Dual Antiviral Therapy for Persistent Coronavirus Disease 2019 and Associated Organizing Pneumonia in an Immunocompromised Host.

The management of patients with prolonged viral shedding and coronavirus disease 2019 symptoms remains unclear. Combining antivirals, as practiced in other infections, is theoretically advantageous. We present a case of persistent, symptomatic severe acute respiratory syndrome coronavirus 2 infection and associated organizing pneumonia that was successfully treated with an extended course of combination antiviral therapy.

Favipiravir in Patients With Early Mild-to-moderate Coronavirus Disease 2019 (COVID-19): A Randomized Controlled Trial.

BACKGROUND: Despite vaccination, many remain vulnerable to coronavirus disease 2019 (COVID-19) and its complications. Oral antivirals to prevent COVID-19 progression are vital. Based on perceived potency and clinical efficacy, favipiravir is widely used to treat COVID-19. Evidence from large randomized controlled trials (RCT) is lacking. METHODS: In this multicenter double-blinded placebo-controlled RCT, adults with early mild-to-moderate COVID-19 were 1:1 randomized to favipiravir or placebo. The study evaluated time to sustained clinical recovery (TT-SCR), COVID-19 progression, and cessation of viral shedding. RESULTS: Of 1187 analyzed patients across 40 centers, 83.3% were Hispanic, 89.0% unvaccinated, 70.3% severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) seronegative, and 77.8% had risk factors for COVID-19 progression. The median time from symptom presentation and from positive test to randomization was 3 and 2 days, respectively. There was no difference in TT-SCR (median of 7 days for both groups; P = .80), COVID-19 progression [11 patients each (1.9% vs 1.8%); P = .96], time to undetectable virus (median = 6 days, 95% confidence interval [CI] [6-8] vs 7 days, 95% CI [6-9]), or in undetectable virus by end of therapy (73.4% vs 72.3%; P = .94). Outcomes were consistent across the analyzed sub-groups. Adverse events were observed in 13.8% and 14.8% of favipiravir-treated and placebo-treated subjects, respectively. Uric acid elevation was more frequent among favipiravir-treated subjects (19.9% vs 2.8%). CONCLUSIONS: Favipiravir was well tolerated but lacked efficacy in TT-SCR, progression to severe COVID-19, or cessation of viral shedding and should not be used to treat patients with COVID-19. (Supported by Appili Therapeutics). CLINICAL TRIALS REGISTRATION: NCT04600895.

VE303, a Defined Bacterial Consortium, for Prevention of Recurrent Clostridioides difficile Infection: A Randomized Clinical Trial.

Importance: The effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clostridia on prevention of Clostridioides difficile infection (CDI) is unknown. Objective: To determine the efficacy of VE303, a defined bacterial consortium of 8 strains of commensal Clostridia, in adults at high risk for CDI recurrence. The primary objective was to determine the recommended VE303 dosing for a phase 3 trial. Design, Setting, and Participants: Phase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from February 2019 to September 2021 at 27 sites in the US and Canada. The study included 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence (defined as aged ≥75 years or ≥65 years with ≥1 risk factors: creatinine clearance <60 mL/min/1.73 m2, proton pump inhibitor use, remote [>6 months earlier] CDI history). Interventions: Participants were randomly assigned to high-dose VE303 (8.0 × 109 colony-forming units [CFUs]) (n = 30), low-dose VE303 (1.6 × 109 CFUs) (n = 27), or placebo capsules (n = 22) orally once daily for 14 days. Main Outcomes and Measures: The primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks using a combined clinical and laboratory definition. The primary efficacy end point was analyzed in 3 prespecified analyses, using successively broader definitions for an on-study CDI recurrence: (1) diarrhea consistent with CDI plus a toxin-positive stool sample; (2) diarrhea consistent with CDI plus a toxin-positive, polymerase chain reaction-positive, or toxigenic culture-positive stool sample; and (3) diarrhea consistent with CDI plus laboratory confirmation or (in the absence of a stool sample) treatment with a CDI-targeted antibiotic. Results: Baseline characteristics were similar across the high-dose VE303 (n = 29; 1 additional participant excluded from efficacy analysis), low-dose VE303 (n = 27), and placebo (n = 22) groups. The participants' median age was 63.5 years (range, 24-96); 70.5% were female; and 1.3% were Asian, 1.3% Black, 2.6% Hispanic, and 96.2% White. CDI recurrence rates through week 8 (using the efficacy analysis 3 definition) were 13.8% (4/29) for high-dose VE303, 37.0% (10/27) for low-dose VE303, and 45.5% (10/22) for placebo (P = .006, high-dose VE303 vs placebo). Conclusions and Relevance: Among adults with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence, high-dose VE303 prevented recurrent CDI compared with placebo. A larger, phase 3 study is needed to confirm these findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03788434.

