This presentation explores how infection and use of anti-infective agents may alter drug pharmacokinetics and pharmacodynamics in the post-transplant period. Transplant recipients are inherently immunocompromised due to the use of immunosuppressive drugs, making them more susceptible to infections. Infections, in turn, may alter the pharmacokinetic and pharmacodynamic properties of both immunosuppressive agents and medicines used to manage infections in transplant recipients. Infectious episodes can potentially lead to changes in gut motility, flora and pH affecting drug absorption and enterohepatic recirculation; altered fluid status and plasma protein levels affecting drug distribution; and altered liver enzyme activity and hepatic and kidney function altering drug elimination. Such alterations may subsequently result in either subtherapeutic drug concentrations or toxicity, complicating the management of both the transplant and the infection. Furthermore, use of antibiotics, antivirals, antifungals with immunosuppressive agents can lead to pharmacokinetic or pharmacodynamic drug-drug interactions. Many drug-drug interactions occur secondary to effects on drug metabolizing enzymes or drug transporters. Certain anti-infective and immunosuppressant drug combinations can also increase the risk of drug toxicity including nephrotoxicity. Infections can additionally exacerbate the inflammatory response, leading to changes in immune system function. In some instances, infections may coexist with, or be difficult to distinguishable from, graft rejection and more studies examining infectious outcomes relative to immunosuppressant level targets are needed. Clinicians need to consider the unique challenges presented by infections in transplant recipients and employ strategies such as therapeutic drug monitoring and careful selection of antimicrobial agents to optimize therapeutic outcomes.

The aim of this symposium in to highlight the duality between a required immunosuppression in solid organ transplant recipients and the associated risk of infection. The symposium will first decipher the alteration of drugs PK and PD during infections in transplant patients. Indeed, a lot of pathophysiological modification can change drugs exposure and effect during infections and their mechanism and clinical impact will be highlighted as a first step. Then, the strategies for immunosuppressive dosing adjustment for infection prevention and the latest immunosuppression net state evaluation approach will be presented and the main results on these topics will be discussed. In the second part of the symposium, a comprehensive overview will be provided to the audience regarding therapeutic drug monitoring and dosing adjustments of immunosuppressive and anti-infective drugs in two clinical situations: bacterial infections, in particular when antituberculous drugs has to be used, and viral infections with a special focus on cytomegalovirus and COVID-19 and their treatment interplay with patient’s immunosuppressive therapy.

Infections with nontuberculous mycobacteria (NTM) are associated with significant disease in vulnerable hosts, including immunocompromised patients and patients with cystic fibrosis (CF). These infections can be challenging to treat due to high rates of resistance and the need for complex multi-drug regimens with prolonged courses. Despite the use of intensive regimens, rates of NTM treatment failure are high. Treatment is further complicated in vulnerable populations due to drug-drug interactions resulting in increased toxicity and altered drug levels. Notable interactions impacting drug metabolism occur between rifamycins and macrolides with immunosuppressive medications such as tacrolimus and cyclosporine. There are also significant interactions of rifamycins with the cystic fibrosis transmembrane conductance regulator modulator therapy elexacaftor-tezacaftor-ivacaftor. Further, numerous potential interactions of antimycobacterial agents and immunosuppressive therapies lead to increased risk of toxicity. Treatment of NTM is further complicated by a lack of PK-PD evidence to support current dosing strategies. Most dosing recommendations are based on typical pathogens such as Pseudomonas, but recent studies indicate that these approaches may not be effective for NTM. More precise TDM is needed in this population, with consideration of unique PK-PD and interactions with other medications, but guidance regarding this approach is sparse. This session will discuss how closer TDM may improve clinical outcome and reduce toxicity during treatment of NTM in immunosuppressed patients and in patients with CF.

Treatment of viral infections in transplant recipients is challenging due to high inter-and intrapatient pharmacokinetic variability of immunosuppressive and antiviral drugs, their narrow therapeutic window and many clinically significant drug-drug interactions. Insufficient exposure can lead to clinical failure or even graft rejection, while overexposure can lead to heightened risk of adverse events and toxicity.
Nirmatrelvir/ritonavir which is used for treatment of early Covid-19 can significantly increase the concentration of immunosuppressants which undergo hepatic metabolism via CYP450. On the other hand overexposure to some antiviral drugs for treatment of CMV can lead to enhanced nephrotoxicity and neurotoxicity, while others can increase the levels of immunosuppressive drugs.
With therapeutic drug monitoring we can tailor antiviral and immunosuppressive treatments to the individual patient. With TDM we can mitigate risk for under-or overexposure. Therapeutic drug monitoring (TDM) of some immunosuppressive drugs, such as calcineurin inhibitors and mammalian target of rapamycin (mTOR) inhibitors used in transplant patients is performed routinely, while TDM of antivirals is not available in all institutions. Management of concurrent treatment with antiviral drugs for treatment of Covid-19 and CMV will be presented with a synthesis of current advances in this field.
Regarding the title, I have made just a small change: TDM and dosing adjustments during viral (CMV and Covid) infections in the transplant recipients.