tions 5 min, 30 min, 2 h, and 8 h after infusion were 257, 177, 82.2, and 17.5 ,ug/ml, respectively. ... The mean distribution volume (VD) was 0.30 liters per kg.
ANTIMICROBIAL AGENTS
AND
Vol. 22, No. 1
CHEMOTHERAPY, July 1982, p. 47-50
0066-4804/82/070047-04$02.00/0
Moxalactam Pharmacokinetics
in
Children
MARIO F. ROMAGNOLI,13 KERRIE FLYNN,1 GEORGE R. SIBER,3 AND DONALD A.
GOLDMANNl12,3* Division of Infectious Diseases,1 Bacteriology Laboratory,2 and Department of Medicine, Children's Hospital Medical Center, and the Division of Infectious Diseases,3 Sidney Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 Received 22 January 1982/Accepted 26 April 1982
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 METHODS Children 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. Thirteen children aged 6 to 15 years with a preoperative diagnosis of acute appendicitis received moxalactam as prophylaxis. Three were excluded from analysis because of errors during processing of blood
specimens. In 2 of the remaining 10 cases, the diagnosis of appendicitis was not confirmed during surgery: one patient had midgut malrotation and the other had a ruptured corpus luteum cyst. Of the eight patients proven to have acute appendicitis at surgery, two were found to have ruptured appendices for which they received therapeutic courses of moxalactam. Thus, first-dose data were available for 10 and subsequentdose data were available for 2 patients in this group. Twenty patients, aged 7 days to 16 years, received therapeutic courses of moxalactam for documented or suspected infections (Table 1). Two patients were excluded from analysis because of thawing of samples before assay. First-dose data were available for all 18 evaluable patients, and subsequent-dose data were available for 10 patients in this group. Dosage and administration. Moxalactam was administered at a dose of 50 mg/kg infused over 30 min every 8 h. Blood samples were obtained by venipuncture or finger/heel puncture at 5, 30, 120, 240, and 480 min after completion of the infusion. Subsequent studies were performed on the third day of therapy. Blood samples were placed on crushed ice immediately after collection. Serum was separated in a 4°C centrifuge and stored at -20°C until assayed. In reconstruction experiments with normal serum, recovery of moxalactam was greater than 90%o after 4 h at room temperature and greater than 90%o after 2 weeks at -20°C. Assay. Moxalactam levels were measured by a highpressure liquid chromatography assay developed by John F. Ericson and A. N. Karabelas at the Pfeiffer Pharmaceutical Sciences Laboratories of the Massachusetts College of Pharmacy, Boston, with the technical assistance of Eli Lilly & Co. Serum proteins were precipitated with isopropanol, and the supernatant was extracted with 4% isoamyl alcohol in chloroform. The aqueous phase was diluted with 0.1 M ammonium acetate (pH 5.0) and injected into a Waters C-18 Radial 47
48
ROMAGNOLI ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Infections in patients receiving therapeutic moxalactam of nfecionNo. patients
No. with bacteremia
Focu ofof infection Focus
Intraabdominal 1 3 sepsis/peritonitis 1 3 Meningitis 2 3 Skin/soft tissue 1 2 Cholangitis 1 Urinary tract 1 Empyema 2 5 No focusa a Febrile, neutropenic children with leukemia. Pak A column; the mobile phase consisted of 32% acetonitrile and 68% Waters Pic-A reagent. Total drug content was measured spectrophotometrically at 270 nM by a peak-height ratio analysis, using cefamandole as an internal standard. The standard curve was linear from 20 to 150 ,Lg/ml. Susceptibility testing. Criteria for susceptibility were a zone of inhibition a20 mm by disk diffusion testing (2), using a 30-Sg disk (Eli Lilly & Co., Indianapolis, Ind.) or a minimal inhibitory concentration (MIC) of
