Pharmacokinetics and cerebrospinal fluid penetration of moxalactam in children with bacterial meningitis

We measured the serum concentrations of moxalactam in 10 children receiving antibiotic prophylaxis for surgery and in 18 children treated for documented or suspected infections. Moxalactam was administered intravenously at a dose of 50 mg/kg every 8 h. After the first dose in 28 patients, mean moxalactam concentrations 5 min, 30 min, 2 h, and 8 h after infusion were 257, 177, 82.2, and 17.5 ,ug/ml, respectively. The mean half-life (T112) was 2.44 h (range: 0.55 to 7.96 h). The mean distribution volume (VD) was 0.30 liters per kg. No significant accumulation was observed with multiple doses. Prophylactic and therapeutic groups had similar serum levels, T112, and VD. The five infants less than 1 year of age had a lower mean 30-min level (P < 0.01), larger VD (P < 0.001) and longer T1/2 (P < 0.025) than the children older than 1 year. A dose of 50 mg/kg produced 30-min levels in excess of 64 ,ug/ml in all patients studied, but 8-h trough levels were below the minimal inhibitory concentration breakpoint of 16 ,g/ml in 32% of patients.Moxalactam is a broad-spectrum beta-lactam antibiotic which is gaining increasing use in the treatment of serious pediatric infections. Its activity against gram-negative bacteria, including Haemophilus influenzae (8), and its penetration into the cerebrospinal fluid (9, 10, 15, 17) make it a reasonable alternative for the treatment of some cases of meningitis. Its activity against Enterobacteriaceae (6,7,13,18) and anaerobes (3) makes it an appealing choice for the treatment of children with ruptured appendix and other intraabdominal infections.The pharmacology of moxalactam has been extensively studied in healthy adults and in adult patients with normal and impaired renal function (1,4,14,16). Since studies in children have been much more limited, we examined the pharmacology of moxalactam in healthy children receiving prophylaxis for abdominal surgery, mainly appendectomy, and in seriously ill children receiving therapy for acute infections. MATERILS AND METHODSChildren from birth to 16 years were eligible for entry into the study. Patients with a history of penicillin or cephalosporin allergy, a history of anaphylaxis to any drug, severe renal insufficiency, or life-threatening infection for which conventional therapy was available were not eligible. Written informed consent was obtained from parents or legal guardians in all cases.

Section: Materils and Methodssupporting

confidence: 89%

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confidence: 99%

Moxalactam pharmacokinetics in children

Romagnoli¹,

Flynn²,

Siber³

et al. 1982

“…In addition, this new cephalosporin derivative is not metabolized in vivo (10,15) and has low protein-binding ability (10), and tubular secretion is unaffected by probenecid (7). These properties are also found with moxalactam (2, 7, 16), which achieves excellent cerebrospinal fluid (CSF) concentrations through inflamed meninges (4,11,12).…”

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confidence: 99%

Pharmacokinetics and bacteriological effect of ceftazidime in experimental Streptococcus pneumoniae, Haemophilus influenzae, and Escherichia coli meningitis

Sakata¹,

Boccazzi²,

McCracken³

1983

The pharmacokinetics and bacteriological effect of ceftazidime were evaluated in rabbits experimentally infected with Streptococcus pneumoniae, Haemophilus irfluenzae type b, and Escherichia coli Kl. The mean penetration of ceftazidime into cerebrospinal fluid after single-dose or constant-infusion administration ranged from 7.8 to 14.9%0. The median cerebrospinal fluid bactericidal titers were 1:64 against S. pneumoniae and H. influenzae and 1:128 against E. coli. The bacterial colony counts in cerebrospinal fluid were reduced by 58% to 100%0 (-2.3 to -3.9 log10 CFU/ml) in 3 h and by 100% (-3.2 to -5.1 log10 CFU/ml) in 9 h of constant infusion, whereas in untreated infected animals, bacterial counts increased from +1.4 to +2.1 log1o CFU/ml in 9 h. These data on ceftazidime compare favorably with those on penicillin, chloramphenicol, netilmicin, and moxalactam in this experimental meningitis model.Ceftazidime is a new 3-lactam antibiotic that has potential for therapeutic use in bacterial meningitis. The agent has in vitro activity against gram-negative bacilli comparable to that of other new cephalosporin derivatives but is more active against Pseudomonas aeruginosa (9, 13). It is also active against 1-lactamasepositive and -negative Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis (3,5), the principal pathogens of meningitis of infancy and early childhood. In addition, this new cephalosporin derivative is not metabolized in vivo (10,15) and has low protein-binding ability (10), and tubular secretion is unaffected by probenecid (7). These properties are also found with moxalactam (2, 7, 16), which achieves excellent cerebrospinal fluid (CSF) concentrations through inflamed meninges (4, 11, 12).The present study was designed to determine the pharmacokinetics of ceftazidime in serum and CSF of healthy young rabbits and those with experimental meningitis due to H. influenzae type b, S. pneumoniae, and Escherichia coli. The results of this investigation are compared with those from previous studies in which conventional antibiotic therapy and moxalactam were evaluated in experimental meningitis caused by the same pathogens (8,11,12 MATERIALS AND METHODSTest organisms. We used S. pneumoniae type 6, H. influenzae type b (,B-lactamase positive), and E. coli Kl, obtained from CSF of patients with meningitis. These organisms were grown in Mueller-Hinton broth containing 50 ,ug of calcium per ml, 25 ,ug of magnesium per ml, and 1% hemolysed horse blood for S. pneumoniae, brain heart infusion broth with Levinthal supplement for H. influenzae, and Mueller-Hinton broth for E. coli. After centrifugation, each organism was suspended in phosphate-buffered saline (0.01 M P04-0.15 M NaCl, pH 7.4) to a concentration of 6 to 8 log10o CFU/ml for inoculation. The minimal bactericidal concentrations of ceftazidime against S. pneumoniae, H. influenza, and E. coli were 0.125, 0.125, and 0.25 ,ug/ml, respectively.Rabbit model. New Zealand white male rabbits, weighing 2 to 3 kg each, were prepared by t...

“…Chloramphenicol is bactericidal for all three of these organisms (10); however, occasional resistance of H. influenzae to chloramphenicol has been reported (6,7,13). In addition, chloramphenicol has potentially serious though infrequent side effects (5). Moxalactam, a newly introduced 3-lactam agent, has appreciable in vitro and in vivo activity against H. influenzae (2,4,8), and recent studies have shown excellent diffusion of moxalactam into the cerebrospinal fluid of patients with meningitis (5,11).…”

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confidence: 99%

“…In addition, chloramphenicol has potentially serious though infrequent side effects (5). Moxalactam, a newly introduced 3-lactam agent, has appreciable in vitro and in vivo activity against H. influenzae (2,4,8), and recent studies have shown excellent diffusion of moxalactam into the cerebrospinal fluid of patients with meningitis (5,11). Accordingly, this antibiotic may be a useful alternative to chloramphenicol in the management of patients with H. influenzae meningitis.…”

mentioning

confidence: 99%

In vitro activity of moxalactam alone and in combination with penicillin against common meningeal pathogens

Azimi¹

1982

Moxalactam demonstrated marked activity against beta-lactamase-positive and -negative Haemophilus influenzae, Streptococcus pneumoniae, and Neisseria meningitidis by both standard minimal inhibitory concentration testing and growth curve studies. Moxalactam was ineffective against S. pneumoniae partially susceptible to penicillin G. Moxalactam (5 micrograms/ml) and penicillin (1 microgram/ml) in combination were indifferent to each other's antibacterial activity, exerting neither synergism nor antagonism against these organisms.