Time to Sustained Recovery Among Outpatients With COVID-19 Receiving Montelukast vs Placebo: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate COVID-19 is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design, Setting, and Participants: This randomized clinical trial (Accelerating COVID-19 Therapeutic Interventions and Vaccines [ACTIV]-6) was conducted from January 27 through June 23, 2023, during the circulation of Omicron subvariants. Participants aged 30 years or older with confirmed SARS-CoV-2 infection and 2 or more acute COVID-19 symptoms for less than 7 days were included across 104 US sites. Interventions: Participants were randomized 1:1 to receive montelukast, 10 mg once daily, or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as ≥3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of health care utilization events (hospitalization, urgent care clinic visit, emergency department visit, or death); COVID-19 clinical progression scale score; and difference in mean time unwell. A modified intention-to-treat approach was used for the analysis. Results: Among 1250 participants who were randomized and received the study drug or placebo, the median age was 53 years (IQR, 42-62 years), 753 (60.2%) were female, and 704 (56.3%) reported receiving 2 or more doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [AHR], 1.02; 95% credible interval [CrI], 0.92-1.12; P = .63 for efficacy). Unadjusted median time to sustained recovery was 10 days (95% CI, 10-11 days) in both groups. No deaths occurred, and hospitalizations were reported for 2 participants (0.3%) in each group; the composite of health care utilization events was reported for 18 participants (2.9%) in the montelukast group and 18 (2.9%) in the placebo group (AHR, 1.01; 95% CrI, 0.45-1.84; P = .48 for efficacy). Five participants (0.4%) experienced serious adverse events (3 [0.5%] in the montelukast group and 2 [0.3%] in the placebo group). Conclusions and Relevance: In this randomized clinical trial of outpatients with mild to moderate COVID-19, treatment with montelukast did not reduce duration of COVID-19 symptoms. These findings do not support the use of montelukast for the treatment of mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Effect of Montelukast vs Placebo on Time to Sustained Recovery in Outpatients with COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of montelukast in reducing symptom duration among outpatients with mild to moderate coronavirus disease 2019 (COVID-19) is uncertain. Objective: To assess the effectiveness of montelukast compared with placebo in treating outpatients with mild to moderate COVID-19. Design Setting and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate the effectiveness of repurposed medications in treating mild to moderate COVID-19. Between January 27, 2023, and June 23, 2023, 1250 participants ≥30 years of age with confirmed SARS-CoV-2 infection and ≥2 acute COVID-19 symptoms for ≤7 days, were included across 104 US sites to evaluate the use of montelukast. Interventions: Participants were randomized to receive montelukast 10 mg once daily or matched placebo for 14 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID clinical progression scale; and difference in mean time unwell. Results: Among participants who were randomized and received study drug, the median age was 53 years (IQR 42-62), 60.2% were female, 64.6% identified as Hispanic/Latino, and 56.3% reported ≥2 doses of a SARS-CoV-2 vaccine. Among 628 participants who received montelukast and 622 who received placebo, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR] 1.02; 95% credible interval [CrI] 0.92-1.12; P(efficacy) = 0.63]). Unadjusted median time to sustained recovery was 10 days (95% confidence interval 10-11) in both groups. No deaths were reported and 2 hospitalizations were reported in each group; 36 participants reported healthcare utilization events (a priori defined as death, hospitalization, emergency department/urgent care visit); 18 in the montelukast group compared with 18 in the placebo group (HR 1.01; 95% CrI 0.45-1.84; P(efficacy)=0.48). Five participants experienced serious adverse events (3 with montelukast and 2 with placebo). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with montelukast does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov ( NCT04885530 ).

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

In Vitro Activity of Omadacycline and Comparator Antibiotics against Extended-Spectrum Beta-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae Urinary Isolates.

