Pharmacokinetics of a clarithromycin suspension in infants and children.

The single- and multiple-dose pharmacokinetics of clarithromycin and its 14-(R)-hydroxylated metabolite in infants and children were studied after oral administration under fasting and nonfasting conditions. Drug absorption appeared to be rapid following a brief delay in its onset; the mean peak concentrations in plasma (Cmax) for clarithromycin were reached within about 3 h under both conditions. The mean Cmax for the parent drug were 3.59 and 4.58 micrograms/ml in single-dose fasting and nonfasting patients, and the respective Cmax for the metabolite were 1.19 and 1.26 micrograms/ml. Data indicate good absorption and no significant effects by food. There was no unusual accumulation in the area under the concentration-time curve and Cmax in the multiple-dose group.

Comparative evaluation of loracarbef and amoxicillin-clavulanate for acute otitis media.

One hundred five infants and children with acute otitis media were randomized to therapy with loracarbef, an experimental carbacephem antibiotic, or amoxicillin-clavulanate (Augmentin), an approved drug for this disease. Ninety-two were evaluable (46 in each group). Middle ear fluid samples obtained for culture before therapy grew Haemophilus spp. in 30% of cases, pneumococci in 29% of cases, and Moraxella catarrhalis in 15% of cases. beta-Lactamase-producing bacteria were found in 37% of patients. Clinical failure occurred in four loracarbef-treated patients and one amoxicillin-clavulanate-treated patient (P = 0.361). Recurrence of acute otitis media was more common in the 2 to 3 weeks after loracarbef treatment (eight patients) than it was after amoxicillin-clavulanate therapy (three patients), but not significantly so (P = 0.197). Thus, combined failure and recurrence occurred in 12 loracarbef-treated patients and four amoxicillin-clavulanate-treated patients (P = 0.052). Gastrointestinal side effects occurred in 13 loracarbef-treated and 21 amoxicillin-clavulanate-treated patients (P = 0.13). Diaper rash was more common with amoxicillin-clavulanate (22 patients) than with loracarbef (10 patients; P = 0.016). Satisfactory results were achieved with both antibiotics, and adverse effects, although common, were minor.

Loracarbef concentrations in middle ear fluid.

Loracarbef concentrations in plasma and middle ear fluid (MEF) were measured in specimens obtained approximately 2 h after doses of 7.5 or 15 mg/kg. The mean +/- standard deviation concentrations in MEF were 2.0 +/- 2.6 mg/liter (48% of the concentration in plasma) after the smaller dose and 3.9 +/- 2.6 mg/liter (42% of the concentration in plasma) after the larger dose. With the larger dose, the concentrations in MEF were greater than the MIC for 90% of strains of the usual pathogens of acute otitis media tested in 16 of 17 specimens.

Pharmacokinetics of LY163892 in infants and children.

Two dosages (7.5 and 15 mg/kg of body weight) of LY163892 were given to infants and children, and five plasma specimens were collected for antibiotic assay during the ensuing 4 h. Peak concentrations of 12.6 and 18.7 micrograms/ml occurred at 45 min. The mean half-lives were 0.85 and 0.78 h, and the mean areas under the curve were 24.4 and 38.0 micrograms.h/ml.

Five vs. ten days of therapy for acute otitis media.

