Marisa Holubar, MD MS

All Publications

• Dr. Marisa Holubar on the "Mentorship Mindset" …promoting learning, building partnerships, and finding fulfillment. Antimicrobial stewardship & healthcare epidemiology : ASHE Holubar, M. 2023; 3 (1): e203

  View details for DOI 10.1017/ash.2023.412

  View details for PubMedID 38028890

  View details for PubMedCentralID PMC10654939

• A quality-improvement approach to urgent-care antibiotic stewardship for respiratory tract infections during the COVID-19 pandemic: Lessons learned. Infection control and hospital epidemiology Ong'uti, S. K., Artandi, M., Betts, B., Weng, Y., Desai, M., Lentz, C., Nelligan, I., Ha, D. R., Holubar, M. K. 2023: 1-6

  Abstract

  OBJECTIVE: We investigated a decrease in antibiotic prescribing for respiratory illnesses in 2 academic urgent-care clinics during the coronavirus disease 2019 (COVID-19) pandemic using semistructured clinician interviews.METHODS: We conducted a quality-improvement project from November 2020 to May 2021. We investigated provider antibiotic decision making using a mixed-methods explanatory design including interviews. We analyzed transcripts using a thematic framework approach to identify emergent themes. Our performance measure was antibiotic prescribing rate (APR) for encounters with respiratory diagnosis billing codes. We extracted billing and prescribing data from the electronic medical record and assessed differences using run charts, p charts and generalized linear regression.RESULTS: We observed significant reductions in the APR early during the COVID-19 pandemic (relative risk [RR], 0.20; 95% confidence interval [CI], 0.17-0.25), which was maintained over the study period (P < .001). The average APRs were 14% before the COVID-19 pandemic, 4% during the QI project, and 7% after the project. All providers prescribed less antibiotics for respiratory encounters during COVID-19, but only 25% felt their practice had changed. Themes from provider interviews included changing patient expectations and provider approach to respiratory encounters during COVID-19, the impact of increased telemedicine encounters, and the changing epidemiology of non-COVID-19 respiratory infections.CONCLUSIONS: Our findings suggest that the decrease in APR was likely multifactorial. The average APR decreased significantly during the pandemic. Although the APR was slightly higher after the QI project, it did not reach prepandemic levels. Future studies should explore how these factors, including changing patient expectations, can be leveraged to improve urgent-care antibiotic stewardship.

  View details for DOI 10.1017/ice.2023.8

  View details for PubMedID 36815249

• Validity of Coronavirus Disease 2019 International Classification of Diseases, Tenth Revision in the Urgent Care Setting and Impact on Antibiotic Prescribing Rates. Open forum infectious diseases Medvedeva, N., Ong'uti, S., Hersh, A. L., Chang, A., Mui, E., Stenehjem, E., Ha, D., Holubar, M. 2023; 10 (2): ofad010

  Abstract

  We validated  different coronavirus disease 2019 (COVID-19) International Classification of Diseases, Tenth Edition (ICD-10) encounter definitions across 2 urgent care clinics. Sensitivity of definitions varied throughout the pandemic. Inclusion of COVID-19 and COVID-19-like illness (CLI) ICD-10s rendered highest sensitivity but lowest specificity. Antibiotic prescribing rates were low for COVID-19 ICD-10 encounters, increasing with CLI ICD-10 encounters.

  View details for DOI 10.1093/ofid/ofad010

  View details for PubMedID 36751646

  View details for PubMedCentralID PMC9897297

• Comprehensive Guidance for Antibiotic Dosing in Obese Adults: 2022 Update. Pharmacotherapy Meng, L., Mui, E., Ha, D. R., Stave, C., Deresinski, S. C., Holubar, M. 2023

  Abstract

  Drug dosing in obese patients continues to be challenging due to a lack of high-quality evidence to guide dosing recommendations. We first published guidance for antibiotic dosing in obese adults in 2017, in which we critically reviewed articles identified from a broad search strategy to develop dosing recommendations for 35 antimicrobials. In this updated narrative review, we searched Pubmed, Web of Science, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific generic antimicrobial names, obese, pharmacokinetics, and others. We reviewed 393 articles, cross-referenced select cited references, and when applicable, referenced drug databases, package inserts, and clinical trial data to update dosing recommendations for 41 antimicrobials. Most included articles were pharmacokinetic studies, other less frequently included articles were clinical studies (mostly small, retrospective), case reports, and very rarely, guidelines. Pharmacokinetic changes are frequently reported, can be variable, and sometimes conflicting in this population, and do not always translate to a documented difference in clinical outcomes, yet are used to inform dosing strategies. Extended infusions, high doses, and therapeutic drug monitoring remain important strategies to optimize dosing in this population. Additional studies are needed to clinically validate proposed dosing strategies, clarify optimal body size descriptors, dosing weight scalars, and estimation method of renal function in obese patients.

  View details for DOI 10.1002/phar.2769

  View details for PubMedID 36703246

• Should a MRSA Nasal Swab Guide Empiric Antibiotic Treatment? NEJM evidence Liu, C., Holubar, M. 2022; 1 (12): EVIDccon2200124

  Abstract

  MRSA Nasal Swab and Empiric Antibiotic TreatmentMRSA nasal screening has emerged as a potential antimicrobial stewardship tool to guide empiric use of anti-MRSA therapy. The authors address diagnostic considerations when performing MRSA nasal screening and clinical situations in which its results may be used to guide empiric antibiotic therapy in hospitalized patients.

  View details for DOI 10.1056/EVIDccon2200124

  View details for PubMedID 38319836

• Shorter durations of antibiotic therapy in organ transplant. Current opinion in organ transplantation Alegria, W., Medvedeva, N., Holubar, M. 2022; 27 (4): 257-262

  Abstract

  PURPOSE OF REVIEW: Recent evidence supports shorter courses of antibiotics for several common infections and prophylactic indications. Unfortunately, solid organ transplant patients are often underrepresented or excluded from these studies. As a result, prolonged antibiotic durations are often used in clinical practice despite a lack of demonstrable benefit. This paper reviews recent publications addressing antibiotic duration of therapy in SOT recipients.RECENT FINDINGS: Although largely limited to observational studies, longer courses of antibiotics for surgical prophylaxis, urinary tract infections, and bloodstream infections have not demonstrated benefit compared to shorter courses. In some instances, longer courses of therapy have been associated with harm (i.e., adverse drug events and development of resistance).SUMMARY: Although the data remains limited, findings from retrospective studies evaluating shorter courses of antibiotics in SOT patients is encouraging. More robust research is desperately needed to define the optimal duration of antibiotics for common infections in SOT patients.

  View details for DOI 10.1097/MOT.0000000000000996

  View details for PubMedID 36354251

• Sustained Reduction in Urgent Care Antibiotic Prescribing During the Coronavirus Disease 2019 Pandemic: An Academic Medical Center's Experience. Open forum infectious diseases Ha, D., Ong'uti, S., Chang, A., Mui, E., Nelligan, I., Betts, B., Lentz, C., Alegria, W., Fox, E., Meng, L., Stenehjem, E., Hersh, A. L., Deresinski, S., Artandi, M., Holubar, M. 1800; 9 (2): ofab662

  Abstract

  We compared antibiotic prescribing before and during the -coronavirus disease 2019 (COVID-19) pandemic at 2 academic urgent care clinics and found a sustained decrease in prescribing driven by respiratory encounters and despite transitioning to telemedicine. Antibiotics were rarely prescribed during encounters for COVID-19 or COVID-19 symptoms. COVID-19 revealed opportunities for outpatient stewardship programs.

  View details for DOI 10.1093/ofid/ofab662

  View details for PubMedID 35111874

• Successful fidaxomicin hospital discharges of adult patients with Clostridioides difficile infections post 2021 guidelines - are economic barriers finally coming down? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Fang, N., Ha, D., Dong, K., Leung, T., Lee, S., Holubar, M., Meng, L. 1800

  Abstract

  We reviewed C.difficile positive patients discharged on fidaxomicin after local adoption of 2021C.difficile infection (CDI) guidelines. From June 14 - Oct 3, 2021, 80% (12/15) had copayments $0-$35, and 27% (4/15) required prior authorization. The 30-day CDI recurrence was 7%.

  View details for DOI 10.1093/cid/ciab1061

  View details for PubMedID 34971358

• Cefiderocol: A new cephalosporin stratagem against multidrug resistant gram-negative bacteria. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Ong'uti, S., Czech, M., Robilotti, E., Holubar, M. 2021

  Abstract

  Cefiderocol is a novel injectable siderophore cephalosporin which hijacks the bacterial iron transport machinery to facilitate cell entry and achieve high periplasmic concentrations. It has broad in vitro activity against gram-negative bacteria, including multidrug resistant (MDR) organisms like carbapenem resistant Enterobacterales (CRE), carbapenem resistant Pseudomonas aeruginosa and Acinetobacter baumannii. It was approved by the Food and Drug Administration (FDA) for the treatment of complicated urinary tract infections and nosocomial pneumonia based on clinical trials demonstrating noninferiority to comparators. In this review, we summarize the available in vitro and clinical data, including recent evidence from 2 phase III clinical trials (APEKS-NP and CREDIBLE-CR), and discuss the place of cefiderocol in the clinician's armamentarium against MDR gram-negative infections.

  View details for DOI 10.1093/cid/ciab757

  View details for PubMedID 34492098

• Effect of rapid methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction screening on vancomycin use in the intensive care unit. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists Diep, C., Meng, L., Pourali, S., Hitchcock, M. M., Alegria, W., Swayngim, R., Ran, R., Banaei, N., Deresinski, S., Holubar, M. 2021

  Abstract

  PURPOSE: To determine the impact of a pharmacist-driven methicillin-resistant Staphylococcus aureus (MRSA) nasal polymerase chain reaction (PCR) screen on vancomycin duration in critically ill patients with suspected pneumonia.METHODS: This was a retrospective, quasi-experimental study at a 613-bed academic medical center with 67 intensive care beds. Adult patients admitted to the intensive care unit (ICU) between 2017 and 2019 for 24 hours or longer and empirically started on intravenous vancomycin for pneumonia were included. The primary intervention was the implementation of a MRSA nasal PCR screen protocol. The primary outcome was duration of empiric vancomycin therapy. Secondary outcomes included the rate of acute kidney injury (AKI), the number of vancomycin levels obtained, the rate of resumption of vancomycin for treatment of pneumonia, ICU length of stay, hospital length of stay, the rate of ICU readmission, and the rate of in-hospital mortality.RESULTS: A total of 418 patients were included in the final analysis. The median vancomycin duration was 2.59 days in the preprotocol group and 1.44 days in the postprotocol group, a reduction of approximately 1.00 day (P < 0.01). There were significantly fewer vancomycin levels measured in the postprotocol group than in the preprotocol group. Secondary outcomes were similar between the 2 groups, except that there was lower AKI and fewer vancomycin levels obtained in the postprotocol group (despite implementation of area under the curve-based vancomycin dosing) as compared to the preprotocol group.CONCLUSION: The implementation of a pharmacist-driven MRSA nasal PCR screen was associated with a decrease in vancomycin duration and the number of vancomycin levels obtained in critically ill patients with suspected pneumonia.

  View details for DOI 10.1093/ajhp/zxab296

  View details for PubMedID 34297040

• Investing in the Future: A Role for Professional Societies to Prepare the Next Generation of Healthcare Leaders through Curriculum Development and Dissemination. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Luther, V. P., Shnekendorf, R., Logan, A., Advani, S. D., Barsoumian, A. E., Beeler, C., Bennani, K., Cherabuddi, K., Holubar, M., Huang, M., Ince, D., Justo, J. A., Lee, M. S., MacDougall, C., Nori, P., Ohl, C. A., Patel, P. K., Pottinger, P. S., Spicer, J. O., Stack, C., Van Schooneveld, T. C., Willis, Z. I. 2021

  Abstract

  Professional societies serve many functions that benefit constituents, however, few professional societies have undertaken the development and dissemination of formal, national curricula to in order to train the future workforce while simultaneously addressing significant healthcare needs. The Infectious Diseases Society of America (IDSA) has developed two curricula for the specific purpose of training the next generation of clinicians in order to ensure the future infectious diseases (ID) workforce is optimally trained to lead antimicrobial stewardship programs; and equipped to meet the challenges of multidrug resistance, patient safety, and healthcare quality improvement. A core curriculum was developed to provide a foundation in antimicrobial stewardship for all ID fellows, regardless of career path. An advanced curriculum was developed for ID fellows specifically pursuing a career in antimicrobial stewardship. Both curricula will be broadly available in the summer of 2021 through the IDSA website.