Limited oral antibiotic options exist for urinary tract infections (UTI) caused by ESBL-producing Enterobacterales. The aim of the study was to evaluate in vitro activity of omadacycline and comparator antibiotics against clinical ESBL-producing and non-ESBL-producing E. coli and K. pneumoniae urinary isolates. 102 isolates each of E. coli and K. pneumoniae were collected from clinical urine specimens in 2019. By design, an equal number of each species were included that tested positive and negative for ESBL production. Omadacycline MICs were determined using gradient test strips and compared to MICs of comparator antibiotics as determined by an automated broth microdilution system. Isolates were considered susceptible to omadacycline if the MIC was ≤4 µg/mL for each species. 54.9% of all ESBL-producing isolates were susceptible to omadacycline, but better susceptibility was observed for ESBL-producing E. coli (74.5%). Omadacycline MICs were 2-4 fold lower for E. coli and K. pneumoniae strains not producing ESBL. The omadacycline MIC 50 and 90 values were 4 and 16 µg/mL, respectively, for all isolates studied. 74.5% of all isolates were considered susceptible to omadacycline. MICs were generally lower for E. coli strains with MIC 50 and 90 values of 4 and 8 µg/mL, respectively (87.3% susceptible), compared with K. pneumoniae. Overall, the most active agents were omadacycline and nitrofurantoin, while other comparator antibiotics were less active. Omadacycline represents a promising oral antibiotic for treating UTI caused by ESBL-producing E. coli, particularly when resistance limits other oral options. Prospective, controlled clinical trials are needed to validate these in vitro results.

Analysis of infections among patients with historical culture positive for extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli or Klebsiella pneumoniae: Is ESBL-targeted therapy always needed?

Objective: Among patients with a history of ESBL infection, uncertainty remains regarding whether all of these patients require ESBL-targeted therapy when presenting with a subsequent infection. We sought to determine the risks associated with a subsequent ESBL infection to help inform empiric antibiotic decisions. Methods: A retrospective cohort study of adult patients with positive index culture for Escherichia coli or Klebsiella pneumoniae (EC/KP) receiving medical care during 2017 was conducted. Risk assessments were performed to identify factors associated with subsequent infection caused by ESBL-producing EC/KP. Results: In total, 200 patients were included in the cohort, 100 with ESBL-producing EC/KP and 100 with ESBL-negative EC/KP. Of 100 patients (50%) who developed a subsequent infection, 22 infections were ESBL-producing EC/KP, 43 were other bacteria, and 35 had no or negative cultures. Subsequent infection caused by ESBL-producing EC/KP only occurred when the index culture was also ESBL-producing (22 vs 0). Among those with ESBL-producing index culture, the incidences of subsequent infection caused by ESBL-producing EC/KP versus other bacterial subsequent infection were similar (22 vs 18; P = .428). Factors associated with subsequent infection caused by ESBL-producing EC/KP include history of ESBL-producing index culture, time ≤180 days between index culture and subsequent infection, male sex, and Charlson comorbidity index score >3. Conclusions: History of ESBL-producing EC/KP culture is associated with subsequent infection caused by ESBL-producing EC/KP, particularly within 180 days after the historical culture. Among patients presenting with infection and a history of ESBL-producing EC/KP, other factors should be considered in making empiric antibiotic decisions, and ESBL-targeted therapy may not always be warranted.

Successful Treatment of Persistent 5-Nitroimidazole-Resistant Trichomoniasis With an Extended Course of Oral Secnidazole Plus Intravaginal Boric Acid.

ABSTRACT: We describe a case of persistent 5-nitroimidazole-resistant trichomoniasis cured after 14 days of oral secnidazole and intravaginal boric acid. Secnidazole may be an important treatment option for resistant trichomoniasis, particularly in women who fail other regimens, including higher doses of oral metronidazole and tinidazole for longer durations of time.

A comparison of active versus passive methods of responding to rapid diagnostic blood culture results.

