Treatment of bacterial meningitis in children]

The initial treatment of infantile and childhood bacterial meningitis is now well standardized, but three current aspects are discussed in this paper. Although classically, ampicillin can still be given as the initial treatment of bacterial meningitis in children, current epidemiologic data demonstrate the emergence of resistant strains of Haemophilus and Pneumococcus, and consequently use of a third-generation cephalosporin should be preferred. Concerning duration of treatment, 4 to 5 days seem adequate for meningococci and 7 days for Haemophilus influenzae and pneumococci. Lastly, the usefulness of adjunctive antiinflammatory treatment is considered. The purpose of this treatment is to lower the risk of cerebral complications and neurosensory impairment. Current data suggest that use of corticosteroids as early as possible may be helpful. Improved understanding of the pathophysiology of pediatric bacterial meningitis has led to other forms of treatment being proposed, but their value remains to be proven.     

Acute bacterial meningitis at the 'Complexe Pédiatrique' of Bangui, Central African Republic

To precis the aetiologies of children meningitis and the susceptibility to antibiotics of bacteria responsible for meningitis in Bangui, we conducted a prospective study between October 2004 and September 2005, at the 'Complexe Pédiatrique de Bangui', Central African Republic (CAR). Children from 1 day to 16 years with suspected meningitis and who underwent a lumbar puncture were enrolled. Gram staining, culture on chocolate blood medium, cell count, biochemistry (protein level, glucose ratio), capsular antigen detection were performed for each cerebrospinal fluid. MICs were determined by the E-test method. Four hundred and seventeen patients were enrolled during the study period; 130 were proven acute bacterial meningitis and 37 probable bacterial meningitis. Among proven bacterial meningitis, Streptococcus pneumoniae was the most common organism responsible for meningitis (62 cases, 48%) followed by Haemophilus influenzae (46 cases, 35%) and by Neisseria meningitidis and Salmonella sp. (8 cases, 6% each). Ninety-four percent and 96% of S. pneumoniae strains tested remain susceptible to benzylpenicilline and chloramphenicol, respectively. A beta-lactamase was detected in 92% of H. influenzae strains tested. However, MICs 50% and 90% for amoxicillin were found to be 1 and 4 mg/l, respectively and 33% of these strains were resistant to chloramphenicol. The global mortality rate was 35% (59/167). This mortality rate was 47% for S. pneumoniae, 33% for H. influenzae, 62% for Salmonella sp. and 13% for N. meningitidis. The probabilistic treatment with ampicillin and chloramphenicol usually administered for children meningitis in Bangui must be reconsidered particularly in cases of H. influenzae meningitis. It is of importance to reduce the presentation delays of children with suspected meningitis in Bangui. The H. influenzae b immunization would allow a dramatic reduction of meningitis cases and deaths in Central African children.     

Non-tubercular bacterial meningitis in children in Antananarivo, Madagascar]

OBJECTIVE: To determine the bacterial causal agents of meningitis and their pattern of resistance, in children more than one month to 14 years of age. METHODS: A 2 years, prospective study (June 1998 to June 2000) on bacterial meningitis in children was carried out in the main hospitals in Antananarivo. The enrollment criteria upon admission were fever with symptoms of meningitis and/or convulsions and/or coma. A lumbar puncture was systematically performed in each child. The aspect of the cerebrospinal fluid was described, the level of protein and glucose estimated, soluble antigens measured. Following the examination of a Gram straining, an aliquot of the fluid was cultured on specific medium. Antimicrobial sensitivity testing of isolated pathogens was performed. RESULTS: Bacterial meningitis was confirmed in 119 children: 95 (80%) and 111 (93%) were less than 12 and 24 months of age, respectively. The sex distribution was 1:1. Three predominant microorganisms were identified: Streptococcus pneumoniae (45%), Haemophilus influenzae b (43%) and Neisseria meningitidis (10%) of which ten of 12 cases were belonging to serogroup B. The other microorganisms isolated were E. coli (2%). S. pneumoniae were found to be sensitive to penicillin G and H. influenzae were found to be sensitive to the third generation cephalosporins. Seven percent of the S. pneumoniae strains were mildly resistant (R + I) to chloramphenicol and between 29 and 50% to aminoglucosides. A moderate resistance against gentamicin and amoxicillin was found in 22-29% of the H. influenzae strains. The mortality rate was high (31%) and among the surviving children 30% presented with neurosensitive disorders. CONCLUSION: According to these data we may recommend the inclusion of vaccination against H. influenzae in the children immunization program in Madagascar. The early diagnosis and treatment with appropriate antibiotics, such as third generation of cephalosporins, are other critical measures to be taken in order to reduce the risk of developing severe complications associated to bacterial meningitis.     