  View details for DOI 10.1093/cid/ciab244

  View details for PubMedID 33730751

• Select controversies in the management of methicillin-resistant Staphylococcus aureus bacteremia: answers and remaining questions from recent evidence. Faculty reviews Suarez, J. F., Ong'uti, S., Holubar, M. 2021; 10: 66

  Abstract

  Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia continues to cause significant morbidity and mortality despite advances in medical therapy. Vancomycin therapy remains the standard of care for most cases of MRSA bacteremia but has pharmacokinetic and pharmacodynamic limitations, dosing complications, and known toxicity. Welcomed clinical trials have recently addressed some of the controversies that plague this field, including optimization of vancomycin dosing and use of combination therapy. In this review, we discuss these trials and their implications for clinical care and future research.

  View details for DOI 10.12703/r/10-66

  View details for PubMedID 34557870

  View details for PubMedCentralID PMC8441996

• Combination Antifungal Therapy for Invasive Mucormycosis in Immunocompromised Hosts: A Single-Center Experience. Open forum infectious diseases Lu, B., Ha, D., Shen, S., Ferguson Toll, J., Kim, A., Kim, S., Mui, E., Deresinski, S., Holubar, M., Alegria, W. 2024; 11 (6): ofae103

  Abstract

  Combination antifungal therapy for invasive mucormycosis remains controversial and is inconsistently defined in prior studies. In a cohort of patients with immunocompromised status and invasive mucormycosis, we found no difference in 6-week mortality with up-front or salvage combination therapy as compared with monotherapy.

  View details for DOI 10.1093/ofid/ofae103

  View details for PubMedID 38887478

  View details for PubMedCentralID PMC11181191

• Insights into Treatment Alternatives for Neurosyphilis: Systematic Literature Review and Meta-Analysis. Sexually transmitted diseases Callado, G. Y., Pardo, I., Gutfreund, M. C., Deliberato, R. O., Holubar, M., Salinas, J. L., Marra, C. M., Perencevich, E. N., Marra, A. R. 2024

  Abstract

  We conducted a systematic literature review and meta-analysis to assess the efficacy of alternative treatments for neurosyphilis. We searched MEDLINE, CINAHL, Embase, Cochrane, Scopus, and Web of Science from database inception to September, 2023, for studies in neurosyphilis that compared penicillin monotherapy to other treatments. We focused on the impact of these therapies on treatment response, but also assessed data regarding reinfection and adverse drug events. Random-effect models were used to obtain pooled mean differences. Of 3,415 screened studies, six met the inclusion criteria for the systematic literature review. Three studies provided quantitative data that allowed for inclusion in the meta-analysis. Our analysis revealed that the efficacy of intravenous ceftriaxone 2 g daily for 10 days (51 patients) did not appear statistically different compared to intravenous penicillin G 18-24 million units daily for 10 days (185 patients) for neurosyphilis (pooled OR, 2.85; 95% CI, 0.41-19.56; I2 = 49%). No statistical difference between ceftriaxone and penicillin was identified in people living with HIV (pooled OR, 4.51; 95% CI, 0.50-40.49; I2 = 34%). We concluded that alternative therapy with IV ceftriaxone appears similar to penicillin, potentially expanding treatment options for neurosyphilis. Other treatment options including doxycycline warrant further study.

  View details for DOI 10.1097/OLQ.0000000000001983

  View details for PubMedID 38661311

• Syphilis Treatment: Systematic Review and Meta-Analysis Investigating Nonpenicillin Therapeutic Strategies. Open forum infectious diseases Callado, G. Y., Gutfreund, M. C., Pardo, I., Hsieh, M. K., Lin, V., Sampson, M. M., Nava, G. R., Marins, T. A., Deliberato, R. O., Martino, M. D., Holubar, M., Salinas, J. L., Marra, A. R. 2024; 11 (4): ofae142

  Abstract

  Background: Penicillin's long-standing role as the reference standard in syphilis treatment has led to global reliance. However, this dependence presents challenges, prompting the need for alternative strategies. We performed a systematic literature review and meta-analysis to evaluate the efficacy of these alternative treatments against nonneurological syphilis.Methods: We searched MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane, Scopus, and Web of Science from database inception to 28 August 2023, and we included studies that compared penicillin or amoxicillin monotherapy to other treatments for the management of nonneurological syphilis. Our primary outcome was serological cure rates. Random-effect models were used to obtain pooled mean differences, and heterogeneity was assessed using the I2 test.Results: Of 6478 screened studies, 27 met the inclusion criteria, summing 6710 patients. The studies were considerably homogeneous, and stratified analyses considering each alternative treatment separately revealed that penicillin monotherapy did not outperform ceftriaxone (pooled odds ratio, 1.66 [95% confidence interval, .97-2.84]; I2 = 0%), azithromycin (0.92; [.73-1.18]; I2 = 0%), or doxycycline (0.82 [.61-1.10]; I2 = 1%) monotherapies with respect to serological conversion.Conclusions: Alternative treatment strategies have serological cure rates equivalent to penicillin, potentially reducing global dependence on this antibiotic.

  View details for DOI 10.1093/ofid/ofae142

  View details for PubMedID 38595955

• "Electronic Phenotyping" Antimicrobials to Facilitate Outpatient Stewardship for Asymptomatic Bacteriuria and Urinary Tract Infection in Renal Transplant. Open forum infectious diseases Zimmet, A. N., Ha, D., Mui, E., Smith, M., Hawkins, M., Alegria, W., Holubar, M. 2024; 11 (3): ofae119

  Abstract

  Asymptomatic bacteriuria and urinary tract infection in renal transplant are important antimicrobial stewardship targets but are difficult to identify within electronic medical records. We validated an "electronic phenotype" of antibacterials prescribed for these indications. This may be more useful than billing data in assessing antibiotic indication in this outpatient setting.

  View details for DOI 10.1093/ofid/ofae119

  View details for PubMedID 38533270

  View details for PubMedCentralID PMC10964979

• Diagnostic testing and antibiotic utilization among inpatients evaluated for coronavirus disease 2019 (COVID-19) pneumonia. Infection control and hospital epidemiology Wimmer, M. R., Griffin, M., Peterson-Weber, A., Schulz, L. T., Hamel, A. G., Schwei, R. J., Fong, K., Burgess, D. R., Brett, M., Hale, C. M., Holubar, M., Jain, R., Larry, R., Spivak, E. S., Newland, H., Njoku, J., Postelnick, M., Walraven, C., Pulia, M. S. 2023: 1-3

  Abstract

  We evaluated diagnostic test and antibiotic utilization among 252 patients from 11 US hospitals who were evaluated for coronavirus disease 2019 (COVID-19) pneumonia during the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron variant pandemic wave. In our cohort, antibiotic use remained high (62%) among SARS-CoV-2-positive patients and even higher among those who underwent procalcitonin testing (68%).

  View details for DOI 10.1017/ice.2023.272

  View details for PubMedID 38151334

• Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference. Open forum infectious diseases Walter, K. S., Kim, E., Verma, R., Altamirano, J., Leary, S., Carrington, Y. J., Jagannathan, P., Singh, U., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Andrews, J. R. 2023; 10 (2): ofad001

  Abstract

  The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference.We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage.Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0-40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17-208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02-1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28-.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23-1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants.Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

  View details for DOI 10.1093/ofid/ofad001

  View details for PubMedID 36751652

  View details for PubMedCentralID PMC9898879

• Risk factors and outcomes associated with persistent vancomycin resistant Enterococcal Bacteremia. BMC infectious diseases Fox, E., Ha, D., Bounthavong, M., Meng, L., Mui, E., Holubar, M., Deresinski, S., Alegria, W. 2022; 22 (1): 855

  Abstract

  BACKGROUND: Prior studies have identified that vancomycin resistant enterococcus (VRE) bacteremia that persists for four days or more is an independent predictor of mortality. Despite this, there is no published data to identify those patients at highest risk of developing persistent VRE bacteremia.METHODS: This was a single center, retrospective, case-control study of adult patients with a VRE bloodstream infection (BSI). Case patients were those with persistent bacteremia (≥4 days despite VRE-directed therapy) and control patients were those with non-persistent bacteremia. Logistic regression was used to assess risk factors associated with persistent VRE BSIs. Secondary outcomes included in-hospital mortality, recurrent bacteremia, and breakthrough bacteremia.RESULTS: During the study period, 24/108 (22%) patients had persistently positive blood cultures. Risk factors for persistent bacteremia included severe neutropenia (OR 2.13), 4 out of 4 positive index blood cultures (OR 11.29) and lack of source control (OR 11.88). In an unadjusted analysis, no statistically significant differences in in-hospital mortality (58% versus 40%; p=0.121), recurrent bacteremia (17% versus 6%; p=0.090), or breakthrough bacteremia (13% versus 7%; p=0.402) were observed between groups.CONCLUSION: Patients with severe neutropenia, 4 out of 4 positive index blood culture bottles, and lack of source control were more likely to develop persistent VRE bacteremia despite directed antibiotic treatment.

  View details for DOI 10.1186/s12879-022-07864-8

  View details for PubMedID 36384497

• Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study. eLife Hu, Z., van der Ploeg, K., Chakraborty, S., Arunachalam, P. S., Mori, D. A., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Hedlin, H., de la Parte, L., Press, K., Ty, M., Tan, G. S., Blish, C., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Butte, A. J., Singh, U., Pulendran, B., Wang, T. T., Jagannathan, P. 2022; 11

  Abstract

  The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

  View details for DOI 10.7554/eLife.77943

  View details for PubMedID 36239699

• Clinical Outcomes of Treated and Untreated C. difficile PCR-Positive/Toxin-Negative Adult Hospitalized Patients: a Quasi-Experimental Noninferiority Study. Journal of clinical microbiology Hogan, C. A., Hitchcock, M. M., Frost, S., Kapphahn, K., Holubar, M., Tompkins, L. S., Banaei, N. 2022: e0218721

  Abstract

  Clostridioides difficile infection (CDI) is routinely diagnosed by PCR, with or without toxin enzyme immunoassay testing. The role of therapy for positive PCR and negative toxin remains unclear. The objective of this study was to determine whether clinical outcomes of PCR+/cycle threshold-based toxin (CT-toxin)- individuals vary by result reporting and treatment strategy. We performed a quasiexperimental noninferiority study comparing clinical outcomes of PCR+/CT-toxin- individuals by reporting PCR result only (most patients treated) with reporting CT-toxin result only (most patients untreated) in a single-center, tertiary academic hospital. The primary outcome was symptomatic PCR+/CT-toxin+ conversion at 8weeks. Secondary outcomes included 7-day diarrhea resolution, hospital length of stay, and 30-day all-cause mortality. A total of 663 PCR+/CT-toxin- test results were analyzed from 632 individuals with a median age of 61years (interquartile range [IQR], 44 to 72) and 50.4% immunocompromised. Individuals in the preintervention group were more likely to have received CDI therapy than those in the intervention group (91.5 versus 15.1%; P < 0.001). Symptomatic toxin conversion at 8weeks and hospital length of stay failed to establish the predefined thresholds for noninferiority. Lack of diarrhea resolution at 7days and 30-day all-cause mortality was similar and established noninferiority (20.0 versus 13.7%; adjusted odds ratio [aOR], 0.57; 90% confidence interval [CI], 0.32 to 1.01; P = 0.1; and 8.6 versus 6.5%; aOR, 0.46; 90% CI, 0.20 to 1.04; P = 0.12). These data support the safety of withholding antibiotics for selected hospitalized individuals with suspected CDI but negative toxin.

  View details for DOI 10.1128/jcm.02187-21

  View details for PubMedID 35611653

• Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Holubar, M., Subramanian, A., Purington, N., Hedlin, H., Bunning, B., Walter, K. S., Bonilla, H., Boumis, A., Chen, M., Clinton, K., Dewhurst, L., Epstein, C., Jagannathan, P., Kaszynski, R. H., Panu, L., Parsonnet, J., Ponder, E. L., Quintero, O., Sefton, E., Singh, U., Soberanis, L., Truong, H., Andrews, J. R., Desai, M., Khosla, C., Maldonado, Y. 2022

  Abstract

  Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries.We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1: 1 to receive placebo or favipiravir (1800mg BID Day 1, 800 mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis.From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48-1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54-1.29; sustained: HR 0.87, 95% CI 0.52-1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment.Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

  View details for DOI 10.1093/cid/ciac312

  View details for PubMedID 35446944

• The impact of coronavirus disease 2019 (COVID-19) on the antimicrobial stewardship pharmacist workforce: A multicenter survey. Antimicrobial stewardship & healthcare epidemiology : ASHE Wimmer, M. R., Schulz, L. T., Hamel, A. G., Schwei, R. J., Fong, K., Burgess, D. R., Brett, M., Hale, C. M., Holubar, M., Jain, R., Larry, R., Spivak, E. S., Newland, H., Njoku, J., Postelnick, M., Walraven, C., Pulia, M. S. 2022; 2 (1): e56

  Abstract

  The coronavirus disease 2019 (COVID-19) pandemic has required healthcare systems and hospitals to rapidly modify standard practice, including antimicrobial stewardship services. Our study examines the impact of COVID-19 on the antimicrobial stewardship pharmacist.A survey was distributed nationally to all healthcare improvement company members.Pharmacist participants were mostly leaders of antimicrobial stewardship programs distributed evenly across the United States and representing urban, suburban, and rural health-system practice sites.Participants reported relative increases in time spent completing tasks related to medication access and preauthorization (300%; P = .018) and administrative meeting time (34%; P = .067) during the COVID-19 pandemic compared to before the pandemic. Time spent rounding, making interventions, performing pharmacokinetic services, and medication reconciliation decreased.A shift away from clinical activities may negatively affect the utilization of antimicrobials.

