Nasopharyngeal carriage of antibiotic-resistant Haemophilus influenzae in healthy children.

We selected 16 schools representing a broad socioeconomic cross-section of metropolitan Omaha and obtained nasopharyngeal cultures for Haemophilus influenzae from 1,084 healthy 4- to 7-year-old children. We found that 34.2% of the children carried nontypable strains and 2.0% carried type b strains. Carriage rates were not influenced by recent illness, family size, or number of people sharing a bedroom. The prevalence of ampicillin-resistant H influenzae in the sample population was 0.9% for nontypable strains and 0.4% for type b strains; it was not significantly different in the group of children who had recently used beta-lactam antibiotics. One child carried a nontypable strain which was resistant to both chloramphenicol and tetracycline, the first chloramphenicol-resistant H influenzae detected in Omaha. A survey of healthy children may be a useful method for projecting a community's risk of disease caused by ampicillin-resistant H influenzae. Among the nasopharyngeal isolates from healthy children, 2.7% of nontypable strains and 18.2% of type b strains were resistant to ampicillin (P less than .01). During the same five-month period in Omaha, clinical failure in the treatment of otitis media with ampicillin was uncommon and four (20.0%) of 20 cases of H influenzae type b bacteremia and meningitis were caused by ampicillin-resistant organisms.     

Haemophilus influenzae type b meningitis resistant to ampicillin and chloramphenicol.

We report two cases of meningitis due to Haemophilus influenzae type b resistant to ampicillin and chloramphenicol. In one child the meningitis was preceded by pneumonia and pleural effusion. Both children responded to treatment with cefotaxime.     

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.     

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.     

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.     

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.     

Haemophilus influenzae type b osteomyelitis.

Three children had osteomyelitis due to Haemophilus influenzae type b. They were seen with signs and symptoms indistinguishable from infection caused by other organisms. One child was initially misdiagnosed as having septic arthritis because of failure to appreciate that Hemophilus may also cause bone infection. In the second patient osteomyelitis and arthritis developed during ampicillin sodium therapy for treatment of Hemophilus meningitis. His initial infection was caused by an ampicillin-sensitive isolate but his orthopedic infection subsequently responded to therapy only after changing to a regimen of chloramphenicol. In the third patient, bone scintigraphy was helpful in diagnosis since serial roentgenograms were not diagnostic of osteomyelitis. The anticapsular antibody responses of these patients were measured by radioimmune assay. The levels found were low but comparable to age-matched control children with H influenzae type b meningitis.     

Purulent meningitis due to flavobacterium meningosepticum in Cameroonian children

Following a number of reports of purulent CSF specimens positive for Flavobacterium meningosepticum in pediatric patients in Yaoundé, a prospective study was carried out in the Department of Pediatrics of the Central Yaoundé Hospital from December 1988 through December 1989. The goals of this study were to determine the incidence of Flavobacterium meningosepticum among infants and children with purulent meningitis, to discover the origin of this pathogen, and to examine its susceptibility to antimicrobial agents. Flavobacterium meningosepticum (18.4% of cases) was second by order of incidence, after pneumococci (50%). Incidences were low for the other pathogens usually described in purulent meningitis (H. influenzae, meningococcus...). All the pneumococcus strains recovered were susceptible to ampicillin. In contrast, 21.43% of strains of Flavobacterium meningosepticum were resistant to both ampicillin and chloramphenicol (the combination currently used as first line therapy in the Department), and 14.25% of strains were resistant to cefotaxime. The origin of the Flavobacterium meningosepticum strains found remains to be discovered. The low incidence of H. influenzae deserves to be reevaluated over the next few years.     

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.     

Evaluation of a rapid beta-lactamase test for detecting ampicillin-resistant strains of Hemophilus influenzae type b.

Chloramphenicol is presently the drug of choice in the initial treatment of serious infections due to Hemophilus influenzae type b. Rapid detection of ampicillin resistance in clinical isolates would facilitate early discontinuation of chloramphenicol therapy in patients infected with ampicillin-sensitive bacteria. A total of 160 strains of H. influenzae type b were tested with a one-hour acidimetric microassay for beta-lactamase activity. All ampicillin-resistant strains rapidly hydrolysed the beta-lactam ring of penicillin. When isolates were encoded and tested without knowledge of their MICs, the 40 ampicillin-resistant strains (MIC greater than or equal to 2 mug/ml) were readily distinguished from 120 sensitive strains. Rapid beta-lactamase assay is therefore a reliable detector of ampicillin resistance in H. influenzae type b.     

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.     

