A Concept Evaluation Study of a New Combination Bictegravir plus Tenofovir Alafenamide Nanoformulation with Prolonged Sustained-Drug-Release Potency for HIV-1 Preexposure Prophylaxis.

The antiretroviral treatment (ART) approach is the best-prescribed approach to date for preexposure prophylaxis (PrEP) for high-risk individuals. However, the daily combination antiretroviral (cARV) regimen has become cumbersome for healthy individuals, leading to nonadherence. Recent surveys showed high acceptance of parenteral sustained-release ART enhancing PrEP adherence. Our approach is to design a parenteral nanoparticle (NP)-based cARV sustained-release (cARV-SR) system as long-acting HIV PrEP. Here, we report a new combination of two potent ARVs (tenofovir alafenamide fumarate [TAF] and bictegravir [BIC]) loaded as a nanoformulation intended as a cARV-SR for PrEP. The BIC+TAF NPs were fabricated by using a standardized in-house methodology. In vitro intracellular kinetics, cytotoxicity, and HIV-1 protection studies demonstrated that BIC+TAF encapsulation prolonged drug retention, reduced drug-associated cytotoxicity, and enhanced HIV protection. In human peripheral blood mononuclear cells, nanoformulated BIC+TAF demonstrated significant (P < 0.05) improvement in the drug's selectivity index by 472 times compared to the BIC+TAF in solution. In vivo pharmacokinetic study of BIC, TAF, and respective drug metabolites in female BALB/c mice after single subcutaneous doses of BIC+TAF NPs demonstrated plasma drug concentrations of BIC and tenofovir above the intracellular 50% inhibitory concentration during the entire 30-day study period and prolonged persistence of both active drugs in the HIV target organs, including the vagina, colon, spleen, and lymph nodes. This report demonstrates that the encapsulation of BIC+TAF in a nanoformulation improved its therapeutic selectivity and the in vivo pharmacokinetics of free drugs. Based on these preliminary studies, we hypothesize that cARV-SR has potential as an innovative once-monthly delivery treatment for PrEP.

Indole-2-Carboxamides Are Active against Mycobacterium abscessus in a Mouse Model of Acute Infection.

Nontuberculous mycobacteria (NTM) pathogens particularly infect patients with structural lung disorders. We previously reported novel indole-2-carboxamides (ICs) that are active against a wide panel of NTM pathogens. This study discloses in vivo data for two lead molecules (compounds 5 and 25) that were advanced for efficacy studies in Mycobacterium abscessus-infected mouse models. Oral administration of the lead molecules showed a statistically significant reduction in the bacterial loads in lung and spleen of M. abscessus-infected mice.

Correction to: Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model.

There are errors in the published article (Volume 34, Number 12, pp. 2749-2755). The errors occurred in pharmacokinetic study design of materials and methods section on page 2750-51.

Development and validation of LC-MS/MS method for quantification of bictegravir in human plasma and its application to an intracellular uptake study.

A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for quantification of bictegravir in human plasma. A small volume of only 50 µL aliquot of plasma was precipitated with acetonitrile containing an internal standard (IS). Chromatographic separation was performed on a Kinetex EVO C18 column, 50 × 3.0 mm, 5 µm using an isocratic mobile phase containing 80:20 acetonitrile-water with 0.1% formic acid. A mass spectrometer was operated in ESI positive multiple reaction monitoring mode using the m/z 450.1/289.1 for bictegravir and 420.1/277.1 for IS. The dynamic range of the method was 1-10,000 ng/mL with a correlation coefficient of ≥0.9991. The precision results of calibration standards were in the range of 0.05-4.57% and accuracies were 95.07-104.70%. The mean extraction recovery was 98.64% with a precision of 2.91%. The method was validated as per US Food and Drug Administration guidelines and was found to be accurate and precise. The method was successfully applied to in vitro cellular uptake study.

LC-MS/MS method for the simultaneous determination of tenofovir, emtricitabine, elvitegravir and rilpivirine in dried blood spots.

