Preliminary evidence for sustained efficacy of CFTR modulator therapy with concomitant rifabutin administration.

The concomitant use of elexacaftor/tezacaftor/ivacaftor (ETI) and strong CYP3A inducers including rifampin and rifabutin is not recommended due to the risk of drug-drug interactions (DDI). This presents a significant challenge to the treatment of non-tuberculous mycobacteria precluding the first line treatment. While rifabutin induces CYP3A activity, its effect appears to be moderate compared to rifampin. In this study, we investigated three cases in which concomitant use of rifabutin and CFTR modulators (ETI or ivacaftor monotherapy) was used, and these cases suggest that addition of rifabutin did not compromise the efficacy of ETI or ivacaftor as evidenced by pulmonary function and sweat chloride testing. A full physiologically based pharmacokinetic model predicted lung concentrations of ETI upon rifabutin coadministration to exceed the half-maximal effective concentrations (EC50) determined from chloride transport in phe508del human bronchial epithelial cells. This study provides preliminary evidence in support of the use of rifabutin in patients receiving ETI.

Infections and antimicrobial prescribing in patients hospitalized with coronavirus disease 2019 (COVID-19) during the first pandemic wave.

Objective: To evaluate the rate of coinfections and secondary infections seen in hospitalized patients with COVID-19 and antimicrobial prescribing patterns. Methods: This single-center, retrospective study included all patients aged ≥18 years admitted with COVID-19 for at least 24 hours to a 280-bed, academic, tertiary-care hospital between March 1, 2020, and August 31, 2020. Coinfections, secondary infections, and antimicrobials prescribed for these patients were collected. Results: In total, 331 patients with a confirmed diagnosis of COVID-19 were evaluated. No additional cases were identified in 281 (84.9%) patients, whereas 50 (15.1%) had at least 1 infection. In total, of 50 patients (15.1%) who were diagnosed with coinfection or secondary infection had bacteremia, pneumonia, and/or urinary tract infections. Patients who had positive cultures, who were admitted to the ICU, who required supplemental oxygen, or who were transferred from another hospital for higher level of care were more likely to have infections. The most commonly used antimicrobials were azithromycin (75.2%) and ceftriaxone (64.9%). Antimicrobials were prescribed appropriately for 55% of patients. Conclusions: Coinfection and secondary infections are common in patients who are critically ill with COVID-19 at hospital admission. Clinicians should consider starting antimicrobial therapy in critically ill patients while limiting antimicrobial use in patients who are not critically ill.

Impact of a vancomycin-resistant Enterococcus (VRE) screening result on appropriateness of antibiotic therapy.

Objective: Vancomycin-resistant Enterococcus (VRE) infections have been associated with increased mortality and poor outcomes. VRE screening has been used to identify colonized patients to prevent transmission; however, little is known about the utility of screening results to guide antibiotic therapy. Design and setting: A retrospective review was performed at a tertiary-care center between June 1, 2015, and May 31, 2018. Patients: All patients who underwent VRE polymerase chain reaction assay (PCR) screening and had a bacterial culture from 7 days before to 90 days after the screening test were included. In total, 1,374 patients who had a VRE screening test met inclusion criteria. Methods: Sensitivity, specificity, and positive and negative predictive values of VRE screening for VRE infection were calculated. The appropriateness of the antibiotic therapy for each patient based on screening results was also assessed. Results: We detected no difference in the appropriateness of antibiotic therapy between patients with a positive screen and those with a negative screen (59.3% vs 61.0%; P = .8657). The VRE PCR demonstrated 54% sensitivity, 89% specificity, a positive predictive value (PPV) of 13% and a negative predictive value (NPV) of 98%. Conclusions: The high NPV and specificity indicate that patients with a negative VRE screening results may not require empiric antibiotic coverage for VRE. Although VRE screening may have utility to detect colonization in high-risk patients, a positive VRE screen is of limited value in determining the need for an antibiotic with VRE culture-directed coverage.

Retrospective Analysis of Adverse Drug Events Between Nafcillin Versus Cefazolin for Treatment of Methicillin-Susceptible Staphylococcus aureus Infections.