In a double blind study 175 patients with acute otitis media were randomized into 2 treatment groups: 10 days of therapy with cefaclor or 5 days of therapy followed by 5 days of placebo. The dosage of cefaclor was 40 mg/kg/day administered orally in equally divided doses at 12-hour intervals. Tympanocentesis before treatment yielded specimens that contained Streptococcus pneumoniae or Haemophilus influenzae or both in 55% of specimens. Branhamella catarrhalis was isolated from 21% of specimens. Culture of material from the ear canal of patients with spontaneous perforation of the tympanic membrane of less than 24 hours duration yielded pneumococci or H. influenzae or both in 38% of specimens and staphylococci in 31%. Patients were scheduled for follow-up examinations at 5 or 6, 10, 30, 60 and 90 days. Of the 175 children 151 were evaluable at 10 days. There were 123 patients with both tympanic membranes intact at the time of diagnosis. There were 6 (10%) treatment failures of therapy in the 59 patients assigned to 5 days of therapy and 4 (6%) failures and 1 (2%) early relapse in the 64 assigned to 10 days of therapy (difference not significant). There were 28 evaluable patients with spontaneous perforation. There were 8 (53%) failures in the 15 children assigned to 5 days of therapy and only 1 (8%) failure in the 13 children assigned to receive 10 days of therapy (P = 0.016, Fisher exact test). Rates of reinfection and persistent middle ear effusion at 10, 30, 60 and 90 days follow-up were not significant different in patients assigned to 5 to 10 days of therapy. In patients with acute otitis media with intact tympanic membranes we have not been able to show any advantage of the standard duration of 10 days of therapy over a shortened course of 5 days. A 5-day course of antibiotic therapy does not appear to be sufficient for children with acute otitis media and spontaneous purulent drainage.

Imipenem and cilastatin in acute osteomyelitis and suppurative arthritis. Therapy in infants and children.

Twenty-five infants and children with acute osteomyelitis (n = 7), suppurative arthritis (n = 11), or both (n = 7) were treated with imipenem and cilastatin sodium. Patients ranged in age from 5 months to 11.3 years. Needle aspiration of infected sites was performed in all patients, and 11 (44%) required further surgical drainage. Imipenem and cilastatin sodium in a dosage of 100 mg/kg/d was used for children 3 years of age or younger, while older ones received 60 mg/kg/d intravenously, divided in four equal doses. Bacterial pathogens were identified in 15 patients (60%): Staphylococcus aureus in five, Haemophilus influenzae b in four, Pseudomonas aeruginosa in two, Streptococcus pneumoniae in one, group A Streptococcus in one, Kingella kingae in one, and Citrobacter amalonaticus in one. All isolates were susceptible to imipenem in vitro. Imipenem and cilastatin therapy was continued for a median of six days followed by treatment with appropriate orally administered antibiotics. Median peak serum bactericidal titers after imipenem and cilastatin infusions were 1:512 for S aureus, 1:32 for H influenzae b, 1:512 for streptococci, and 1:16 for gram-negative rods. All but one patient with P aeruginosa osteomyelitis responded favorably to imipenem and cilastatin. The median duration until resolution of symptoms was six days. Imipenem and cilastatin infusions were well tolerated, and side effects included maculopapular rash in one patient, watery diarrhea in one, and mild transient elevation of alanine aminotransferase levels in three. Because of imipenem and cilastatin's unusually broad spectrum of activity and its relative safety, this drug combination can be used for the initial, empiric therapy of acute bone and joint infections in pediatric patients.

Possible association of mycoplasma and viral respiratory infections with bacterial meningitis.

The presence of viral infection was evaluated in 160 children older than three months with bacterial meningitis who were admitted to Children's Medical Center or Parkland Memorial Hospital, Dallas, TX, between October 1979 and March 1982. Results were compared with a single serologic specimen in 138 children without meningitis. A recent history of upper respiratory infection was obtained from 60% of patients, including 10/13 with pneumococcal, 9/16 with meningococcal, and 77/131 with Haemophilus influenzae meningitis. Viral infection was documented by serologic response (23.8%) or viral isolation (13.2%) in 63/160 (40%) of patients with meningitis. There were 23 positive cultures (one patient with both adenovirus and respiratory syncytial virus). Picornaviruses, including two rhinoviruses, were isolated from six of the 24 subjects without meningitis who had viral cultures. There were 69 serologic conversions in meningitis patients, with 12 patients converting to two organisms and four patients converting to three organisms. Viral diagnoses included: adenovirus, 32 children; respiratory syncytial virus, 14; influenza A, 8; influenza B, 4; parainfluenza (1, 2, and 3), 12; picornaviruses, 9; herpes simplex virus, 1; and cytomegalovirus, 1. Additionally, 6/15 seroconverted to Mycoplasma pneumoniae. The acute geometric mean serum antibody titers of meningitis patients were lower than those of the comparison group for adenovirus (3.5 vs. 6.6, p less than or equal to 0.001) and influenza B (1.2 vs. 1.6, p less than or equal to 0.05). Twenty nine of 131 patients with H. influenzae had evidence of recent adenovirus infection. Primary infection with adenoviruses and possibly influenza B or mycoplasma precedes development of bacterial meningitis in some patients and may be a predisposing factor.