  View details for DOI 10.1017/ash.2022.37

  View details for PubMedID 36483364

  View details for PubMedCentralID PMC9726570

• Incidence and prevalence of COVID-19 within a healthcare worker cohort during the first year of the SARS-CoV-2 pandemic. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Doernberg, S. B., Holubar, M., Jain, V., Weng, Y., Lu, D., Bollyky, J. B., Sample, H., Huang, B., Craik, C. S., Desai, M., Rutherford, G. W., Maldonado, Y., CHART Study Consortium 2022

  Abstract

  BACKGROUND: Preventing SARS-CoV2 infections in healthcare workers (HCWs) is critical for healthcare delivery. We aimed to estimate and characterize the prevalence and incidence of COVID-19 in a US HCW cohort and to identify risk factors associated with infection.METHODS: We conducted a longitudinal cohort study of HCWs at 3 Bay Area medical centers using serial surveys and SARS-CoV-2 viral and orthogonal serological testing, including measurement of neutralizing antibodies. We estimated baseline prevalence and cumulative incidence of COVID-19. We performed multivariable Cox proportional hazards models to estimate associations of baseline factors with incident infections and evaluated the impact of time-varying exposures on time to COVID-19 using marginal structural models.RESULTS: 2435 HCWs contributed 768 person years of follow-up time. We identified 21/2435 individuals with prevalent infection, resulting in a baseline prevalence of 0.86% (95% CI, 0.53% to 1.32%). We identified 70/2414 (2.9%) incident infections yielding a cumulative incidence rate of 9.11 cases per 100 person years (95% CI 7.11 to 11.52). Community contact with a known COVID-19 case most strongly correlated with increased hazard for infection (HR 8.1, 95% CI, 3.8, 17.5). High-risk work-related exposures (i.e., breach in protective measures) drove an association between work exposure and infection (HR 2.5, 95% CI, 1.3-4.8). More cases were identified in HCW when community case rates were high.CONCLUSION: We observed modest COVID-19 incidence despite consistent exposure at work. Community contact was strongly associated with infections but contact at work was not unless accompanied by high-risk exposure.

  View details for DOI 10.1093/cid/ciac210

  View details for PubMedID 35279023

• Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity. Science translational medicine Chakraborty, S., Gonzalez, J. C., Sievers, B. L., Mallajosyula, V., Chakraborty, S., Dubey, M., Ashraf, U., Cheng, B. Y., Kathale, N., Tran, K. Q., Scallan, C., Sinnott, A., Cassidy, A., Chen, S. T., Gelbart, T., Gao, F., Golan, Y., Ji, X., Kim-Schulze, S., Prahl, M., Gaw, S. L., Gnjatic, S., Marron, T. U., Merad, M., Arunachalam, P. S., Boyd, S. D., Davis, M. M., Holubar, M., Khosla, C., Maecker, H. T., Maldonado, Y., Mellins, E. D., Nadeau, K. C., Pulendran, B., Singh, U., Subramanian, A., Utz, P. J., Sherwood, R., Zhang, S., Jagannathan, P., Tan, G. S., Wang, T. T. 1800: eabm7853

  Abstract

  A damaging inflammatory response is implicated in the pathogenesis of severe coronavirus disease 2019 (COVID-19), but mechanisms contributing to this response are unclear. In two prospective cohorts, early non-neutralizing, afucosylated IgG antibodies specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were associated with progression from mild to more severe COVID-19. In contrast to the antibody structures that were associated with disease progression, antibodies that were elicited by mRNA SARS-CoV-2 vaccines were instead highly fucosylated and enriched in sialylation, both modifications that reduce the inflammatory potential of IgG. To study the biology afucosylated IgG immune complexes, we developed an in vivo model that revealed that human IgG-Fc gamma receptor (FcgammaR) interactions could regulate inflammation in the lung. Afucosylated IgG immune complexes isolated from COVID-19 patients induced inflammatory cytokine production and robust infiltration of the lung by immune cells. By contrast, vaccine-elicited IgG did not promote an inflammatory lung response. Together, these results show that IgG-FcgammaR interactions are able to regulate inflammation in the lung and may define distinct lung activities associated with the IgG that are associated with severe COVID-19 and protection against infection with SARS-CoV-2.

  View details for DOI 10.1126/scitranslmed.abm7853

  View details for PubMedID 35040666

• Race-ethnicity and COVID-19 Vaccination Beliefs and Intentions: A Cross-Sectional Study among the General Population in the San Francisco Bay Area. Vaccines Weng, Y., Lu, D., Bollyky, J., Jain, V., Desai, M., Lindan, C., Boothroyd, D., Judson, T., Doernberg, S. B., Holubar, M., Sample, H., Huang, B., Maldonado, Y., Rutherford, G. W., Grumbach, K., On Behalf Of The California Pandemic Consortium 1800; 9 (12)

  Abstract

  OBJECTIVE: The study was designed to compare intentions to receive COVID-19 vaccination by race-ethnicity, to identify beliefs that may mediate the association between race-ethnicity and intention to receive the vaccine and to identify the demographic factors and beliefs most strongly predictive of intention to receive a vaccine.DESIGN: Cross-sectional survey conducted from November 2020 to January 2021, nested within a longitudinal cohort study of the prevalence and incidence of SARS-CoV-2 among a general population-based sample of adults in six San Francisco Bay Area counties (called TrackCOVID). Study Cohort: In total, 3161 participants among the 3935 in the TrackCOVID parent cohort responded.RESULTS: Rates of high vaccine willingness were significantly lower among Black (41%), Latinx (55%), Asian (58%), Multi-racial (59%), and Other race (58%) respondents than among White respondents (72%). Black, Latinx, and Asian respondents were significantly more likely than White respondents to endorse lack of trust of government and health agencies as a reason not to get vaccinated. Participants' motivations and concerns about COVID-19 vaccination only partially explained racial-ethnic differences in vaccination willingness. Concerns about a rushed government vaccine approval process and potential bad reactions to the vaccine were the two most important factors predicting vaccination intention.CONCLUSIONS: Vaccine outreach campaigns must ensure that the disproportionate toll of COVID-19 on historically marginalized racial-ethnic communities is not compounded by inequities in vaccination. Efforts must emphasize messages that speak to the motivations and concerns of groups suffering most from health inequities to earn their trust to support informed decision making.

  View details for DOI 10.3390/vaccines9121406

  View details for PubMedID 34960152

• High Completion of COVID-19 Vaccination Among Health Care Workers Despite Initial Self-Reported Vaccine Reluctance. Open forum infectious diseases Jain, V., Doernberg, S. B., Holubar, M., Huang, B., Bollyky, J., Sample, H., Weng, Y., Lu, D., Desai, M., Maldonado, Y., Rutherford, G. 2021; 8 (10): ofab446

  View details for DOI 10.1093/ofid/ofab446

  View details for PubMedID 34734101

• Case-control study evaluating risk factors for SARS-CoV-2 outbreak amongst healthcare personnel at a tertiary care center. American journal of infection control Rosser, J. I., Tayyar, R., Giardina, R., Kolonoski, P., Kenski, D., Shen, P., Steinmetz, L. M., Hung, L., Xiao, W., Bains, K., Morrison, T., Madison, A., Chang, S., Tompkins, L., Pinsky, B. A., Holubar, M. 2021

  Abstract

  BACKGROUND: Despite several outbreaks of SARS-CoV-2 amongst healthcare personnel (HCP) exposed to COVID-19 patients globally, risk factors for transmission remain poorly understood.METHODS: We conducted an outbreak investigation and case-control study to evaluate SARS-CoV-2 transmission risk in an outbreak among HCP at an academic medical center in California that was confirmed by whole genome sequencing.RESULTS: A total of 7/9 cases and 93/182 controls completed a voluntary survey about risk factors. Compared to controls, cases reported significantly more patient contact time. Cases were also significantly more likely to have performed airway procedures on the index patient, particularly placing the patient on high flow nasal cannula, continuous positive airway pressure (CPAP), or bilevel positive airway pressure (BiPAP) (OR=11.6; 95% CI=1.7-132.1).DISCUSSION: This study highlights the risk of nosocomial infection of SARS-CoV-2 from patients who become infectious midway into their hospitalization. Our findings also reinforce the importance of patient contact and aerosol-generating procedures as key risk factors for HCP infection with SARS-CoV-2.CONCLUSIONS: Re-testing patients for SARS-CoV-2 after admission in suspicious cases and using N95 masks for all aerosol-generating procedures regardless of initial patient SARS-CoV-2 test results can help reduce the risk of SARS-COV-2 transmission to HCP.

  View details for DOI 10.1016/j.ajic.2021.09.004

  View details for PubMedID 34536502

• Post-vaccination SARS-CoV-2 infections and incidence of presumptive B.1.427/B.1.429 variant among healthcare personnel at a northern California academic medical center. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Jacobson, K. B., Pinsky, B. A., Montez Rath, M. E., Wang, H., Miller, J. A., Skhiri, M., Shepard, J., Mathew, R., Lee, G., Bohman, B., Parsonnet, J., Holubar, M. 2021

  Abstract

  BACKGROUND: Although mRNA-based SARS-CoV-2 vaccines report ≥90% efficacy, breakthrough infections occur. Little is known about the effectiveness of these vaccines against SARS-CoV-2 variants, including the highly-prevalent B.1.427/B.1.429 variant in California..METHODS: In this quality improvement project, we collected demographic and clinical information from post-vaccine SARS-CoV-2 cases (PVSCs), defined as health care personnel (HCP) with positive SARS-CoV-2 NAAT after receiving ≥1 vaccine dose. Available specimens were tested for L452R, N501Y and E484K mutations by RT-PCR. Mutation prevalence was compared among unvaccinated, early post-vaccinated (<=14 days after dose 1), partially vaccinated (positive test >14 days after dose 1 and ≤14 days after dose 2) and fully vaccinated (>14 days after dose 2) PVSCs.RESULTS: From December 2020-April 2021, >=23,090 HCPS received at least1 dose of an mRNA-based SARS-CoV-2 vaccine, and 660 HCP cases of SARS-CoV-2 occurred of which 189 were PVSCs. Among the PVSCs, 114 (60.3%), 49 (25.9%) and 26 (13.8%) were early post-vaccination, partially vaccinated, and fully vaccinated, respectively. Of 261 available samples from vaccinated and unvaccinated HCP, 103 (39.5%), including 42 PVSCs (36.5%), had L452R mutation presumed to be B.1.427/B.1.429,. When adjusted for community prevalence of B.1.427/B.1.429, PVSCs did not have significantly elevated risk for infection with B.1.427/B.1.429 compared with unvaccinated HCP.CONCLUSIONS: Most PVSCs occurred prior to expected onset of full, vaccine-derived immunity. Presumptive B.1.427/B.1.429 was not more prevalent in post-vaccine cases than in unvaccinated SARS-CoV-2 HCP. Continued infection control measures, particularly ≤14 days post-vaccination, and continued variant surveillance in PVSCs is imperative to control future SARS-CoV-2 surges.

  View details for DOI 10.1093/cid/ciab554

  View details for PubMedID 34137815

• Association of Race/Ethnicity With Likeliness of COVID-19 Vaccine Uptake Among Health Workers and the General Population in the San Francisco Bay Area. JAMA internal medicine Grumbach, K., Judson, T., Desai, M., Jain, V., Lindan, C., Doernberg, S. B., Holubar, M. 2021

  View details for DOI 10.1001/jamainternmed.2021.1445

  View details for PubMedID 33783471

• Strand Specific Reverse Transcription PCR for Detection of Replicating SARS-CoV-2 EMERGING INFECTIOUS DISEASES Hogan, C. A., Huang, C., Sahoo, M. K., Wang, H., Jiang, B., Sibai, M., Holubar, M., Mathew, R., Zehnder, J., Pinsky, B. A. 2021; 27 (2): 632–35

  Abstract

  We developed an assay that detects minus-strand RNA as a surrogate for actively replicating severe acute respiratory syndrome coronavirus 2. We detected minus-strand RNA in 41 persons with coronavirus disease up to 30 days after symptom onset. This assay might inform clinical decision-making about patient infectiousness.

