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.

Translation and linguistic validation of the Persian version of the International consultation on Incontinence Questionnaire Vaginal Symptoms.

BACKGROUND: There is no validated measurement tool to assess vaginal symptoms (VS), sexual matter (SS), and quality of life (QOL) among Persian-speaking women. This study aimed at translating and assessing the validity and reliability of the Persian version of the International Consultation on Incontinence Questionnaire for Vaginal Symptoms (PICIQ-VS). MATERIALS AND METHODS: In this cross-sectional study, after obtaining permission from the International Consultation on Incontinence Questionnaire (ICIQ) Advisory Board, the English version of ICIQ-VS was translated into Persian per a standard translate and back translate process, and the validity and reliability were studied. Two hundred women with and without pelvic organ prolapse were asked to complete the PICIQ-VS (mean age: 52.1, range: 22-84 years). A panel of 10 experts evaluated the content and face validity of the questionnaire. Cronbach's alpha examined the internal consistency reliability of the measure. To evaluate the test-retest reliability, we redistributed the questionnaire among 30 patients 2 weeks after their initial visit using intra-class correlation coefficient (ICC). RESULTS: Content and face validity of the questionnaire was confirmed after some light modification (content validity ratio ranged from 0.69 to 1.00, and content validity index ranged from 0.79 to 1.00). PICIQ-VS showed an acceptable internal consistency and stability reliability (VS: α = 0.64, ICC = 0.84; SM: α = 0.69, ICC = 0.88; and total scale: α = 0.72, ICC = 0.91, respectively). Significant differences were observed between the asymptomatic and symptomatic groups for VS and the total score (P < 0.05). CONCLUSION: In the light of the results, interestingly, PICIQ-VS could be utilized as a valid and reliable tool to assess the VS among Persian-speaking women, both in research and clinical practice.

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.

Association of daptomycin dosing regimen and mortality in patients with VRE bacteraemia: a review.

VRE are associated with ∼1300 deaths per year in the USA. Recent literature suggests that daptomycin, a cyclic lipopeptide antibiotic with concentration-dependent bactericidal activity, is the preferred treatment option for VRE bacteraemia, yet the optimal dosing strategy for this indication has not been established. In vitro evidence suggests that higher-than-labelled doses of daptomycin are required to optimally treat VRE bacteraemia and to inhibit the development of resistance. However, concern of dose-dependent toxicities, notably increases in creatine phosphokinase and the development of rhabdomyolysis, are a barrier to initiating high-dose schemes in clinical practice. Thus, the effectiveness and safety of high-dose daptomycin regimens in clinical practice have remained unclear. While early studies failed to identify differences in mortality, newer, larger investigations suggest high-dose (≥9 mg/kg) daptomycin is associated with reduced mortality in patients with VRE bacteraemia compared with standard (6 mg/kg) dosing regimens. Additionally, the high-dose regimens appear to be safe and may be associated with improved microbiological outcomes. The purpose of this review is to examine the published evidence on the effectiveness and safety of high-dose daptomycin compared with standard dosing regimens for VRE bacteraemia.

A multicentre stewardship initiative to decrease excessive duration of antibiotic therapy for the treatment of community-acquired pneumonia.

Background: The increased emphasis on pneumonia-related performance measures and patient outcomes has led hospitals to implement multifaceted approaches to quickly identify patients with community-acquired pneumonia (CAP), start timely therapy and reduce readmission. However, there has been minimal focus on duration of therapy (DOT) and patients often receive prolonged antibiotic courses. The IDSA and American Thoracic Society (IDSA/ATS) CAP guidelines recommend 5 days of therapy for clinically stable patients that quickly defervesce and stewardship teams are well positioned to influence prescribing practices. Objectives: Determine the impact of a prospective stewardship intervention on total antibiotic DOT and associated clinical outcomes in hospitalized patients with CAP. Methods: This multicentre, quasi-experimental study evaluated three concurrent interventions over a 6 month period to promote appropriate DOT. All centres updated institutional CAP guidelines to promote IDSA/ATS-concordant DOT, provided education and conducted daily audit and feedback with intervention to provide patient-specific DOT recommendations. Results: A total of 600 patients with CAP were included (307 in the historical control group and 293 in the stewardship intervention group). The stewardship intervention increased compliance with DOT recommendations (42% versus 5.6%, P < 0.001) and reduced the median DOT per patient (6 versus 9 days, P < 0.001). Clinical outcomes, including mortality, readmission with pneumonia, presentation to the emergency centre/clinic with pneumonia and incidence of Clostridium difficile infection within 30 days of discharge, were not different between groups. Conclusions: This multicentre evaluation of a stewardship intervention in hospitalized CAP patients reduced the total antibiotic DOT and increased guideline-concordant DOT without adversely affecting patient outcomes.