Objective: To compare 2 methods of communicating polymerase chain reaction (PCR) blood-culture results: active approach utilizing on-call personnel versus passive approach utilizing notifications in the electronic health record (EHR). Design: Retrospective observational study. Setting: A tertiary-care academic medical center. Patients: Adult patients hospitalized with ≥1 positive blood culture containing a gram-positive organism identified by PCR between October 2014 and January 2018. Methods: The standard protocol for reporting PCR results at baseline included a laboratory technician calling the patient's nurse, who would report the critical result to the medical provider. The active intervention group consisted of an on-call pager system utilizing trained pharmacy residents, whereas the passive intervention group combined standard protocol with real-time in-basket notifications to pharmacists in the EHR. Results: Of 209 patients, 105, 61, and 43 patients were in the control, active, and passive groups, respectively. Median time to optimal therapy was shorter in the active group compared to the passive group and control (23.4 hours vs 42.2 hours vs 45.9 hours, respectively; P = .028). De-escalation occurred 12 hours sooner in the active group. In the contaminant group, empiric antibiotics were discontinued faster in the active group (0 hours) than in the control group and the passive group (17.7 vs 7.2 hours; P = .007). Time to active therapy and days of therapy were similar. Conclusions: A passive, electronic method of reporting PCR results to pharmacists was not as effective in optimizing stewardship metrics as an active, real-time method utilizing pharmacy residents. Further studies are needed to determine the optimal method of communicating time-sensitive information.

Antifungal Resistance and the Role of New Therapeutic Agents.

Purpose of Review: Advances in health care over time have led to an evolution in the epidemiology of invasive fungal infections. There is an increasing concern for antifungal resistance and emergence of less common fungal species for which optimal therapies are not well defined. The purpose of this review is to describe mechanisms of antifungal resistance and to evaluate the modern role of new and investigational antifungals. Recent Findings: Isavuconazole and ibrexafungerp represent the two newest antifungal agents. Evidence from in vivo and in vitro studies has been published recently to help define their place in therapy and potential roles in treating resistant fungi. Isavuconazole is a broad-spectrum triazole antifungal with evidence to support its use in invasive aspergillosis and mucormycosis. Its utility in treating voriconazole-resistant Candida should be confirmed with susceptibility testing if available. Ibrexafungerp is an oral glucan synthase inhibitor with little cross-resistance among currently available antifungals, including echinocandins. It is a promising new agent for invasive candidiasis, including azole-resistant Candida species, and in combination therapy with voriconazole for aspergillosis. Multiple antifungals, some with novel mechanisms, are in development, including rezafungin, oteseconazole, olorofim, fosmanogepix, and opelconazole. Summary: Both isavuconazole and ibrexafungerp are welcome additions to the arsenal of antifungals, and the prospect of more antifungal options in the future is encouraging. Such an array of antifungals will be important as antifungal resistance continues to expand alongside evolving medical practices. However, managing resistant fungal infections will grow in complexity as the unique role of each new agent is defined.

Analysis of accumulated SARS-CoV-2 seroconversion in North Carolina: The COVID-19 Community Research Partnership.

INTRODUCTION: The COVID-19 Community Research Partnership is a population-based longitudinal syndromic and sero-surveillance study. The study includes over 17,000 participants from six healthcare systems in North Carolina who submitted over 49,000 serology results. The purpose of this study is to use these serology data to estimate the cumulative proportion of the North Carolina population that has either been infected with SARS-CoV-2 or developed a measurable humoral response to vaccination. METHODS: Adult community residents were invited to participate in the study between April 2020 and February 2021. Demographic information was collected and daily symptom screen was completed using a secure, HIPAA-compliant, online portal. A portion of participants were mailed kits containing a lateral flow assay to be used in-home to test for presence of anti-SARS-CoV-2 IgM or IgG antibodies. The cumulative proportion of participants who tested positive at least once during the study was estimated. A standard Cox proportional hazards model was constructed to illustrate the probability of seroconversion over time up to December 20, 2020 (before vaccines available). A separate analysis was performed to describe the influence of vaccines through February 15, 2021. RESULTS: 17,688 participants contributed at least one serology result. 68.7% of the population were female, and 72.2% were between 18 and 59 years of age. The average number of serology results submitted per participant was 3.0 (±1.9). By December 20, 2020, the overall probability of seropositivity in the CCRP population was 32.6%. By February 15, 2021 the probability among healthcare workers and non-healthcare workers was 83% and 49%, respectively. An inflection upward in the probability of seropositivity was demonstrated around the end of December, suggesting an influence of vaccinations, especially for healthcare workers. Among healthcare workers, those in the oldest age category (60+ years) were 38% less likely to have seroconverted by February 15, 2021. CONCLUSIONS: Results of this study suggest more North Carolina residents may have been infected with SARS-CoV-2 than the number of documented cases as determined by positive RNA or antigen tests. The influence of vaccinations on seropositivity among North Carolina residents is also demonstrated. Additional research is needed to fully characterize the impact of seropositivity on immunity and the ultimate course of the pandemic.

