BACKGROUND Historically, there is perceived pressure to achieve therapeutic levels of tacrolimus quickly after heart transplant (HT). We evaluated the association between time within therapeutic tacrolimus range and time to therapeutic trough and rejection in the 30 days following HT. METHODS This is a single-center retrospective cohort study of consecutive adult HT patients receiving immunosuppression. Goal trough tacrolimus levels were 10-15 ng/ml. Surveillance endomyocardial biopsies were performed weekly for 4 weeks. Outcomes included the effect of time to and timein-therapeutic tacrolimus range (Rosendaal method) on 30-day clinical rejection, 1R/1B, and 2R or higher histologic occurrences. RESULTS We reviewed 67 HT patients (median age 58.8 yrs). For clinical rejection versus no-rejection groups, the median (25th, 75th percentile) time to therapeutic tacrolimus levels was 9.5 (8, 12.3) days versus 9.0 (7, 13) days (p=0.623). The median time-in-therapeutic tacrolimus range was 34.1% (23.2, 42.2) versus 36.2% (19.9, 51.2), respectively (p=0.512). Similarly, we observed no significant differences in time to and time-in-therapeutic tacrolimus range in patients who developed grade 1R/1B (p=0.650 and p=0.725) or grade 2R or higher histology (p=0.632 and p=0.933). CONCLUSIONS Our small single-center analysis suggests that neither time to nor time in therapeutic tacrolimus range predicted acute rejection within 30 days of HT.

Candida spp. are the fourth leading cause of nosocomial blood stream infections in North America. Candida glabrata is the second most frequently isolated species, and rapid development of antifungal resistance has made treatment a challenge. In this study, we investigate the therapeutic potential of metformin, a biguanide with well-established action for diabetes, as an antifungal agent against C. glabrata. Both wild type and antifungal-resistant isolates of C. glabrata were subjected to biguanide and biguanide-antifungal combination treatment. Metformin, as well as other members of the biguanide family, were found to have antifungal activity against C. glabrata, with MIC50 of 9.34 ± 0.16 mg/mL, 2.09 ± 0.04 mg/mL and 1.87 ± 0.05 mg/mL for metformin, phenformin and buformin, respectively. We demonstrate that biguanides enhance the activity of several antifungal drugs, including voriconazole, fluconazole, and amphotericin, but not micafungin. The biguanide-antifungal combinations allowed for additional antifungal effects, with fraction inhibition concentration indexes ranging from 0.5 to 1. Furthermore, metformin was able to lower antifungal MIC50 in voriconazole and fluconazole-resistant clinical isolates of C. glabrata. We also observed growth reduction of C. glabrata with rapamycin and an FIC of 0.84 ± 0.09 when combined with metformin, suggesting biguanide action in C. glabrata may be related to inhibition of the mTOR complex. We conclude that the biguanide class has direct antifungal therapeutic potential and enhances the activity of select antifungals in the treatment of resistant C. glabrata isolates. These data support the further investigation of biguanides in the combination treatment of serious fungal infections.

Urinary tract infections represent one of the most frequent reasons for hospitalization. As a result of their prevalence from community-based origins as well as those which develop in hospital setting, this constellation of infections represents a tremendous burden to the global healthcare system. Areas covered: Over the last several decades the management of these infections has become more complicated due to the underlying comorbid conditions of the patients as well as escalating antimicrobial resistance to many of the most frequently used oral and parenteral agents. One such example is the emergence of extend spectrum β-lactamase-producing (ESBL) bacteria that render many of the most frequently utilized oral and parenteral penicillin and cephalosporin based regimens of little clinical utility. As such new treatment strategies are required to effectively manage the growing population of patients with multi-drug resistant bacteria. Expert commentary: Herein, we review some of the current literature which reveals the challenges associated with the contemporary management of UTIs, while presenting strategies such as the implementation of clinical pathways that have the potential to enhance the quality and efficiency of care while reducing the overall cost of care.

AZD7442 (tixagevimab-cilgavimab) is a combination of two human monoclonal antibodies for preexposure prophylaxis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among highrisk patients who do not mount a reliable vaccine response. Foremost among these are hematologic malignancy patients with limited clinical trial or real-world experience to assess the effectiveness of this combination treatment since the emergence of Omicron and its subvariants. We performed a retrospective study of 892 highrisk hematologic malignancy patients who received AZD7442 at Memorial Sloan Kettering Cancer Center in New York City from January 1, 2022 to July 31, 2022. We evaluated demographic, clinical, and laboratory characteristics and performed regression analyses to evaluate risk factors for breakthrough infection. We also evaluated the impact of updated AZD7442 dosing regimens on the risk of breakthrough infection. Among 892 patients, 98 (10.9%) had a breakthrough infection during the study period. A majority received early outpatient treatment (82%) and eventually eight (8.2%) required hospitalization for management of Coronavirus Disease 2019 (COVID-19), with a single instance of severe COVID-19 and death. Patients who received a repeat dose or a higher first-time dose of AZD7442 had a lower incidence of breakthrough infection. Univariate analyses did not reveal any significant predictors of breakthrough infection. While AZD7442 is effective at reducing SARS-CoV-2 breakthrough infection in patients with hematologic malignancies, no risk factors reliably predicted risk of infection. Patients who received updated dosing regimens as per Food and Drug Administration guidelines had better protection against breakthrough infection.

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