Following a year of valganciclovir prophylaxis, a lung transplant recipient developed cytomegalovirus (CMV) infection that became resistant to ganciclovir, as confirmed by detection of UL97 kinase mutation M460V and a previously uncharacterized UL54 DNA polymerase mutation L516P. The latter mutation is now shown to confer ganciclovir and cidofovir resistance. As predicted from the viral genotype, foscarnet therapy was effective, but resumption of valganciclovir as secondary prophylaxis resulted in a plasma viral load rebound to 3.6 log10 copies/mL several weeks later. Valganciclovir was then replaced by letermovir, resulting in gradual viral load reduction in the first 5 weeks to below the quantitation limit (2.7 log10 copies/mL) for one week, followed by 10 weeks of rising viral loads reaching 4.3 log10 copies/mL while on letermovir. At this point, CMV genotypic testing revealed UL56 mutation C325Y, which confers absolute resistance to letermovir. Retreatment with foscarnet was successful. This case adds to the considerable list of proven ganciclovir resistance mutations, and provides an early experience with letermovir resistance after off-label therapeutic use. This experience is consistent with in vitro observations of rapid emergence of letermovir-resistant CMV after drug exposure.

Background Lung transplant recipients are at heightened risk for nocardiosis compared to other solid organ transplant recipients, with incidence rates as high as 9% and up to 30% associated mortality. No controlled studies assessing risk factors for nocardiosis in this high‐risk population have been reported. Methods Patients undergoing lung transplantation at a single center between 2012 and 2018 and diagnosed with nocardiosis post‐transplant were matched 1:2 to uninfected control subjects on the basis of age, transplant date, and sex. Results The incidence of nocardiosis in this lung transplant population was 3.4% (20/586), occurring a median of 9.4 months (range 4.4‐55.2) post‐transplant. In multivariable analysis, consistent use of trimethoprim/sulfamethoxazole (TMP/SMX) in the 12 weeks prior to diagnosis was independently associated with protection against nocardiosis (OR 0.038; 95% CI 0.01‐0.29; P = .002). Augmented immunosuppression in the 6 months prior to diagnosis was independently associated with the development of nocardiosis (OR 9.94; 95% CI 1.62‐ 61.00; P = .013). Six case patients (30%) had disseminated disease; all‐cause 6‐month mortality was 25%. The most common species was Nocardia farcinica (7/17 isolates), which was associated with dissemination and mortality. The most active antibiotics were TMP/SMX (100%), linezolid (100%), and amikacin (76%). Imipenem was only active against 4/17 isolates (24% susceptibility), with two isolates becoming non‐susceptible later in therapy. Conclusions Trimethoprim/sulfamethoxazole prophylaxis was shown to be protective against nocardiosis in lung transplant recipients, while augmented immunosuppression conferred increased risk. Institutional epidemiologic data are needed to best guide empiric therapy for Nocardia, as historical in vitro data may not predict local susceptibilities.

Background Lung transplant recipients residing in the endemic region are vulnerable to severe morbidity and mortality from Coccidioides. As infection risk persists beyond the first post-transplant year, investigations evaluating extended prophylaxis durations are needed. The purpose of this study is to assess the incidence of coccidioidomycosis among lung transplant recipients receiving universal lifelong azole antifungal prophylaxis. Methods Recipients transplanted 2013-2018 and initiated on azole antifungal prophylaxis at a lung transplantation center in Arizona were included and followed through 2019 or until death, second transplant, or loss to follow-up. Recipients who died or received treatment for coccidioidomycosis during the transplant admission, or who had received a previous transplant were excluded. The primary outcome was proven or probable coccidioidomycosis with new asymptomatic seropositivity assessed secondarily. Results A total of 493 lung transplant recipients were included, with 82% initiated on itraconazole prophylaxis, 9.3% on voriconazole, and 8.5% on posaconazole. Mean age at transplant was 62 years, 77% were diabetic, and 8% were seropositive for Coccidioides pre-transplant. After a median follow-up of 31 months, one proven infection and one case of new asymptomatic seropositivity (1/493 each, 0.2% incidence) occurred during the study period. The single coccidioidomycosis case occurred 5 years post-transplant in a patient who had azole prophylaxis stopped several months prior. Although within-class switches were common throughout the study period, permanent discontinuation of azole prophylaxis was rare (1.4% at end of follow-up). Conclusions Universal lifelong azole prophylaxis was associated with a low rate of coccidioidomycosis among lung transplant recipients residing in endemic regions.