CHICAGO – Doripenem was a safe and effective treatment for pediatric patients with septicemia, pneumonia, and other infections in a phase-III trial of 95 children.
Two or three 20-mg/kg doses of the parenteral carbapenem antibiotic cured the infections of 92 of the children enrolled in the multicenter trial. The microbiological cure rate among the 75 subjects in whom at least one bacterial pathogen was isolated at baseline was 92%, reported Dr. Keisuke Sunakawa of Kitasato University, Tokyo.
Doripenem (Doribax) is approved in the United States for the treatment of complicated intra-abdominal infections and complicated urinary tract infections in adults. It is also approved for nosocomial pneumonia in Europe and for a variety of bacterial infections, including septicemia and pneumonia, in Japan, Dr. Sunakawa said at the annual Interscience Conference on Antimicrobial Agents and Chemotherapy.
Because of the drug’s antibacterial activity against known causative pathogens in pediatric infections, including penicillin-resistant Streptococcus pneumoniae (PRSP) and beta-lactamase–nonproducing, ampicillin-resistant Haemophilus influenzae (BLNAR), the investigators sought to determine its safety and efficacy in children. Toward this end, they enrolled 100 children between the ages of 2 months and 13 years with pneumonia, urinary tract infections, middle otitis, septicemia, and other infections.
Because doripenem does not have specific pediatric dosing recommendation, the investigators performed a Monte Carlo simulation based on a pharmacokinetic-pharmacodynamic model, which suggested that 20 mg/kg given two or three times daily would provide optimal coverage, Dr. Sunakawa said in a poster presentation. Patients received infusions based on this dosing regimen for a maximum of 14 days and were followed up 7 days after the last dose. The primary end point was the clinical cure rate at the end of therapy.
Of the 95 children (50 boys and 45 girls) included in the final analysis, 58 had pneumonia, 12 had urinary tract infections, 8 had otitis media, and 17 had septicemia or other infections, with mean treatment durations of 6.4, 6.4, 6.5, and 6.1 days, respectively.
The clinical response rates by infection type at the end of therapy were 97% for pneumonia, 100% for urinary tract infections, 100% for middle otitis, and 94% for septicemia and other infections, he said.
The one treatment "failure" was a patient in the latter group with perimandibular phlegmon who stopped treatment because she underwent additional endodontic surgery at another hospital. The recurrence/reinfection rate at follow-up was 1.4%, Dr. Sunakawa at the meeting, which was sponsored by the American Society for Microbiology.
When assessed by microbiological response, 6 of the 75 patients in whom at least one baseline pathogen had been detected failed treatment, including one patient with gram-negative H. influenzae and five with polymicrobial (S. pneumoniae and H. influenzae) infection, he reported.
"Of the drug-resistant genes [identified by PCR], all but three were cured with doripenem," he said, including one PRSP infection, one BLNAR infection, and one beta-lactamase–producing, amoxicillin clavulanate–resistant H. influenzae infection.
Regarding safety, "the adverse events were consistent with those observed at the 250- to 1,000-mg dose in adults," Dr. Sunakawa stated. "There were no new safety signals, and there were no central nervous system events, such as seizures, which are a concern for this drug class."
At least one adverse event was reported in 2 of the patients who received twice-daily doses (40%) and 54 of those who had thrice-daily doses (57%). The most common adverse events were diarrhea or loose stool, followed by injection site reactions and increased platelet count, ALT, AST, and eosinophil count, Dr. Sunakawa said. No events observed in the twice-daily dosing group and 27 in the thrice-daily dosing group were considered to be drug related, he said.
The results suggest that treatment with doripenem may be a good option for severe, intractable pediatric infections, particularly in light of the increasing frequency of drug-resistant pathogens, Dr. Sunakawa concluded. The drug is not yet indicated for use in children in the United States, Europe, or Japan.
Dr. Sunakawa disclosed serving as a scientific advisor for Shionogi & Co.