A simple, short, and rugged LC-MS/MS method for the simultaneous determination of tenofovir, emtricitabine, elvitegravir and rilpivirine was developed and validated. Dried blood spots were prepared with 25 µL of spiked whole blood. A 3 mm punch was extracted with methanol containing labeled internal standards. Ten microliters was injected into the LC-MS/MS using isocratic mobile phase composed of 0.1% formic acid in water and 0.1% formic acid in acetonitrile (45: 55 v/v) at a flow rate of 0.25 mL/min. The method was validated in the range of 10-2000 ng/mL for all four analytes. The intra-assay accuracy (RE) of the method was -4.73-4.78, 1.35-2.89, -8.89 to -0.49 and - 1.40-1.81 for tenofovir, emtricitabine, elvitegravir and rilpivirine, respectively. The inter-assay accuracy was within ±15% of nominal and precision (CV) was <15%. The hematocrit effect on quantification was nonsignificant at the tested hematocrit levels (35-70%). The dried blood spot method showed good agreement with the plasma method, and hence can be used as an alternative to plasma method.

An Enhanced Emtricitabine-Loaded Long-Acting Nanoformulation for Prevention or Treatment of HIV Infection.

Among various FDA-approved combination antiretroviral drugs (cARVs), emtricitabine (FTC) has been a very effective nucleoside reverse transcriptase inhibitor. Thus far, FTC is the only deoxycytidine nucleoside analog. However, a major drawback of FTC is its large volume distribution (averaging 1.4 liters/kg) and short plasma half-life (8 to 10 h), necessitating a high daily dosage. Thus, we propose an innovative fabrication method of loading FTC in poly(lactic-co-glycolic acid) polymeric nanoparticles (FTC-NPs), potentially overcoming these drawbacks. Our nanoformulation demonstrated enhanced FTC loading (size of <200 nm and surface charge of -23 mV) and no to low cytotoxicity with improved biocompatibility compared to those with FTC solution. An ex vivo endosomal release assay illustrated that NP entrapment prolongs FTC release over a month. Intracellular retention studies demonstrate sustained FTC retention over time, with approximately 8% (24 h) to 68% (96 h) release with a mean retention of ∼0.74 µg of FTC/105 cells after 4 days. An in vitro HIV-1 inhibition study demonstrated that FTC-NP treatment results in a 50% inhibitory concentration (IC50) ∼43 times lower in TZM-bl cells (0.00043 µg/ml) and ∼3.7 times lower (0.009 µg/ml) in peripheral blood mononuclear cells (PBMCs) than with FTC solution (TZM-bl cells, 0.01861, and PBMCs, 0.033 µg/ml). Further, on primary PBMCs, FTC-NPs also illustrate an HIV-1 infection blocking efficacy comparable to that of FTC solution. All the above-described studies substantiate that FTC nanoformulation prolongs intracellular FTC concentration and inhibition of HIV infection. Therefore, FTC-NPs potentially could be a long-acting, stable formulation to ensure once-biweekly dosing to prevent or treat HIV infection.

Nanoformulations of Rilpivirine for Topical Pericoital and Systemic Coitus-Independent Administration Efficiently Prevent HIV Transmission.

Vaginal HIV transmission accounts for the majority of new infections worldwide. Currently, multiple efforts to prevent HIV transmission are based on pre-exposure prophylaxis with various antiretroviral drugs. Here, we describe two novel nanoformulations of the reverse transcriptase inhibitor rilpivirine for pericoital and coitus-independent HIV prevention. Topically applied rilpivirine, encapsulated in PLGA nanoparticles, was delivered in a thermosensitive gel, which becomes solid at body temperature. PLGA nanoparticles with encapsulated rilpivirine coated the reproductive tract and offered significant protection to BLT humanized mice from a vaginal high-dose HIV-1 challenge. A different nanosuspension of crystalline rilpivirine (RPV LA), administered intramuscularly, protected BLT mice from a single vaginal high-dose HIV-1 challenge one week after drug administration. Using transmitted/founder viruses, which were previously shown to establish de novo infection in humans, we demonstrated that RPV LA offers significant protection from two consecutive high-dose HIV-1 challenges one and four weeks after drug administration. In this experiment, we also showed that, in certain cases, even in the presence of drug, HIV infection could occur without overt or detectable systemic replication until levels of drug were reduced. We also showed that infection in the presence of drug can result in acquisition of multiple viruses after subsequent exposures. These observations have important implications for the implementation of long-acting antiretroviral formulations for HIV prevention. They provide first evidence that occult infections can occur, despite the presence of sustained levels of antiretroviral drugs. Together, our results demonstrate that topically- or systemically administered rilpivirine offers significant coitus-dependent or coitus-independent protection from HIV infection.