Collaborative Antimicrobial Stewardship: Working with Microbiology.

There have been tremendous advances in methodologies available for detection and identification of organisms causing infections. Providers can now obtain identification results and antimicrobial susceptibility results in a shorter period of time. However, declining health care resources highlight the importance of selecting the right test at the right time to maximize diagnostic benefits. Therefore, the role of the antimicrobial stewardship team in the clinical microbiology laboratory has expanded to include diagnostic stewardship and provision of guidance on test selection for diagnosis and management of infection. This review focuses on the experience of our group in collaborative stewardship, emphasizing successes and challenges.

'Likelihood to be diagnosed or misdiagnosed': application to meta-analytic data for cognitive screening instruments.

Aim: To extend use of the recently described 'likelihood to be diagnosed or misdiagnosed' (LDM) metric for test accuracy studies through application to recent meta-analytic data of commonly used cognitive screening instruments. Methods: Raw data (true positives and negatives, false positives and negatives) were extracted from meta-analyses (minimum 5 studies or 1000 patients), from which LDM was calculated. LDM values were compared with those previously reported for single test accuracy studies. Results: LDM values for diagnosis of dementia ranged from around two to seven, and for diagnosis of mild cognitive impairment from two to three. LDM values based on meta-analytic data were larger than those reported for individual studies. Conclusion: LDM is an easily calculated and potentially useful unitary, global metric for test accuracy studies.

MACE for the Diagnosis of Dementia and MCI: 3-Year Pragmatic Diagnostic Test Accuracy Study.

BACKGROUND/AIMS: The Mini-Addenbrooke's Cognitive Examination (MACE) is a relatively new short cognitive screening instrument for the detection of patients with dementia and mild cognitive impairment (MCI). Few studies of the MACE have been reported hitherto. The aim of this study was to undertake a pragmatic diagnostic test accuracy study of MACE in a large cohort of patients seen in a dedicated cognitive disorders clinic. METHODS: MACE was administered to consecutive patients referred to a neurology-led Cognitive Function Clinic over the course of 3 years to assess its performance for the diagnosis of dementia and MCI using various test metrics. RESULTS: In a cohort of 599 patients, the prevalence of dementia and MCI by criterion diagnosis was 0.17 and 0.29, respectively. MACE had a high sensitivity (> 0.9) and negative predictive values (> 0.8) with large effect sizes (Cohen's d > 1) for the diagnosis of both dementia and MCI but a low specificity (< 0.5) and positive predictive values (≤0.5). CONCLUSION: MACE is an acceptable test for the assessment of cognitive complaints in a secondary care setting with good metrics for identifying cases of both dementia and MCI.

Extended infusion compared to standard infusion cefepime as empiric treatment of febrile neutropenia.

Background Extended infusion (EI) dosing provides a longer time above the minimum inhibitory concentration, which is important for the clinical success of ß-lactam antibiotics, especially for patients with impaired immunity. The aim of this study was to determine the feasibility and clinical impact of administering cefepime by EI as treatment of febrile neutropenia. Methods This was a prospective, randomized, comparative pilot study. All patients received cefepime 2 g IV every 8 h, with the first dose administered using a 30-min infusion. After the first dose, patients were randomized to receive cefepime over 30 min as a standard infusion (SI) or 3 h (EI). Patients were >18 years old with febrile neutropenia (neutrophil count <500 cells/mm3 and temperature >38.0ºC) and received chemotherapy or stem cell transplant as treatment for malignancy. Patients were excluded for the following: allergy to a cephalosporin, creatinine clearance (CrCl) < 50 mL/min, receipt of concurrent Gram-negative antimicrobial, sepsis, or solid tumor malignancy. The primary outcome was defervescence by 72 h. Secondary outcomes included time to defervescence, clinical success, in-hospital mortality, hospital length of stay, and need for additional antimicrobials. Main results Sixty-three patients were enrolled: 33 in the SI arm and 30 in the EI arm. The groups were similar with regard to age, gender, weight, estimated creatinine clearance, and duration of neutropenia. None of the patients in the EI arm withdrew due to practical complications of receiving EI cefepime. Twenty-three patients in the SI arm and 20 patients in the EI arm defervesced by 72 h ( p = 0.99). There were no differences in secondary outcome measures; however, patients in the EI arm appeared to have defervesced more rapidly (median 19 vs. 41 h, p = 0.305). Conclusion Administration of cefepime by EI for the treatment of febrile neutropenia is feasible. Larger clinical trials are necessary to determine if EI cefepime imparts a clinical benefit in the treatment of febrile neutropenia.