Chloramphenicol or ceftriaxone, or both, as treatment for meningitis in developing countries?

AIMS: To determine in children with meningitis whether there is any difference in mortality and neurological sequelae using chloramphenicol as first line treatment, with a change to ceftriaxone if chloramphenicol resistance is shown in vitro, compared to using ceftriaxone as first line treatment, with a change to chloramphenicol if there is no evidence of in vitro resistance. METHODS: An observational study with a retrospective control group nested within a randomised trial of fluid management for bacterial meningitis where clinical care was standardised. Chloramphenicol is standard treatment for bacterial meningitis in Papua New Guinea. In the first 150 cases we used chloramphenicol and only changed treatment to ceftriaxone if chloramphenicol resistance for cerebrospinal fluid isolates was proved. After finding 20% of Haemophilus influenzae were resistant to chloramphenicol, and that most affected children had poor outcomes, we changed to an alternative strategy. In the next 196 cases first line treatment was ceftriaxone and treatment was changed to chloramphenicol if the isolated bacteria were found to be susceptible. RESULTS: When chloramphenicol was used as first line treatment for meningitis followed by ceftriaxone when in vitro resistance was shown, there was invariably a very poor outcome in chloramphenicol resistant disease (71% of children died or had severe neurological complications). Using ceftriaxone as first line treatment was effective in reducing mortality and neurological sequelae from chloramphenicol resistant Haemophilus influenzae type (71% v 9%, relative risk 0.13; 95% CI 0.02 to 0.87; p = 0.013). Changing to chloramphenicol if there was no evidence of in vitro resistance was less than half the cost of empirical use of ceftriaxone for a full course for all children with meningitis. CONCLUSIONS: Using a third generation cephalosporin as first line treatment is effective in dealing with the problem of poor outcomes from meningitis due to Haemophilus influenzae that is resistant to chloramphenicol, and a strategy of changing to chloramphenicol if in vitro susceptibility is shown will reduce the use of expensive third generation cephalosporins without comprising on clinical outcomes. This highlights the urgent need to reduce the costs of third generation cephalosporins, to improve bacteriological services in developing countries, and to introduce effective and affordable vaccines against H influenzae and Streptococcus pneumoniae.     

Rapid diagnosis of bacterial meningitis by using multiplex PCR and real time PCR

BACKGROUND: The purpose of the present study was to improve a method for a rapid identification of bacteria in bacterial meningitis by using multiplex polymerase chain reaction (PCR). METHODS: Ten species of bacteria which cause meningitis in children were investigated, and cerebrospinal fluid from patients with purulent meningitis was studied. The ribosomal RNA genes of bacteria are essential, and are highly conserved in the bacterial kingdoms with consensus region. The 23S rRNA region shows a larger variation among species than in the 16S rRNA region. The authors set primers in the universal region and specific region of 23S rRNA, then amplified these regions by multiplex PCR and real-time PCR. RESULTS: All species of bacteria showed one band by PCR using universal primer. Haemophilus influenzae and Streptococcus pneumoniae showed two bands by multiplex PCR using a combination of universal primers and specific primers. The authors detected H. influenzae within 15 min by using real-time PCR. CONCLUSION: It was possible to identify clinically significant bacterial species in cerebrospinal fluid by multiplex PCR, and to identify H. influenzae by real-time PCR within a short period.     

Effect of ampicillin and chloramphenicol against Haemophilus influenzae.

Synergy, determined by isobolograms constructed from the minimal inhibitory concentrations of combinations of ampicillin and chloramphenicol, was observed against six of 13 ampicillin-susceptible Haemophilus influenzae type b isolates and against five of eight ampicillin-resistant strains by using a small inoculum of 10(4) colony forming units (CFU) per milliliter. Synergy occurred against nine of 13 ampicillin-susceptible and against two of eight ampicillin-resistant strains using a large inoculum of 10(7) CFU/ml. When synergy was not observed, additive effects occurred against the remainder of isolates. Additive effects were also observed against single strains of chloramphenicol-resistant, nontypeable H. influenzae and H. parainfluenzae. No antagonism was observed. These data indicate that ampicillin and chloramphenicol may be synergistic against a significant number of H. influenzae strains depending on inoculum size, but the effect is unpredictable for a given isolate. These data support the recommendation that ampicillin and chloramphenicol both be used as initial therapy for patients with suspected bacterial meningitis.     