Current Treatment Options for Acute Skin and Skin-structure Infections.

Acute bacterial skin and skin-structure infections (ABSSSIs) are a common reason for seeking care at acute healthcare facilities, including emergency departments. Staphylococcus aureus is the most common organism associated with these infections, and the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA) has represented a considerable challenge in their treatment. To address this need, a number of new antibiotics have been developed for the treatment of ABSSSIs in the past several years. Most of these agents focus primarily on gram-positive organisms, particularly MRSA; however, there has not been an oral agent that can reliably treat MRSA, as well as relevant gram-negative pathogens. Acute skin infections that involve mixed gram-positive and gram-negative pathogens must also be considered as they can be associated with discordant antimicrobial therapy. Here, I review ABSSSI treatment guidelines in the hospital setting and discuss current and future antibiotic options for treatment of this commonly encountered infection.

Efficacy of bezlotoxumab based on timing of administration relative to start of antibacterial therapy for Clostridium difficile infection.

Background: The fully human monoclonal antibody bezlotoxumab binds Clostridioides (Clostridium) difficile toxin B and reduces recurrence rates in patients with C. difficile infection (CDI) receiving antibacterial treatment for a primary or recurrent episode. Objectives: To investigate whether the timing of bezlotoxumab administration relative to the onset of antibacterial treatment affected clinical outcome in the Phase 3 trials MODIFY I (NCT01241552) and MODIFY II (NCT01513239). Methods: Initial clinical cure and CDI recurrence rates of participants who received bezlotoxumab or placebo were summarized by timing of infusion relative to the start of antibacterial drug treatment for CDI: 0-2, 3-4 and ≥5 days after onset. Results: Of 1554 total participants, 649 (41.8%), 469 (30.1%) and 436 (28.1%) received an infusion 0-2, 3-4 and ≥5 days after onset of antibacterial treatment for CDI, respectively. Regardless of timing of administration, there were no differences in initial clinical cure rates between participants receiving bezlotoxumab (range 77.8% to 81.4%) or placebo (77.8% to 81.7%). Bezlotoxumab efficacy was unaffected by timing of administration; rates of CDI recurrence were lower versus placebo in all subgroups (range 19.3% to 22.8% for bezlotoxumab and 31.7% to 35.8% for placebo). Timing of administration also had no effect on time to resolution of diarrhoea, which was achieved by the end of antibacterial treatment in ∼95% of participants in both bezlotoxumab and placebo groups. Conclusions: Bezlotoxumab is effective in preventing CDI recurrence and can be administered at any time before ending antibacterial drug treatment.

Disseminated mucormycosis masquerading as rejection early after orthotopic heart transplantation.

Mucorales organisms are an uncommon cause of invasive fungal infections after solid organ transplantation but are associated with great morbidity and mortality. We report a fatal case of disseminated Cunninghamella infection early after heart transplantation. The patient developed graft dysfunction and elevated markers of myocyte injury and autopsy revealed fulminant fungal myocarditis. This case highlights the need for a high index of suspicion in immunocompromised patients who are not improving with standard antimicrobial therapy.

