John D. Nelson

Clinical pharmacology and efficacy of vancomycin in pediatric patients

The emergence of staphylococci resistant to multiple antibiotics and the lack of information on pharmacology, efficacy, and safety of vancomycin in pediatric patients prompted this study. In vitro susceptibility studies showed that 33 to 50% of staphylococci tested were resistant to nafcillin, methicillin, cephalothin, and gentamicin, whereas none were resistant to vancomycin. Pharmacokinetic data of vancomycin were evaluated in 55 pediatric patients and was characterized by the two-compartment open-system kinetic model. Mean peak serum concentrations in infants and children after 10 and 15 mg/kg doses ranged from 25.2 to 32.5 μg/ml. The 10 mg/kg dose in newborn infants resulted in substantially lower peak values. Mean serum elimination phase half-life values correlated inversely with gestational and chronologic age and ranged from 2.2 to 9.8 hours. The CSF penetration in three infants with staphylococcal ventriculoperitoneal shunt infections ranged from 7 to 21%. Sixteen patients with staphylococcal diseases were successfully treated with vancomycin. In these patients peak serum vancomycin concentrations greater than 25 μg/ml and trough concentrations less than 12 μg/ml produced satisfactory inhibitory and bactericidal titers. Laboratory studies and auditory function tests did not reveal any drug-related abnormalities. Dosage schedules were formulated from these data. Indications and precautions for vancomycin therapy in infants and children are presented.

Gram-negative enteric bacillary meningitis: A twenty-one-year experience

We reviewed our experience with gram-negative enteric bacillary meningitis in neonates and infants from 1969 through 1989. Ninety-eight patients were identified. Their ages were from 1 day to 2 years with a median of 10 days. In 25 patients (26%), predisposing factors were identified, the most common of which were neural tube defects and urinary tract anomalies. The causative agents were Escherichia coli (53%), Klebsiella-Enterobacter species (16%), Citrobacter diversus (9%), Salmonella species (9%), Proteus mirabilis (4%), Serratia marcescens (3%), Bacteroides fragilis (3%), and Aeromonas species (2%). At the time of diagnosis, Gram-stained smears of cerebrospinal fluid revealed gram-negative bacilli in 61% of patients. The causative organism was cultured from blood obtained from 55% of patients, and 21% had positive urine culture results. The cerebrospinal fluid leukocyte counts ranged from 0 to 80,600 cells/mm3, and the cerebrospinal fluid/serum glucose concentration ratio was less than 0.5 in 72% of patients. Antimicrobial regimens varied greatly. After initiation of antibiotic therapy, an average of 3 days was needed for eradication of bacteria from cerebrospinal fluid. The case-fatality rate was 17%, and 61% of survivors had long-term sequelae that included seizure disorders, hydrocephalus, physical disability, developmental delay, and hearing loss.

Management of atypical mycobacterial lymphadenitis in childhood: a review based on 380 cases.

The medical and surgical therapy of 82 cases of atypical mycobacterial adenitis from Dallas and 298 cases from the literature was reviewed. The 92% cure rate in 149 patients with total surgical excision alone was comparable to the 95% cure rate in 156 patients when excision was followed by antituberculous drug therapy. With incision and drainage in 63 patients the cure rate was 16% whether drugs were given or not. Ten patients were initially treated with antituberculous drugs alone and only one was cured. It is concluded that total surgical excision is definitive therapy for this disease and that antituberculous drugs should be used only when surgery cannot be performed or when complete excision is not possible.

Oral antibiotic therapy for skeletal infections of children: II. Therapy of osteomyelitis and suppurative arthritis

Antimicrobial regimens consisting of a brief initial period of parenteral therapy followed by oral therapy were investigated in infants and children with suppurative bone and joint disease. There were 30 patients with acute hematogenous disease (19 osteomyelitis; three osteoarthritis; eight arthritis) and five with subacute or chronic osteomyelitis. Disease was due to Staphylococcus aureus in 26, Hemophilus influenzae in five, streptococci in three, and S. aureus plus Streptococcus pyogenes in one patient. Pus was removed by surgical drainage or needle aspiration. Oral therapy was monitored by assay of antibiotic concentration and bactericidal activity in serum. Adjustments in dosage were made when necessary to assure a peak serum bactericidal titer of at least 1:8. One patient progressed to chronic osteomyelitis but all other patients with acute disease responded well. Oral therapy provides increased patient comfort and decreases the risk of nosocomial infection associated with prolonged intravenous therapy. It should be carried out only under carefully monitored conditions in hospital to assure compliance and adequacy of serum bactericidal activity.

Oral antibiotic therapy for skeletal infections of children. I. Antibiotic concentrations in suppurative synovial fluid.

