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Giving Critically Ill Children with Sepsis the Best Possible Antibiotic Therapy

Kelli Paice, MD*+
Katie Pavia, MD*+
Sonya Tang Girdwood, MD, PhD*@
Jennifer Kaplan, MD, MS+
Divisions of Critical Care Medicine+, Clinical Pharmacology* and Hospital Medicine@

When sick children with suspected infections arrive in the Pediatric Intensive Care Unit (PICU), the key therapy we use to treat them is broad-spectrum antibiotics. The most common antibiotics used to treat children are “beta-lactams,” which kill bacteria by targeting their cell wall. Beta-lactam antibiotics include familiar names like penicillin, but also critically important intravenous (“IV”) drugs used in the hospital like ceftriaxone, cefepime, piperacillin-tazobactam, and meropenem. A common mantra in the PICU is that the earlier antibiotics are started, the better! However, perhaps just as importantly, we need to be sure the doses we use lead to concentrations that maximize bacterial killing and minimize unnecessary toxicity to the child.
Physicians and researchers at Cincinnati Children’s are leading the way in studying the pharmacokinetics of beta-lactams in the pediatric ICU. Pharmacokinetics, or “PK” refers to how medications are absorbed, dispersed, metabolized, and cleared in the body. The changes in physiology that we see in critically ill children (lower blood pressure, higher heart rates, fever, need for respiratory support, or kidney injury, as just a few examples) mean that the same antibiotic dose can yield very different antibiotic concentrations compared to what might be measured in non-critically ill children. Further, when medications are studied to create packaging labels with recommendations for dose amount and frequency, critically ill children are not the population used in the studies to make these recommendations. Despite these concerns, levels of beta-lactam antibiotics are not routinely measured, making the assurance of effective dosing all the more unknown. Our current practice using a standard “one-size-fits-all” approach, in which the same dose and dosing intervals are prescribed for all patients, may not provide the best care to patients in the PICU.

For these reasons, our team is working to optimize antibiotic treatment through via multiple aims: 1. understand how to ensure adequate antibiotic concentrations in critically ill children; 2. recognize and avoid beta-lactam associated toxicities; and 3. determine when antibiotic dosing should be adjusted from the standard weight-based strategy. Projects underway include developing models to predict ceftriaxone and piperacillin-tazobactam levels in critically ill children; assessing how fluids given during early severe sepsis therapy affect meropenem concentrations; and defining cefepime-associated neurotoxicity and understanding which patients are most at risk.

Our team includes Kelli Paice, MD and Katie Pavia, MD, two 3rd year critical care and clinical pharmacology fellows (both have been awarded National Institutes of Health T32 fellowships in Pediatric Clinical Pharmacology and will be staying at CCHMC for an additional year devoted to research); Sonya Tang Girdwood, MD, PhD from the Divisions of Hospital Medicine and Clinical Pharmacology; and Jennifer Kaplan, MD, MS who is the Director of Clinical Research for the Division of Critical Care Medicine.

In the coming year we will be conducting multiple additional research studies in the PICU with the help of our clinical research coordinators, clinical research nurses, and colleagues from the Division of Clinical Pharmacology. Much of our work makes use of “opportunistic sampling”, where we obtain blood left over from labs collected for use in clinical care and measure the antibiotic concentrations in the remaining sample. This technique helps overcome one of the classic challenges of research in pediatric patients – avoiding a high burden of “pokes” and blood loss in our smallest patients. We aim to be one of the first children’s hospitals in the United States to provide in-house β-lactam antibiotic assays and an antibiotic precision dosing service to provide clinicians information on precision dosing of antibiotics. Overall, our team’s goal is to move closer to the ideal of “precision medicine” – where every child can be treated with medicines and procedures that are tailored to their unique physiology, genetics, and clinical situation.

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