Etiological profile of bacterial meningitis in a small hospital

OBJECTIVE: To determine the etiologic profile of cases of meningitis treated at a small hospital in Ribeir?o Preto, State of S?o Paulo, and to compare it to those reported for other communities.METHODS: a retrospective study was conducted on 103 patients admitted from January 1992 to July 1996 with clinical and laboratory diagnosis of bacterial meningitis. The clinical criteria for diagnosis were based on patient history and physical signs and symptoms, and the laboratory criteria were based on cerebrospinal fluid examination (aspect, cytology, biochemistry, Gram staining, culture and countercurrent immunoelectrophoresis) and blood culture.RESULTS: The etiologic agent was identified in 81.5% of cases: Haemophilus influenzae type b in 32%, Neisseria meningitides in 25.2%, Streptococcus pneumoniae in 8.7%, Staphylococcus aureus and epidermidis in 8.7%, and others agents in 6.9%. CONCLUSIONS: The study showed that the cases of bacterial meningitis treated at the Santa Lydia Hospital of Ribeir?o Preto are caused by the same agents detected in other places, with Haemophilus influenzae type b being the predominant one. The study also suggests that when many people are involved in the collection of material for laboratory tests, recovery of the agent may become difficult.     

Meningitis due to Haemophilus influenzae other than type b: case report and review.

A 4-month-old female infant with meningitis caused by Haemophilus influenzae type f had a hospital course complicated by sterile subdural effusions and persistent neurologic abnormalities. One year later she was normal in all respects. The infant's mother had serum bactericidal antibodies to H. influenzae type b but not to type f. During recovery the patient had no bactericidal antibodies to type b, and the type f organism could not be maintained in her serum. Review of the literature identified 40 cases of meningitis reported as caused by H. influenzae other than type b. An evaluation of the ten cases described as due to encapsulated strains (a, e, and f) shows that the age distribution and clinical features are similar to those of meningitis caused by type b. Only five cases of meningitis caused by unencapsulated H. influenzae have been described. Four of the patients were older than the usual age range for type b meningitis and two had prior head trauma. A large clinical trial in Finland with a two-year observation period has demonstrated no untoward increase in non-b H. influenzae meningitis in recipients of a type b vaccine. Serious infections caused by other H. influenzae types will continue to occur sporadically and may increase in frequency when an effective vaccine against type b is widely used in infants.     

Endophthalmitis associated with Haemophilus influenzae type b bacteremia and meningitis.

The unusual occurrence of endophthalmitis associated with Haemophilus influenzae type b bacteremia and meningitis was confirmed in three young children during a five-year period. In contrast to bacterial endophthalmitis attributed to other microorganisms, these three infections resolved completely within a few days with conventional antimicrobial therapy. Endophthalmitis is but one of the apparently increasing number of unsuual complications that may be observed as a result of H influenzae type b bacteremia.     

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.     

Effectiveness of haemophilus influenzae type B conjugate vaccine for prevention of meningitis in Senegal

A total of 24 cases of hospitalized, laboratory-confirmed Haemophilus influenzae type b (Hib) meningitis were identified through a regional pediatric bacterial meningitis surveillance system. Each case was matched by age and residence to 4 neighborhood controls. The adjusted vaccine effectiveness for ≥ 2 doses was 95.8% (95% confidence interval, 67.9%-99.4%). Hib vaccine appears to be highly effective in preventing Hib meningitis in Senegal.     

Introduction of Haemophilus influenzae type B conjugate vaccine into routine immunization in Ghana and its impact on bacterial meningitis in children younger than five years

This report shows the impact of a pentavalent vaccine that includes Haemophilus influenzae type b (Hib) conjugate vaccine on bacterial meningitis in children younger than 5 years in Ghana. A review of the first 3 years of a pediatric bacterial meningitis surveillance program, started in August 2001 in Accra, Ghana, was undertaken. There was a significant reduction, P = 0.042 and 0.017, in percentage of purulent meningitis in children younger than 1 year, comparing the first year when the vaccine was introduced, to the second and third years, respectively.     

