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.     

Rapidly increasing prevalence of beta-lactamase-nonproducing, ampicillin-resistant Haemophilus influenzae type b in patients with meningitis

A total of 395 Haemophilus influenzae strains from 226 Japanese institutions participating in the Nationwide Surveillance Study Group for Bacterial Meningitis were received from 1999 to 2002. All strains were analyzed by PCR to identify the resistance genes, and their susceptibilities to beta-lactam agents were determined. Of these strains, 29.1% were beta-lactamase nonproducing and ampicillin (AMP) susceptible (BLNAS) and lacked all resistance genes; 15.4% were beta-lactamase producing and AMP resistant and had the bla(TEM-1) gene; 30.6% were beta-lactamase nonproducing and AMP resistant (low-BLNAR) and had a Lys-526 or His-517 amino acid substitution in ftsI encoding PBP 3; 13.9% were beta-lactamase nonproducing and AMP resistant (BLNAR) and had an additional substitution of Thr-385 in ftsI; 9.1% were amoxicillin-clavulanic acid resistant (BLPACR I) and had the bla(TEM-1) gene and a Lys-526 or His-517 amino acid substitution in ftsI; and 1.8% showed resistance similar to that of the BLPACR I group (BLPACR II) but had bla(TEM-1) gene and ftsI substitutions, as was the case for the BLNAR strains. All but three strains were serotype b. The prevalence of BLNAR strains has increased rapidly: 0% in 1999, 5.8% in 2000, 14.1% in 2001, and 21.3% in 2002. The MICs at which 90% of BLNAR isolates were inhibited were as follows: AMP, 16 micro g/ml; cefotaxime, 1 micro g/ml; ceftriaxone, 0.25 micro g/ml; and meropenem, 0.5 micro g/ml. All of these values were higher than those for the BLNAS counterpart strains. The relatively wide distributions of the beta-lactam MICs for BLNAR strains presumably reflect variations in ftsI gene mutations. Pulsed-field gel electrophoresis suggested the rapid spread of specific H. influenzae type b strains throughout Japan. Expedited vaccination, rapid identification, and judicious antibiotic use could slow their spread.     

Therapeutic activity of ceftazidime and eleven other beta-lactam antibiotics against experimental Haemophilus influenzae, type b meningitis

Twelve beta-lactams (11 cephalosporins and aztreonam) were compared in an infant rat model of Haemophilus influenzae, type b meningitis. Ceftazidime was the most effective compound tested and showed greater activity than cefuroxime, latamoxef (moxalactam) and cefotaxime--all of which have been used successfully in clinical haemophilus meningitis in children.     

Pharmacokinetics and therapeutic efficacy of imipenem, ceftazidime, and ceftriaxone in experimental meningitis due to an ampicillin- and chloramphenicol-resistant strain of Haemophilus influenzae type b.

The pharmacokinetics and therapeutic efficacy of imipenem, ceftazidime, and ceftriaxone were compared with those of ampicillin and chloramphenicol in rabbits with experimental meningitis due to an ampicillin- and chloramphenicol-resistant strain of Haemophilus influenzae type b. The mean bacterial colony counts in cerebrospinal fluid were reduced by 49% (-1.85 log10 CFU/ml), 92% (-3.37 log10 CFU/ml), and 92% (-4.30 log10 CFU/ml) after a single dose of imipenem, ceftazidime, and ceftriaxone, respectively. The median peak cerebrospinal fluid bactericidal titers against this multiply resistant strain of H. influenzae were 1:4 for thienamycin, 1:16 for ceftazidime, and 1:256 for ceftriaxone. By contrast, no bactericidal activity was observed in cerebrospinal fluid and the mean concentrations of H. influenzae were either unchanged or slightly increased in animals treated with ampicillin or chloramphenicol.     

Comparison of cotrimoxazole, ampicillin, and chloramphenicol in treatment of experimental Haemophilus influenzae type B meningitis.