Thirty-Day Readmissions in Hospitalized Patients Who Received Bezlotoxumab With Antibacterial Drug Treatment for Clostridium difficile Infection.

Clinical Trials Registration: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).

Empiric therapy for hospital-acquired, Gram-negative complicated intra-abdominal infection and complicated urinary tract infections: a systematic literature review of current and emerging treatment options.

BACKGROUND: Empiric therapy for healthcare-associated infections remains challenging, especially with the continued development of Gram-negative organisms producing extended-spectrum ß-lactamases (ESBLs) and the threat of multi-drug-resistant organisms. Current treatment options for resistant Gram-negative infections include carbapenems, tigecycline, piperacillin-tazobactam, cefepime, ceftazidime, and two recently approved therapies, ceftolozane-tazobactam and ceftazidime-avibactam. METHODS: This systematic literature review surveys the published clinical trial evidence available since 2000 in support of both current and emerging treatment options in the settings of complicated intra-abdominal infection (cIAI) and complicated urinary tract infection (cUTI). When available, clinical cure rates for patients with infections from ESBL-producing strains are provided, as is information about efficacy against Pseudomonas aeruginosa. RESULTS: Clinical trial evidence to guide selection of empiric antibiotic therapy in patients with complicated, hospital-acquired, Gram-negative IAIs and UTIs is limited. Though most of the clinical trials explored in this overview enrolled patients with complicated infections, often patients with severe infections and multiple comorbidities were excluded. CONCLUSIONS: Practitioners in the clinical setting who are treating patients with complicated, hospital-acquired, Gram-negative IAIs and UTIs need to consider the possibility of polymicrobial infections, antibiotic-resistant organisms, and/or severely ill patients with multiple comorbidities. There is a severe shortage of evidence-based research to guide the selection of empiric antibiotic therapy for many patients in this setting. New therapies recently approved or in late-stage development promise to expand the number of options available for empiric therapy of these hospital-acquired, Gram-negative infections.

The efficacy of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bloodstream infection in patients with impaired renal function.

BACKGROUND: Concerns regarding the efficacy of daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections in patients with impaired renal function are reflected in a recent package insert change by the Food and Drug Administration (FDA). However, this decision was based on a small subgroup analysis and it is unclear if this is a true association. METHODS: We conducted a retrospective cohort study of patients with MRSA bacteremia treated at a tertiary hospital from 2001 to 2011 and who received either vancomycin or daptomycin. We used propensity score and multivariable logistic regression to assess the outcome of treatment failure, via blinded adjudication, in daptomycin- vs vancomycin-treated subjects and the interaction with renal function. RESULTS: One hundred fifty patients were analyzed, 100 in the vancomycin arm and 50 in the daptomycin arm. The average age was 61 years, and 60% were men. Of patients treated with daptomycin or vancomycin, 29 (58%) and 51 (51%), respectively, had an estimated glomerular filtration rate (GFR) <50 mL/minute/1.73 m(2). Compared with vancomycin, the usage of daptomycin in patients was not significantly associated with treatment failure in patients with a GFR >50 mL/minute/1.73 m(2) (odds ratio [OR], 0.45; 95% confidence interval [CI], .11 -1.79), nor in patients with a GFR of <50 mL/minute/1.73 m(2) (OR, 0.46; 95% CI, .11 -1.94). There was no significant interaction between them (P = .54). CONCLUSIONS: In patients with MRSA bacteremia, daptomycin efficacy was not affected by GFR level and was similar to vancomycin's efficacy. Although our sample size was small, it was larger than than the one used by the FDA. However, smaller differences may be significant with a larger sample size.

Fidaxomicin versus vancomycin for Clostridium difficile infection.