  View details for DOI 10.3201/eid2702.204168

  View details for Web of Science ID 000631538500043

  View details for PubMedID 33496233

  View details for PubMedCentralID PMC7853532

• Intraoperative bacitracin irrigations for the prevention of surgical site infections-Consider the alternatives - CORRIGENDUM. Infection control and hospital epidemiology Meng, L., Deresinski, S., Holubar, M. 2021; 42 (2): 252

  View details for DOI 10.1017/ice.2020.1382

  View details for PubMedID 33570483

• Reactivation of Chagas Disease in a Patient With an Autoimmune Rheumatic Disease: Case Report and Review of the Literature. Open forum infectious diseases Czech, M. M., Nayak, A. K., Subramanian, K. n., Suarez, J. F., Ferguson, J. n., Jacobson, K. B., Montgomery, S. P., Chang, M. n., Bae, G. H., Raghavan, S. S., Wang, H. n., Miranti, E. n., Budvytiene, I. n., Shoor, S. M., Banaei, N. n., Rieger, K. n., Deresinski, S. n., Holubar, M. n., Blackburn, B. G. 2021; 8 (2): ofaa642

  Abstract

  Reactivation of Chagas disease has been described in immunosuppressed patients, but there is a paucity of literature describing reactivation in patients on immunosuppressive therapies for the treatment of autoimmune rheumatic diseases. We describe a case of Chagas disease reactivation in a woman taking azathioprine and prednisone for limited cutaneous systemic sclerosis (lcSSc). Reactivation manifested as indurated and erythematous cutaneous nodules. Sequencing of a skin biopsy specimen confirmed the diagnosis of Chagas disease. She was treated with benznidazole with clinical improvement in the cutaneous lesions. However, her clinical course was complicated and included disseminated CMV disease and subsequent septic shock due to bacteremia. Our case and review of the literature highlight that screening for Chagas disease should be strongly considered for patients who will undergo immunosuppression for treatment of autoimmune disease if epidemiologically indicated.

  View details for DOI 10.1093/ofid/ofaa642

  View details for PubMedID 33575423

  View details for PubMedCentralID PMC7863873

• SARS-CoV-2 subgenomic RNA kinetics in longitudinal clinical samples Open Forum Infectious Diseases Verma, R., Kim, E., Martinez, G., Jagannathan, ., Rustagi, A., Parsonnet, J., Bonilla, H., Khosla, C., Holubar, M., Subramanian, A., Singh, ., Maldonado, Y., Blish, C., Andrews, J. 2021

  View details for DOI 10.1093/ofid/ofab310

• Evaluation of the Infectious Diseases Society of America's Core Antimicrobial Stewardship Curriculum for Infectious Diseases Fellows. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Spicer, J. O., Armstrong, W. S., Schwartz, B. S., Abbo, L. M., Advani, S. D., Barsoumian, A. E., Beeler, C., Bennani, K., Holubar, M., Huang, M., Ince, D., Justo, J. A., Lee, M. S., Logan, A., MacDougall, C., Nori, P., Ohl, C., Patel, P. K., Pottinger, P. S., Shnekendorf, R., Stack, C., Van Schooneveld, T. C., Willis, Z. I., Zhou, Y., Luther, V. P. 2021

  Abstract

  Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here, we study its impact.ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows' knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation ("pre-curriculum") and compared to first-year fellows who complete the curriculum the following year ("post-curriculum").Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a "formal" curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows' confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P=0.028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning.Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors.

  View details for DOI 10.1093/cid/ciab600

  View details for PubMedID 34192322

• Post-vaccination SARS-CoV-2 infections and incidence of the B.1.427/B.1.429 variant among healthcare personnel at a northern California academic medical center. medRxiv : the preprint server for health sciences Jacobson, K. B., Pinsky, B. A., Rath, M. E., Wang, H., Miller, J. A., Skhiri, M., Shepard, J., Mathew, R., Lee, G., Bohman, B., Parsonnet, J., Holubar, M. 2021

  Abstract

  Distribution of mRNA-based SARS-CoV-2 vaccines to healthcare personnel (HCP) in the United States began in December 2020, with efficacy > 90%. However, breakthrough infections in fully vaccinated individuals have been reported. Meanwhile, multiple SARS-CoV-2 variants of concern have emerged worldwide, including the B.1.427/B.1.429 variant first described in California. Little is known about the real-world effectiveness of the mRNA-based SARS-CoV-2 vaccines against novel variants including B.1.427/B.1.429.In this quality improvement project, post-vaccine SARS-CoV-2 cases (PVSCs) were defined as individuals with positive SARS-CoV-2 nucleic acid amplification test (NAAT) after receiving at least one dose of a SARS-CoV-2 vaccine. Chart extraction of demographic and clinical information was performed, and available specimens meeting cycle threshold value criteria were tested for L452R, N501Y and E484K mutations by RT-PCR.From December 2020 to March 2021, 189 PVSCs were identified out of 22,729 healthcare personnel who received at least one dose of an mRNA-based SARS-CoV-2 vaccine. Of these, 114 (60.3%) occurred within 14 days of first vaccine dose (early post-vaccination), 49 (25.9%) within 14 days of the second vaccine dose (partially vaccinated), and 26 (13.8%) > 14 days after the second dose (fully vaccinated). Of 115 samples available for mutation testing, 42 were positive for L452R alone, presumptive of B.1.427/B.1.429; three had N501Y mutation alone and none were found with E484K mutation. Though on univariate analysis partially- and fully-vaccinated PVSCs were more likely than early post-vaccination PVSCs to be infected with presumptive B.1.427/B.1.429, when adjusted for community prevalence of B.1.427/B.1.429 at the time of infection, partially- and fully-vaccinated PVSC did not have statistically significantly elevated risk ratios for infection with this variant (RR 1.40, 95% CI 0.81-2.43 and RR 1.13, 95% CI 0.59-2.16, respectively).The great majority of PVSCs occurred prior to the expected onset of full, vaccine-derived immunity. Although the B.1.427/B.1.429 variant did not represent a significantly higher proportion of PVSCs than expected, numbers were small and there was a trend towards higher representation in the partially- and fully-vaccinated subset. Continued infection control measures in the workplace and in the community including social distancing and masking, particularly in the early days post-vaccination, as well as continued variant surveillance in PVSCs, is imperative in order to anticipate and control future surges of infection.

  View details for DOI 10.1101/2021.04.14.21255431

  View details for PubMedID 33907767

  View details for PubMedCentralID PMC8077590

• The prevalence of COVID-19 in healthcare personnel in an adult and pediatric academic medical center. American journal of infection control Shepard, J., Kling, S. M., Lee, G., Wong, F., Frederick, J., Skhiri, M., Holubar, M., Shaw, J. G., Stafford, D., Schilling, L., Kim, J., Ick Chang, S., Frush, K., Hadhazy, E. 2021; 49 (5): 542–46

  Abstract

  BACKGROUND: It is vital to know which healthcare personnel (HCP) have a higher chance of testing positive for severe acute respiratory syndrome coronavirus 2 (COVID-19).METHODS: A retrospective analysis was conducted at Stanford Children's Health (SCH) and Stanford Health Care (SHC) in Stanford, California. Analysis included all HCP, employed by SCH or SHC, who had a COVID-19 reverse transcriptase polymerase chain reaction (RT-PCR) test resulted by the SHC Laboratory, between March 1, 2020 and June 15, 2020. The primary outcome was the RT-PCR percent positivity and prevalence of COVID-19 for HCP and these were compared across roles.RESULTS: SCH and SHC had 24,081 active employees, of which 142 had at least 1 positive COVID-19 test. The overall HCP prevalence of COVID-19 was 0.59% and percent positivity was 1.84%. Patient facing HCPs had a significantly higher prevalence (0.66% vs 0.43%; P = .0331) and percent positivity (1.95% vs 1.43%; P = .0396) than nonpatient facing employees, respectively. Percent positivity was higher in food service workers (9.15%), and environmental services (5.96%) compared to clinicians (1.93%; P < .0001) and nurses (1.46%; P < .0001), respectively.DISCUSSION AND CONCLUSION: HCP in patient-facing roles and in support roles had a greater chance of being positive of COVID-19.

  View details for DOI 10.1016/j.ajic.2021.01.004

  View details for PubMedID 33896582

• Cost-effectiveness of bezlotoxumab and fidaxomicin for initial Clostridioides difficile infection. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases Chen, J. n., Gong, C. L., Hitchcock, M. M., Holubar, M. n., Deresinski, S. n., Hay, J. W. 2021

  Abstract

  Treatment of Clostridioides difficile infection (CDI) has undergone significant change in recent years with the introduction of fidaxomicin and bezlotoxumab. This study evaluated the cost-effectiveness of fidaxomicin and bezlotoxumab for initial CDI compared to standard therapy with oral vancomycin.A Markov model with 8 health states was built based on transition probabilities, costs, and health utilities derived from literature to evaluate the cost-effectiveness of standard fidaxomicin, bezlotoxumab plus vancomycin, and extended-pulsed fidaxomicin vs. standard oral vancomycin over a lifetime horizon from the United States societal perspective.For overall CDI treatment, oral vancomycin had the lowest cost of $39,178 and was associated with a gain of 11.64 quality-adjusted life years (QALYs). Standard fidaxomicin had a relatively higher QALY gain of 11.94 than vancomycin at an incremental cost of $495 per QALY. Bezlotoxumab plus vancomycin led to a QALY gain of 11.77 at an incremental cost of $17,746 per QALY, and extended-pulsed fidaxomicin regimen had a QALY gain of 11.65 at an incremental cost of $205,841 per QALY. At the willingness-to-pay (WTP) threshold of $150,000 per QALY, bezlotoxumab plus vancomycin and fidaxomicin were always cost-effective compared to vancomycin alone, yielding incremental net monetary benefits (INMBs) of $17,011 and $44,308, respectively. One-way sensitivity analysis suggested that the probabilities of sustained cure from the initial episode were the most sensitive inputs, and results were overall not particularly sensitive to any drug costs.Based on a WTP threshold of $150,000, fidaxomicin and bezlotoxumab plus vancomycin were estimated to be more cost-effective for treating an episode of CDI and preventing further recurrence than standard of care vancomycin. The addition of bezlotoxumab to vancomycin and extended-pulsed fidaxomicin were dominated by standard fidaxomicin.

  View details for DOI 10.1016/j.cmi.2021.04.004

  View details for PubMedID 33878506

• SARS-CoV-2 Seroprevalence in Healthcare Personnel in Northern California Early in the COVID-19 Pandemic. Infection control and hospital epidemiology Rosser, J. I., Roltgen, K., Dymock, M., Shepard, J., Martin, A., Hogan, C. A., Blomkalns, A., Mathew, R., Parsonnet, J., Pinsky, B. A., Maldonado, Y. A., Boyd, S. D., Chang, S., Holubar, M., Stanford Healthcare COVID-19 Workforce Response Group 2020: 1–27

  Abstract

  OBJECTIVE: We aimed to assess the magnitude of unidentified SARS-CoV-2 infections in our healthcare personnel (HCP) early in the COVID-19 pandemic and evaluate risk factors for infection in order to identify areas for infection control practice improvement in a northern California academic medical center.METHODS: We reviewed the anti-SARS-CoV-2 receptor binding domain (RBD) IgG serologic test results and self-reported risk factors for seropositivity among 10,449 asymptomatic HCP who underwent voluntary serology testing between April 20 and May 20, 2020.RESULTS: In total, 136 employees (1.3%) tested positive for SARS-CoV-2 IgG. This included 41 (30.1%) individuals who had previously tested positive for SARS-CoV-2 by nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) between March 13 and April 16, 2020. In multivariable analysis, employees of Hispanic ethnicity (OR = 2.01; 95% CI = 1.22-3.46) and those working in environmental services/food services/patient transport (OR = 4.81; 95% CI = 2.08-10.30) were at increased risk for seropositivity compared to other groups. Employees reporting a household contact with COVID-19 were also at higher risk for seropositivity (OR = 3.25; 95% CI = 1.47-6.44), but those with a work exposure were not (OR = 1.27; 95% CI = 0.58-2.47). Importantly, one-third of seropositive individuals reported no prior symptoms, no suspected exposures, and no prior positive RT-PCR test.CONCLUSION: In this study, SARS-CoV-2 seropositivity among HCP early in the northern California epidemic appeared to be quite low and was more likely attributable to community rather than occupational exposure.