To evaluate cotrimoxazole in the treatment of bacterial meningitis, we compared its action with that of ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis. Both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of infected rabbits, reaching 40 and 26%, respectively, of their simultaneous serum levels. Levels measured 30 and 60 min after intravenous injection exceeded the minimum inhibitory concentration of this combination for H. influenzae by 10- to 100-fold. The mean ratio of trimethoprim to sulfamethoxazole in cerebrospinal fluid was 1:22. Cotrimoxazole was as effective as ampicillin in therapy of beta-lactamase-negative H. influenzae meningitis and as effective as chloramphenicol for a beta-lactamase positive strain. These findings corroborate favorable preliminary clinical experience reported by others and indicate that cotrimoxazole deserves further study in the therapy of bacterial meningitis.     

Pharmacokinetics and bacteriological efficacy of cefoperazone, ceftriaxone, and moxalactam in experimental Streptococcus pneumoniae and Haemophilus influenzae meningitis.

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

Synergistic action of nafcillin and ampicillin against ampicillin-resistant Haemophilus influenzae type b bacteremia and meningitis in infant rats.

Infant rats with bacteremia and meningitis induced by ampicillin-resistant Haemophilus influenzae type b were treated with ampicillin and nafcillin, alone or in combination. Neither ampicillin alone (in 19 animals) nor nafcillin alone (in 20 animals) sterilized the blood or cerebrospinal fluid of any treated infant rat. When the combination of ampicillin and nafcillin was used, blood cultures were negative in 18 of 19 infant rats, and cerebrospinal fluid cultures were sterile in 15 of 19 when cultured 30 h after initiation of treatment. In vitro results demonstrated definite synergism between ampicillin and nafcillin against ampicillin-resistant H. influenzae type b. The study suggests that such synergism also exists in vivo.     

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.     

Treatment of experimental Haemophilus influenzae type b meningitis with 1-oxa-beta-lactam (LY127935)

1-Oxa-beta-lactam (LY127935) (Shionogi 6059-S) is a new type beta-lactam antibiotic having a broad spectrum of antibacterial activity. It is highly active against ampicillin-resistant strains of Haemophilus influenzae exhibiting minimal inhibitory concentrations as low as 0.06 microgram/ml. This compound also has the ability to penetrate into the cerebrospinal fluid of both normal and infected infant rats and attains approximately 10% of the corresponding blood levels. LY127935 was evaluated for its ability to treat ampicillin-resistant H. influenzae meningitis in an established experimental model using infant rats. Rats with ampicillin-resistant H. influenzae meningitis were treated subcutaneously three times daily for 2 days with various dose levels of LY127935. When given in doses as low as 10 mg/kg, LY127935 sterilized the blood and cerebrospinal fluid in all rats examined at 1 and 5 days posttreatment. In contrast, ampicillin was not effective at this dose in eliminating H. influenzae from the blood and cerebrospinal fluid of infected rats. LY127935 was effective against experimental ampicillin-resistant H. influenzae meningitis in the dosages employed.     

Efficacy of cefmenoxime in experimental group B streptococcal bacteraemia and meningitis

Cefmenoxime, a new semisynthetic cephalosporin, was evaluated in vitro and in vivo in comparison with penicillin G against a type III group B streptococcal strain. In vitro, the minimal inhibitory and minimal bactericidal concentrations of the two drugs were very close (less than or equal to 2 dilutions). In-vivo studies using experimental bacteraemia and meningitis in newborn rats revealed that despite similar drug levels, cefmenoxime had significantly greater bactericidal titres in blood at 6-7 h after administration and bacterial clearance from blood was significantly faster with cefmenoxime than with penicillin G at the end of one day of treatment. In addition, all animals with cefmenoxime therapy had bactericidal titres in cerebrospinal fluid greater than or equal to 1:8 at 1-2 h after administration, whereas most (67%) animals receiving penicillin G had titres less than 1:8. However, overall efficacy of cefmenoxime was similar to that of penicillin G. These findings suggest that cefmenoxime may be an effective alternative against group B streptococcal infection.     

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.     

