Smith PB, Cotten CM, Hudak ML, Sullivan JE, Poindexter BB, Cohen-Wolkowiez M, Boakye-Agyeman F, Lewandowski A, Anand R, Benjamin DK Jr, Laughon MM; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.
Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach.
Early this summer, Lucas,* a one-month-old infant born 9 weeks prematurely, was receiving routine respiratory support in the neonatal intensive care unit at the University of North Carolina Children’s Hospital when he suddenly developed a dangerous neck abscess. Upon testing, the infection was found to be caused by methicillin-resistant Staphylococcus aureus (MRSA) bacteria. Staphylococcus infections in general can be life-threatening in the NICU, but because MRSA is resistant to many commonly used antibiotic therapies, Lucas’ treatment options were limited from the outset.
Dr. Jackie Patterson, UNC Children’s Hospital
Neonatologist Jackie Patterson, who was caring for Lucas in the NICU, immediately turned to the medical literature to determine the best course of treatment. During her search, she found an article published in the May 2016 issue of Antimicrobial Agents and Chemotherapy that was directly relevant to Lucas’ case. The article reported results from a trial sponsored by the Pediatric Trials Network (PTN) that explored dosing for antibiotics including clindamycin in infants being treated for staph infections.
Clindamycin was originally approved by the FDA in 1997 and is used to treat bacterial infections when other antibiotics, including penicillin and methicillin, are ineffective. The PTN “Anti-Staph Trio” study, a multicenter trial that evaluated 3 different antibiotic therapies for staph infections, was designed to identify drug dosages appropriate for use in term and pre-term infants—information that was not available in existing product labeling.
By combining their findings with pharmacokinetic and safety data from two other studies, the authors were able to describe a dosing regimen for clindamycin in premature infants based on postmenstrual age and total body weight that would allow physicians to effectively treat the infection while avoiding unwanted side effects.
Dr. Patterson knew, based on lab results, that Lucas’ particular strain of MRSA was sensitive to clindamycin. Thanks to the data published in the PTN study, she was able to choose a dosing strategy that would be most effective for Lucas.
“After only a couple of days, we saw a dramatic improvement with no adverse effects,” she said. Lucas recovered completely by the end of the week-long treatment, and was discharged healthy later in the summer.
Although Lucas’s parents had initial concerns about the treatment, they were reassured when Dr. Patterson referenced the study.
“We were confident about our treatment because of the literature,” she said. “This made the family confident in us.”
However, Dr. Patterson noted that this is not always the case, pointing out that information to guide dosing for infants and premature neonates is often sorely lacking.
“In pediatrics, we’re often extrapolating from adult data,” Dr. Patterson said. “In part because families are reluctant to enroll their children in clinical trials, it’s hard to find data specifically related to infants and children.”
Bridging this gap is a key goal for the PTN, an alliance of more than 100 clinical research sites cooperating in the design and conduct of pediatric clinical trials. Sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the PTN works to improve healthcare for the youngest patients by providing much-needed information on optimal dosing of commonly used drugs.
“The work that PTN is doing is critical,” Dr. Patterson said. “Especially when working with life-threatening conditions in the newborn population, the more science behind our medical practices, the more confident we can be that we will deliver the best outcomes for our patients and their families.”
*Name has been changed to protect confidentiality.
Antimicrobial Agents and Chemotherapy • March 2017.
Smith MJ, Gonzalez D, Goldman JL, Yogev R, Sullivan JE, Reed MD, Anand R, Martz K, Berezny K, Benjamin DK Jr, Smith PB, Cohen-Wolkowiez M, Watt K; Best Pharmaceuticals for Children Act—Pediatric Trials Network Steering Committee.
Although obesity is prevalent among children in the United States, pharmacokinetic (PK) data for obese children are limited. Clindamycin is a commonly used antibiotic that may require dose adjustment in obese children due to its lipophilic properties. We performed a clindamycin population PK analysis using data from three separate trials. A total of 420 samples from 220 children, 76 of whom had a body mass index greater than or equal to the 95th percentile for age, were included in the analysis. Compared to other metrics, total body weight (TBW) was the most robust measure of body size.
Dr. Barry Bloom and Ms. Paula Delmore at Wesley Medical Center in Wichita, Kansas, have enrolled the first baby into the Pharmacokinetics of Anti-staphylococcal Antibiotics in Infants trial. The infant—born at 24 weeks gestation and now 52 days old—is receiving clindamycin, one of three anti-staphylococcal antibiotics routinely used in preemies to treat staphylococcal infections.
Seventy percent of late-onset infections in the neonatal intensive care unit are due to staphylococcal species, many of which are methicillin-resistant. Infants with these infections experience long hospitalizations and have an increased risk of septic shock, severe necrotizing pneumonia, and neurodevelopmental impairment, as well as a high risk of death (up to 40%). Rifampin, clindamycin, and ticarcillin-clavulanate are used to fight staphylococcal species, but the correct dosing and safety of these antibiotics has not been established for all infant populations.
This study will measure the levels of rifampin, clindamycin, or ticarcillin-clavulanate in enrolled babies, thereby gauging how the infant body absorbs and distributes the drugs. By understanding these pharmacokinetic properties, we can determine the best doses for treating staphylococcal infections in these vulnerable patients.
The trial will enroll up to 32 infants for each drug. The drugs will be given over 2–4 days, and the infants will be monitored for another 7 days for any drug side effects. To find out more about this study, visit ClinicalTrials.org.