Acute epiglottitis: therapeutic consequences of change in the resistance of Haemophilus influenzae serotype B

From July 1977 to May 1987, 27 children with acute epiglottitis were treated in our intensive care unit. Haemophilus influenzae type b was identified by positive blood culture in 14 of 27 cases. Until 1983 the first 11 children were treated with ampicillin (100 mg/kg) for a mean duration of 10 days according to the standard therapeutic regimen and/or proven sensitivity from blood cultures (5 of 11 cases). The first finding of an ampicillin resistant Haemophilus influenza type b strain dates from January 1984. From this date on initial antibiotic therapy consisted of cefotaxime (100 mg/kg). Blood cultures proved good sensitivity to cefotaxime (100%) but an increasing rate of resistance to ampicillin (3 of 9 identified strains). Haemophilus influenzae septicemia in acute epiglottitis is verified by the isolation of Haemophilus influenzae type b from blood cultures (14/27) and the additional pneumonias (14/27). Additional meningitis as seen is a very rare complication. Facing these potentially life-threatening secondary foci of this invasive infection, an effective antibiotic therapy is mandatory. Our experiences confirm recommendations from US, UK, Australia, and Spain, where ampicillin was replaced by third generation cephalosporins as initial antibiotic therapy due to the increasing rate of resistance of Haemophilus influenzae type b.     

Chloramphenicol-resistant Haemophilus influenzae meningitis in young urban Nigerian children

In a developing country like Nigeria, the unusual emergence of Haemophilus influenzae type b, resistant to cost-effective antimicrobials, is of serious concern. We report three cases of H. influenzae type b meningitis in young Nigerian children in whom clinical and bacteriological features of resistance to chloramphenicol were identified. One of the cases had concomitant resistance to ampicillin (multiple-drug resistance). Significant anaemia was an associated feature in two cases, one of whom had a recent measles infection. All three cases were malnourished. The possible mechanisms of antimicrobial resistance in H. influenzae infections are highlighted while the need for periodic surveillance of antibiotic resistance profiles in resource-poor countries is emphasized. The potential value of prophylactic measures like H. influenzae type b conjugate immunization is discussed.     

Antibiotic Susceptibility of Type b Haemophilus influenzae and Streptococcus pneumoniae, and Antibiotic Concentration in Cerebrospinal Fluid

Antibiotic susceptibilities of 38 type b Haemophilus influenzae and 28 Streptococcus pneumoniae strains isolated from cerebrospinal fluid, blood and other specimens between 1973 and 1988 were studied. Minimal inhibitory concentrations (MICs) of ampicillin against 10 β-lactamase positive and 28 negative H. influenzae isolates were 32–64 and 0.25 μg/ml, respectively. The MIC of chloramphenicol against one of the β-lactamase positive H. influenzae strains was 8 but MICs against the rest of the organisms were 0.5–1 μg/ml. MICs of cefotaxime, ceftriaxone and cefuroxime against all H. influenzae strains were 0.016, 0.008 and 0.5 μg/ml, respectively. No S. pneumoniae isolates were resistant to penicillin G and MICs of this drug were 0.016–0.032 μg/ml. MICs of cefotaxime, ceftriaxone and cefuroxime against all S. pneumoniae strains were 0.016–0.032, 0.016–0.032 and 0.032–0.063 μg/ml, respectively. MICs of chloramphenicol against 15, 4 and 9 of S. pneumoniae isolates were 2, 8 and 16 μg/ml, respectively. Antibiotic concentrations in the cerebrospinal fluid of patients with bacterial meningitis after intravenous administration of ampicillin (50–70 mg/kgx4/day), penicillin G (31–63 mg/kgx4/day), cefotaxime (50 mg/kgx4/day) and chloramphenicol (25 mg/kgx4/day) were 4.70±1.83 (n=11), 0.57±0.32 (n=7), 4.97±2.60 (n=9) and 8.52±3.54 μg/ml (n=3), respectively. The initial choice of antibiotics in older children with bacterial meningitis is a combination of ampicillin (75 mg/kgx4/day) and cefotaxime (50 mg/kgx4/day) to cover ampicillin-resistant H. influenzae, S. pneumoniae , and Listeria monocytogenes in Japan. These antibiotics should be changed according to the causative organisms and their antibiotic susceptibilities.     

Initial treatment of bacterial meningitis in Yaounde, Cameroon: theoretical benefits of the ampicillin-chloramphenicol combination versus chloramphenicol alone.

A prospective 6-month study in Yaounde evaluated 49 children aged from 2 months to 8 years, hospitalized with bacterial meningitis. They were randomly assigned to one of two initial treatment groups, either an ampicillin-chloramphenicol combination (group A) or chloramphenicol alone (group B). The majority of patients were infected with Haemophilus influenzae, and the majority of deaths were caused by Streptococcus pneumoniae. Altogether, 17.9% of Haemophilus influenzae isolates were ampicillin-resistant and 3.6% chloramphenicol-resistant. We found no isolate resistant to both antibiotics. Response to both treatments was similar in both groups. The theoretical risk of treatment failure with ampicillin was higher than with the ampicillin-chloramphenicol combination (p less than 0.05). There was no statistically significant difference between the risk of treatment failure with the ampicillin-chloramphenicol combination and the risk with chloramphenicol alone (p less than 0.05), but the latter was increased by the occurrence of chloramphenicol-resistant isolates of Streptococcus pneumoniae (11.1%). Although treatment with an ampicillin-chloramphenicol combination is four times more expensive than treatment with chloramphenicol alone, costwise it is also one-quarter the price of a third-generation cephalosporin (moxalactam). At present, the ampicillin-chloramphenicol combination can be suggested as the first choice for initial treatment considering both the epidemiological data and the cost/efficiency ratio in the area of Yaounde.     