BACKGROUND: Clostridium difficile infection is a serious diarrheal illness associated with substantial morbidity and mortality. Patients generally have a response to oral vancomycin or metronidazole; however, the rate of recurrence is high. This phase 3 clinical trial compared the efficacy and safety of fidaxomicin with those of vancomycin in treating C. difficile infection. METHODS: Adults with acute symptoms of C. difficile infection and a positive result on a stool toxin test were eligible for study entry. We randomly assigned patients to receive fidaxomicin (200 mg twice daily) or vancomycin (125 mg four times daily) orally for 10 days. The primary end point was clinical cure (resolution of symptoms and no need for further therapy for C. difficile infection as of the second day after the end of the course of therapy). The secondary end points were recurrence of C. difficile infection (diarrhea and a positive result on a stool toxin test within 4 weeks after treatment) and global cure (i.e., cure with no recurrence). RESULTS: A total of 629 patients were enrolled, of whom 548 (87.1%) could be evaluated for the per-protocol analysis. The rates of clinical cure with fidaxomicin were noninferior to those with vancomycin in both the modified intention-to-treat analysis (88.2% with fidaxomicin and 85.8% with vancomycin) and the per-protocol analysis (92.1% and 89.8%, respectively). Significantly fewer patients in the fidaxomicin group than in the vancomycin group had a recurrence of the infection, in both the modified intention-to-treat analysis (15.4% vs. 25.3%, P=0.005) and the per-protocol analysis (13.3% vs. 24.0%, P=0.004). The lower rate of recurrence was seen in patients with non­North American Pulsed Field type 1 strains. The adverse-event profile was similar for the two therapies. CONCLUSIONS: The rates of clinical cure after treatment with fidaxomicin were noninferior to those after treatment with vancomycin. Fidaxomicin was associated with a significantly lower rate of recurrence of C. difficile infection associated with non­North American Pulsed Field type 1 strains. (Funded by Optimer Pharmaceuticals; ClinicalTrials.gov number, NCT00314951.)

Efficacy of Fecal Microbiota, Live-jslm (REBYOTA®), Among Patients Exposed to Non-Clostridioides difficile Infection Antibiotics: Post Hoc Subgroup Analysis of a Phase 2 Open-Label Study.

Background: Antibiotic use is a major risk factor for recurrent Clostridioides difficile infection (CDI) due to the associated disruption in gut microbiota. Fecal microbiota, live-jslm (REBYOTA®; RBL, previously RBX2660), is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration to prevent recurrent CDI in adults following standard-of-care antibiotic treatment. To investigate the impact of non-CDI antibiotics on the durability of RBL, a subgroup analysis was conducted on PUNCH™ Open-Label study participants who received non-CDI antibiotics during the period between RBL administration and up to 2 years after. Methods: Participants in PUNCH™ Open-Label who received non-CDI antibiotics after RBL administration were included in this subgroup analysis. Treatment response was defined as the absence of CDI diarrhea needing retreatment at the last evaluable time point (8 weeks, 6 months, 1 year, or 2 years) after RBL administration. Results: Among participants from PUNCH™ Open-Label, 43 received non-CDI antibiotics after RBL administration but before CDI recurrence as evaluated over a 2-year period. Across all evaluable time points, 86% (37/43) of participants had a treatment response regardless of when non-CDI antibiotic exposure occurred. Treatment response was sustained for a median 470 days (IQR, 212-648) from the first day of non-CDI antibiotic use. Most participants (5/6) with CDI recurrences received a high-risk antibiotic. Conclusions: RBL remained efficacious in participants with a history of recurrent CDI after subsequent non-CDI antibiotic exposure. Clinical Trials Registration: NCT02589847 (https://clinicaltrials.gov/study/NCT02589847).

Renal impairment and clinical outcomes of Clostridium difficile infection in two randomized trials.