Pharmacokinetic and Tissue Distribution Profile of Long Acting Tenofovir Alafenamide and Elvitegravir Loaded Nanoparticles in Humanized Mice Model.

PURPOSE: Non-adherence to the antiretroviral (ARV) regimen is a critical factor in determining efficacy of ARV drugs for pre-exposure prophylaxis (PrEP). A long-acting parenteral formulation may be an effective alternative to daily oral dosing. A pharmacokinetic and tissue distribution study of drug-loaded nanoparticle (NP) was performed in female humanized CD34+-NSG mice. METHODS: Mice received 200 mg/kg each of tenofovir alafenamide (TAF) and elvitegravir (EVG) as free drugs (TAF + EVG solution) or as drug loaded NP (TAF + EVG NP) formulation by subcutaneous (SubQ) administration. Plasma and tissue were collected to determine tenofovir (TFV) and EVG concentrations using LC-MS/MS. Non-compartmental analysis was performed using WinNonlin. RESULTS: SubQ administration of TAF + EVG NP formulation resulted in long residence time and exposure for both drugs. The AUC(0-72h) of TFV and EVG was 14.1 ± 2.0, 7.2 ± 1.8 µg × hr./mL from drugs in solution (free) and the AUC(0-14day) for the same drugs was 23.1 ± 4.4, 39.7 ± 6.7 µg × hr./mL from NPs. The observed elimination half-life (t1/2) for TFV of free and NPs were 14.2 h, 5.1 days and for EVG 10.8 h, 3.3 days, respectively. CONCLUSION: This study documents that a TAF + EVG NP provides sustained release, which can overcome patient non-adherence to dosing and may facilitate prediction of appropriate protective drug concentration for HIV prophylaxis.

Topical Tenofovir Disoproxil Fumarate Nanoparticles Prevent HIV-1 Vaginal Transmission in a Humanized Mouse Model.

Preexposure prophylaxis (PrEP) with 1% tenofovir (TFV) vaginal gel has failed in clinical trials. To improve TFV efficacy in vaginal gel, we formulated tenofovir disoproxil fumarate nanoparticles in a thermosensitive (TMS) gel (TDF-NP-TMS gel). TDF-NPs were fabricated using poly(lactic-co-glycolic acid) (PLGA) polymer and an ion-pairing agent by oil-in-water emulsification. The efficacy of TDF-NP-TMS gel was tested in humanized bone marrow-liver-thymus (hu-BLT) mice. Hu-BLT mice in the treatment group (Rx; n = 15) were administered TDF-NP-TMS gel intravaginally, having TDF at 0.1%, 0.5%, and 1% (wt/vol) concentrations, whereas the control (Ctr; n = 8) group received a blank TMS gel. All Rx mice (0.1% [n = 4], 0.5% [n = 6], and 1% [n = 5]) were vaginally challenged with two transmitted/founder (T/F) HIV-1 strains (2.5 × 10(5) 50% tissue culture infectious doses). Rx mice were challenged at 4 h (0.1%), 24 h (0.5%), and 7 days (1%) posttreatment (p.t.) and Ctr mice were challenged at 4 h p.t. Blood was drawn weekly for 4 weeks postinoculation (p.i.) for plasma viral load (pVL) using reverse transcription-quantitative PCR. Ctr mice had positive pVL within 2 weeks p.i. Rx mice challenged at 4 h and 24 h showed 100% protection and no detectable pVL throughout the 4 weeks of follow-up (P = 0.009; Mantel-Cox test). Mice challenged at 7 days were HIV-1 positive at 14 days p.i. Further, HIV-1 viral RNA (vRNA) in vaginal and spleen tissues of Rx group mice with negative pVL were examined using an in situ hybridization (ISH) technique. The detection of vRNA was negative in all Rx mice studied. The present studies elucidate TDF-NP-TMS gel as a long-acting, coitus-independent HIV-1 vaginal protection modality.

Development and validation of a simple and isocratic reversed-phase HPLC method for the determination of rilpivirine from tablets, nanoparticles and HeLa cell lysates.

