June 2000
BOSTON - The first pediatric study of intravenous (IV) linezolid (Zyvox, Pharmacia Corp.) followed by oral linezolid showed the drug is safe and efficacious for the treatment of community-acquired pneumonia (CAP) in children. Researchers concluded that it deserves further study for serious infections in children.
Linezolid is the first of a new class of oxazolidinone antibiotics to reach clinical trials. It is active in vitro against antibiotic-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus MRSA), vancomycin-resistant enterococci and antibiotic-resistant Streptococcus pneumoniae. Linezolid was recently approved by the Food and Drug Administration for the treatment of CAP and uncomplicated skin and skin structure infections in adults.
Investigators from 13 U.S. sites and one Australian site, with colleagues from Pharmacia Corp., conducted a phase 2, open-labeled, multicenter study to demonstrate the safety, tolerance and pharmacokinetics of linezolid and its efficacy in children with CAP who required hospitalization.
"Inclusion criteria included children 12 months to 17 years hospitalized with pneumonia," said Sheldon L. Kaplan, MD, professor of pediatrics at Baylor College of Medicine and chief of the Infectious Disease Service at Texas Children's Hospital in Houston.
"The baseline chest X-rays had to show new or progressive
infiltrate and consolidation or pleural fluid. Two or more typical clinical
findings of bacterial pneumonia had to be present and patients had to have a
fever, white blood count of 
10,000 or 
4,500
per µL. They also had to be completely immunized against Haemophilus
influenzae type b and influenza."
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Sixty-six patients were included in the study, with a median age of 3 years: 71% were between 2 and 6 years and 25% were 12 to 24 months. Study patients were given 10 mg/kg of linezolid every 12 hours by IV, then switched to oral linezolid suspension at the same dose given every 12 hours. The mean duration of IV treatment was 4.8 days and 8.4 days for oral treatment, with a range from two to 27 days and four to 21 days, respectively.
On study day two, serum concentrations of linezolid were obtained prior to, and two hours following, each dose. Efficacy was assessed during follow-up visits seven to 14 days after the last dose was administered. Baseline and follow-up chest X-rays were obtained, and laboratory monitoring was performed at baseline, on days three, nine, 15 and 22, and at follow-up.
According to Kaplan, chest X-ray infiltrates were patchy in 12 children, moderate in 22, mixed in two and dense in 25. Pleural effusions were present in 18 children. The respiratory rate range was between 20 and 88 respirations per minute.
Eight bacterial isolates were recovered from blood or pleural fluid cultures. One patient had group A streptococcus, six had pneumococcal isolates, two were resistant to penicillin, one was not susceptible to ceftriaxone (Rocephin, Roche) and one patient had MRSA.
Total linezolid administration lasted a mean of 12 days, with a range from six to 41 days: 88% of the children received at least nine days of combined therapy. Nine children had a chest tube placed and four underwent surgical procedures. Seventy-three percent of the study patients were afebrile by the third day of therapy and 86% were afebrile by day six.
"The mean peak (serum) of linezolid in this group of patients was 9.5 mg/mL. Ninety percent of the patients had levels exceeding 4.3 mg/mL," said Kaplan, who is also a member of the Infectious Diseases in Children editorial board. "We were able to obtain linezolid levels in the pleural fluid of four patients. Three patients had levels exceeding 4 mg/mL. The MIC90 (1 mg/mL) for pneumococcus is 1 to 2 mg and the MIC90 for S. aureusis up to 4 mg. One of the patients had a level of 1.4 mg/mL approximately eight hours after infusion."
At the end of therapy, 49 (74%) of 66 patients were considered cured, 13 improved, one had treatment failure and three were considered indeterminate. At follow-up, 61 (92%) of 66 were considered cured, including seven patients with S. pneumoniaeor other streptococcal infection. One patient had treatment failure and four were indeterminate, mostly because they continued to have a cough, according to Kaplan.
Treatment failure occurred in a 1-year-old child who had MRSA pneumonia and effusion.
"The patient actually improved, and by day six the respiratory rate had declined and the fever was down. But by day eight, fever recurred, repeat blood and pleural fluid culture grew MRSA. The linezolid MIC90 for the isolate was 2 mg/mL, which was unchanged from the original isolate," said Kaplan.
"On day 13, linezolid was discontinued and vancomycin was initiated. The patient had successful treatment after 14 days of vancomycin. Why this patient failed treatment is unclear. It's possible that serum and pleural fluid linezolid levels were not above the MIC for a long enough portion of the dosing interval for successful treatment."
Adverse events included diarrhea (10%), loose stool (5%), vomiting and rash (4%-5%), neutropenia (8%) and eosinophilia .500/mm3 (18%). Elevated alanine transaminase (75 IU/L to 253 IU/L) and lipase occurred in five and three patients, respectively.
"One patient developed severe neutropenia: a 21-month-old with a baseline absolute neutrophil count (ANC) of 2,700. By day three, the ANC was 500 and linezolid was discontinued. Four days after linezolid was discontinued, the ANC dropped to 58, but 11 days after it was discontinued it climbed back up to 2,700. This patient probably had severe neutropenia occur early because of an underlying viral infection that was the cause of pneumonia," said Kaplan.
Patients were evaluated if they had received at least 80% of study medication and returned for a follow-up visit. They were not considered a treatment failure unless they had been treated for at least two days, and were not considered cured unless they received five days of treatment.
Patients were considered cured if normalization of all clinical signs and symptoms of pneumonia and lack of progression of all abnormalities on chest X-rays occurred. Treatment failure was classified as progression of signs and symptoms of pneumonia after at least two days of treatment and progression of chest X-rays abnormalities. Patients were considered indeterminate if their circumstances precluded classification.
For more information:
- Kaplan S, Patterson L, Edwards K, et. al. Linezolid in the treatment of community-acquired pneumonia. Abstract 1569. Presented at the Pediatric Academic Societies and American Academy of Pediatrics joint meeting. May 12-16, 2000. Boston.
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