Background: Nafcillin or cefazolin are drugs of choice for methicillin-susceptible Staphylococcus aureus (MSSA) infections. Prior studies indicate a higher incidence of acute kidney injury (AKI) with nafcillin, although AKI classification and time to occurrence is not well described. Objective: To characterize the incidence and time to adverse drug events for nafcillin versus cefazolin in the inpatient setting. Methods: A retrospective cohort study evaluated hospitalized, adult patients receiving intravenous nafcillin or cefazolin for treatment of MSSA infection. Incidence and time to AKI based on RIFLE criteria were measured. Secondary end points included antibiotic discontinuation and incidence of neutropenia, thrombocytopenia, elevated transaminases, and Clostridioides difficile infection (CDI). Results: Of 324 patients who received nafcillin (n = 119) or cefazolin (n = 205), higher rates of AKI were found for nafcillin versus cefazolin (19% vs 2%, respectively; P < 0.0001). Median time to AKI with nafcillin was 6.5 days (range, 3-14 days). The majority of patients were classified as RIFLE "Risk" stratum. Nafcillin treatment discontinuations were more frequent than for cefazolin (17.6% vs 0.9%, respectively; P < 0.0001). Nafcillin was an independent predictor of AKI (odds ratio = 12.4; 95% CI = 4.14-47.60, P < 0.0001). No differences in neutropenia, thrombocytopenia, elevated transaminases, or CDI were observed. Conclusion and Relevance: Nafcillin displayed higher rates of AKI at a median of 1 week of therapy, which provides a framework for clinician monitoring and consideration of antibiotic modification. Most patients developed "Risk" class AKI (RIFLE classification), which may be reversible with prompt intervention.

Is It Actionable? An Evaluation of the Rapid PCR-Based Blood Culture Identification Panel on the Management of Gram-Positive and Gram-Negative Blood Stream Infections.

BACKGROUND: There is growing interest in the use of rapid blood culture identification (BCID) in antimicrobial stewardship programs (ASPs). Although many studies have looked at its clinical and economic utility, its comparative utility in gram-positive and gram-negative blood stream infections (BSIs) has not been as well characterized. METHODS: The study was a quasi-experimental retrospective study at the Mayo Clinic in Phoenix, Arizona. All adult patients with positive blood cultures before BCID implementation (June 2015 to December 2015) and after BCID implementation (June 2016 to December 2016) were included. The outcomes of interest included time to first appropriate antibiotic escalation, time to first appropriate antibiotic de-escalation, time to organism identification, length of stay, infectious diseases consultation, discharge disposition, and in-hospital mortality. RESULTS: In total, 203 patients were included in this study. There was a significant difference in the time to organism identification between the pre- and post-BCID cohorts (27.1 hours vs 3.3 hours, P < .0001). BCID did not significantly reduce the time to first appropriate antimicrobial escalation or de-escalation for either gram-positive BSIs (GP-BSIs) or gram-negative BSIs (GN-BSIs). Providers were more likely to escalate antimicrobial therapy in GP-BSIs after gram stain and more likely to de-escalate therapy in GN-BSIs after susceptibilities. Although there were no significant differences in changes in antimicrobial therapy for organism identification by BCID vs traditional methods, more than one-quarter of providers (28.1%) made changes after organism identification. There were no differences in hospital length of stay or in-hospital mortality comparing pre- vs post-BCID. CONCLUSIONS: Although BCID significantly reduced the time to identification for both GP-BSIs and GN-BSIs, BCID did not reduce the time to first appropriate antimicrobial escalation and de-escalation.

Effect of Antimicrobial Stewardship Program Guidance on the Management of Uncomplicated Skin and Soft Tissue Infections in Hospitalized Adults.

OBJECTIVE: To assess the effect of an antimicrobial stewardship program (ASP)-bundled initiative on the appropriate use of antibiotics for uncomplicated skin and soft tissue infections (uSSTIs) at 2 academic medical centers in Pittsburgh, Pennsylvania. PATIENTS AND METHODS: A retrospective preintervention and postintervention study was conducted to compare management of patients admitted with uSSTIs before and after the implementation of the bundled initiative. The preintervention period was from August 1, 2014, through March 31, 2015, and the postintervention period was from August 1, 2015, through March 31, 2016. RESULTS: A total of 160 patients were included in the preintervention cohort, and 163 were included in the postintervention cohort. Compared with the preintervention group, the mean duration of therapy decreased (12.5 days vs 8.8 days; P<.001) and an appropriate duration of less than 10 days increased in more patients (20.6% [33 of 160] vs 68.7% [112 of 163]; P<.001) in the postintervention period. Fewer patients were exposed to antimicrobials with extended gram-negative (44.4% [71 of 160] vs 9.2% [15 of 163]; P<.001), anaerobic (39.4% [63 of 160] vs 9.8% [16 of 163]; P<.001), and antipseudomonal (16.3% [26 of 160] vs 1.8% [3 of 163]; P<.001) coverage. The mean length of stay decreased from 3.6 to 2.2 days (P<.001) without an increase in 30-day readmissions (6.3% [10 of 160] vs 4.9% [8 of 163]; P=.64). The ASP made recommendations for 125 patients, and 96% were accepted. CONCLUSION: Implementation of an ASP-bundled approach aimed at optimizing antibiotic therapy in the management of uSSTIs led to shorter durations of narrow-spectrum therapy as well as shorter hospital length of stay without adversely affecting hospital readmissions.