In the present investigation, a simple and isocratic HPLC-UV method was developed and validated for determination of rilpivirine (RPV) from dosage forms (tablets and nanoparticles) and biological matrices like HeLa cell lysates. The separation and analysis of RPV was carried out under isocratic conditions using (a) a Gemini reversed-phase C18 column (5 µm; 4.6 × 150 mm) maintained at 35°C, (b) a mobile phase consisting of a mixture of acetonitrile and 25 m m potassium dihydrogen phosphate (in the ratio 50:50 v/v) at a flow rate of 0.6 mL/min and (c) atazanavir as an internal standard. The total run time was 17 min and the analysis of RPV and internal standard was carried out at 290 nm. The method was found to be linear (r(2) value > 0.998), specific, accurate and precise over the concentration range of 0.025-2 µg/mL. The lower limit of quantification was 0.025 µg/mL, the limit of detection was 0.008 µg/mL and the recovery of RPV was >90%. The stability of the RPV analytical method was confirmed at various conditions such as room temperature (24 h), -20°C (7 days), three freeze-thaw cycles and storage in an autosampler (4°C for 48 h). The method was successfully applied for the determination of RPV from conventional dosage forms like tablets, from polymeric nanoparticles and from biological matrices like HeLa cell lysates.

Hepatitis C therapy: Looking toward interferon-sparing regimens.

OBJECTIVE: To describe chronic hepatitis C virus (HCV) infection, including its epidemiology and pathophysiology; review current treatment options for HCV infection; recognize investigational agents being studied as part of interferon-free therapy; and summarize clinical trials for the new agents. DATA SOURCES: PubMed for 2004 through August 2014 using search terms hepatitis C, American Association for the Study of Liver Diseases, sofosbuvir, simeprevir, and as needed specific names of other agents in development during this time; news articles and news releases about company actions with regard to clinical trials and filings for marketing approval in the United States. STUDY SELECTION: At the discretion of the author based on clinical relevance of study and relevance to national guidelines for HCV therapy. RESULTS: HCV infection is an important medical and public health problem in the United States and worldwide that can cause cirrhosis, hepatocellular carcinoma, and liver failure. The advent of newly developed targeted therapies is changing the treatment paradigm for this disease. Although traditional therapy with pegylated interferon and ribavirin remain therapeutic options, direct-acting agents such as sofosbuvir (Sovaldi-Gilead) and simeprevir (Olysio-Janssen) are producing faster, earlier, and improved treatment response with fewer adverse effects. The combination of anti-HCV agents and the duration of treatment are based on genotype, patient treatment status, and patient risk factors. The dramatic and sustained clearance of the virus with these drugs makes sustained virologic response a reality for patients who are unable to tolerate pegylated interferon. The downside is their high cost, which may make them economically unsustainable. However, for patients infected with HCV, the potential for a cure and improved quality of life may now be a reality. CONCLUSION: HCV, a well-known blood-borne disease associated with significant morbidity and mortality worldwide, can be effectively and safely treated with new anti-HCV agents such as SOF. While these new medications are in their early days of real-world practice, they offer hope that cure is truly possible.

Assessing appropriateness of antimicrobial therapy: in the eye of the interpreter.

To address the increase of drug-resistant bacteria and widespread inappropriate use of antimicrobials, many healthcare institutions have implemented antimicrobial stewardship programs to promote appropriate use of antimicrobials and optimize patient outcomes. However, a consensus definition of appropriate use is lacking. We conducted a multicenter observational study to compare 4 definitions of appropriateness--a study site-specific definition, use supported by susceptibility data, use supported by electronic drug information resources (Clinical Pharmacology/Micromedex), or study site principal investigator (PI) opinion-among patients receiving 1 or more of 13 identified antimicrobials. Data were collected for 262 patients. Overall, appropriateness with the 4 definitions ranged from 79% based on PI opinion to 94% based on susceptibility data. No single definition resulted in consistently high appropriate use for all target antimicrobials. For individual antimicrobials, the definitions with the highest rate of appropriate use were Clinical Pharmacology/Micromedex support (6 of 7 antimicrobials) and susceptibility data (5 of 7 antimicrobials). For specific indications, support from susceptibility data resulted in the highest rate of appropriate use (4 of 7 indications). Overall comparisons showed that appropriateness assessed by PI opinion differed significantly compared with other definitions when stratified by either target antimicrobial or indication. The significant variability in the rate of appropriate use highlights the difficulty in developing a standardized definition that can be used to benchmark judicious antimicrobial use.