The Addition of Intravenous Metronidazole to Oral Vancomycin is Associated With Improved Mortality in Critically Ill Patients With Clostridium difficile Infection.

BACKGROUND: The optimal therapy for critically ill patients with Clostridium difficile infection (CDI) is not known. We aimed to evaluate mortality among critically ill patients with CDI who received oral vancomycin (monotherapy) vs oral vancomycin with intravenous (IV) metronidazole (combination therapy). METHODS: A single-center, retrospective, observational, comparative study was performed. Patients with a positive C. difficile assay who received oral vancomycin while bedded in an intensive care unit (ICU) between June 2007 and September 2012 were evaluated. Patients meeting ≥3 of the following criteria were included: albumin <2.5 g/dL, heart rate >90 bpm, mean arterial pressure <60 mmHg, white blood cell count ≥15 000 cells/mL, age >60 years, serum creatinine ≥1.5 times baseline, or temperature ≥100.4°F. Patients in the combination therapy group received IV metronidazole within 48 hours after initiating vancomycin. Patients <18 years or with unrelated gastrointestinal disease were excluded. The primary outcome was in-hospital mortality. Patients were matched using Acute Physiology and Chronic Health Evaluation II scores. RESULTS: Eighty-eight patients were included, 44 in each group. Patient characteristics were similar although more patients in the combination group had renal disease. Mortality was 36.4% and 15.9% in the monotherapy and combination therapy groups, respectively (P = .03). Secondary outcomes of clinical success, length of stay, and length of ICU stay did not differ between groups. CONCLUSIONS: Our data are supportive of the use of combination therapy with oral vancomycin and IV metronidazole in critically ill patients with CDI. However, prospective, randomized studies are required to define optimal treatment regimens in this limited population of CDI patients.

Zidovudine as modern day salvage therapy for HIV infection.

Resistance to the first-line NRTIs, tenofovir and emtricitabine, does not generally confer resistance to zidovudine. The objective of this study was to describe the efficacy of zidovudine as modern day salvage antiretroviral therapy. This was a single-center, retrospective, observational, cohort study. Adult HIV-positive patients prescribed a zidovudine-containing regimen between 2005 and 2010 were identified from a computer database. All patients had failed at least one prior antiretroviral regimen before zidovudine. The primary outcome measure was virologic success at 24 weeks. Other efficacy and safety outcomes were determined, including virologic success at 48 and 96 weeks, CD4 count change from baseline, and incidence of adverse effects. Sixty-nine subjects were enrolled. The mean age was 43 years, 70% were male, and 85.5% were black. Most patients were highly antiretroviral experienced. At 24 weeks, 63.8% and 72.5% of patients achieved HIV RNA less than 50 and 400 c/mL, respectively. The median change in CD4 count from baseline to week 24 was +70 cells/mm(3). The percent of patients who discontinued zidovudine due to adverse effects was 10%. In this highly treatment-experienced population, zidovudine as part of a salvage regimen appeared effective. Gastrointestinal adverse effects were reported, but zidovudine-associated metabolic effects were uncommon, suggesting zidovudine was generally well tolerated.

BK virus encephalitis: case report, review of the literature, and description of a novel treatment modality.