Appropriateness of antibiotic management of uncomplicated skin and soft tissue infections in hospitalized adult patients.

BACKGROUND: Skin and soft tissue infections (SSTIs) are a leading cause for hospitalizations in the United States. Few studies have addressed the appropriateness of antibiotic therapy in the management of SSTIs without complicating factors. We aimed to determine the appropriateness of antibiotic treatment duration for hospitalized adult patients with uncomplicated SSTIs. METHODS: This was a retrospective analysis performed at two academic medical centers in Pittsburgh, Pennsylvania on patients aged 18 years and older with primary ICD-9 code for SSTIs admitted August 1st, 2014-March 31st, 2015. The primary outcome was the appropriateness of antibiotic treatment duration for uncomplicated SSTIs. Secondary objectives included the appropriateness of antibiotic agent spectrum, duration of inpatient length of stay (LOS), utilization of blood cultures and advanced imaging modalities, and re-hospitalization for SSTI within 30 days of discharge from the index admission. RESULTS: A total of 163 episodes were included in the cohort. The mean duration of total antibiotic therapy was 12.6 days. Appropriate duration was defined as receipt of total antibiotic duration of less than 10 days and occurred in 20.2% of patients. Twenty eight percent of patients received antibiotics for greater than 14 days. Seventy three (44.8%) patients received greater than 24 h of inappropriate extended spectrum gram-negative coverage; 65 (39.9%) received anaerobic coverage. CONCLUSIONS: In the majority of patients, treatment duration was excessive. Inappropriate broad spectrum antibiotic selection was utilized with regularity for SSTIs without complicating factors. The management of uncomplicated SSTIs represents a significant opportunity for antimicrobial stewardship.

Parallel walk test: its correlation with balance and motor functions in people with chronic stroke.

OBJECTIVES: To investigate (1) the intrarater, interrater, and test-retest reliability of the times and scores generated in the parallel walk test (PWT); (2) their correlations with impairments and activity limitations of individuals with stroke; and (3) the cutoff times that best discriminate individuals with stroke from healthy elderly subjects. DESIGN: Cross sectional study. SETTING: University-based rehabilitation center. PARTICIPANTS: Participants (N=72) comprised individuals with stroke (n=37) and healthy individuals (n=35). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The PWT was administered along with the Fugl-Meyer Motor Assessment of the Lower Extremities (FMA-LE), handheld dynamometer measurements of ankle dorsiflexor and plantarflexor muscle strength, the 5-Times-Sit-to-Stand Test, the Berg Balance Scale (BBS), a limits of stability (LOS) test, the 10-m walk test (10-MWT), and the timed Up and Go (TUG) test. RESULTS: PWT times and scores showed good to excellent intrarater, interrater, and test-retest reliability in individuals with stroke. PWT times using paths of 3 different widths significantly correlated with FMA-LE scores, 5-Times-Sit-to-Stand Test times, BBS scores, some LOS test results, 10-MWT gait speed, and TUG test times. PWT times of 6.30 to 7.48 seconds, depending on the path width, were shown reliably to discriminate individuals with stroke from healthy individuals. CONCLUSION: The PWT is a reliable, easy-to-administer clinical tool for assessing dynamic walking balance in individuals with chronic stroke.

Characterization of enterohemorrhagic Escherichia coli strains based on acid resistance phenotypes.

Acid resistance is perceived to be an important property of enterohemorrhagic Escherichia coli strains, enabling the organisms to survive passage through the acidic environment of the stomach so that they may colonize the mammalian gastrointestinal tract and cause disease. Accordingly, the organism has developed at least three genetically and physiologically distinct acid resistance systems which provide different levels of protection. The glutamate-dependent acid resistance (GDAR) system utilizes extracellular glutamate to protect cells during extreme acid challenges and is believed to provide the highest protection from stomach acidity. In this study, the GDAR system of 82 pathogenic E. coli isolates from 34 countries and 23 states within the United States was examined. Twenty-nine isolates were found to be defective in inducing GDAR under aerobic growth conditions, while five other isolates were defective in GDAR under aerobic, as well as fermentative, growth conditions. We introduced rpoS on a low-copy-number plasmid into 26 isolates and were able to restore GDAR in 20 acid-sensitive isolates under aerobic growth conditions. Four isolates were found to be defective in the newly discovered LuxR-like regulator GadE (formerly YhiE). Defects in other isolates could be due to a mutation(s) in a gene(s) with an as yet undefined role in acid resistance since GadE and/or RpoS could not restore acid resistance. These results show that in addition to mutant alleles of rpoS, mutations in gadE exist in natural populations of pathogenic E. coli. Such mutations most likely alter the infectivity of individual isolates and may play a significant role in determining the infective dose of enterohemorrhagic E. coli.