Breaking down the barriers: challenges with development and implementation of an industry-sponsored antimicrobial stewardship data collection and analysis tool.

Partnership between clinicians and the pharmaceutical industry with a focus on antimicrobial stewardship research initiatives is a necessary step toward meeting the shared goals of combating inappropriate antimicrobial use, improving patient outcomes, and minimizing resistance development. Achieving these goals requires outcomes-focused data collection and monitoring tools for antimicrobial stewardship programs (ASP) that consider real-world data about how antimicrobials are used to treat patients. Here we highlight the experiences and challenges associated with the development and implementation of an industry-sponsored electronic antimicrobial stewardship data collection and analysis tool (AS-DCAT). The benefits and risks of the industry-sponsored AS-DCAT from the perspectives of the sponsoring company and participating sites are discussed. Barriers encountered as well as general considerations and recommendations for preventing or overcoming those barriers for future studies and tool development are provided.

A comparison of clinical outcomes associated with dosing metronidazole every 8 hours versus every 12 hours: a systematic review and metaanalysis.

Background: Metronidazole treats obligate anaerobic bacterial and protozoal infections, with an elimination half-life of around 8 hours. The long elimination half-life, the favorable ratio of steady-state serum levels to minimum inhibitory concentration, and the presence of active metabolites have led to the consideration of metronidazole use at 12-hour dosage intervals. This systematic review aimed to compare the clinical outcomes of twice-daily and thrice-daily metronidazole dosing. Methods: Using the PRISMA checklist, we searched five databases to systematically identify all relevant studies published up to June 16, 2023. Results: The final analysis included two published retrospective cohort studies of hospitalized adult patients: a single site study (n = 200) and a multisite study (n = 85) of "good" quality, as measured by the Newcastle-Ottawa scale. The reported baseline characteristics of the 8-hour and 12-hour dosing groups were comparable, and neither study identified significant differences in primary and secondary clinical outcomes. Metaanalysis of the need to escalate antibiotic therapy also showed no statistically significant differences using the Mantel-Haenszel fixed-effect method (95% confidence interval: 47.6% lower to 6.4 times higher risk, P = 0.34) and inverse-variance method (risk ratio: 1.87; 95% confidence interval: 0.52-6.65, P = 0.34). Conclusions: This review suggests that dosing metronidazole every 12 hours is as effective as every-8-hour dosing for hospitalized patients with anaerobic infections. These encouraging findings would benefit from validation by a multicenter randomized controlled trial since there would be many benefits to a 12-hour dosing interval while achieving similar clinical outcomes with traditional dosing. The studies in this systematic review excluded patients with Clostridioides difficile and central nervous system and amebiasis infections, so the findings do not apply to these infection types.

Diagnosis and Outcomes of Fungal Co-Infections in COVID-19 Infections: A Retrospective Study.

The SARS-CoV-2 pandemic has resulted in a public health emergency with unique complications such as the development of fungal co-infections. The diagnosis of fungal infections can be challenging due to confounding imaging studies and difficulty obtaining histopathology. In this retrospective study, 173 patients with COVID-19 receiving antifungal therapy due to concern for fungal co-infection were evaluated. Patient characteristics, clinical outcomes, and the utility of fungal biomarkers were then evaluated for continuation of antifungal therapy. Data were collected from the electronic health record (EPIC) and analyzed using SPSS (version. 28, IBM, Inc., Armonk, NY, USA) Data are presented as mean ± SD or percentages. A total of 56 COVID-19 patients were diagnosed with fungal co-infection and 117 COVID-19 + patients had no fungal infection. Significantly fewer female patients were in the fungal+ group compared to COVID-19 control patients (29% in fungal+ compared to 51% in controls p = 0.005). Fungal diagnostics were all significantly higher in fungal+ patients. These include 1,4-beta-D-glucan (BDG), fungal culture, and bronchoalveolar lavage galactomannan (BAL GM). Intensive care unit hospitalization, mechanical ventilation, and mortality in fungal+ patients with COVID-19 were significantly higher than in control patients. Finally, significantly more fungal+ patients received voriconazole, isavuconazonium, or amphotericin B therapies, whereas control patients received significantly more short-course fluconazole. COVID-19+ patients with fungal co-infection were significantly more likely to be in the ICU and mechanically ventilated, and they result in higher mortality compared to control COVID-19 patients. The use of fungal diagnostics markers were helpful for diagnosis.

