patients, of whom eight had been pretreated with antibiotics. The knee and hip were most often affected overall (73/122), although the ankle was as frequently involved with Haemophilus influenzae type b (6/20). Eighty patients' condition resolved with no sequelae; 18 were unavailable for follow-up. Of the 13 patients with permanent sequelae, ten had had hip joint infections. Although Staphylococcus aureus was isolated from patients of all ages, H influenzae type b was the most frequent pathogen in children 6 through 59 months of age.     

Predictors of bacterial meningitis in the era after Haemophilus influenzae.

OBJECTIVE: To determine if, in the era after Haemophilus influenzae type b, the cerebrospinal fluid (CSF) white blood cell (WBC) count can be safely used to stratify children suspected of having bacterial meningitis into low- and high-risk groups. DESIGN: Retrospective analysis of CSF samples. SETTING: Tertiary care pediatric center in Toronto, Ontario, between January 1, 1992, and October 1, 1996. PATIENTS: All CSF samples collected on children aged 2 months to 17 years were included. The final database consisted of 1617 atraumatic samples from children without prior neurologic or immunologic disease who underwent a lumbar puncture to assess the possibility of community-acquired bacterial meningitis. MAIN OUTCOME MEASURES: The predictive values of CSF WBC count, differential, protein, and glucose. RESULTS: There were 44 cases of bacterial meningitis. Five had 3 CSF WBCs per microliter or less, and 6 had 4 to 30 CSF WBCs per microliter. The negative predictive value of CSF specimens with 30 WBCs per microliter or less for bacterial meningitis was 99.3%. Cerebrospinal fluid samples with greater than 30 WBCs per microliter had a likelihood ratio for bacterial meningitis of 10.3 (95% confidence interval, 8.0-13.1) and a positive predictive value of 22.3%. Other significant predictors of bacterial meningitis included age, CSF glucose, protein, gram stain, CSF-serum glucose ratio, and peripheral blood band count. CONCLUSIONS: Given the occurrence of bacterial meningitis in children in the absence of CSF pleocytosis, other factors should be considered when managing children with suspected bacterial meningitis. Children older than 6 months with 30 CSF WBCs per microliter or less are at low risk for bacterial meningitis. If clinically stable and without other laboratory markers of bacterial meningitis, hospital admission and empiric antibiotic therapy may be unwarranted.     

Safety and immunogenicity of Haemophilus influenzae type b oligosaccharide-CRM197 conjugate vaccine in infants aged 15 to 23 months

A total of 268 infants aged 15 to 23 months received one dose of a vaccine composed of Haemophilus influenzae type b oligosaccharides covalently linked to the nontoxic diphtheria toxin variant CRM197 (HbOC; HibTITER). Side effects associated with vaccination were infrequent, transient, and mild. One month after a single vaccination, the anti-H influenzae type b capsular polysaccharide antibody concentration rose from a geometric mean prevaccination level of 0.20 microgram/mL to 13.77 micrograms/mL. Of these infants, 99% had a postvaccination level greater than or equal to 1.00 microgram/mL, a level associated with long-term protection. The immune response was long-lived: all of the children who were monitored 17 to 27 months after vaccination had concentrations greater than or equal to 1.00 microgram/mL. The anti-H influenzae type b capsular polysaccharide antibody generated was predominantly of the IgG isotype and IgG1 subclass. The immune sera had bactericidal activity in vitro and conferred passive protection in the infant rat meningitis model.     

Facial cellulitis and Haemophilus meningitis in infants

Two cases of facial cellulitis due to Haemophilus influenzae serotype b are reported in 2 infants aged 3 and 6 months. Bacteriological diagnosis relied on blood cultures. Association with bacterial meningitis emphasizes the necessity of a systematic cerebrospinal fluid examination and the choice of antibiotherapy.     

Epidemiology of invasive Haemophilus influenzae type b infections in Bedouins and Jews in southern Israel

We report the epidemiology of invasive Haemophilus influenzae type b disease requiring hospital intervention in Southern Israel, an area that contains two ethnic populations, Bedouins and Jews. The study is based on 107 blood or cerebrospinal fluid culture-positive cases during the years 1984 to 1988. The annual incidence rate among children younger than 5 years of age was 51/100,000 (48/100,000 for Jews and 58/100,000 for Bedouins). Thirty-nine percent of patients had meningitis, 32% had pneumonia and 31% had otitis media. Epiglottitis was present in only one case (less than 1%). The median age was 8 months. Twenty-six percent of the cases were 6 months old or younger, 75% were 1 year old or younger and 87% were 18 months old or younger. Ninety-five percent of all meningitis cases occurred during the first 18 months of life. A projected number of 2938 hospitalization days and 9.8 deaths/year for a population in which 100,000 births occur yearly was calculated. The major impact of invasive H. influenzae type b infections and the very young age involved justify initiation of H. influenzae vaccine studies in our region.     