BACKGROUND/AIMS: Patients with chronic kidney disease (CKD) have increased risk for Clostridium difficile infection (CDI) and for subsequent mortality. We determined the effect of CKD on response to treatment for CDI. METHODS: This is a post hoc analysis of two randomized controlled phase 3 trials that enrolled patients with CDI. Patients received either fidaxomicin 200 mg b.i.d. or vancomycin 125 mg q.i.d. for 10 days. Univariate and multivariate analyses compared end points by treatment received and CKD stage. RESULTS: At baseline, 27, 21, and 9% of the patients had stage 2 (60-89 ml/min/1.73 m(2)), stage 3 (30-59), and stage 4 or higher (<30) CKD. Cure rates were similar for normal (91%) and stage 2 CKD (92%), but declined to 80% for stage 3 and to 75% for stage 4 CKD (p < 0.001 for trend). Time to resolution of diarrhea (TTROD) increased with stage 3 and stage 4 CKD. CDI recurrence rates 4 weeks after treatment were 16, 20, 27, and 24% for normal, stage 2, stage 3, and stage 4 or higher CKD, respectively. Mortality increased with CKD stage. In multivariate analyses, stage 3 or higher CKD correlated with lower odds of cure, greater chance of recurrence, and lower odds of sustained response 28 days after treatment. Initial cure rates were similar in the vancomycin or fidaxomicin groups; however, the rate of recurrence was higher following vancomycin treatment independent of renal function. The presence of immunosuppression did not alter this effect. CONCLUSION: Progressive CKD is associated with increased TTROD, lower cure rates, and higher recurrence rates with treatment of CDI.

Derivation and validation of a simple clinical bedside score (ATLAS) for Clostridium difficile infection which predicts response to therapy.

BACKGROUND: Clostridium difficile infection (CDI) continues to be a frequent and potentially severe infection. There is currently no validated clinical tool for use at the time of CDI diagnosis to categorize patients in order to predict response to therapy. METHODS: Six clinical and laboratory variables, measured at the time of CDI diagnosis, were combined in order to assess their correlation with treatment response in a large CDI clinical trial database (derivation cohort). The final categorization scheme was chosen in order to maximize the number of categories (discrimination) while maintaining a high correlation with clinical cure assessed two days after the end of therapy. Validation of the derived scoring scheme was done on a second large CDI clinical trial database (validation cohort). A third comparison was done on the two pooled databases (pooled cohort). RESULTS: In the derivation cohort, the best discrimination and correlation with cure was seen with a five-component ATLAS score (age, treatment with systemic antibiotics, leukocyte count, albumin and serum creatinine as a measure of renal function), which divided CDI patients into 11 groups (scores of 0 to 10 inclusive) and was highly correlated with treatment outcome (R(2) = 0.95; P<0.001). This scheme showed excellent prediction of cure in the validation cohort (overall Kappa = 95.2%; P<0.0001), as well as in the pooled cohort, regardless of treatment (fidaxomicin or vancomycin). CONCLUSIONS: A combination of five simple and commonly available clinical and laboratory variables measured at the time of CDI diagnosis, combined into a scoring system (ATLAS), are able to accurately predict treatment response to CDI therapy. The ATLAS scoring system may be useful in stratifying CDI patients so that appropriate therapies can be chosen to maximize cure rates, as well as for categorization of patients in CDI therapeutic studies in order allow comparisons of patient groups.

Misleading Positive Serology for Cat Scratch Disease following Administration of Intravenous Immunoglobulin.