Intramuscular ceftriaxone in the treatment of childhood meningitis due to Haemophilus influenzae type F

OBJECTIVE: To describe a case of meningitis caused by Haemophilus influenzae type f (Hif) in a child. CASE SUMMARY: A 2.5-year-old white girl (18 kg) was hospitalized because of acute ataxia. The cerebrospinal fluid culture grew H. influenzae, which was later identified as type f. Therapy was limited by the inability to gain intravenous access. Treatment was initiated with dexamethasone 8 mg (0.44 mg/kg) intramuscularly, one dose on the day prior to initiation of ceftriaxone therapy, and intramuscular ceftriaxone 2 g (111 mg/kg/dose) once a day. After the first day, dexamethasone was administered at 3 mg (0.17 mg/kg/d) orally four times per day for four days. Within two days, the patient became afebrile and improved significantly. The remaining treatments were given during daily hospital visits on an outpatient basis. No complications occurred during the follow-up visits. DISCUSSION: The clinical presentation and therapeutic management of Hif meningitis is similar to that of H. influenzae type b (Hib) meningitis. Factors that may predispose a child to infections caused by Hif include upper respiratory tract infections, day care attendance, Down syndrome, and immunodeficiency. Hif meningitis usually is treated with a third-generation cephalosporin (frequently ceftriaxone). Although most often administered intravenously, intramuscular ceftriaxone can provide a satisfactory clinical outcome in a child with adequate peripheral perfusion but limited intravenous access. The majority of reported cases of Hif meningitis resolve with appropriate antibiotic therapy; however, long-term neurologic sequelae occasionally occur. CONCLUSIONS: Hif occasionally causes pediatric meningitis. In a patient with good perfusion and difficult intravenous access, daily intramuscular administration of ceftriaxone can be an effective treatment option. In this case, Hif meningitis occurred abruptly and resolved within 48 hours of initiation of ceftriaxone and dexamethasone without long-term sequelae. The risks of giving dexamethasone appear to be minimal, although efficacy for preventing Hif complications remains to be proven.     

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.     

High prevalence of type b beta-lactamase-non-producing ampicillin-resistant Haemophilus influenzae in meningitis: the situation in Japan where Hib vaccine has not been introduced

OBJECTIVES: To study yearly changes in resistance and to identify ftsI mutations in beta-lactamase-non-producing ampicillin-resistant (BLNAR) and TEM-1 beta-lactamase-producing amoxicillin/clavulanic acid-resistant (BLPACR) isolates of Haemophilus influenzae from patients with meningitis. METHODS: Between January 2000 and December 2004, we received 621 isolates of H. influenzae from 285 member institutions of the Nationwide Surveillance Study Group for Bacterial Meningitis. All isolates were analysed by PCR to identify resistance genes and tested for susceptibility to beta-lactams. The ftsI gene was sequenced in all BLNAR and BLPACR isolates. RESULTS: All but four isolates were of serotype b. The isolates could be divided into six classes, namely beta-lactamase-non-producing ampicillin-susceptible (25.0%), TEM-1 beta-lactamase-producing ampicillin-resistant (11.0%), beta-lactamase-non-producing low-level ampicillin-resistant with N526K or R517H substitution in the ftsI gene (30.4%), BLNAR with an S385T substitution together with either N526K or R517H substitution in ftsI (22.2%), BLPACR-I with either a N526K or R517H substitution in ftsI (9.5%) and BLPACR-II with an S385T substitution together with either a N526K or R517H substitution in ftsI (1.9%). The prevalence of BLNAR has increased rapidly, from 5.8% in 2000 to 34.5% in 2004. All BLNAR and BLPACR-II strains were classified into nine subgroups on the basis of substitution patterns in the ftsI gene. The MICs of cephalosporin antibiotics for H. influenzae transformants into which the ftsI genes from BLNAR strains of each of the nine subgroups were introduced increased to varying degrees depending on the mutations. CONCLUSIONS: The results suggest that introduction of H. influenzae type b (Hib) vaccination into infants and children is necessary for the prevention of severe Hib infections in Japan.     

