Use of Ceftazidime-Avibactam in Infants and Children

Marcia L. Buck, PharmD, FCCP, FPPAG, BCPPS

Disclosures

Pediatr Pharm. 2019;25(5) 

In This Article

Clinical Experience

There have been only limited reports of ceftazidime-avibactam use in infants, children, and adolescents prior to the FDA approval for pediatric patients. In 2018, Tamma and colleagues at Johns Hopkins Hospital described their experience treating a 2-month-old infant with a refractory infection.[9] The patient was a previously full-term infant with a congenital diaphragmatic hernia that had been surgically repaired at 2 weeks but remained hospitalized for respiratory support. At 2 months, she developed fevers and hypotension requiring vasopressors and was started on cefepime and vancomycin empirically. Cultures grew Gram-negative rods that were subsequently speciated as Burkholderia cepacia complex (Bcc). Treatment was changed to intravenous trimethoprim-sulfamethoxazole and daily blood cultures were continued.

Ceftazidime was added on day 6 of the infection for persistent bacteremia. The ceftazidime MIC at that time was 8 mcg/mL. With continued bacteremia in spite of removing all central IV catheters, the ceftazidime was changed to a continuous infusion on day 12. Four days later, ceftazidime was replaced with extended infusion meropenem and the trimethoprim-sulfamethoxazole continued. On day 32 of positive blood cultures, treatment was changed to ceftazidime-avibactam 50 mg/kg (40 mg/kg ceftazidime and 10 mg/kg avibactam) as an extended infusion over 8 hours and given every 8 hours. Antimicrobial sensitivity testing had revealed that the Bcc was highly sensitive to ceftazidime-avibactam, with a zone of inhibition of 33 mm (with the breakpoint for susceptibility defined as > 18 mm) and an MIC of 2 mcg/mL. Within 24 hours of initiating the change in therapy, the patient had her first negative blood culture. She was treated for an additional 6 weeks without further issues and remained infection-free at 10-month follow-up. Genomic sequencing of the Bcc isolate revealed a Pen-like beta-lactamase.

Earlier this year, Hobson and colleagues at the Robert Debré Hospital in Paris reported the use of ceftazidime-avibactam in a 3-year-old girl with a refractory infection following chemotherapy for a relapse of acute lymphoblastic leukemia.[10] She presented with a fever and neutropenia, and was found to be bacteremic. Her initial culture grew a K. pneumoniae strain producing CTX-M-1. She was successfully treated with imipenem, but 8 days later was found to have a multidrug-resistant NDM-1-producing strain of Morganella morganii. The MIC values were > 256 mcg/mL for ceftazidime, 3 mcg/mL for meropenem, > 32 mcg/mL for imipenem, 4 mcg/mL for aztreonam, and 0.016 mcg/mL for ceftazidime-avibactam. The patient received aztreonam 100 mg/kg/day and ceftazidime-avibactam 150 mg/kg/day for 10 days, with resolution of the infection, negative cultures, and no further signs of relapse at 6-month follow-up.

The manufacturer conducted two controlled studies of ceftazidime-avibactam to support their request for FDA approval of a pediatric indication. Effectiveness in pediatric cIAI was demonstrated in a multicenter randomized, single-blind, active-comparator controlled trial of 83 patients ranging from 3 months to 18 years of age. Patients were randomized in a 3:1 ratio to receive either ceftazidime-avibactam and metronidazole or meropenem. Children and adolescents 2 to 18 years of age received a ceftazidime-avibactam dose of 62.5 mg/kg (50 mg/kg ceftazidime and 12.5 mg/kg of avibactam) up to a maximum of 2.5 grams, while infants 3 months up to 6 months of age were given a dose of 50 mg/kg (40 mg/kg ceftazidime and 10 mg/kg avibactam), infused over 2 hours every 8 hours in combination with metronidazole 20 mg/kg IV every 8 hours. Patients treated with meropenem were given a dose of 20 mg/kg IV every 8 hours. Patients were treated for 72 hours with their assigned study drug, but could then be switched to oral therapy to complete 7 to 15 days of treatment by the site investigator.

The majority of the patients in the study were being treated for a perforated appendix or a peri-appendiceal abscess. Mean age of the study patients was 11 years, with a range of 3 to17 years. There were no infants in the ceftazidime-avibactam group. Sixty-nine patients had at least one positive bacterial culture; 50 in the combination group and 19 in the meropenem group. The most common organisms were E coli, in 80% of patients, and P. aeruginosa in 33%. The test-of-cure visit was scheduled between 8 and 15 days after the last dose of the study drug. Clinical cure was defined as resolution of all acute signs and symptoms or improvement such that antibiotics were discontinued.

In the intention-to-treat population, 56 of 61 patients (91.8%) in the ceftazidime-avibactam plus metronidazole group and 21 of the 22 meropenem patients (95.5%) were categorized as having a clinical cure. Clinical cure rates in the patients with positive cultures were 45 of 50 patients (90%) in the combination group and 18of 19 patients (94.7%) in the meropenem group. In patients with E. coli infections, the clinical cure rates were 90.5% for ceftazidime-avibactam and 92.3% for meropenem. Clinical cure rates for P. aeruginosa were 85.7% and 88.9%, respectively. Although the results of this study have not been published, the results are available at www.ClinicalTrials.gov, NCT 02475733).

A subsequent multicenter single-blind active-comparator safety and tolerability study was conducted by the manufacturer in 95 infants, children, and adolescents from 3 months to 18 years of age with cUTI.[2] Patients were randomized to either ceftazidime-avibactam at the same doses as in the previous study or cefepime given at the standard recommended dose for age and weight. The median patient age was 4.2 years, with a range of 3.5 to 18 years. Most of the patients had been diagnosed with pyelonephritis, and 77 had at least one Gram-negative pathogen in the urine, with E. coli found in 92%. Clinical cure was defined in a manner similar to the earlier study. Microbiological cure was defined as eradication of the organism identified at the baseline urine culture. Clinical cure was reported in 48 of 54 (88%) of the ceftazidime-avibactam patients and 19 of the 23 cefepime patients (83%). Microbiological cure was seen in 43 (80%) and 14 (61%) patients in the two groups. Neither of the two tests was powered to determine a statistically significant difference in clinical efficacy.

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