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.     

Follow-up of prospective randomized trial of ampicillin or chloramphenicol versus moxalactam treatment of Haemophilus influenzae type b meningitis

In a prospective randomized trial, moxalactam administered to 66 children was compared with ampicillin or chloramphenicol given to 68 children for the treatment of Haemophilus influenzae type b meningitis. Acute morbidity and mortality rates were equivalent between the two treatment groups. At 2 years after discharge, the results of psychologic tests (Bayley Scales of Infant Development or McCarthy Scales of Children's Abilities) were also equivalent between the two treatment groups for patients remaining in the study.     

Relapse of Hemophilus influenzae type b meningitis after combined antibiotic therapy: report of a case.

Antibiotic therapy of bacterial meningitis is being reevaluated due to reports of ampicillin-resistant strains of Hemophilus influenzae type b. The infant reported had a relapse of H. influenzae type b meningitis after an excellent clinical and bacteriologic response to an initial course of combined antibiotic therapy including chloramphenicol. This relapse is postulated to be due to localized cerebral vasculitis which was not treated for a sufficient period of time during the initial course of therapy. The patient responded well to a second course of penicillin and chloramphenicol. Since the use of pencillin and chloramphenicol will be increasing, the clinician should be aware that bacteriologic relapse of H. influenzae type b meningitis may occur with chloramphenicol therapy.     

Cefuroxime versus ampicillin plus chloramphenicol in childhood bacterial meningitis: a multicenter randomized controlled trial

In a multicenter randomized trial, 107 children with bacterial meningitis were initially given either cefuroxime or ampicillin plus chloramphenicol. Patients were alternately assigned to 7- or 10-day courses of the designated antimicrobial regimen. CSF isolates included Haemophilus influenzae type b (89, of which 25% were beta-lactamase positive), Streptococcus pneumoniae, and Neisseria meningitidis. Although mean CSF bactericidal titers against Haemophilus isolates were 1:6 in each treatment group, H. influenzae was cultured from CSF in four of 39 patients receiving cefuroxime, 24 to 48 hours after initiation of therapy, compared with none of 40 patients given ampicillin plus chloramphenicol (P = 0.11). Clinical cure rates were similar (95%); one death occurred in each group. One child given cefuroxime had persistent meningitis after 5 days of therapy, and mastoiditis with secondary bacteremia developed in one on day 10. Three patients had relapse or reinfection. One patient who received cefuroxime for 10 days had a relapse of epiglottitis 17 days later, and of the patients given ampicillin plus chloramphenicol, one had a relapse of meningitis 1 week after 7 days of therapy, and bacteremia developed in one 42 days after completion of 10 days of therapy. No increase in either in-hospital complications or relapses occurred with a 7-day treatment course. Proof of the equivalence of the antibiotic regimens and the efficacy of 7-day courses of treatment, as well as the consequences of delayed CSF sterilization, will require additional investigation.     

流感嗜血杆菌患儿分离株的血清分型和耐药模式研究

目的　了解流感嗜血杆菌患儿分离株的血清分型和体外耐药模式。方法　对本院2 0 0 1年 8月～ 2 0 0 2年 7月经apiNH卡鉴定的 2 4 7株流感嗜血杆菌 ,用玻片凝集法进行血清分型 ,用Kirby Bauer法检测其对 13种抗生素的敏感性 ,并用E test法检测氨苄西林的最低抑菌浓度。用头孢硝噻酚法检测 β内酰胺酶。 结果　不可分型流感嗜血杆菌 15 3株 ,占细菌总数 6 1 9% ,可分型菌株94株 ,占 38 1% ;可分型株在男女患儿中的分离率分别为 4 3 2 % (70 / 16 2 )和 2 8 2 % (2 4 / 85 ) ,差异有显著性 (χ2 =3 95 ,P <0 0 5 )。可分型菌株中d型构成比达 90 4 % ,b型仅 1 1%。 4 1株菌株(16 6 % )产生 β内酰胺酶。 2 33株菌株成功完成药敏试验 ,结果显示 :85 4 %的菌株对氨苄西林敏感 ,对头孢克洛、头孢噻肟、头孢曲松、亚胺培南、利福平、克拉霉素和氯霉素的敏感率分别高达98 7%、99 6 %、99 6 %、99 6 %、98 7%、91 0 %和 90 6 %。所有的菌株均对氨苄西林 /舒巴坦、阿莫西林 /克拉维酸和氧氟沙星敏感。菌株对甲氧苄啶 磺胺甲基异恶唑的耐药率最高 ,达 4 5 9%。可分型株对氨苄西林和甲氧苄啶 磺胺甲基异恶唑的耐药率显著高于不可分型株。β内酰胺酶阳性菌多重耐药率显著高于阴性菌 (χc2 =14 6 8,P <0 0 0 1