  View details for DOI 10.1017/ice.2020.1358

  View details for PubMedID 33292895

• A Case of Postoperative Methicillin-Resistant Staphylococcus aureus Enterocolitis in an 81-Year-Old Man and Review of the Literature. The American journal of case reports Gururangan, K., Holubar, M. K. 2020; 21: e922521

  Abstract

  BACKGROUND Nosocomial diarrhea affects 12% to 32% of hospitalized patients. Before the development of the Clostridium difficile cytotoxin assay in the 1970s, Staphylococcus aureus was frequently implicated as a cause of hospital-acquired infectious colitis, particularly in association with recent antibiotic therapy or abdominal surgery. Decreased utilization of stool culture has reduced the recognition of S. aureus as a rare, but historically important, cause of enterocolitis. CASE REPORT An 81-year-old man with no recent history of travel, exposure to potential infectious sources (e.g., sick contacts, animals, undercooked foods), or antibiotic or proton-pump inhibitor use was admitted for a Whipple procedure (expanded intraoperatively with total pancreatectomy, splenectomy, and portal vein resection) for stage III pancreatic adenocarcinoma. On postoperative day (POD) 5, the patient developed large-volume watery diarrhea that did not improve with tube feeding cessation and oral pancreatic enzyme replacement. He subsequently became clinically septic on POD10, and workup revealed severe radiographic sigmoid and rectal colitis and methicillin-resistant S. aureus (MRSA) bacteremia. Polymerase chain reaction testing for C. difficile was negative twice (POD5 and POD12). He was diagnosed with MRSA proctocolitis and improved with initiation of oral and intravenous vancomycin. CONCLUSIONS We describe a case of staphylococcal enterocolitis, a previously common cause of nosocomial diarrhea that has become increasingly underappreciated since the advent of culture-independent stool testing for C. difficile. Increased awareness of this entity, especially when Clostridium assays are negative, may guide more effective treatment of hospital-acquired infection.

  View details for DOI 10.12659/AJCR.922521

  View details for PubMedID 32989210

• Impact of Rapid Antimicrobial Susceptibility Testing in Gram-negative Rod Bacteremia: A Quasi-Experimental Study. Journal of clinical microbiology Hogan, C. A., Ebunji, B., Watz, N., Kapphahn, K., Rigdon, J., Mui, E., Meng, L., Alegria, W., Holubar, M., Deresinski, S., Banaei, N. 2020

  Abstract

  Background: Clinical justification for rapid antimicrobial susceptibility testing (AST) in Gram-negative rod (GNR) bacteremia is compelling; however, evidence supporting its value is sparse. We investigated the impact of rapid AST on clinical and antimicrobial stewardship outcomes in real-world practice.Methods: We performed a before and after quasi-experimental study from February 2018 to July 2019 at a tertiary hospital of the 24-hour/day, 7-day/week implementation of the direct VITEK2 AST method from positive blood culture broth for GNR bacteremia with electronic isolate-specific de-escalation comments, and daytime antibiotic stewardship program (ASP) intervention. The primary outcome was time to appropriate antibiotic escalation or de-escalation, and secondary outcomes included time to oral antibiotic step-down, hospital length-of-stay (LOS), all-cause 30-day mortality, 7-day incidence of acute kidney injury (AKI) and 30-day incidence of C. difficile infection (CDI).Results: A total of 671 GNR isolates were included from 643 adult patients. Among patients for whom antibiotic change occurred after rapid AST result, rapid AST was associated with a trend in decreased time to escalation or de-escalation (hazard ratio 1.22, 95% CI 0.99-1.51; p=0.06), with median times of 52.3 vs 42.2 hours. Secondary outcomes were similar in both groups including median time to oral antibiotic step-down, LOS, all-cause mortality, and incidence of AKI and CDI.Conclusion: Rapid AST led to improved stewardship measures but did not impact clinical patient outcomes. These results highlight that multiple variables in addition to timing of AST result contribute to clinical outcome and that further intervention may be required to clinically justify rapid AST implementation.

  View details for DOI 10.1128/JCM.00360-20

  View details for PubMedID 32434782

• Intraoperative bacitracin irrigations for the prevention of surgical site infections-Consider the alternatives. Infection control and hospital epidemiology Meng, L., Deresinski, S., Holubar, M. 2020: 1–2

  View details for DOI 10.1017/ice.2020.67

  View details for PubMedID 32366347

• Large-Scale Testing of Asymptomatic Healthcare Personnel for Severe Acute Respiratory Syndrome Coronavirus 2. Emerging infectious diseases Hogan, C. A., Gombar, S. n., Wang, H. n., Röltgen, K. n., Shi, R. Z., Holubar, M. n., Chang, S. I., Lee, G. M., Boyd, S. D., Zehnder, J. n., Pinsky, B. A. 2020; 27 (1)

  Abstract

  Large-scale, 1-time testing of >12,000 asymptomatic healthcare personnel in California, USA, during April-June 2020 showed that prevalence of severe acute respiratory syndrome coronavirus 2 was low (<1%). Testing might identify asymptomatic and presymptomatic persons, including some with high viral burden, enabling prompt implementation of measures to limit nosocomial spread.

  View details for DOI 10.3201/eid2701.203892

  View details for PubMedID 33256889

• Bacteremia due to Methicillin-Resistant Staphylococcus aureus: An Update on New Therapeutic Approaches. Infectious disease clinics of North America Holubar, M. n., Meng, L. n., Alegria, W. n., Deresinski, S. n. 2020

  Abstract

  Vancomycin and daptomycin are options for the initial treatment of patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Treatment options for persistent MRSA bacteremia or bacteremia due to vancomycin-intermediate or vancomycin-resistant strains include daptomycin, ceftaroline, and combination therapies. There is a critical need for high-level evidence from clinical trials to allow optimally informed decisions in the treatment of MRSA bacteremia.

  View details for DOI 10.1016/j.idc.2020.04.003

  View details for PubMedID 33011050

• Is Daptomycin plus Ceftaroline Associated with Better Clinical Outcomes than Standard of Care Monotherapy for Staphylococcus aureus Bacteremia? Antimicrobial agents and chemotherapy Kalil, A. C., Holubar, M., Deresinski, S., Chambers, H. F. 2019; 63 (11)

  View details for DOI 10.1128/AAC.00900-19

  View details for PubMedID 31640977

• Is Daptomycin plus Ceftaroline Associated with Better Clinical Outcomes than Standard of Care Monotherapy for Staphylococcus aureus Bacteremia? ANTIMICROBIAL AGENTS AND CHEMOTHERAPY Kalil, A. C., Holubar, M., Deresinski, S., Chambers, H. F. 2019; 63 (11)

  View details for DOI 10.1128/AAC.01347-19

  View details for Web of Science ID 000492306300018

• Antimicrobial resistance in methicillin-resistant Staphylococcus aureus to newer antimicrobial agents. Antimicrobial agents and chemotherapy Watkins, R. R., Holubar, M., David, M. Z. 2019

  Abstract

  Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) result in significant morbidity and mortality for patients in both community and health care settings. This is primarily due to the difficulty in treating MRSA, which is often resistant to multiple classes of antibiotics. Understanding the mechanisms of antimicrobial resistance (AMR) in MRSA provides insight into the optimal use of antimicrobial agents in clinical practice and also underpins critical aspects of antimicrobial stewardship programs. In this review we delineate the mechanisms, prevalence, and clinical importance of resistance to antibiotics licensed in the past 20 years that target MRSA, as well as new drugs in the pipeline which are likely to be licensed soon. Current gaps in scientific knowledge about MRSA resistance mechanisms are discussed, and topics in the epidemiology of AMR in S. aureus that require further investigation are highlighted.

  View details for DOI 10.1128/AAC.01216-19

  View details for PubMedID 31527033

• Oral Fluoroquinolone or Trimethoprim-sulfamethoxazole vs. SS-lactams as Step-Down Therapy for Enterobacteriaceae Bacteremia: Systematic Review and Meta-analysis. Open forum infectious diseases Punjabi, C., Tien, V., Meng, L., Deresinski, S., Holubar, M. 2019

  Abstract

  BACKGROUND: Using published data, we sought to compare outcomes in patients transitioned to either oral fluoroquinolones (FQ) or trimethoprim-sulfamethoxazole (TMP-SMX) versus SS-lactams (BL's) after an initial intravenous (IV) course for gram-negative rod (GNR) bacteremia.METHODS: We conducted a systematic review of PubMed and EMBASE and published IDWeek abstracts. We included studies that reported all-cause mortality and/or infection recurrence in patients transitioned to oral FQ/TMP-SMX and BL's.RESULTS: Eight retrospective studies met inclusion criteria with data for 2,289 patients, of whom 65% were transitioned to oral FQ, 7.7% to TMP-SMX, and 27.2% to BL's. Follow up periods ranged from 21 to 90 days. All-cause mortality was not significantly different between patients transitioned to either FQ/TMP-SMX or BL's (OR 1.13; 95%CI, 0.69-1.87). Overall recurrence of infection, either bacteremia or the primary site, occurred more frequently in patients transitioned to oral BL's vs. FQ's (OR 2.05, 95% CI 1.17 to 3.61). Analysis limited to recurrent bacteremia was similarly suggestive although limited by small numbers (OR 2.32, 95% CI 0.99 to 5.44). However, based on known pharmacokinetics/pharmacodynamics, prescribed SS-lactam dosing regimens were frequently suboptimal.CONCLUSIONS: In the step-down IV to oral treatment of GNR bacteremia, we found insufficient data regarding outcomes after oral TMP-SMX; however, selection of a FQ over commonly utilized SS-lactam regimens may reduce chances of infection recurrence. While this may be a class effect, it may simply be the result of inadequate dosing of SS-lactams. Additional investigations are warranted to determine outcomes with TMP-SMX and optimized oral SS-lactam dosing regimens.

  View details for DOI 10.1093/ofid/ofz364

  View details for PubMedID 31412127

• Conversion from Vancomycin Trough Concentration-Guided Dosing to Area Under the Curve-Guided Dosing Using Two Sample Measurements in Adults: Implementation at an Academic Medical Center PHARMACOTHERAPY Meng, L., Wong, T., Huang, S., Mui, E., Nguyen, V., Espinosa, G., Desai, J., Holubar, M., Deresinski, S. 2019; 39 (4): 433–42

  View details for DOI 10.1002/phar.2234

  View details for Web of Science ID 000466401200002

• Conversion from Vancomycin Trough Concentration-Guided Dosing to Area Under the Curve-Guided Dosing Using Two Sample Measurements in Adults: Implementation at an Academic Medical Center. Pharmacotherapy Meng, L., Wong, T., Huang, S., Mui, E., Nguyen, V., Espinosa, G., Desai, J., Holubar, M., Deresinski, S. 2019

  Abstract

  STUDY OBJECTIVE: The optimal pharmacodynamic parameter for prediction of efficacy of vancomycin is the area under the concentration-time curve (AUC), and current published data indicate that dosing based on vancomycin trough concentrations is an inaccurate substitute. In this study, our objective was to compare the achievement of therapeutic target attainment after switching from a trough-based to an AUC-based dosing strategy as a part of our institution's vancomycin-per-pharmacy protocol.DESIGN: Prospective, observational, quality assurance study.SETTING: Academic medical center.PATIENTS: A total of 296 hospitalized adults who received vancomycin and monitoring under our institution's vancomycin-per-pharmacy protocol were included in the analysis. The pre-implementation, retrospective comparison group consisted of 179 patients in whom vancomycin was initiated using a trough-based dosing strategy between November 22, 2017, and January 22, 2018. The post-implementation group included 117 patients in whom vancomycin was initiated using an AUC-based dosing strategy using two-point sampling between June 19, 2018, and July 19, 2018, after hospital-wide implementation of this protocol on June 19, 2018.MEASUREMENTS AND MAIN RESULTS: AUC values were calculated from two vancomycin concentrations (peak and trough). The primary outcome was achievement of therapeutic AUC values (400-800 mg∙hr/L) in the post-implementation group or therapeutic trough level values (10-20 mg/L) in the pre-implementation group. Only 98 (55%) of 179 initial trough values were therapeutic in the pre-implementation group (trough-only dosing method) versus 86 (73.5%) of 117 initial AUC values in the post-implementation group (AUC-based dosing method) (p=0.0014). A lower proportion of supratherapeutic AUC values was observed in the post-implementation group compared with supratherapeutic trough concentrations in the pre-implementation group (1.7% vs 18%, p<0.0001). Sixty-two percent of patients with initially therapeutic AUC values had subsequent trough value increases of 25% or greater, occurring at a median of 6 days of vancomycin therapy. Nephrotoxicity occurred in 11% of patients in the pre-implementation versus 9.4% in the post-implementation group (p=0.70).CONCLUSION: Compared with a trough concentration-based dosing strategy, AUC-based dosing using two-point sampling improved therapeutic target attainment. Implementation is feasible at any hospital that performs vancomycin peak concentration testing and is a feasible alternative to using Bayesian software for estimating AUC. This approach should also be directly compared with AUC-based dosing using Bayesian software. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30739349