Cat scratch disease (CSD), caused by Bartonella henselae, usually presents as regional lymphadenopathy/lymphadenitis, known as typical CSD or as atypical CSD, which includes, among others, neurological manifestations. Serology for anti-B. henselae IgG antibodies is the most commonly used diagnostic tests for CSD. Intravenous immunoglobulin (IVIG) is given for an increasing number of medical conditions and may cause interference with serological testing. We report six patients with neurological manifestations and two patients with Kawasaki disease mimicking typical CSD, mistakenly diagnosed as CSD due to false-positive serology following IVIG therapy. Bartonella IgG serology was positive one to six days after IVIG administration and reverted to negative in seven of eight patients or significantly decreased (1 patient) ≤30 days later. In patients with CSD, IgG titers remained essentially unchanged 15-78 days after the positive serum sample. An additional eight patients treated with IVIG for various conditions were evaluated prospectively. All were seronegative one day pre-IVIG infusion, five patients demonstrated an increase in the IgG titers one to three days after IVIG administration, one interpreted as positive and four as intermediate, whereas three patients remained seronegative, suggesting that false seropositivity after IVIG therapy may not occur in all patients. Treatment with IVIG can result in false-positive serology for B. henselae. Increased awareness to the misleading impact of IVIG is warranted to avoid misinterpretation. Repeat testing can distinguish between true and false serology. Preserving serum samples prior to IVIG administration is suggested.

Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients With Mild to Moderate COVID-19: A Phase 2 Randomized Clinical Trial.

Importance: Oral anthelmintic niclosamide has potent in vitro antiviral activity against SARS-CoV-2. Repurposed niclosamide could be a safe and efficacious COVID-19 therapy. Objective: To investigate whether niclosamide decreased SARS-CoV-2 shedding and duration of symptoms among patients with mild to moderate COVID-19. Design, Setting, and Participants: This randomized, placebo-controlled clinical trial enrolled individuals testing positive for SARS-CoV-2 by polymerase chain reaction with mild to moderate symptoms of COVID. All trial participants, investigators, staff, and laboratory personnel were kept blind to participant assignments. Enrollment was among individuals reporting at Tufts Medical Center and Wellforce Network in Massachusetts for outpatient COVID-19 testing. The trial opened to accrual on October 1, 2020; the last participant enrolled on April 20, 2021. Trial exclusion criteria included hospitalization at time of enrollment or use of any experimental treatment for COVID-19, including vaccination. Enrollment was stopped before attaining the planned sample size when COVID-19 diagnoses decreased precipitously in Massachusetts. Data were analyzed from July through September 2021. Interventions: In addition to receiving current standard of care, participants were randomly assigned on a 1:1 basis to receive niclosamide 2 g by mouth daily for 7 days or identically labeled placebo at the same dosing schedule. Main Outcomes and Measures: Oropharyngeal and fecal samples were self-collected for viral shedding measured by reverse-transcriptase-polymerase-chain-reaction on days 3, 7, 10, and 14, and an additional fecal sample was collected on day 21. A telehealth platform was developed to conduct remote study visits, monitor symptoms, and coordinate sample collection via couriers. The primary end point was the proportion of participants with viral clearance in respiratory samples at day 3 based on the intention-to-treat sample. Mean times to viral clearance and symptom resolution were calculated as restricted mean survival times and accounted for censored observations. Results: Among 73 participants, 36 individuals were enrolled and randomized to niclosamide and 37 individuals to placebo. Participant characteristics were similar across treatment groups; among 34 patients receiving placebo and 33 patients receiving niclosamide in the intention-to-treat sample, mean (SD) age was 36.0 (13.3) years vs 36.8 (12.9) years and there were 21 (61.8%) men vs 20 (60.6%) men. The overall mean (SD) age was 36.4 (13.0) years. For the primary end point, 66.67% (95% CI, 50.74% to 81.81%) of participants receiving niclosamide and 55.88% (95% CI, 40.27% to 72.73%) of participants receiving placebo had oropharyngeal SARS-CoV-2 clearance at day 3 (P = .37). Among 63 participants with symptoms, niclosamide did not significantly shorten symptom duration, which was 12.01 (95% CI, 8.82 to 15.2) days in the niclosamide group vs 14.61 (95% CI, 11.25 to 17.96) days in the placebo group (mean difference, -2.6 [95% CI, -7.23 to 2.03] days). Niclosamide was well-tolerated; the most commonly reported adverse events in the placebo and niclosamide groups were headaches (11 patients [32.4%] vs 7 patients [21.2%]; P = .31) and cough (8 patients [23.5%] vs 7 patients [21.2%]; P = .82). Conclusions and Relevance: In this randomized clinical trial, there was no significant difference in oropharyngeal clearance of SARS-CoV-2 at day 3 between placebo and niclosamide groups. Confirmation in larger studies is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT04399356.