OBJECTIVE: To describe a case of BK virus encephalitis with attempted direct antiviral therapy, review the reported cases of BK virus in the central nervous system, and report the novel use of intravenous cimetidine in place of oral probenecid to minimize the toxicities of intravenous cidofovir. CASE SUMMARY: A 36-year-old male with acute myelomonocytic leukemia and subsequent myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplant. His course was complicated by severe graft-versus-host disease involving his skin and gastrointestinal tract. Five weeks after transplantation, he developed fever and confusion. Magnetic resonance imaging was suggestive of limbic encephalitis and cerebrospinal fluid tested positive for BK virus. Therapy with intravenous cidofovir was thought to be indicated. Although probenecid is commonly used to minimize the toxicities of cidofovir, the patient's severe graft-versus-host disease raised concerns about absorption of oral medications. Based on animal models and pharmacokinetic data, intravenous cimetidine was used in place of oral probenecid. Despite these therapies, the patient's mental status did not improve. He developed progressive organ system failure, and care was ultimately withdrawn. DISCUSSION: BK virus is increasingly described as a cause of encephalitis. The majority of reported cases have occurred in immunocompromised patients and have generally had a poor outcome. This case describes attempted antiviral therapy using cidofovir, the antiviral agent used most frequently in other syndromes due to BK virus. Intravenous cimetidine is a novel modality used to minimize ocular and renal toxicities frequently seen with cidofovir, and we believe this warrants further investigation. CONCLUSIONS: BK virus may be a cause of encephalitis in immunocompromised hosts, and cidofovir represents a possible treatment option. Intravenous cimetidine can be considered to minimize toxicities associated with cidofovir use in patients unable to tolerate or absorb oral probenecid.

Optimizing empiric antibiotic therapy in patients with severe ß-lactam allergy.

Antibiotic selection is challenging in patients with severe ß-lactam allergy due to declining reliability of alternate antibiotics. Organisms isolated from these patients may exhibit unique resistance phenotypes. The objective of this study was to determine which alternate antibiotics or combinations provide adequate empirical therapy for patients with ß-lactam allergy who develop Gram-negative infections at our institution. We further sought to determine the effects of risk factors for drug resistance on empirical adequacy. A retrospective analysis was conducted for adult patients hospitalized from September 2009 to May 2010 who had a severe ß-lactam allergy and a urine, blood, or respiratory culture positive for a Gram-negative organism and who met predefined criteria for infection. Patient characteristics, culture and susceptibility data, and predefined risk factors for antibiotic resistance were collected. Adequacies of ß-lactam and alternate antibiotics were compared for all infections and selected subsets. The primary outcome was adequacy of each alternate antibiotic or combination for all infections. One hundred sixteen infections (40 pneumonias, 67 urinary tract infections, and 9 bacteremias) were identified. Single alternate agents were adequate less frequently than ß-lactams and combination regimens. Only in cases without risk factors for resistance did single-agent regimens demonstrate acceptable adequacy rates; each factor conferred a doubling of risk for resistance. Resistance risk factors should be considered in selecting empirical antibiotics for Gram-negative pathogens in patients unable to take ß-lactams due to severe allergy.

Vanishing bile duct syndrome in human immunodeficiency virus infected adults: a report of two cases.

Vanishing bile duct syndrome (VBDS) is a group of rare disorders characterized by ductopenia, the progressive destruction and disappearance of intrahepatic bile ducts leading to cholestasis. Described in association with medications, autoimmune disorders, cancer, transplantation, and infections, the specific mechanisms of disease are not known. To date, only 4 cases of VBDS have been reported in human immunodeficiency virus (HIV) infected patients. We report 2 additional cases of HIV-associated VBDS and review the features common to the HIV-associated cases. Presentation includes hyperbilirubinemia, normal liver imaging, and negative viral and autoimmune hepatitis studies. In HIV-infected subjects, VBDS occurred at a range of CD4+ T-cell counts, in some cases following initiation or change in antiretroviral therapy. Lymphoma was associated with two cases; nevirapine, antibiotics, and viral co-infection were suggested as etiologies in the other cases. In HIV-positive patients with progressive cholestasis, early identification of VBDS and referral for transplantation may improve outcomes.