EFFICACY AND SAFETY OF LETERMOVIR FOR CYTOMEGALOVIRUS PROPHYLAXIS IN THORACIC ORGAN TRANSPLANTATION: A SYSTEMATIC REVIEW AND META-ANALYSIS This systematic review1 and meta-analysis evaluated the efficacy and safety of letermovir for cytomegalovirus (CMV) prophylaxis in thoracic organ transplant recipients, including heart and lung transplants. Three hundred and eighty patients from 11 retrospective studies were analyzed. The analysis showed a low rate of breakthrough CMV infection (3.7%), low discontinuation due to adverse effects (1.7%), and improvement in leukopenia in majority of the patients. Low-level CMV viremia was found to be in 15.8%. Two studies compared letermovir with valganciclovir and found no statistically significant difference in breakthrough CMV infections. Overall, the authors concluded that letermovir appeared to be an effective and well-tolerated alternative for CMV prophylaxis in thoracic transplant recipients. DISCUSSION The study emphasizes on real-world outcomes, demonstrating the safety profile of letermovir. The results however are limited by retrospective study designs, short follow-up periods, and confounding data, as many patients were switched to letermovir after developing cytopenias. The observed improvements in leukopenia may be due to discontinuation of valganciclovir, rather than due to direct effects of letermovir. While this review focuses on thoracic transplantation, recent observational studies in the liver transplant cohort2 have also reported improved tolerability, fewer treatment interruptions, and successful completion of CMV prophylaxis with letermovir, particularly among those intolerant to valganciclovir. However, they too are based on small, nonrandomized cohorts with limited follow-up and do not demonstrate superiority over standard prophylactic regimens. Similar patterns have been noted in kidney transplant recipients,3 where more robust evidence is available. In the Indian context, where high medication costs and nonuniform access to CMV viral load monitoring are prevalent, routine first-line use of letermovir for all solid organ transplants may not be practical. In addition, drug interactions with calcineurin inhibitors such as tacrolimus, sirolimus, and everolimus need therapeutic drug monitoring (TDM). Letermovir TDM is currently not available easily in India. Hence, letermovir appears most suitable as a targeted second-line prophylactic for selected kidney, liver, and thoracic transplant recipients who are intolerant to valganciclovir. Well-designed prospective studies conducted in resource-limited settings are necessary before broad recommendations. INCIDENCE AND FACTORS ASSOCIATED WITH RAPID BLOOD CULTURE STERILIZATION AMONG PATIENTS RECEIVING ERTAPENEM COMBINATION THERAPY FOR METHICILLIN-SUSCEPTIBLESTAPHYLOCOCCUS AUREUS BACTEREMIA This multicenter retrospective study4 examined the rate of rapid blood culture clearance in patients with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia treated with ertapenem combination therapy. A total of 197 patients were included, nearly half of whom had definite endocarditis. Despite that, 85% achieved blood culture sterilization within 72 h of ertapenem initiation. Delayed blood culture clearance was mainly associated with higher oxacillin MIC (≥0.5 μg/mL) and greater illness severity and septic shock and not other clinical factors such as endocarditis, injection drug use, diabetes, or delayed source control. The authors propose that given the high rate of early clearance, a short 3-day course of ertapenem combination therapy could be considered as a stewardship-focused strategy in selected patients. DISCUSSION The rationale for adding ertapenem in MSSA bacteremia arises from pharmacodynamic observations in persistent infections with high bacterial burden, such as endocarditis and deep-seated abscesses. Standard β-lactams show reduced bactericidal activity due to the inoculum effect and incomplete saturation of penicillin-binding proteins (PBPs) in such cases. Ertapenem has high affinity for multiple PBPs, and hence, when combined with cefazolin or antistaphylococcal penicillins, it results in more complete PBP coverage and prolonged time above the minimum inhibitory concentration, leading to better bactericidal activity. This synergistic effect provides the pharmacological basis for faster clearance seen in refractory cases.5 While this study supports this concept by demonstrating high rates of early sterilization, its retrospective design and exclusion of patients who cleared bacteremia before ertapenem initiation limit the analysis of causality. It is unclear how many patients would have cleared bacteremia without ertapenem use, and faster clearance did not clearly improve the survival rate. In addition, hypoalbuminemia was not associated with delayed clearance in this cohort, although prior work by the same authors had suggested that low albumin levels may prolong bacteremia, possibly due to altered antibiotic pharmacokinetics.6 In the Indian context, where carbapenem resistance is a major concern, routine use of ertapenem for MSSA bacteremia should be avoided. This strategy should be restricted to selected cases of persistent or complicated bacteremia until prospective studies show clear clinical benefit. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Sujata Rege (Thu,) studied this question.