Predicting high vancomycin minimum inhibitory concentration in methicillin-resistant Staphylococcus aureus bloodstream infections.

BACKGROUND: Increased mortality, treatment failure, and hospital length of stay have been reported in patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia when their isolates have a vancomycin minimum inhibitory concentration (MIC) > 1 µg/mL. Automated testing often fails to identify these isolates. We developed a simple clinical rule to predict vancomycin MIC of 2 µg/mL in patients with MRSA bacteremia. METHODS: This cohort study was conducted at a tertiary care hospital and an affiliated acute rehabilitation facility. Consecutive patients with MRSA bacteremia from 2001 through 2007 were prospectively identified. Patient characteristics were examined for their association with high vancomycin MIC and a predictive model was created. RESULTS: A total of 296 MRSA bacteremic episodes among 272 patients were identified; 19% of the episodes had isolates with a vancomycin MIC of 2 µg/mL. Variables associated with a vancomycin MIC of 2 µg/mL included older age (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.5-10.4); prior vancomycin (OR, 3.8; 95% CI, 1.9-7.6) or daptomycin (OR, 7.9; 95% CI, 1.8-34.0) exposure; the presence of a nontunneled central venous catheter (OR, 1.9; 95% CI, 1.1-3.4) or prosthetic heart valve (OR, 3.6; 95% CI, 1.3-10.0); a history of MRSA bacteremia (OR, 3.0; 95% CI, 1.6-5.6); and the presence of sepsis (OR, 2.7; 95% CI, 1.4-5.1) or shock (OR, 2.2; 95% CI, 1.1-4.2) at the time of culture. The final predictive rule included age > 50 years (3 points), prior vancomycin exposure (2 points), history of MRSA bacteremia (2 points), history of chronic liver disease (2 points), and presence of a nontunneled central venous catheter (1 point). A score cutoff of ≥ 4 resulted in a sensitivity of 75% and specificity of 59% (negative predictive value, 91%; positive predictive value, 30%). CONCLUSIONS: Several factors that predict high vancomycin MIC were identified, and a simple predictive tool was created to help clinicians determine which patients are likely to have MRSA isolates with high vancomycin MIC.

Appraising contemporary strategies to combat multidrug resistant gram-negative bacterial infections--proceedings and data from the Gram-Negative Resistance Summit.

The emerging problem of antibiotic resistance, especially among Gram-negative bacteria (GNB), has become a serious threat to global public health. Very few new antibacterial classes with activity against antibiotic-resistant GNB have been brought to market. Renewed and growing attention to the development of novel compounds targeting antibiotic-resistant GNB, as well as a better understanding of strategies aimed at preventing the spread of resistant bacterial strains and preserving the efficacy of existing antibiotic agents, has occurred. The Gram-Negative Resistance Summit convened national opinion leaders for the purpose of analyzing current literature, epidemiologic trends, clinical trial data, therapeutic options, and treatment guidelines related to the management of antibiotic-resistant GNB infections. After an in-depth analysis, the Summit investigators were surveyed with regard to 4 clinical practice statements. The results then were compared with the same survey completed by 138 infectious disease and critical care physicians and are the basis of this article.

Efficacy of fidaxomicin versus vancomycin as therapy for Clostridium difficile infection in individuals taking concomitant antibiotics for other concurrent infections.