• Deep sequencing prompts the modification of a real-time RT-PCR for the serotype-specific detection of polioviruses JOURNAL OF VIROLOGICAL METHODS Holubar, M., Sahoo, M. K., Huang, C., Mohamed-Hadley, A., Liu, Y., Waggoner, J. J., Troy, S. B., Garcia-Garcia, L., Ferreyra-Reyes, L., Maldonado, Y., Pinsky, B. A. 2019; 264: 38–43

  View details for DOI 10.1016/j.jviromet.2018.11.007

  View details for Web of Science ID 000456222300006

• Dual reporting of Clostridioides difficile PCR and predicted toxin result based on PCR cycle threshold reduces treatment of toxin-negative patients without increases in adverse outcomes. Journal of clinical microbiology Hitchcock, M. M., Holubar, M. n., Hogan, C. A., Tompkins, L. S., Banaei, N. n. 2019

  Abstract

  Nucleic acid amplification tests are commonly used to diagnose C. difficile infection (CDI). Two-step testing with toxin enzyme immunoassay is recommended to discriminate between infection and colonization but requires additional resources. Prior studies showed that PCR cycle threshold (CT) can predict toxin positivity with high negative predictive value. Starting Oct. 2016, predicted toxin result (CT-Toxin) based on a validated cut-off was routinely reported at our facility. To evaluate the clinical efficacy of this reporting, all adult patients with positive GeneXpert PCR from Oct. 2016 through Oct. 2017 underwent chart review to measure recurrence of or conversion to a CT-Toxin+ result and 30-day all-cause mortality. There were 482 positive PCR tests in 430 unique patients, 282 CT-Toxin+ and 200 CT-Toxin-. Patient characteristics were similar at testing, though CT-Toxin+ patients had a higher WBC count (12.5 v. 9.3 k/μL; p=0.001). All cases (n=21) of fulminant CDI had a CT-Toxin+ result. Index CT-Toxin+ patients were significantly more likely to have a CT-Toxin+ result within 90 days than CT-Toxin- patients (17.4% [n=49] v. 8.0% [n=16]; p=0.003). Thirty-day all-cause mortality was higher in CT-Toxin- patients (11.1% v. 6.8%; p=0.1), though no deaths in CT-Toxin- patients were directly attributable to CDI. Of 200 CT-Toxin- patients, 51.5% (n=103) were treated for CDI. The rate of conversion to a CT-Toxin+ result (8.8% v. 7.2%; p=0.8) and all-cause mortality (8.8% v. 13.4%; p=0.3) were similar between treated and untreated CT-Toxin- patients. CT-based toxin prediction may identify patients at higher risk for CDI-related complications and reduce treatment among CT-Toxin- patients.

  View details for DOI 10.1128/JCM.01288-19

  View details for PubMedID 31511334

• Antimicrobial Resistance in Sexually Transmitted Infections. Journal of travel medicine Tien, V. n., Punjabi, C. n., Holubar, M. K. 2019

  Abstract

  Rationale for review International travel facilitates the spread of drug-resistant infections, including sexually transmitted infections (STI). In 2016, the World Health Organization highlighted the global burden of "curable" STIs, estimating 376 million new infections of gonorrhea, chlamydia, syphilis, and trichomoniasis annually, with considerable geographic variation in both the burden of disease and prevalence of resistance. Travelers' risk of contracting and transmitting drug-resistant STIs depends in part on their geographic exposure. In this review, we describe the epidemiology of antimicrobial resistance (AMR) and the management of these four common STIs and Mycoplasma genitalium, an increasingly recognized cause of non-gonococcal urethritis. Key findings Multi-drug and extensively-drug resistant gonorrhea strains have been associated with international spread, particularly in travelers returning from Southeast Asia. Chlamydia is the most common bacterial STI worldwide. Although in vitro resistance has been reported, surveillance data suggests that clinically significant resistance to macrolides and tetracyclines is rare. Macrolide resistance in syphilis is now endemic in much of the world but there is no documented penicillin resistance, which remains first-line therapy. Trichomoniasis is the most common non-viral STI worldwide. Although clinical failure after treatment occurs, resistance to metronidazole is thought to be uncommon. Mycoplasma genitalium exhibits intrinsic resistance to many antibiotics, and the prevalence of resistance to both first- and second-line regimens (macrolides and fluoroquinolones) is increasing worldwide, with limited alternative therapeutic options. Recommendations International travelers are at risk for acquiring resistant STIs with limited therapeutic options. Improved diagnostics are urgently needed to improve AMR surveillance and the management of infected patients. As no vaccinations are currently available for these STIs, and pre-exposure prophylaxis is an area of active study with limited data, condom use is critical for prevention. Travel medicine providers should incorporate STI risk reduction counselling, with an emphasis on condom use, into the routine pre-travel consultation.

  View details for DOI 10.1093/jtm/taz101

  View details for PubMedID 31840758

• Antimicrobial Resistance: A global public health emergency further exacerbated by international travel. Journal of travel medicine Holubar, M. n. 2019

  View details for DOI 10.1093/jtm/taz095

  View details for PubMedID 31776565

• Protocol Paper: Oral Poliovirus Vaccine Transmissibility in Communities After Cessation of Routine Oral Poliovirus Vaccine Immunization CLINICAL INFECTIOUS DISEASES Sarnquist, C., Holubar, M., Garcia-Garcia, L., Ferreyra-Reyes, L., Delgado-Sanchez, G., Pablo Cruz-Hervert, L., Montero-Campos, R., Altamirano, J., Purington, N., Boyle, S., Modlin, J., Ferreira-Guerrero, E., Canizales-Quintero, S., Diaz Ortega, J., Desai, M., Maldonado, Y. A. 2018; 67: S115–S120

  View details for DOI 10.1093/cid/ciy606

  View details for Web of Science ID 000450051800016

• Lab Protocol Paper: Use of a High-throughput, Multiplex Reverse-transcription Quantitative Polymerase Chain Reaction Assay for Detection of Sabin Oral Polio Vaccine in Fecal Samples CLINICAL INFECTIOUS DISEASES van Hoorebeke, C., Huang, C., Leary, S., Holubar, M., Altamirano, J., Halpern, M. S., Sommer, M., Maldonado, Y. 2018; 67: S121–S126

  View details for DOI 10.1093/cid/ciy648

  View details for Web of Science ID 000450051800017

• Characterization of Household and Community Shedding and Transmission of Oral Polio Vaccine in Mexican Communities With Varying Vaccination Coverage CLINICAL INFECTIOUS DISEASES Altamirano, J., Purington, N., Behl, R., Sarnquist, C., Holubar, M., Garcia-Garcia, L., Ferreyra-Reyes, L., Montero-Campos, R., Pablo Cruz-Hervert, L., Boyle, S., Modlin, J., van Hoorebeke, C., Leary, S., Huang, C., Sommer, M., Ferreira-Guerrero, E., Delgado-Sanchez, G., Canizales-Quintero, S., Diaz Ortega, J., Desai, M., Maldonado, Y. A. 2018; 67: S4–S17

  View details for DOI 10.1093/cid/ciy650

  View details for Web of Science ID 000450051800002

• Deep Sequencing Prompts the Modification of a Real-time RT-PCR for the Serotype-Specific Detection of Polioviruses. Journal of virological methods Holubar, M., Sahoo, M. K., Huang, C., Mohamed-Hadley, A., Liu, Y., Waggoner, J. J., Troy, S. B., Garcia-Garcia, L., Ferreyra-Reyes, L., Maldonado, Y., Pinsky, B. A. 2018

  Abstract

  Polioviruses are members of the Enterovirus C species and asymptomatic fecal shedding allows for their transmission and persistence in a community, as well as the emergence of vaccine-derived polioviruses. Using three serotype-specific real-time RT-PCR (rRT-PCR) assays, the shedding and circulation of oral poliovirus vaccine (OPV) strains was previously investigated in a prospective cohort of MFexican children, their contacts, and nearby sewage. Subsequently, a deep sequencing approach targeting the P1 genomic region was applied to characterize OPV strains previously detected by rRT-PCR. Amplifiable RNA was obtained for sequencing from 40.3% (58/144) of stool samples and 71.4% (15/21) of sewage using nucleic acids extracted directly from primary rRT-PCR-positive specimens. Sequencing detected one or more OPV serotypes in 62.1% (36/58) of stool and 53.3% (8/15) of sewage samples. All stool and sewage samples in which poliovirus was not detected by deep sequencing contained at least one non-polio enterovirus C (NPEV-C) strain. To improve screening specificity, a modified, two-step, OPV serotype-specific multiplex rRT-PCR was evaluated. In stool specimens, the overall agreement between the original assays and the multiplex was 70.3%. By serotype, the overall agreement was 95.7% for OPV serotype-1 (S1), 65.6% for S2, and 96.1% for S3. Furthermore, most original rRT-PCR positive/multiplex rRT-PCR negative results were collected in the summer and fall months, consistent with NPEV-C circulation patterns. In conclusion, this deep sequencing approach allowed for the characterization of OPV sequences directly from clinical samples and facilitated the implementation of a more specific multiplex rRT-PCR for OPV detection and serotyping.

  View details for PubMedID 30447245

• Protocol Paper: Oral Poliovirus Vaccine Transmissibility in Communities After Cessation of Routine Oral Poliovirus Vaccine Immunization. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Sarnquist, C., Holubar, M., Garcia-Garcia, L., Ferreyra-Reyes, L., Delgado-Sanchez, G., Cruz-Hervert, L. P., Montero-Campos, R., Altamirano, J., Purington, N., Boyle, S., Modlin, J., Ferreira-Guerrero, E., Canizales-Quintero, S., Diaz Ortega, J. L., Desai, M., Maldonado, Y. A. 2018; 67 (suppl_1): S115–S120

  Abstract

  Background: We aimed to elucidate household and community-level shedding and transmission of trivalent oral polio vaccine (tOPV) in communities with inactivated polio vaccine (IPV) routine immunization after tOPV is administered during a national health week (NHW).Methods: We conducted a 3-arm, randomized trial with data collected at baseline through 10 weeks post-NHW in households with at least 1 child <5 years old in 3 semi-rural communities in Orizaba, Mexico. Selected communities were geographically isolated but socio-demographically similar. Each community was assigned an oral polio vaccine (OPV) immunization rate: 10, 30, or 70% of participating households. From 2653 households in the 3 communities, ~150 households per community were selected, for 466 in total. Households were randomized as vaccinated or unvaccinated, with only 1 child under 5 in the vaccinated household receiving OPV during the February 2015 NHW. No other community members received OPV during this NHW. Stool samples were collected up to 10 weeks post-vaccination for all members of the 466 study households and were analyzed for the presence of OPV serotypes using a multiplex polymerase chain reaction assay.Results: We will report on the factors associated with, and incidence and duration of, household and community shedding and transmission of OPV. The secondary outcomes will characterize temporal and geospatial OPV serotype shedding patterns.Conclusions: The current global polio eradication plan relies on transitioning away from OPV to IPV. This study contributes to understanding patterns of OPV shedding and transmission dynamics in communities with primary IPV immunity, in order to optimize the reduction of OPV transmission.

  View details for PubMedID 30376084

• Lab Protocol Paper: Use of a High-throughput, Multiplex Reverse-transcription Quantitative Polymerase Chain Reaction Assay for Detection of Sabin Oral Polio Vaccine in Fecal Samples. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America van Hoorebeke, C., Huang, C., Leary, S., Holubar, M., Altamirano, J., Halpern, M. S., Sommer, M., Maldonado, Y. 2018; 67 (suppl_1): S121–S126

  Abstract

  Background: Global polio eradication efforts rely in part on molecular methods of detecting polioviruses, both wild and vaccine strains, from human and environmental samples. Previous assays used for detection of Sabin oral polio vaccine (OPV) in fecal samples have been labor and time intensive and vary in their sensitivity and specificity.Methods: We developed a high-throughput, multiplex reverse-transcription quantitative polymerase chain reaction assay able to detect all 3 OPV strains in fecal samples. The assay used a KingFisher Duo Prime system for viral RNA isolation and extraction. Positive samples were retested and Sanger sequenced for verification of Sabin serotype identity.Results: The 95% lower limit of detection was determined to be 3 copies per reaction for Sabin 1 and 3 and 4 copies per reaction for Sabin 2, with no cross-reactivity between the 3 serotypes and their primers. A total of 554 samples (3.6%) were positive, with 304 positive samples (54.9%) containing >1 serotype. Of the positive samples, 476 (85.9%) contained enough RNA to be sequenced, and of these all sequences were Sabin serotypes. The previous assay we used could process 48 samples in a 10-hour period, whereas the new assay processed >100 samples in 6 hours.Conclusions: The new high-throughput, multiplex reverse-transcription quantitative polymerase chain reaction assay allowed for sensitive and specific detection of OPV serotypes while greatly decreasing sample handling and processing time. We were able to sequence 72.4% of the 210 positive samples in the cycle threshold range of 35-37.

