Bio

Bio


Dr. Marisa Holubar specializes in the treatment of infectious diseases and works primarily in the inpatient setting. She is particularly interested in antimicrobial stewardship and hospital epidemiology.

Clinical Focus


  • Infectious Disease

Academic Appointments


Administrative Appointments


  • Associate Medical Director, Stanford Antimicrobial Safety and Sustainability Program (2015 - Present)
  • Associate Medical Director, Infection Prevention, Stanford Hospital and Clinics (2015 - Present)

Boards, Advisory Committees, Professional Organizations


  • Physician, California Department of Public Health Healthcare Associated Infections Advisory Committee (2016 - Present)

Professional Education


  • Fellowship:Stanford University School of Medicine Registrar (2013) CA
  • Board Certification: Infectious Disease, American Board of Internal Medicine (2012)
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2009)
  • Residency:Brown University (2009) RI
  • Medical Education:University of Wisconsin School of Medicine (2005) WI
  • Masters, Stanford University, Epidemiology and Clinical Research (2014)

Publications

All Publications


  • 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 DOI 10.1002/phar.2023

    View details for Web of Science ID 000414966600012

    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 DOI 10.1371/journal.pone.0185594

    View details for Web of Science ID 000412845100022

    View details for PubMedID 29023555

    View details for PubMedCentralID PMC5638237

  • 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

  • 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

    View details for PubMedCentralID PMC5332092

  • 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

    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 DOI 10.1136/postgradmedj-2016-134617

    View details for PubMedID 28663352

  • 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 Web of Science ID 000350083600004

    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