Waterhouse-Friderichsen syndrome caused by Haemophilus influenzae type b in an immunocompetent young adult

A previously healthy 19-year-old woman had a febrile illness with hypotension, progressive cyanosis, and an evolving petechial rash. Despite aggressive therapy in the face of shock and disseminated intravascular coagulation, the patient suffered a cardiac arrest and could not be resuscitated. Haemophilus influenzae type b was cultured from the blood and echovirus 30 from the cerebrospinal fluid post mortem. Fulminant H influenzae type b infection in an immunocompetent adult is rare but should be recognized as a possible cause of the Waterhouse-Friderichsen syndrome.     

Mechanism of resistance of an ampicillin-resistant, beta-lactamase-negative clinical isolate of Haemophilus influenzae type b to beta-lactam antibiotics

The mechanism of non-beta-lactamase-mediated beta-lactam resistance in a clinical isolate of Haemophilus influenzae type b was studied. This clinical isolate showed up to a 32-fold increase in MICs of a wide variety of beta-lactams, including moxalactam and cefotaxime, although no beta-lactamase activity was detected, even after attempted induction. Transformation of broad-spectrum beta-lactam resistance into ampicillin-susceptible H. influenzae RDnov was accomplished. Examination of the outer membrane protein profile of the resistant parent by sodium dodecyl sulfate-polyacrylamide gel electrophoresis of Triton X-100-extracted membranes revealed an unusual major outer membrane protein band at a molecular weight of 45,000. This outer membrane protein profile did not transform with beta-lactam resistance. Permeability differences were noted between the resistant strain and the nonisogenic susceptible strain of H. influenzae, although these penetration differences were not transformed. Comparison of the penicillin-binding protein profile of a resistant transformant with that of a susceptible parent with both whole-membrane preparations and whole-cell labeling, revealed a major reduction in binding affinity to penicillin-binding proteins 3a and 3b (molecular weights, 68,000 and 65,000, respectively). Thus, alteration in penicillin-binding proteins 3a and 3b correlated with the beta-lactam resistance.     

Complicated meningitis caused by a rare serotype of Haemophilus influenzae in Portugal

We report a case of meningitis due to Haemophilus influenzae serotype d strain in an infant. As far as we know, this is the first report of a serotype d strain, responsible for childhood invasive disease in Europe, demonstrating an emerging of H. influenzae non-b serotype, in the post-vaccination era.     

In vitro and in vivo synergism between amoxicillin and clavulanic acid against ampicillin-resistant Haemophilus influenzae type b.

Eight strans of ampicillin-resistant beta-lactamase-producing Haemophilus influenzae type b were studied in vitro for synergy between amoxicillin and clavulanic acid. The minimal inhibitory concentrations for amoxicillin alone were 6.25 to 12.5 microgram/ml, and for clavulanic acid alone they were 12.5 to 25 microgram/ml. However, seven of eight strains were inhibited by a combination of 0.36 microgram of amoxicillin and 0.36 microgram of clavulanic acid per ml. Infant rat models of bacteremia and meningitis were used to test the efficacy of amoxicillin and clavulanic acid alone and in combination upon four strains of ampicillin-resistant H. influenzae. Neither amoxicillin alone (27 animals) nor clavulanic acid alone (20 animals) sterilized the blood or cerebrospinal fluid of the animals. In contrast, 30 of 33 blood cultures and 29 of 33 cerebrospinal fluid cultures were sterile when a combination of the two drugs in the same dosages was used. The observed in vitro and in vivo synergism between amoxicillin and clavulanic acid suggests that the combination may be effective therapy for invasive infections in humans caused by ampicillin-resistant H. influenzae type b.     

Effect of cefotaxime or ceftriaxone treatment on nasopharyngeal Haemophilus influenzae type b colonization in children.

The effects of cefotaxime and ceftriaxone treatment on nasopharyngeal carriage of Haemophilus influenzae type b (Hib) were prospectively studied with 53 children with invasive Hib disease. Nasopharyngeal aspirates were monitored during therapy. Hib was eliminated within 2 days in 92% of patients and was eliminated in all patients after the third day of antibiotic treatment.