Differences in the epidemiology of childhood community-acquired bacterial meningitis between two ethnic populations cohabiting in one geographic area

A comparison of the epidemiology of community-acquired bacterial meningitis between Jewish and Bedouin populations cohabiting one geographical area is reported here. During the years 1981 to 1985, 100 children younger than 13 years old with community-acquired bacterial meningitis were hospitalized. Seventy-one patients were younger than 12 months. The principal bacteria isolated were Haemophilus influenzae 42%; Streptococcus pneumoniae 29% and Neisseria meningitidis 20%. The case fatality rate was 12%. The chance of acquiring meningitis during the first 5 years of life was twice as common among Bedouins than among Jews (328/100,000 vs. 173/100,000, respectively; P less than 0.0001). The most common cause of meningitis during the first year of life was S. pneumoniae among Bedouins and H. influenzae among Jews. Meningitis caused by H. influenzae and S. pneumoniae was usually associated with respiratory morbidity during fall and winter among Jews, but with diarrheal morbidity during summer and fall among Bedouins. Since the most prevalent type of morbidity among Jews results from respiratory infections and among Bedouins from diarrhea, our findings suggest that community-acquired bacterial meningitis is associated with the type of morbidity most prevalent in the community at any given season rather than with a specific type of infection.     

Fifteen years of experience with bacterial meningitis.

BACKGROUND: Introduction of Haemophilus influenzae type b (Hib) vaccines has dramatically altered the epidemiology of bacterial meningitis in children. The goal of this study was to describe these changes in a pediatric teaching hospital. METHODS: Patient charts at Children's Hospital and Regional Medical Center, Seattle, were identified by diagnosis codes and reviewed retrospectively. The 1981 to 1995 time period was chosen to incorporate three distinct 5-year periods: before the use of unconjugated Hib vaccine; between the unconjugated and conjugate vaccines; and after the conjugate vaccines were available for routine immunization of infants. RESULTS: Bacterial meningitis was identified in 806 cases. In 13 premature infant cases Escherichia coli was most frequently isolated (6 cases). Group B Streptococcus, E. coli and Listeria monocytogenes were the most common pathogens in 87 neonatal cases. The most common pathogens in 706 cases of childhood meningitis were H. influenzae, Streptococcus pneumoniae and Neisseria meningitidis. H. influenzae was the most common pathogen in the first two time periods (73 and 69% of childhood cases, respectively), but not so in the third period (16%). CONCLUSIONS: A changing pattern in childhood meningitis was observed during the study period. H. influenzae cases dramatically declined, altering the relative proportions of other pathogens, S. pneumoniae and N. meningitidis. However, the number of cases caused by these latter pathogens remained steady.     

Haemophilus influenzae septicaemia in the neonate: Report of two cases and review of the English literature

Two neonates with early onset respiratory illness were found to have Haemophilus influenzae septicaemia. One of them died. A review of the English literature showed that Haemophilus influenzae septicaemia is increasing in incidence. Almost all cases presented with respiratory distress in the first 2 days. Other associated features included meningitis, arthritis, conjunctivitis and cellulitis. The mortality, which averaged 52%, was high, especially in premature babies. The septicaemia was caused by ascending infection from the colonized maternal birth canal, and most cases were caused by nontypable strains of Haemophilus influenzae. Because of the occurrence of ampicillin or chloramphenicol resistance, a third generation cephalosporin is the treatment of choice for known cases of serious infection.     

Invasive Haemophilus influenzae type B diseases in Bangladesh, with increased resistance to antibiotics

