Bacterial sepsis and septic shock are among the most common causes of admission to pediatric intensive care units (PICU) in the United States. Morbidity and mortality remain high for neonates, infants and children with increasingly complicated comorbidities (cancer, trauma, complex genetic and anatomic anomalies) with many being immune compromised from breaches in anatomic barriers with catheters (intravenous, bladder, pleural/mediastinal space, abdominal) as well as secondary to immune-ablative and immune-suppressive therapy. All children who present to the PICU with sepsis syndrome receive empiric antimicrobial therapy. Currently, doses of antimicrobial agents used for children in the PICU are based on pharmacokinetic descriptions of drug distribution and elimination in children without severe infections; this population is usually excluded from participation in FDA mandated clinical trials for safety and efficacy of new antibacterial agents. For infants and children with bacterial sepsis, attaining an antimicrobial drug exposure that is adequate for microbiologic and clinical cure is essential for survival. In these children, dramatic and rapid changes in kidney function during the first days of hospitalization for sepsis based on changes in cardiac output and organ perfusion can lead to increased or decreased renal elimination of antibiotics. Additional reasons for inadequate antibiotic exposure include leakage of fluids and antibiotics into tissues (capillary leak syndrome) and changes in circulating blood volume following massive intravenous fluid resuscitation (up to 100 mL/kg), not uncommon in septic shock. We plan to analyze antibiotic exposure and renal function in critically ill children receiving FDA-approved doses of a standard-of-care (SOC), generic beta-lactam antibiotic with broad spectrum antibacterial activity, meropenem, focusing on each of the first 3 days of admission, when the most dramatic alterations in physiology occur. By measuring plasma and urine concentrations in 50 children daily for the first 3 days in the PICU, we can define the adequacy of beta-lactam exposure with current SOC therapy. We will create pharmacokinetic-pharmacodynamic models, that can allow us to analyze physiologic factors, renal toxicity and function, sepsis scores, and laboratory tests/biomarkers that may be associated with subtherapeutic or potentially toxic exposures. Ultimately, we plan to present new antibiotic dosing guidelines for children with sepsis in the PICU, with the potential to optimize daily dosing to save lives and decrease sepsis-mediated morbidity.
It is essential that children with overwhelming bacterial infections are given therapeutic doses of antibiotics active against the infecting pathogens. Remarkably, FDA studies for antibiotic approval exclude children with sepsis and shock; pharmaceutical sponsors are unwilling to take on risks to support such studies. We propose to conduct the first prospective study of adequacy of antibiotic exposure in children during the first 3 days of hospitalization, when risk of death from sepsis is highest.