Role of genital mycoplasmas in young infants with suspected sepsis.

To establish the prevalence of Mycoplasma hominis and Ureaplasma urealyticum in infants up to 3 months of age with suspected sepsis, blood, cerebrospinal fluid, and urine specimens from 203 patients with clinical signs and symptoms of sepsis were cultured for Mycoplasma in addition to routine bacterial cultures. Proved bacterial infections were identified in 24 patients, four of whom had bacteremia. M. hominis and U. urealyticum were not isolated from any of the 191 blood and 199 CSF specimens tested. Of 170 specimens of urine cultured for Mycoplasma, M. hominis was isolated in six patients, U. urealyticum in nine patients, and both organisms in one patient. Twelve of the positive cultures were voided urine specimens, and four were suprapubic bladder aspiration specimens. Genital mycoplasmas appear to be uncommon causes of sepsis or meningitis in young infants. Further studies are required to assess their role in abnormal conditions of the urinary tract in childhood.

Comparison of piperacillin vs. ticarcillin plus tobramycin in the treatment of acute pulmonary exacerbations of cystic fibrosis.

During a 22-month period 35 children with cystic fibrosis received 52 courses of antibiotic therapy for acute pulmonary exacerbations, including 26 cases of therapy with piperacillin and 26 courses with ticarcillin plus tobramycin. Groups were similar in age (5 vs. 5.4 years), disease severity based on Schwachman scores and presenting symptoms. Pseudomonas aeruginosa was the most common organism isolated in 90% of sputum cultures. Mean minimal inhibitory concentrations for piperacillin, ticarcillin and tobramycin were 8, 64 and 1 microgram/ml, respectively. Piperacillin pharmacokinetic data revealed an average half-life in serum of 36 minutes. Peak serum concentrations averaged 144 micrograms/ml, and after 4 hours serum concentrations continued to exceed the P. aeruginosa 90% minimal inhibitory concentration in 50% of children. The dosage requirement for tobramycin was quite variable, necessitated monitoring of aminoglycoside serum concentrations and in most cases resulted in at least one dosage adjustment. Emergence of resistant bacteria was not seen in 26 courses of piperacillin therapy. Both regimens were effective and well-tolerated. Single agent therapy has the advantage of providing reliable serum concentrations and, in contrast to the standard therapy, does not necessitate monitoring of serum drug concentrations.

Comparative treatment trial of augmentin versus cefaclor for acute otitis media with effusion.

A total of 150 children with acute otitis media were randomly allocated to treatment with amoxicillin-potassium clavulanate (Augmentin) or with cefaclor. Each drug was given in a daily dosage of approximately 40 mg/kg in three divided doses for ten days. Tympanocentesis done before treatment yielded specimens that contained pneumococcus or Haemophilus sp or both in 67% of specimens. Viridans group streptococci were isolated from 10% of specimens and Branhamella catarrhalis from 6%. Patients were scheduled for follow-up examinations at midtreatment, end of therapy, and at 30, 60, and 90 days. Of the 150 children, 130 were evaluable. Five of 60 patients (8%) treated with cefaclor were considered therapeutic failures because of persistent purulent drainage and isolation of the original pathogen or suprainfection. There were no failures among patients treated with Augmentin (P = .019). Rates of relapse, recurrent acute otitis media with effusion, and persistent middle ear effusion were comparable in the two groups of patients. Diaper rash, or loose stools, or both were significantly more common in children treated with Augmentin (34%) than in those taking cefaclor (12%), but in no case was it necessary to discontinue medication because of these mild side effects (P = .002). Cefaclor therapy was discontinued in one patient because of severe abdominal pain and vomiting. In this study, treatment with Augmentin was superior to treatment with cefaclor in the acute phase of acute otitis media with effusion, but Augmentin produced more adverse effects. The rates of persistent middle ear effusion and recurrent acute otitis media with effusion were comparable with the two regimens.

