Utility of Therapeutic Drug Management (TDM) in Managing Plazomicin Pharmacokinetic (PK) Variability in Patients With Infections Due to Carbapenem-Resistant Enterobacteriaceae (CRE)

Abstract

Background. Variability of antibiotic PK in the critically ill can result in adverse outcomes. TDM for aminoglycosides helps to reduce PK variability and risk of nephrotoxicity. Plazomicin, a novel aminoglycoside active against carbapenem-resistant Enterobacteriaceae (CRE) is in development to treat patients with serious infections. In the CARE study (ACHN-490-007), a non-randomized cohort of patients with bloodstream infection (BSI), hospital-acquired/ventilator-associated pneumonia (HAP/ VAP) or complicated urinary tract infection (cUTI) due to CRE receive plazomicin treatment with dosing guided by TDM. The aims of this analysis are to assess the frequency of dose adjustment based on TDM and to evaluate renal function in the first 10 patients enrolled. Methods. Initial plazomicin doses were chosen based on weight, with adjustment by renal function or use of continuous renal replacement therapy (CRRT). TDM samples were drawn on Days 1, 4 and 8 and on other days if warranted by patient status. Plazomicin doses were adjusted based on TDM results to achieve a steady-state AUC0-24 of -262 mg/L hr (target range 200 to 400 mg/L hr). Serum creatinine was evaluated daily on therapy and at test of cure (TOC). Results. Nine patients were male and the median age was 74 years. Four patients had BSI, 5 HAP/VAP, and 1 cUTI. All infections were due to Klebsiella pneumoniae; 8 isolates were confirmed to be carbapenem resistant and 8 were non-susceptible to at least one aminoglycoside. Renal function at baseline was highly variable, ranging from renal failure requiring CRRT to augmented renal clearance (creatinine clearance range 36 to 224 mL/min by Cockcroft-Gault). Patients received 4 to 14 days of plazomicin. One to 3 dose adjustments, informed by TDM, were required in 8 patients. Two patients experienced transient rises in creatinine (60-87%) early in therapy, which resolved within 2 days. Renal injury in a third patient on day 8 was assessed by the investigator as related to septic shock. No patients showed renal injury at TOC. Conclusion. Early data from this study illustrate the utility of TDM in managing PK variability in the critically ill. With the use of TDM, plazomicin was not associated with substantial kidney injury in this subset of critically ill patients with CRE. This project was funded under BARDA Contract No. HHSO100201000046C.