Antimicrobial Pharmacokinetics in Xenotransplantation: A Priority for Patient Safety and Outcomes

Xenotransplantation may provide a viable, long-term solution to the organ shortage crisis. Genetically engineered swine are an ideal organ source due to the similarities in anatomy, physiology, and biochemistry with humans.1,2 The fields of veterinary medicine and animal husbandry have experience with effective dosing for routine antimicrobial use in swine, although pharmacokinetic (PK) parameters are not directly translatable in pig-to-human xenotransplantation. Understanding the PK of antimicrobials has implications for the effective management of infections in xenotransplantation, including clinical response to treatment, monitoring for antimicrobial-related adverse events (eg, toxicities, Clostridioides difficile infection), surveillance for reactivation of opportunistic infections, such as human herpesviruses, antibiotic prophylaxis, and prevention of the development of multidrug-resistant organisms. Specifically, antimicrobial PK can be studied to inform dosing and therapeutic drug monitoring practices in xenotransplantation. To date, there are limited PK and outcome data for antimicrobial agents and limited data on the antimicrobials that may be used to treat source pig-derived viruses. Nonhuman primate studies have been used to study the PK of immunosuppressants in xenotransplantation, but similar PK studies for antimicrobials are limited.3 Vancomycin metabolites were studied in a human decedent case to show that the PK properties of vancomycin were near expected values.3,4 We performed daptomycin therapeutic drug monitoring in a porcine GGTA1 KO xenothymokidney recipient with a left ventricular assist device whose posttransplant course was complicated by daptomycin-resistant Enterococcus faecalis bacteremia, treated with intravenous daptomycin in combination with intravenous ceftaroline for synergy. We measured daptomycin peak and trough levels for 4 days. The median peak and trough levels were 23 and 8.9 µg/mL, respectively, and the calculated Area under the concentration-time curve to minimum inhibitory concentration ratio (AUC/MIC) was consistently <20. Despite low AUC/MIC, bacteremia cleared rapidly. This single case highlights the potentialvalue of PK monitoring of antimicrobials to assess safety and efficacy and optimize patient outcomes.5 In the setting of the first in-human xenotransplantation cases and the initiation of clinical trials, we have established a working group to study the PK properties of antimicrobials in xenotransplantation. Xenotransplant products also vary in gene edits that can impact PK profiles. We advocate a systematic approach to studying antimicrobial PK in clinical trials to optimize care for individual xenotransplantation recipients and further enhance patient safety. These principles are summarized in Figure 1.FIGURE 1.: Rationale for study of antimicrobial pharmacokinetics in xenotransplantation.