Randomized trial of cefamandole plus amdinocillin versus cefamandole in serious pediatric infections.

In a randomized, prospective clinical trial cefamandole therapy was compared with cefamandole plus amdinocillin in infants and children with suspected bacterial infections. Fifty-two infections in 50 patients with bone and joint (19 infections), pulmonary (19 infections), soft tissue (eight infections), and urinary tract (6 infections) diseases were treated. Bacterial infection was documented in 31 patients. All isolates were susceptible to cefamandole except one strain of Serratia marcescens, which was susceptible to the combination. In vitro synergy was demonstrated in all coliform bacilli, in three of seven Haemophilus strains, and in six of 16 gram-positive cocci. No correlation between degree of serum bactericidal activity and presence or absence of synergy could be demonstrated. One patient treated with cefamandole died; all other patients responded promptly to therapy without serious adverse drug effects.

Oral v topical erythromycin therapies for chlamydial conjunctivitis.

Results of oral and topical erythromycin therapy in 41 infants under 4 months of age with chlamydial conjunctivitis were evaluated in randomized clinical trial. After three weeks of treatment, relapse or reinfection of the eye occurred in four of 19 patients (21%) in the topical therapy group and in three of 22 patients (13.6%) in the oral therapy group (p less than .69). In the topical therapy group, chlamydiae were isolated from nasopharyngeal cultures of eight patients (42%) during or after therapy. Chlamydiae were eradicated from the nasopharynx of the six colonized patients treated with oral erythromycin. All relapses responded to a course of oral erythromycin therapy. We conclude that both modes of therapy are comparable for treatment of chlamydial conjunctivitis, but that oral therapy has the advantage of eradicating nasopharyngeal colonization.

Benefits and risks of sequential parenteral--oral cephalosporin therapy for suppurative bone and joint infections.

Seventy-five infants and children with suppurative skeletal infections were managed with a sequential parenteral-oral regimen of cephalosporin antibiotic therapy. Initially, parenteral antibiotics (cefamandole for 48 patients and cefuroxime for 27 patients) were given for a median of 5 days. Oral therapy was with large doses of cefaclor (150 mg/kg/day) or cephalexin (100 mg/kg/day). Eight patients (11%) had inadequate serum bactericidal activity with cefaclor. Six of them were successfully managed with alternative oral antibiotics, and parenteral therapy resumed in one patient. Chronic disease developed in a child who was continued on oral cloxacillin therapy in spite of absent serum bactericidal activity. It is concluded that oral therapy can be successful for the majority of patients but that it is hazardous and not indicated if careful laboratory monitoring of compliance and serum bactericidal activity cannot be performed.

Pharmacologic interactions among chloramphenicol, phenytoin and phenobarbital.

Bioactive chloramphenicol was measured in the sera of 34 infants and children receiving intravenous chloramphenicol succinate (25 mg/kg/dose) as therapy for meningitis, pneumonia, brain abscess or Rocky Mountain spotted fever. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations of chloramphenicol were 25.3 and 13.4 micrograms/ml, respectively. Concurrent administration of chloramphenicol succinate and phenobarbital in six patients resulted in reduced peak and trough concentrations of chloramphenicol of 16.6 and 7.5 micrograms/ml, respectively (P less than 0.05). Concurrent administration of chloramphenicol succinate and phenytoin in six patients resulted in an elevated mean peak serum concentration of chloramphenicol of 41.7 micrograms/ml (P less than 0.05). Five other patients treated with phenytoin had indeterminate serum chloramphenicol half-lives with chloramphenicol concentrations of 29 to 90 micrograms/ml. Potentially toxic chloramphenicol concentrations occurred in 9 of 17 controls, 0 of 6 patients who had received phenobarbital (P = 0.001) and 11 of 11 patients who had received phenytoin (P = 0.008). Patients receiving combined chloramphenicol succinate and anticonvulsant therapy require monitoring of serum concentrations of drug and adjustments in the dose of chloramphenicol succinate administered.

