Refractory and Resistant Cytomegalovirus After Hematopoietic Cell Transplant in the Letermovir Primary Prophylaxis Era.

BACKGROUND: Cytomegalovirus (CMV) reactivation is one of the most common infectious complications after allogeneic hematopoietic cell transplant (HCT) and may result in significant morbidity and mortality. Primary prophylaxis with letermovir demonstrated a reduction in clinically significant CMV infections (CS-CMVi) in clinical trials of CMV-seropositive HCT recipients. This study aims at exploring the effect of primary letermovir prophylaxis in this population on the incidence and outcomes of refractory or resistant CMV infections. METHODS: This is a single-center, retrospective cohort study of 537 consecutive CMV-seropositive allogeneic HCT recipients cared for between March 2016 and October 2018. Baseline demographics, HCT characteristics, CMV infections, treatment, and mortality data were collected from the electronic medical record. CMV outcomes were defined according to the recently standardized definitions for clinical trials. Characteristics and outcomes were assessed according to receipt of primary letermovir prophylaxis. RESULTS: Of 537 patients identified, 123 received letermovir for primary prophylaxis during the first 100 days after HCT; 414 did not. In a multivariate analysis, primary prophylaxis with letermovir was associated with reductions in CS-CMVi (hazard ratio [HR] 0.26; 95% confidence interval [CI], 0.16-0.41), CMV end-organ disease (HR 0.23; 95% CI, 0.10-0.52), refractory or resistant CMV infection (HR 0.15; 95% CI, 0.04-0.52), and nonrelapse mortality at week 48 (HR 0.55; 95% CI, 0.32-0.93). There was neither resistant CMV nor CMV-related mortality in the primary letermovir prophylaxis group. CONCLUSIONS: Primary letermovir prophylaxis effectively prevents refractory or resistant CMV infections and decreases nonrelapse mortality at week 48, as well as CS-CMVi and CMV disease after allogeneic HCT.

The Impact of Penicillin Skin Testing on Aztreonam Stewardship and Cost Savings in Immunocompromised Cancer Patients.

OBJECTIVE: Reported penicillin allergies result in alternative antimicrobial use and are associated with worse outcomes and increased costs. Penicillin skin testing (PST) has recently been shown to be safe and effective in immunocompromised cancer patients, yet its impact on antimicrobial costs and aztreonam utilization has not been evaluated in this population. METHOD: From September 2017 to January 2018, we screened all admitted patients receiving aztreonam. Those with a self-reported history of possible immunoglobulin E (IgE)-mediated reaction to penicillin were eligible for PST with oral challenge. RESULTS: A total of 129 patients were screened, and 49 patients were included and underwent testing. Sixteen patients (33%) had hematologic malignancies and 33 patients (67%) had solid tumors. After PST with oral challenge, 46 patients (94%) tested negative, 1 patient tested positive on oral challenge, and 2 patients had indeterminate results. The median time from admission to testing was 2 days (interquartile range, 1-4). After testing negative, 33 patients (72%) were switched to beta-lactam therapy, which resulted in a total of 390 days of beta-lactam therapy. For identical therapy durations, the direct total antibiotic cost was $15 138.89 for beta-lactams versus $78 331.50 for aztreonam, resulting in $63 192.61 in projected savings. A significant reduction in median days of aztreonam therapy per 1000 patient days (10.0 vs 8.0; P = .005) was found during the intervention period. CONCLUSIONS: Use of PST in immunocompromised cancer patients receiving aztreonam resulted in improved aztreonam stewardship and significant cost savings. Our study demonstrates that PST with oral challenge should be considered in all cancer patients with reported penicillin allergies.

Safety, Efficacy, and Clinical Impact of Penicillin Skin Testing in Immunocompromised Cancer Patients.

BACKGROUND: Use of penicillin skin testing (PST) to rule out penicillin (PCN) allergies is safe and effective in immunocompetent patients; however, data on immunocompromised patients are limited. OBJECTIVE: We aimed to determine safety, efficacy, and clinical impact of PST in immunocompromised patients with cancer. METHODS: A quality improvement process establishing a PST service was implemented at MD Anderson Cancer Center. Adult patients admitted to leukemia and genitourinary medical oncology (GUMO) services with history of possible type I reactions to PCN were eligible for testing. RESULTS: Between April and October 2017, 218 patients with reported PCN allergies were screened; 100 met inclusion criteria and underwent PST (67 leukemia, 33 GUMO). The most common reported allergy was to PCN (64%), with 61% reporting cutaneous reactions and 79% reporting reactions more than 20 years ago. PST with oral challenge results were overwhelmingly negative (95%); only 4% tested positive, and 1 test result was indeterminate (negative histamine control). After negative PST and oral challenge results, 51% patients were transitioned to PCN-based antibiotics during the same hospitalization. During the follow-up period (median 177 days), 65 of 95 patients were readmitted (185 total readmissions), and 51 patients required antibiotic therapy, with 37 receiving a PCN-based antibiotic (accounting for 336 days of therapy). No patient who received PCN-based antibiotics experienced an immediate-type allergic reaction. CONCLUSIONS: Our findings support PST use in immunocompromised hosts. The widespread use of PST in patients with cancer will allow for optimal use of antimicrobial therapy and stewardship, which are vital in a population at increased risk for infections.