  View details for PubMedID 30376092

• Characterization of Household and Community Shedding and Transmission of Oral Polio Vaccine in Mexican Communities With Varying Vaccination Coverage. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Altamirano, J., Purington, N., Behl, R., Sarnquist, C., Holubar, M., Garcia-Garcia, L., Ferreyra-Reyes, L., Montero-Campos, R., Cruz-Hervert, L. P., Boyle, S., Modlin, J., van Hoorebeke, C., Leary, S., Huang, C., Sommer, M., Ferreira-Guerrero, E., Delgado-Sanchez, G., Canizales-Quintero, S., Diaz Ortega, J. L., Desai, M., Maldonado, Y. A. 2018; 67 (suppl_1): S4–S17

  Abstract

  Background: The World Health Assembly 2012 Polio Eradication and Endgame Strategic Plan calls for the eventual cessation of all oral polio vaccines (OPVs), to be replaced with inactivated polio vaccine (IPV); however, IPV induces less robust mucosal immunity than OPV. This study characterized household and community OPV shedding and transmission after OPV vaccination within primarily IPV-vaccinated communities.Methods: Households in 3 IPV-vaccinated Mexican communities were randomized to receive 3 levels of OPV vaccination coverage (70%, 30%, or 10%). Ten stool samples were collected from all household members over 71 days. Analysis compared vaccinated subjects, household contacts of vaccinated subjects, and subjects in unvaccinated households. Logistic and Cox regression models were fitted to characterize transmission of OPV by coverage and household vaccination status.Results: Among 148 vaccinated children, 380 household contacts, and 1124 unvaccinated community contacts, 78%, 18%, and 7%, respectively, shed OPV. Community and household contacts showed no differences in transmission (odds ratio [OR], 0.67; 95% confidence interval [CI], .37-1.20), in shedding trajectory (OR, 0.61; 95% CI, .35-1.07), or in time to shedding (hazard ratio, 0.68; 95% CI, .39-1.19). Transmission began as quickly as 1 day after vaccination and persisted as long as 71 days after vaccination. Transmission within unvaccinated households differed significantly across vaccination coverage communities, with the 70% community experiencing the most transmissions (15%), and the 10% community experiencing the least (4%). These trends persisted over time and in the time to first shedding analyses.Conclusions: Transmission did not differ between household contacts of vaccinees and unvaccinated households. Understanding poliovirus transmission dynamics is important for postcertification control.

  View details for PubMedID 30376097

• A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback POSTGRADUATE MEDICAL JOURNAL Hom, J., Kumar, A., Evans, K. H., Svec, D., Richman, I., Fang, D., Smeraglio, A., Holubar, M., Johnson, T., Shah, N., Renault, C., Ahuja, N., Witteles, R., Harman, S., Shieh, L. 2017; 93 (1106): 725–29

  View details for DOI 10.1136/postgradmedj-2016-134617

  View details for Web of Science ID 000416160200005

• Comprehensive Guidance for Antibiotic Dosing in Obese Adults PHARMACOTHERAPY Meng, L., Mui, E., Holubar, M. K., Deresinski, S. C. 2017; 37 (11): 1415–31

  Abstract

  Physiologic alterations seen in obesity commonly impact the pharmacokinetics (PK) and pharmacodynamics (PD) of antibiotics and may result in suboptimal dosing in this expanding but understudied population. Much of the published clinical and PK evidence to date consists of small patient populations and are retrospective with, not infrequently, heterogeneous results that in some cases are contradictory. In the last 10 years, additional antimicrobial PK/PD and clinical data encompassing prolonged infusion strategies and examination of critically ill populations have emerged to inform antimicrobial dosing in obesity. In this narrative review, we critically review literature on dosing, PK, and possible dosing strategies in obese adults. We searched PubMed, Scopus, and the Cochrane Library using Medical Subject Headings including anti-infectives, specific antimicrobial names, obese, pharmacokinetics, and others. We reviewed articles, cross-referenced select cited references, and when applicable, referenced drug databases and package inserts to develop dosing recommendations. We provide an overall critical review of the available data regarding PK and dosing issues including dosing recommendations in both critically ill and noncritically ill patients with significant obesity. We developed dosing recommendations for 34 antimicrobials based on 121 articles of the 2336 identified by the search strategy. Although 11 of these do not appear to require dose adjustment, obesity-specific dosing guidance is provided for the remaining 23 antimicrobials. Additional studies are needed to better understand and resolve discrepant published results regarding the PK of antibiotics to establish optimal dosing strategies in obese adults. Alternative dosing strategies, such as extended infusions, should be considered for time-dependent antibiotics (e.g., β-lactams) in obese patients to achieve PD targets reliably. Therapeutic drug monitoring across the spectrum of antimicrobials is of increasing importance in this and other populations to ensure optimized dosing.

  View details for PubMedID 28869666

• Assessing the individual risk of fecal poliovirus shedding among vaccinated and non-vaccinated subjects following national health weeks in Mexico PLOS ONE Ferreyra-Reyes, L., Pablo Cruz-Hervert, L., Troy, S. B., Huang, C., Sarnquist, C., Delgado-Sanchez, G., Canizales-Quintero, S., Holubar, M., Ferreira-Guerrero, E., Montero-Campos, R., Rodriguez-Alvarez, M., Mongua-Rodriguez, N., Maldonado, Y., Garcia-Garcia, L. 2017; 12 (10): e0185594

  Abstract

  Mexico introduced inactivated polio vaccine (IPV) into its routine immunization (RI) schedule in 2007 but continued to give trivalent oral polio vaccine (tOPV) twice a year during national health weeks (NHW) through 2015.To evaluate individual variables associated with poliovirus (PV) shedding among children with IPV-induced immunity after vaccination with tOPV and their household contacts.We recruited 72 children (both genders, ≤30 months, vaccinated with at least two doses of IPV) and 144 household contacts (both genders, 2 per household, children and adults) between 08/2010 and 09/2010 in Orizaba, Veracruz. Three NHW took place (one before and two after enrollment). We collected fecal samples monthly for 12 months, and tested 2500 samples for polioviruses types 1, 2 and 3 with three serotype-specific singleplex real-time RT-PCR (rRT-PCR) assays. In order to increase the specificity for OPV virus, all positive and 112 negative samples were also processed with a two-step, OPV serotype-specific multiplex rRT-PCR.We estimated adjusted hazard ratios (HR) and 95% CI using Cox proportional hazards regression for recurrent events models accounting for individual clustering to assess the association of individual variables with the shedding of any poliovirus for all participants and stratifying according to whether the participant had received tOPV in the month of sample collection.216 participants were included. Of the 2500 collected samples, using the singleplex rRT-PCR assay, PV was detected in 5.7% (n = 142); PV1 in 1.2% (n = 29), PV2 in 4.1% (n = 103), and PV3 in 1.9% (n = 48). Of the 256 samples processed by multiplex rRT-PCR, PV was detected in 106 (PV1 in 16.41% (n = 42), PV2 in 21.09% (n = 54), and PV3 in 23.05% (n = 59). Both using singleplex and multiplex assays, shedding of OPV among non-vaccinated children and subjects older than 5 years of age living in the same household was associated with shedding of PV2 by a household contact. All models were adjusted by sex, age, IPV vaccination and OPV shedding by the same individual during the previous month of sample collection.Our results provide important evidence regarding the circulation of poliovirus in a mixed vaccination context (IPV+OPV) which mimics the "transitional phase" that occurs when countries use both vaccines simultaneously. Shedding of OPV2 by household contacts was most likely the source of infection of non-vaccinated children and subjects older than 5 years of age living in the same household.

  View details for PubMedID 29023555

• Feasibility and applicability of antimicrobial stewardship in immunocompromised patients. Current opinion in infectious diseases Robilotti, E., Holubar, M., Seo, S. K., Deresinski, S. 2017

  Abstract

  Antimicrobial stewardship is the primary intervention in the battle against antimicrobial resistance, but clinicians do not always apply many key antimicrobial stewardship principles to patients with significant immune defects due to lack of data and fear of bad outcomes. We review evidence regarding the application of stewardship principles to immunocompromised patients, with a focus on solid organ and hematopoietic stem cell transplant recipients.Antimicrobial stewardship programs (ASPs), targeting immunocompromised patient populations such as oncology and transplant, are gaining traction. Emerging literature suggests that several stewardship interventions can be adapted to immunocompromised hosts and improve antimicrobial utilization, but data supporting improved outcomes is very limited.The application of antimicrobial stewardship principles to immunocompromised patients is feasible, necessary, and urgent. As antimicrobial stewardship programs gain momentum across a diverse range of healthcare settings more immunocompromised patients will fall under their purview. It is imperative that centers applying antimicrobial stewardship principles share their experience and establish collaborative research efforts to advance our knowledge base in applying antimicrobial stewardship initiatives to immunocompromised host populations, both in terms of programmatic success and patient outcomes.

  View details for DOI 10.1097/QCO.0000000000000380

  View details for PubMedID 28542093

• Detection of Emerging Vaccine-Related Polioviruses by Deep Sequencing. Journal of clinical microbiology Sahoo, M. K., Holubar, M., Huang, C., Mohamed-Hadley, A., Liu, Y., Waggoner, J. J., Troy, S. B., Garcia-Garcia, L., Ferreyra-Reyes, L., Maldonado, Y., Pinsky, B. A. 2017

  Abstract

  Oral poliovirus vaccine can mutate to regain neurovirulence. To date, evaluation of these mutations has been performed primarily on culture-enriched isolates by using conventional Sanger sequencing. We therefore developed a culture-independent, deep-sequencing method targeting the 5' untranslated region (UTR) and P1 genomic region to characterize vaccine-related poliovirus variants. Error analysis of the deep-sequencing method demonstrated reliable detection of poliovirus mutations at levels of <1%, depending on read depth. Sequencing of viral nucleic acids from the stool of vaccinated, asymptomatic children and their close contacts collected during a prospective cohort study in Veracruz, Mexico, revealed no vaccine-derived polioviruses. This was expected given that the longest duration between sequenced sample collection and the end of the most recent national immunization week was 66 days. However, we identified many low-level variants (<5%) distributed across the 5' UTR and P1 genomic region in all three Sabin serotypes, as well as vaccine-related viruses with multiple canonical mutations associated with phenotypic reversion present at high levels (>90%). These results suggest that monitoring emerging vaccine-related poliovirus variants by deep sequencing may aid in the poliovirus endgame and efforts to ensure global polio eradication.

  View details for DOI 10.1128/JCM.00144-17

  View details for PubMedID 28468861

• Infection Rates. Journal of clinical microbiology Truong, C. Y., Gombar, S., Wilson, R., Sundararajan, G., Tekic, N., Holubar, M., Shepard, J., Madison, A., Tompkins, L., Shah, N., Deresinski, S., Schroeder, L. F., Banaei, N. 2017

  Abstract

  Health care-onset health care facility-associated Clostridium difficile infection (HO-CDI) is overdiagnosed for several reasons, including the high prevalence of C. difficile colonization and the inability of hospitals to limit testing to patients with clinically significant diarrhea. We conducted a quasiexperimental study from 22 June 2015 to 30 June 2016 on consecutive inpatients with C. difficile test orders at an academic hospital. Real-time electronic patient data tracking was used by the laboratory to enforce testing criteria (defined as the presence of diarrhea [≥3 unformed stools in 24 h] and absence of laxative intake in the prior 48 h). Outcome measures included C. difficile test utilization, HO-CDI incidence, oral vancomycin utilization, and clinical complications. During the intervention, 7.1% (164) and 9.1% (211) of 2,321 C. difficile test orders were canceled due to absence of diarrhea and receipt of laxative therapy, respectively. C. difficile test utilization decreased upon implementation from an average of 208.8 tests to 143.0 tests per 10,000 patient-days (P < 0.001). HO-CDI incidence rate decreased from an average of 13.0 cases to 9.7 cases per 10,000 patient-days (P = 0.008). Oral vancomycin days of therapy decreased from an average of 13.8 days to 9.4 days per 1,000 patient-days (P = 0.009). Clinical complication rates were not significantly different in patients with 375 canceled orders compared with 869 episodes with diarrhea but negative C. difficile results. Real-time electronic clinical data tracking is an effective tool for verification of C. difficile clinical testing criteria and safe reduction of inflated HO-CDI rates.