Absent or minimal cerebrospinal fluid abnormalities in Haemophilus influenzae meningitis

A case of Haemophilus influenzae type b (Hib) meningitis in which the diagnosis and treatment were delayed because of normal cerebrospinal fluid analysis is presented. A retrospective review was conducted at two children's hospitals to determine the frequency and clinical characteristics of patients with Hib meningitis whose spinal fluid had a normal total white blood cell count, normal chemistries, and negative Gram stain, but subsequent growth of Hib in culture. Of 379 cases of Hib meningitis, two had completely normal CSF, and two had CSF containing small numbers of polymorphonuclear cells as the sole abnormality. In three of the four cases, the duration of symptoms was less than 24 hours, and appropriate therapy was significantly delayed because of benign-appearing CSF. Normal CSF cell counts, chemistries, and Gram stain do not exclude the possibility of bacterial meningitis, and one should remain suspicious when a child has clinical findings suggesting meningitis.     

Ampicillin-chloramphenicol-resistant Haemophilus influenzae: plasmid-mediated resistance in bacterial meningitis

A 4-month-old infant with congenital heart disease and sepsis and arthritis, and subsequently meningitis, caused by an antibiotic-resistant strain of Haemophilus influenzae type b, failed to respond to sequential therapy with ampicillin and trimethoprim/sulfamethoxazole. Following treatment with ceftizoxime, the infant was well for 42 days, until he returned to the hospital and died. A total of 10 Haemophilus influenzae type b isolates, all outer membrane protein subtype 51, was isolated from the pretreatment blood and synovium, cerebrospinal fluid and subdural fluids, and the petrous pyramids at autopsy. Pretreatment isolates had no detectable plasmid DNA, chloramphenicol acetyltransferase or beta-lactamase; the minimal inhibitory concentration for ampicillin (AM) and chloramphenicol (CM) was 0.2 and 0.8 microgram/ml, respectively. However, all cerebrospinal fluid isolates had a 42-44 mD plasmid and produced chloramphenicol acetyltransferase and beta-lactamase; the minimal inhibitory concentration of these isolates to AM and CM were 12.5 and 25 micrograms/ml, respectively, and were also resistant to tetracycline and sulfonamide. Resistance to AM and CM was cotransferred by filter-mating conjugation at a frequency of one to two transconjugants per 10(5) to an Rd haemophilus recipient. Posttreatment isolates from the petrous pyramids also were resistant to AM and CM and produced chloramphenicol acetyltransferase and beta-lactamase activity, but had no plasmid DNA. These findings and data from genetic studies suggested that plasmid-bearing antibiotic-resistant Haemophilus influenzae type b was selected from a heterogenous population, and that the AM/CM resistance transposons were incorporated into the bacterial chromosome.     

Bacterial meningitis in older children

A review was performed of 25 cases of bacterial meningitis in previously healthy children aged 6 years or older during a 10-year period. The rate of infection in this age group relative to all cases of pediatric bacterial meningitis was 4%. Pathogens included Haemophilus influenzae type b in 10 cases (40%), Neisseria meningitidis in 9 cases (36%), and Streptococcus pneumoniae in 6 cases (24%). Physical findings revealed 21 patients (84%) with some degree of altered consciousness and 25 patients (100%) with nuchal rigidity. In all instances, the cerebrospinal fluid exhibited pleocytosis with a predominance of polymorphonuclear leukocytes. Eleven patients (44%) were afebrile on presentation. Of 22 surviving patients, 10 (45%) were afebrile without subsequent fever after administration of the initial dose of antibiotics, in 5 (23%) fever resolved within 24 hours, and in 6 (27%) fever resolved within 48 hours of treatment; there was no instance of prolonged or secondary fever noted. Death occurred in 3 cases (12%). Bacterial meningitis is uncommon in older children. As compared with younger children, older children with bacterial meningitis commonly present without fever and tend to have their fever resolve shortly after effective antibiotic therapy is initiated without manifesting prolonged or secondary fever patterns. Haemophilus influenzae type b is a common cause of bacterial meningitis in children aged 6 years or older; empirical antibiotic therapy in this clinical situation should include treatment of this pathogen.