Cefuroxime therapy for pneumonia in infants and children.

Because Streptococcus pneumoniae, Haemophilus influenzae b and Staphylococcus aureus are the major causes of bacterial pneumonia in infancy, we customarily have given a beta-lactam antibiotic and chloramphenicol as initial antibiotic therapy. Cefuroxime (75 mg/kg/day divided every 8 hours iv or im) was evaluated as single drug therapy in an open study of 100 infants and children with suspected bacterial pneumonia. The mean serum concentration of cefuroxime 30 minutes after a 15-minute infusion of 25 mg/kg iv was 29.1 micrograms/ml, and the volume of distribution was 695 ml/kg. Pleural fluid concentrations in 3 specimens were 2.2, 8.5 and 11 micrograms/ml. Median age of patients was 15 months. Bacterial etiology was established in 20 patients: H. influenzae b (8 patients); pneumococcus (8 patients); S. aureus (2 patients); Group A streptococcus (1 patient); Neisseria meningitidis B (1 patient). All organisms were susceptible to 1.25-micrograms/ml doses or less of cefuroxime. The mean number of days was 3.1 until patients became afebrile and 5.1 until respiratory symptoms were gone. Eosinophilia occurred in 10 patients. Cefuroxime is safe and effective single drug therapy for pneumonia in infants and children.

Pharmacokinetics of potassium clavulanate in combination with amoxicillin in pediatric patients.

Two dosages of a liquid suspension formulation of amoxicillin and potassium clavulanate were tested in 34 infants and children. The smaller dosage resulted in suboptimal plasma concentrations. With a greater dosage (3.3 mg of clavulanate per kg and 13.3 mg of amoxicillin per kg), the mean peak plasma concentrations were 1.6 micrograms clavulanic acid per ml and 4.9 micrograms amoxicillin per ml.

Oral or intravenous trimethoprim-sulfamethoxazole therapy for shigellosis.

A review of the literature concerning shigellosis treated with trimethoprim-sulfamethoxazole (TMP-SMZ) revealed comparative studies of 149 cases and noncomparative studies of 147 cases. Bacteriologic and clinical success rates were greater than or equal to 90% and TMP-SMZ compared favorably with alternative drug therapy. In the present study TMP-SMZ was given intravenously as initial therapy to 11 children hospitalized for severe shigella colitis. Bacteriologic and clinical responses were comparable to those observed with oral TMP-SMZ therapy. Pharmacokinetic studies revealed substantial differences between the responses of these children and those reported for adult patients; a higher ratio of SMZ to TMP (50:1) was found in children. It is concluded that TMP-SMZ is effective therapy for shigellosis and is the drug of choice in areas where ampicillin resistance is prevalent.

Pharmacokinetics of erythromycin ethylsuccinate and estolate in infants under 4 months of age.

We studied the pharmacokinetics of erythromycin estolate and ethylsuccinate suspensions in infants under 4 months of age who were being treated for chlamydial infections or pertussis. We conducted our studies after the initial dose of 10 mg/kg and subsequently during steady-state treatment. The estolate preparation resulted in higher peak concentrations in sera, and its absorption and elimination half-lives were longer. Peak concentrations occurred 3 h after a dose with the estolate preparation and 1 h after a dose with the ethylsuccinate preparation. The area under the curve for the estolate preparation was about three times greater than that for the ethylsuccinate preparation. Based on these findings, we recommend that erythromycin estolate suspensions be given to young infants at 8- or 12-h intervals (30 mg/kg per day in three divided doses or 20 mg/kg per day in two divided doses) and that erythromycin ethylsuccinate is best given at 6-h intervals (40 mg/kg per day in four divided doses).