  View details for DOI 10.1128/JCM.02319-16

  View details for PubMedID 28250001

• Educating front-line clinicians about antimicrobial resistance LANCET INFECTIOUS DISEASES Robilotti, E., Holubar, M., Nahrgang, S., van de Sande-Bruinsma, N., Wong, D., Deresinski, S. 2017; 17 (3): 257–58

  View details for PubMedID 28244382

  View details for PubMedCentralID PMC5505870

• A high value care curriculum for interns: a description of curricular design, implementation and housestaff feedback. Postgraduate medical journal Hom, J. n., Kumar, A. n., Evans, K. H., Svec, D. n., Richman, I. n., Fang, D. n., Smeraglio, A. n., Holubar, M. n., Johnson, T. n., Shah, N. n., Renault, C. n., Ahuja, N. n., Witteles, R. n., Harman, S. n., Shieh, L. n. 2017

  Abstract

  Most residency programmes do not have a formal high value care curriculum. Our goal was to design and implement a multidisciplinary high value care curriculum specifically targeted at interns.Our curriculum was designed with multidisciplinary input from attendings, fellows and residents at Stanford. Curricular topics were inspired by the American Board of Internal Medicine's Choosing Wisely campaign, Alliance for Academic Internal Medicine, American College of Physicians and Society of Hospital Medicine. Our topics were as follows: introduction to value-based care; telemetry utilisation; lab ordering; optimal approach to thrombophilia work-ups and fresh frozen plasma use; optimal approach to palliative care referrals; antibiotic stewardship; and optimal approach to imaging for low back pain. Our curriculum was implemented at the Stanford Internal Medicine residency programme over the course of two academic years (2014 and 2015), during which 100 interns participated in our high value care curriculum. After each high value care session, interns were offered the opportunity to complete surveys regarding feedback on the curriculum, self-reported improvements in knowledge, skills and attitudinal module objectives, and quiz-based knowledge assessments.The overall survey response rate was 67.1%. Overall, the material was rated as highly useful on a 5-point Likert scale (mean 4.4, SD 0.6). On average, interns reported a significant improvement in their self-rated knowledge, skills and attitudes after the six seminars (mean improvement 1.6 points, SD 0.4 (95% CI 1.5 to 1.7), p<0.001).We successfully implemented a novel high value care curriculum that specifically targets intern physicians.

  View details for PubMedID 28663352

• Impact of vaccine herd-protection effects in cost-effectiveness analyses of childhood vaccinations. A quantitative comparative analysis. PloS one Holubar, M., Stavroulakis, M. C., Maldonado, Y., Ioannidis, J. P., Contopoulos-Ioannidis, D. 2017; 12 (3)

  Abstract

  Inclusion of vaccine herd-protection effects in cost-effectiveness analyses (CEAs) can impact the CEAs-conclusions. However, empirical epidemiologic data on the size of herd-protection effects from original studies are limited.We performed a quantitative comparative analysis of the impact of herd-protection effects in CEAs for four childhood vaccinations (pneumococcal, meningococcal, rotavirus and influenza). We considered CEAs reporting incremental-cost-effectiveness-ratios (ICERs) (per quality-adjusted-life-years [QALY] gained; per life-years [LY] gained or per disability-adjusted-life-years [DALY] avoided), both with and without herd protection, while keeping all other model parameters stable. We calculated the size of the ICER-differences without vs with-herd-protection and estimated how often inclusion of herd-protection led to crossing of the cost-effectiveness threshold (of an assumed societal-willingness-to-pay) of $50,000 for more-developed countries or X3GDP/capita (WHO-threshold) for less-developed countries.We identified 35 CEA studies (20 pneumococcal, 4 meningococcal, 8 rotavirus and 3 influenza vaccines) with 99 ICER-analyses (55 per-QALY, 27 per-LY and 17 per-DALY). The median ICER-absolute differences per QALY, LY and DALY (without minus with herd-protection) were $15,620 (IQR: $877 to $48,376); $54,871 (IQR: $787 to $115,026) and $49 (IQR: $15 to $1,636) respectively. When the target-vaccination strategy was not cost-saving without herd-protection, inclusion of herd-protection always resulted in more favorable results. In CEAs that had ICERs above the cost-effectiveness threshold without herd-protection, inclusion of herd-protection led to crossing of that threshold in 45% of the cases. This impacted only CEAs for more developed countries, as all but one CEAs for less developed countries had ICERs below the WHO-cost-effectiveness threshold even without herd-protection. In several analyses, recommendation for the adoption of the target vaccination strategy depended on the inclusion of the herd protection effect.Inclusion of herd-protection effects in CEAs had a substantial impact in the estimated ICERs and made target-vaccination strategies more attractive options in almost half of the cases where ICERs were above the societal-willingness to pay threshold without herd-protection. More empirical epidemiologic data are needed to determine the size of herd-protection effects across diverse settings and also the size of negative vaccine effects, e.g. from serotype substitution.

  View details for DOI 10.1371/journal.pone.0172414

  View details for PubMedID 28249046

• Bacteremia due to Methicillin-Resistant Staphylococcus aureus New Therapeutic Approaches INFECTIOUS DISEASE CLINICS OF NORTH AMERICA Holubar, M., Meng, L., Deresinski, S. 2016; 30 (2): 491-?

  Abstract

  This article reviews recent clinical evidence for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Vancomycin remains the initial antibiotic of choice for the treatment of patients with MRSA bacteremia and endocarditis due to isolates with vancomycin minimum inhibitory concentration ≤2 μg/mL, whereas daptomycin is an effective alternative, and ceftaroline seems promising. Treatment options for persistent MRSA bacteremia or bacteremia due to vancomycin-intermediate or vancomycin-resistant strains include daptomycin, ceftaroline, and combination therapies. There is a critical need for high-level evidence from clinical trials to allow optimally informed decisions in the treatment of MRSA bacteremia and endocarditis.

  View details for DOI 10.1016/j.idc.2016.02.009

  View details for Web of Science ID 000378466900010

  View details for PubMedID 27208769

• Shedding of Oral Poliovirus Vaccine (OPV) by HIV-Infected and -Uninfected Mothers of OPV-Vaccinated Zimbabwean Infants. Journal of the Pediatric Infectious Diseases Society Holubar, M., Troy, S. B., Nathoo, K., Stranix-Chibanda, L., Musingwini, G., Srinivas, N., Huang, C., Junn, A., Halpern, M. S., Maldonado, Y. A. 2016

  Abstract

  Community circulation of oral poliovirus vaccine (OPV) likely begins with household transmission. We analyzed stool collected from Zimbabwean mothers who were infected with human immunodeficiency virus (HIV) and those who were uninfected with HIV 1 to 24 weeks after infant oral poliovirus vaccination. Overall, only 5% of the mothers had detectable OPV (16 of 304) despite high infant shedding rates. OPV shedding was similar between HIV-infected mothers and those who were uninfected (11 [6.4%] of 171 vs 5 [3.8%] of 133, respectively) and between mothers of HIV-infected infants and those of uninfected infants (2 [3.5%] of 57 vs 9 [6.3%] of 144, respectively). Mothers of vaccinated infants are unlikely to shed OPV, even when they are infected with HIV.

  View details for PubMedID 26759497

• Immunodeficiency-related vaccine-derived poliovirus (iVDPV) cases: A systematic review and implications for polio eradication VACCINE Guo, J., Bolivar-Wagers, S., Srinivas, N., Holubar, M., Maldonado, Y. 2015; 33 (10): 1235-1242

  Abstract

  Vaccine-derived polioviruses (VDPVs), strains of poliovirus mutated from the oral polio vaccine, pose a challenge to global polio eradication. Immunodeficiency-related vaccine-derived polioviruses (iVDPVs) are a type of VDPV which may serve as sources of poliovirus reintroduction after the eradication of wild-type poliovirus. This review is a comprehensive update of confirmed iVDPV cases published in the scientific literature from 1962 to 2012, and describes clinically relevant trends in reported iVDPV cases worldwide.We conducted a systematic review of published iVDPV case reports from January 1960 to November 2012 from four databases. We included cases in which the patient had a primary immunodeficiency, and the vaccine virus isolated from the patient either met the sequencing definition of VDPV (>1% divergence for serotypes 1 and 3 and >0.6% for serotype 2) and/or was previously reported as an iVDPV by the World Health Organization.We identified 68 iVDPV cases in 49 manuscripts reported from 25 countries and the Palestinian territories. 62% of case patients were male, 78% presented clinically with acute flaccid paralysis, and 65% were iVDPV2. 57% of cases occurred in patients with predominantly antibody immunodeficiencies, and the overall all-cause mortality rate was greater than 60%. The median age at case detection was 1.4 years [IQR: 0.8, 4.5] and the median duration of shedding was 1.3 years [IQR: 0.7, 2.2]. We identified a poliovirus genome VP1 region mutation rate of 0.72% per year and a higher median percent divergence for iVDPV1 cases. More cases were reported from high income countries, which also had a larger age variation and different distribution of immunodeficiencies compared to upper and lower middle-income countries.Our study describes the incidence and characteristics of global iVDPV cases reported in the literature in the past five decades. It also highlights the regional and economic disparities of reported iVDPV cases.

  View details for DOI 10.1016/j.vaccine.2015.01.018

  View details for PubMedID 25600519

• Community circulation patterns of oral polio vaccine serotypes 1, 2, and 3 after mexican national immunization weeks. journal of infectious diseases Troy, S. B., Ferreyra-Reyes, L., Huang, C., Sarnquist, C., Canizales-Quintero, S., Nelson, C., Báez-Saldaña, R., Holubar, M., Ferreira-Guerrero, E., García-García, L., Maldonado, Y. A. 2014; 209 (11): 1693-1699

  Abstract

  Background. With wild poliovirus nearing eradication, preventing circulating vaccine-derived poliovirus (cVDPV) by understanding oral polio vaccine (OPV) community circulation is increasingly important. Mexico, where OPV is given only during biannual national immunization weeks (NIWs) but where children receive inactivated polio vaccine (IPV) as part of their primary regimen, provides a natural setting to study OPV community circulation. Methods. In total, 216 children and household contacts in Veracruz, Mexico, were enrolled, and monthly stool samples and questionnaires collected for 1 year; 2501 stool samples underwent RNA extraction, reverse transcription, and real-time polymerase chain reaction (PCR) to detect OPV serotypes 1, 2, and 3. Results. OPV was detected up to 7 months after an NIW, but not at 8 months. In total, 35% of samples collected from children vaccinated the prior month, but only 4% of other samples, contained OPV. Although each serotype was detected in similar proportions among OPV strains shed as a result of direct vaccination, 87% of OPV acquired through community spread was serotype 2 (P < .0001). Conclusions. Serotype 2 circulates longer and is transmitted more readily than serotypes 1 or 3 after NIWs in a Mexican community primarily vaccinated with IPV. This may be part of the reason why most isolated cVDPV has been serotype 2.

  View details for DOI 10.1093/infdis/jit831

  View details for PubMedID 24367038

  View details for PubMedCentralID PMC4017366

• Incident Hepatitis C Virus Infection among US HIV-Infected Men Enrolled in Clinical Trials CLINICAL INFECTIOUS DISEASES Taylor, L. E., Holubar, M., Wu, K., Bosch, R. J., Wyles, D. L., Davis, J. A., Mayer, K. H., Sherman, K. E., Tashima, K. T. 2011; 52 (6): 812-818

  Abstract

  Outbreaks of sexually transmitted hepatitis C virus (HCV) infection have been reported among human immunodeficiency virus (HIV)-infected men who have sex with men in Europe, Australia, and New York. Whether this is occurring across the United States is unknown.We determined incidence of HCV infection during 1996-2008 among male participants of the AIDS Clinical Trial Group Longitudinal Linked Randomized Trials cohort, a long-term study of HIV-infected persons randomized into selected US-based clinical trials. We evaluated associations with self-reported injection drug use (IDU), time-varying CD4(+) cell count, and HIV RNA level with use of multivariate Poisson regression. No sexual or non-IDU risk factor data was available.A total of 1830 men had an initial negative HCV antibody test result and at least 1 subsequent HCV antibody test result, contributing >7000 person-years. At the time of the initial negative HCV antibody test result, 94% of men were receiving highly active antiretroviral therapy (HAART) and 6% reported current or prior IDU. Thirty-six seroconverted, with overall incidence of .51 cases per 100 person-years (95% confidence interval, .36-.70). Mean age at seroconversion was 46 years. Seroconversion was associated with IDU (25% of seroconverters reported IDU history vs 5% of nonseroconverters; P < .001), whereas 75% (n = 27) of seroconverters reported no IDU (incidence, 2.67 cases per 100 person-years among IDUs, .40 cases per 100 person-years among non-IDUs). Seroconversion was associated with HIV RNA level >400 copies/mL (44% at time of antibody positivity vs 21% at time of last negative antibody test result; P = .02) but not with CD4(+) cell count.Incident HCV infection occurs in HIV-infected men involved in US HIV therapeutic trials, primarily through nonparenteral means, despite engagement in care and HAART. HCV antibody development was not related to immune status but was associated with inadequate HIV suppression. At-risk HIV-infected persons should have access to HCV surveillance.

  View details for DOI 10.1093/cid/ciq201

  View details for Web of Science ID 000288020300018

  View details for PubMedID 21282184

  View details for PubMedCentralID PMC3106260