OBJECTIVE: To determine the prevalence, age-group distribution, serotype, and antibiotic susceptibility patterns of invasive Haemophilus influenzae type b (Hib) isolates in Bangladeshi children because data regarding Hib diseases in developing countries are scarce, which has led to delay of the introduction of Hib vaccine in these countries. METHODS: Children diagnosed with meningitis (n = 1412) and pneumonia (n = 2434) were enrolled in this surveillance study for Hib invasive diseases. Cerebrospinal fluid (CSF) and blood specimens, and the subsequent isolates, were processed using standard procedures. RESULTS: During 1993 to 2003, 455 H influenzae strains were isolated from patients with meningitis (n = 425) and pneumonia (n = 30), and an additional 68 Hib meningitis cases were detected by latex agglutination (LA) testing. Overall, 35% of pyogenic meningitis cases were a result of H influenzae, 97.1% of which were Hib. Most (91.4%) cases occurred during the first year of life. Resistance to ampicillin, chloramphenicol, and cotrimoxazole was 32.5%, 21.5%, and 49.2%, respectively. There was a trend toward increasing resistance for all three drugs. Resistance to ampicillin and chloramphenicol was almost universally coexistent and was associated with increased sequelae compared with the patients infected with susceptible strains (31% [23/75] vs 11% [21/183]; P <.001). CONCLUSION: Hib is the most predominant cause of meningitis in young Bangladeshi children. Resistance to ampicillin and chloramphenicol and the high cost of third-generation cephalosporin highlight the importance of disease prevention through vaccination against Hib.     

Nontypeable Haemophilus influenzae meningitis in children: phenotypic and genotypic characterization of isolates

BACKGROUND: With the decline in the incidence of invasive Haemophilus influenzae type b disease as result of routine immunization of infants, the potential emergence of nontypeable H. influenzae (NTHi) strains as important pathogens has been suggested. METHODS: From June 1997 to July 2006, 9 cases of NTHi meningitis in children aged < or =60 months were detected. The 9 NTHi isolates were characterized. Antimicrobial susceptibility patterns were determined by E-test. The transpeptidase domain of penicillin binding protein 3 of a beta-lactamase negative ampicillin-resistant strain was sequenced. Genetic relatedness among isolates was assessed by pulsed field gel electrophoresis and by multilocus sequence typing. The presence of HMW and Hia adhesins and hemagglutinating fimbriae was investigated by PCR and Western Blotting. RESULTS: The 9 cases of NTHi meningitis did not occur in specific risk groups, except for one patient. Of the 9 NTHi isolates, 2 were beta-lactamase producers and 1 showed the beta-lactamase negative ampicillin-resistant phenotype. Sequencing of the penicillin binding protein 3 revealed novel amino acid substitutions. A high degree of genetic diversity among isolates was demonstrated by pulsed field gel electrophoresis. Multilocus sequence genotyping confirmed that the 9 NTHi isolates did not belong to related phylogenetic clusters. HMW adhesins were found in 2 isolates, and 5 strains possessed Hia. No hemagglutinating fimbriae were detected, even though 2 isolates contained hifA gene sequences. CONCLUSION: NTHi isolates from cases of meningitis in children are genetically diverse. Distribution of adhesins among the isolates we examined is unusual: most strains express Hia that generally occurs in a minority of strains in NTHi, suggesting that this adhesin may play a role in virulence mechanisms of NTHi causing meningitis.     

A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children

Fifty children with bacterial meningitis were prospectively randomized to receive cefotaxime (50 mg/kg/dose every 6 hours) or ampicillin and chloramphenicol in standard doses. Twenty-three patients received cefotaxime and 27 received standard therapy. Bacterial isolates included: Haemophilus influenzae (29), Streptococcus pneumoniae (eight), Neisseria meningitidis (eight), group B streptococci (three), and Salmonella enteritidis (two). Ten (34%) of the H. influenzae isolates were resistant to ampicillin, nine on the basis of beta-lactamase production. All strains were susceptible to cefotaxime. Clinical cure rates for the cefotaxime (100%) and standard therapy (96%) groups were similar; survival without detectable sequelae was similar, at 78% and 77%, respectively. The duration of therapy, 11.1 +/- 2.4 days (range 10 to 21 days) vs 11.9 +/- 3.9 days (range 10 to 21 days), and days to defervescence, 4.7 +/- 2.6 days (range 1 to 14 days) vs 5.6 +/- 2.9 days (range 2 to 17 days), were similar in the cefotaxime and standard therapy groups, respectively. No adverse drug reactions or side effects were noted in either group. Cefotaxime was found to be as safe and effective as standard therapy for the treatment of bacterial meningitis in children.     

Haemophilus influenzae meningitis: an evolving therapeutic regimen.

Ampicillin sodium has been the drug of choice in the treatment of Haemophilus influenzae meningitis. The development of ampicillin-resistant strains forces the clinician to focus on alternative therapies. We describe two patients in whom neutropenia was noted secondary to chloramphenicol administration, and streptomycin sulfate and sulfonamides were employed. An historical perspective summarizing the evolution of available therapeutic regimens is presented.