To evaluate the feasibility of oral antibiotic treatment for pyogenic arthritis, one or more oral doses of antibiotics were substituted for the drugs being used for parenteral therapy. Synovial fluid and serum specimens obtained at randomized times after an oral dose of ampicillin, cephalexin, cloxacillin, dicloxacillin, or penicillin G were assayed for antibiotic content and antibacterial activity. Seventy specimens from 21 infants and children were studied. Peak synovial fluid concentrations were greater than 60% of peak serum concentrations with all drugs tested and there was adequate inhibitory activity against bacteria commonly causing arthritis. The degree of antibiotic binding to serum protein had no apparent effect on the degree of penetration into pyogenic synovial fluid.

Double-blind treatment study of shigellosis comparing ampicillin, sulfadiazine, and placebo

A double-blind treatment study comparing ampicillin, sulfadiazine, and placebo was performed in 52 infants and children hospitalized for shigellosis. Bacteriological failure rates in patients treated with placebo and sulfadiazine were 75 per cent and 39 per cent, respectively, compared with 6 per cent in ampicillin-treated patients. Clinical failure occurred in 56 per cent of patients treated with placebo, 39 per cent in sulfadiazine-treated patients and in none of the patients who received ampicillin. Ampicillin is a safe and highly effective drug for the treatment of shigellosis.

Acute Mastoiditis in Infants and Children

During a 25-year period, 57 cases of acute mastoiditis occurred in infants and young children who ranged in age from 2 months to 12 years of age. All patients had abnormalities of the tympanic membrane and most had fever and localized edema and redness of the overlying skin. Fifty per cent of the infants who were less than one year of age had swelling primarily above the involved ear pushing the pinna out and down. By contrast, older children had swelling of the skin overlying the mastoid process which produced the classical finding of an elevated earlobe. Mastoid roentgenograms were a useful adjunct to diagnosis, revealing concurrent osteomyelitis in 9 patients. A diagnosis of specific bac terial etiology was made in 80 per cent of the patients in whom cultures were performed. Streptococcus pneumoniae, Staphylococcus aureus and Streptococcus pyogenes were the bacteria most frequently isolated. Unusual manifestations or serious complications occurred in 53 per cent of the patients, including one death (due to meningitis). These data indicate that the frequency of serious complications from acute mastoiditis has not declined over the past 3 decades.

Infections in children caused by the HB group of bacteria

The HB bacteria are a group of fastidious gram-negative organisms of low pathogenicity and are unusual causes of infection in normal infants and children. Eight pediatric patients with infections caused by HB bacteria are presented. Six of these eight patients had deep tissue abscesses including empyema, meningitis, peritonitis, and osteomyelitis. These patients may have been predisposed to infection because of altered host defense mechanisms, underlying chronic diseases, or trauma. The HB bacteria morphologically resemble Hemophilus influenzae but are differentiated by their colonial formation and biochemical reactions. The HB bacteria are frequently resistant to penicillin and ampicillin. Treatment with tetracycline or chloramphenicol should be instituted until susceptibility studies are available.

Absorption of ampicillin and nalidixic acid by infants and children with acute shigellosis.

Thirty‐seven infants and children with acute shigellosis were treated with orally administered ampicillin or nalidixic acid. Peak plasma levels and dose‐response curves suggested two patient populations. Five of 16 patients receiving nalidixic acid had a pronounced delay in absorption, while the others had the anticipated peak levels and plasma half‐lifes. All patients had a lower percentage of conjugated drug and of drug present as the hydroxynalidixic acid metabolite on the first day of treatment than during convalescence. Thus, some patients with diarrhea had altered absorption and all had altered metabolism of nalidixic acid during the acute phase of shigellosis. In 10 of 21 ampicillin‐treated patients there were depressed plasma levels and prolonged half‐lifes. These were statistically likely to be younger, to have more severe diarrhea, and to have lower body weight than those with normal peak plasma levels and plasma clearance rates.

Comparison of trimethoprim-sulfamethoxazole and ampicillin therapy for shigellosis in ambulatory patients**

One hundred seventy-four infants and children with acute diarrhea were treated as ambulatory patients with either ampicillin (100 mg/kg/day orally in four divided doses) or trimethoprim sulfamethoxazole (10 mg TMP and 50 mg SMX/kg/day orally in two divided doses). There were 65 patients with shigellosis. Responses of those treated with TMP/SMX and of those with susceptible Shigella treated with ampicillin were comparable. Patients with resistant organisms failed to respond to ampicillin. All Shigella , including ampicillin-resistant strains, were susceptible in vitro to TMP/SMX, and patients with ampicillin-resistant strains responded favorably to treatment with TMP/SMX. TMP/SMX appears to be the best, currently available drug for the treatment of shigellosis.