Sharon Shelton

Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin- and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of approximately 10(4) CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.

Dilemmas in diagnosis and management of cephalosporin-resistant Streptococcus pneumoniae meningitis

We recently managed an infant with meningitis caused by Streptococcus pneumoniae in whom ceftriaxone failed to sterilize the cerebrospinal fluid after 6 days of therapy. This strain, which had a penicillin minimal inhibitory concentration (MIC) of 2 micrograms/ml, appeared susceptible to ceftriaxone (MIC < 0.5 micrograms/ml) when evaluated by a commercial MIC panel (Microtech Medical Systems, Inc., Aurora, CO) but was found to have a ceftriaxone MIC of 4 micrograms/ml when evaluated by conventional microtiter broth dilution technique. Furthermore ceftriaxone therapy of meningitis induced with this strain in a rabbit model was ineffective. Thirteen of 112 pneumococcal strains (11.6%) isolated recently at Childrens Medical Center of Dallas were penicillin-resistant, and 3 of these were highly penicillin-resistant (MIC > or = 2 micrograms/ml). The incidence of pneumococcal strains with cefotaxime MICs > or = 1.0 micrograms/ml has increased from 0 of 258 from 1981 to 1983 to 5 of 112 (4.5%) from 1991 to 1992. The definition of cephalosporin resistance for pneumococci requires modification and further studies of the antibiotic management of meningitis caused by such strains are needed because resistance to cephalosporins is increasing and the extended spectrum cephalosporins may be ineffective as sole therapy.

Ceftriaxone versus ampicillin and chloramphenicol for treatment of bacterial meningitis in children.

78 patients with bacterial meningitis were evaluated in a prospective, randomised study comparing twice-daily ceftriaxone as single-drug therapy with ampicillin and chloramphenicol given every 6 h. The groups were comparable in age, sex, days of illness before admission, and bacterial colony counts in cerebrospinal fluid (CSF). The pathogens were Haemophilus influenzae type b (54 cases), streptococci (9 cases), meningococci (9 cases), and unknown (6 cases). In 40 CSF specimens obtained 4-12 h after initiation of therapy, cultures were negative in 57% of the ceftriaxone patients and in 42% of the others. The mean falls in the CSF bacterial colony counts were 4.7 and 5.0 log10 colony-forming units/ml, respectively. Mean bactericidal activity in CSF was significantly greater in the ceftriaxone than in the conventional treatment group at the beginning and end of therapy. There were no significant differences in clinical responses or in frequency of complications, except for mild diarrhoea, which occurred in 16 ceftriaxone patients and in 8 in the other group (p less than 0.05).

Relatively penicillin-resistant pneumococcal infections in pediatric patients

Two hundred fifty-eight isolates of Streptococcus pneumoniae obtained from 232 infants and children at Childrens Medical Center, Dallas, from November 1, 1981, to March 31, 1983, were screened for susceptibility to penicillin. On 1-μg oxacillin disks 21 strains (8%) had zones of inhibition of 17 mm or less, and the tubedilution minimal inhibitory concentrations of penicillin were from 0.125 to 0.5 μg/ml. These strains were designated as relatively resistant S. pneumoniae (RRSP). Prior therapy with a beta-lactam agent had occurred in 56% of patients with RRSP disease compared with 14% of randomly selected children with infections due to susceptible strains of S. pneumoniae (P = 0.009). Fifteen children (6%) had diseases due to RRSP ranging from sepsis or meningitis to otitis media or conjunctivitis. Four children, including the two patients with meningitis, had unsatisfactory responses to therapy with a betalactam antibiotic. Vancomycin or chloramphenicol is preferred for therapy of disease due to RRSP.

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.

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.

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.

Pharmacokinetics and cerebrospinal fluid bactericidal activity of ceftriaxone in the treatment of pediatric patients with bacterial meningitis.

Single-dose pharmacokinetics of ceftriaxone were determined in 19 patients with proven bacterial meningitis. The dosage was 50 mg of ceftriaxone per kg. The plasma concentration time curve declined in a biexponential manner. The mean peak plasma concentration was 207 micrograms/ml, and the elimination half-life was 4 h. In 12 patients, multiple-dose pharmacokinetics were determined after a loading dose of 75 mg of ceftriaxone per kg, followed by 50-mg/kg doses every 8 h in 5 patients or every 12 h in 7 patients. The mean peak plasma concentration was 230 micrograms/ml after the first dose and 263 micrograms/ml after the last dose. Of 12 patients, 5 had trough values that were larger after multiple doses than after a single dose. Mean penetration of ceftriaxone into cerebrospinal fluid was 3.1%. The median cerebrospinal fluid bactericidal titer against the patients pathogens was greater than 1:1,024 and less than 1:2,048. The drug was well tolerated without adverse effects.

Evaluation of CP-99,219, a new fluoroquinolone, for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis.

CP-99,219 is a new fluoroquinolone that has excellent activity against gram-positive organisms including penicillin- and cephalosporin-resistant Streptococcus pneumoniae strains. In our well-established rabbit model of meningitis, we conducted experiments to determine the concentrations of CP-99,219 in cerebrospinal fluid (CSF) after intravenous administration and its ability to eradicate two penicillin-resistant pneumococcal isolates. The peak and trough concentrations of CP-99,219 in the CSF were from 19 to 25% of the concentrations simultaneously obtained in serum and were unaffected by concomitant dexamethasone administration. Compared with untreated (control) animals, three doses of CP-99,219 given 5 h apart significantly reduced the bacterial count in CSF by 5 to 6 log10 CFU at 10 h. Although 47% of the dexamethasone-treated animals and 18% of those not given the steroid had positive cultures at 24 h (14 h after administration of the last antibiotic dose), the mean bacterial counts did not change from those observed at 10 h. Additionally, only results for animals infected with one of the two pneumococcal strains appeared to be affected by concomitant dexamethasone therapy.

In vitro susceptibility of gram-negative bacilli from pediatric patients to moxalactam, cefotaxime, Ro 13-9904, and other cephalosporins.

Moxalactam, Ro 13-9904, cefotaxime, cefoperazone, older cephalosporins, and four aminoglycosides were tested in vitro against 432 strains of gram-negative bacteria isolated from pediatric patients. The new drugs were uniformly active against coliform bacilli obtained from patients with meningitis and against aminoglycoside-resistant coliform bacilli.