Oral Versus Aerosolized Ribavirin for the Treatment of Respiratory Syncytial Virus Infections in Hematopoietic Cell Transplant Recipients.

BACKGROUND: The use of oral ribavirin (RBV) for respiratory syncytial virus (RSV) infections is not well studied. With the drastic increase in the cost of aerosolized RBV, we aimed to compare outcomes of hematopoietic cell transplant (HCT) recipients treated with oral or aerosolized RBV for RSV infections. METHODS: We reviewed the records of 124 HCT recipients with RSV infections treated with oral or aerosolized RBV from September 2014 through April 2017. An immunodeficiency scoring index (ISI) was used to classify patients as low, moderate, or high risk for progression to lower respiratory infection (LRI) or death. RESULTS: Seventy patients (56%) received aerosolized RBV and 54 (44%) oral RBV. Both groups had a 27% rate of progression to LRI (P = 1.00). Mortality rates did not significantly differ between groups (30-day: aerosolized 10%, oral 9%, P = 1.00; 90-day: aerosolized 23%, oral 11%, P = .10). Classification and regression tree analysis identified ISI ≥7 as an independent predictor of 30-day mortality. For patients with ISI ≥7, 30-day mortality was significantly increased overall, yet remained similar between the aerosolized and oral therapy groups (33% for both). After propensity score adjustment, Cox proportional hazards models showed similar mortality rates between oral and aerosolized therapy groups (30-day: hazard ratio [HR], 1.12 [95% confidence interval {CI}, .345-3.65, P = .845). CONCLUSIONS: HCT recipients with RSV infections had similar outcomes when treated with aerosolized or oral RBV. Oral ribavirin may be an effective alternative to aerosolized RBV, with potential significant cost savings.

Letermovir for the prevention of cytomegalovirus infection in adult cytomegalovirus-seropositive hematopoietic stem cell transplant recipients.

INTRODUCTION: Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with significant morbidity and mortality. Although available anti-CMV therapies may be effective for the prevention of CMV, they are plagued by unacceptable toxicities that prohibit their use in the post-transplant period. Recently studied CMV-active agents, such as maribavir and brincidofovir, failed to reduce the incidence of CMV infection in HCT recipients. Letermovir represents the first agent in the non-nucleoside 3,4 dihydro-quinazoline class of CMV viral terminase complex inhibitors, with activity solely against CMV. The positive results from the recently published Phase III study of letermovir for prevention of CMV infection in CMV-seropositive allo-HCT recipients led to its approval as a prophylactic agent for CMV in multiple countries. Areas covered: In this review, we will evaluate this novel agent with a focus on letermovir mechanism of action, pharmacokinetics and metabolism, clinical efficacy, and safety and toxicities. Expert commentary: With the introduction of letermovir, prevention of CMV infection in allo-HCT recipients may shift considerably, from a predominantly preemptive strategy to one that utilizes this novel therapy for prophylaxis.

ZnT2-overexpression represses the cytotoxic effects of zinc hyper-accumulation in malignant metallothionein-null T47D breast tumor cells.

Human breast tumors accumulate abnormally high levels of zinc (Zn). As a result, numerous studies have implicated Zn hyper-accumulation in the etiology of breast cancer. Zinc accumulation can be cytotoxic, therefore cells have Zn-buffering mechanisms, such as metallothioneins (MT) and vesicular sequestration, which tightly regulate Zn homeostasis. The Zn transporter ZnT2 sequesters Zn into intracellular vesicles and thus can protect cells from Zn cytotoxicity. Herein, we report that malignant breast tumor (T47D) cells do not express MT but have approximately 4-fold greater Zn levels compared with non-malignant breast (MCF-10A) cells. Zinc accumulation coincided with ZnT2 over-expression and increased vesicular Zn pools. In this study, we hypothesized that ZnT2 suppression would eliminate protection from Zn accumulation and result in cytotoxicity in malignant breast tumor cells. Suppression of ZnT2 significantly increased cytoplasmic Zn pools (1.6-fold) as assessed with a Zn-responsive reporter assay containing four metal response elements (4X-MRE) fused to luciferase. Increased cytoplasmic Zn pools activated apoptosis in a caspase-independent manner. We observed significant generation of reactive oxygen species (ROS) (2.3-fold), lysosomal swelling and cathepsin D leakage in ZnT2-attenuated compared with ZnT2-expressing cells. Most importantly, tumor cell viability and tumor formation were significantly decreased (approximately 25%) in ZnT2-attenuated cells compared with ZnT2-expressing cells. Our data indicate that ZnT2 over-expression protects malignant MT-null breast tumor cells from Zn hyper-accumulation by sequestering Zn into intracellular vesicles. Moreover, our results implicate Zn compartmentalizing mechanisms as novel targets for breast cancer therapy.