BACKGROUND: Treatment guidelines recommend stopping all implicated antibiotics at the onset of Clostridium difficile infection (CDI), but many individuals have persistent or new infections necessitating the use of concomitant antibiotics (CAs). We used data from 2 phase 3 trials to study effects of CAs on response to fidaxomicin or vancomycin. METHODS: Subjects with CDI were treated for 10 days with fidaxomicin 200 mg every 12 hours or vancomycin 125 mg every 6 hours, assessed for resolution of symptoms, and followed up for an additional 4 weeks for evidence of recurrence. Rates of cure, recurrence, and global cure (cure without recurrence) were determined for subgroups of subjects defined by CA use and treatment group. RESULTS: CAs were prescribed for 27.5% of subjects during study participation. The use of CAs concurrent with CDI treatment was associated with a lower cure rate (84.4% vs 92.6%; P < .001) and an extended time to resolution of diarrhea (97 vs 54 hours; P < .001). CA use during the follow-up was associated with more recurrences (24.8% vs 17.7%; not significant), and CA administration at any time was associated with a lower global cure rate (65.8% vs 74.7%; P = .005). When subjects received CAs concurrent with CDI treatment, the cure rate was 90.0% for fidaxomicin and 79.4% for vancomycin (P = .04). In subjects receiving CAs during treatment and/or follow-up, treatment with fidaxomicin compared with vancomycin was associated with 12.3% fewer recurrences (16.9% vs 29.2%; P = .048). CONCLUSIONS: Treatment with CAs compromised initial response to CDI therapy and durability of response. Fidaxomicin was significantly more effective than vancomycin in achieving clinical cure in the presence of CA therapy and in preventing recurrence regardless of CA use.

Impact of Letermovir Use for Cytomegalovirus Prophylaxis on Re-Hospitalization Following Allogeneic Hematopoietic Stem Cell Transplantation: An Analysis of a Phase III Randomized Clinical Trial.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with substantial healthcare resource use, particularly when recipients develop cytomegalovirus (CMV) infection. Letermovir reduced post-HSCT CMV infection risk compared with placebo in a previous phase III trial. This analysis evaluated letermovir's impact on re-hospitalization post-transplant. METHODS: Using data from a phase III, multicenter, randomized clinical trial (NCT02137772, registered May 14, 2014), this study assessed CMV-associated and all-cause re-hospitalizations at weeks 14, 24, and 48 post-transplant among recipients of letermovir versus placebo. Unstandardized re-hospitalization rates and days were reported; standardized rates and days were estimated accounting for censoring due to death or early study discontinuation. RESULTS: Unstandardized rates (95% confidence interval [CI]) of all-cause re-hospitalization in letermovir versus placebo recipients at weeks 14, 24, and 48 were 36.6% (31.4-42.1) versus 47.6% (39.9-55.4), 49.2% (43.7-54.8) versus 55.9% (48.1-63.5), and 55.7% (50.1-61.2) versus 60.6% (52.8-68.0), respectively. Unstandardized mean total duration (95% CI) of re-hospitalization with letermovir versus placebo at weeks 14, 24, and 48 were 7.6 (5.9-9.8) versus 11.3 (8.6-14.8), 13.9 (11.2-17.2) versus 15.5 (11.9-20.1), and 18.0 (14.8-21.9) versus 20.7 (15.8-27.1) days, respectively. Similar results were found in CMV-associated re-hospitalization outcomes and standardized rates and days of all-cause re-hospitalizations. CONCLUSIONS: In this post-hoc analysis, letermovir was associated with lower rates of CMV-associated and all-cause re-hospitalizations with a shorter length of stay (especially within the first 14 weeks post-transplant).

Corrigendum to: Renal Impairment, C. difficile Recurrence, and the Differential Effect of Bezlotoxumab: A Post Hoc Analysis of Pooled Data From 2 Randomized Clinical Trials.

[This corrects the article DOI: 10.1093/ofid/ofaa248.].