Disease-based antimicrobial stewardship: a review of active and passive approaches to patient management.

Although new antimicrobial stewardship programmes (ASPs) often begin by targeting the reduction of antimicrobial use, an increasing focus of ASPs is to improve the management of specific infectious diseases. Disease-based antimicrobial stewardship emphasizes improving patient outcomes by optimizing antimicrobial use and increasing compliance with performance measures. Directing efforts towards the comprehensive management of specific infections allows ASPs to promote the shift in healthcare towards improving quality, safety and patient outcome metrics for specific diseases. This review evaluates published active and passive disease-based antimicrobial stewardship interventions and their impact on antimicrobial use and associated patient outcomes for patients with pneumonia, acute bacterial skin and skin structure infections, bloodstream infections, urinary tract infections, asymptomatic bacteriuria, Clostridium difficile infection and intra-abdominal infections. Current literature suggests that disease-based antimicrobial stewardship effects on medical management and patient outcomes vary based on infectious disease syndrome, resource availability and intervention type.

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.

Significant Publications on Infectious Diseases Pharmacotherapy in 2018.

PURPOSE: To summarize the top 10 most influential peer-reviewed infectious diseases (ID) pharmacotherapy articles published in the year 2018. SUMMARY: Members of the Houston Infectious Diseases Network (HIDN) nominated articles that were thought to have most notably contributed to ID pharmacotherapy in 2018, including those related to human immunodeficiency virus (HIV). A total of 26 articles were nominated: 22 articles pertaining to general ID pharmacotherapy and 4 articles involving HIV/AIDS. To select the most significant articles of 2018, a survey was created and distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) asking members to vote on their top 10 general ID publications and 1 HIV publication. Of the 462 members surveyed, 213 (46%) and 108 (23%) voted for general ID pharmacotherapy- and HIV-related articles, respectively. The top article(s) for both categories are summarized. CONCLUSION: With the increased emphasis on antimicrobial stewardship initiatives and the growing problem of multidrug-resistant (MDR) organisms, the amount of ID literature centered on stewardship, appropriate treatment durations, and newly approved antimicrobial agents continues to expand, making it challenging for clinicians to stay informed on the most relevant publications. This review summarizes significant ID-related publications in 2018 with the goal of aiding clinicians in staying up to date on the most noteworthy publications in ID pharmacotherapy.

Significant Publications on Infectious Diseases Pharmacotherapy in 2017.

PURPOSE: The most significant peer-reviewed articles pertaining to infectious diseases (ID) pharmacotherapy, as selected by panels of ID pharmacists, are summarized. SUMMARY: Members of the Houston Infectious Diseases Network (HIDN) were asked to nominate peer-reviewed articles that they believed most contributed to the practice of ID pharmacotherapy in 2017, including the areas of human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). A list of 33 articles related to general ID pharmacotherapy and 4 articles related to HIV/AIDS was compiled. A survey was distributed to members of the Society of Infectious Diseases Pharmacists (SIDP) for the purpose of selecting 10 articles believed to have made the most significant impact on general ID pharmacotherapy and the single significant publication related to HIV/AIDS. Of 524 SIDP members who responded, 221 (42%) and 95 (18%) members voted for general pharmacotherapy- and HIV/AIDS-related articles, respectively. The highest ranked articles are summarized below. CONCLUSION: Remaining informed on the most significant ID-related publications is a challenge when considering the large number of ID-related articles published annually. This review of significant publications in 2017 may aid in that effort.

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.