Sex and Race Disparities in Hepatocellular Carcinoma Surveillance in Patients With Chronic Hepatitis B During COVID-19: A Single-Center Retrospective Review.

Background: The management of patients with chronic hepatitis B (CHB) is complex and spans multiple medical specialties. As a result of this complexity, patients with CHB often do not receive adequate monitoring including hepatocellular carcinoma (HCC) surveillance with abdominal ultrasonography. Previous studies have identified multiple factors associated with decreased HCC surveillance. We aimed to identify the impact of race and sex on HCC surveillance in patients with CHB. Methods: We performed a single health system chart review between January 2018 and January 2022. Differences between sex and race were evaluated using the Chi-square test and Fisher's exact test, and continuous variables were analyzed using analysis of variance (ANOVA). Results: A total of 248 patient records between January 2018 and January 2022 were evaluated. In total 37% of females were adequately screened for HCC in any of the 6-month time frames compared to 26% of males. During the coronavirus disease 2019 (COVID-19) surge, surveillance rates were reduced in both men and women. During the first 6 months of the COVID-19 surge, there was a significant difference in screening between men and women (19% vs. 35%, P = 0.026). There was a decrease in HCC screening across all races during the COVID-19 surge; however, no significant difference when comparing races was found. Conclusion: Men received less HCC surveillance compared to women. These differences were more pronounced during the COVID-19 pandemic surge. Obtaining appropriate surveillance is important and retrospective evaluations can help us determine the presence of health-related social needs so that progress can be made toward achieving health equity.

Assessment of the impact of centralized bioMérieux BACT/ALERT® VIRTUO® blood culture system (VIRTUO) implementation on outcomes in patients with gram-negative bacteremia.

BACKGROUND: We evaluated pre- and postimplementation of Virtuo on outcome in patients with gram-negative bacteremia using a quasiexperimental time-in-motion design. METHODS: Becton Dickinson BACTEC™ 9000 series (Bactec) (2018) and Virtuo system (2020) were utilized in a decentralized and centralized process, respectively. Data collected in August-December in 2018 and 2020 were analyzed with SPSS (ver 28). RESULTS: For 185 patients in each time period, patient age, gender, length of hospitalization were not different. However, blood culture (BC) volume was significantly lower in 2020 (7.1 ± 2.6 mL) compared to 2018 (8.9 ± 1.9 mL). Time from BC draw and time from pathogen identification (ID) to treatment change were both significantly faster in 2020 (52.9 ± 38.3 hours; 15.1 ± 27.4 hours), compared to 2018 (65.0 ± 46.3 hours; 23.8 ± 33.8), respectively. CONCLUSIONS: Replacement of decentralized Bactec with centralized Virtuo, resulted in significant improvement in management of patients gram-negative bacteremia.

Structural Determinants of Indole-2-carboxamides: Identification of Lead Acetamides with Pan Antimycobacterial Activity.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is one of the leading causes of death in developing countries. Non-tuberculous mycobacteria (NTM) infections are rising and prey upon patients with structural lung diseases such as chronic obstructive pulmonary disease (COPD) and cystic fibrosis. All mycobacterial infections require lengthy treatment regimens with undesirable side effects. Therefore, new antimycobacterial compounds with novel mechanisms of action are urgently needed. Published indole-2-carboxamides (IC) with suggested inhibition of the essential transporter MmpL3 showed good potency against whole-cell M.tb, yet had poor aqueous solubility. This project focused on retaining the required MmpL3 inhibitory pharmacophore and increasing the molecular heteroatom percentage by reducing lipophilic atoms. We evaluated pyrrole, mandelic acid, imidazole, and acetamide functional groups coupled to lipophilic head groups, where lead acetamide-based compounds maintained high potency against mycobacterial pathogens, had improved in vitro ADME profiles over their indole-2-carboxamide analogs, were non-cytotoxic, and were determined to be MmpL3 inhibitors.

Improving understanding and utilization of the antibiogram among medical residents.

In this quality improvement project, we sought to increase the understanding and utilization of the antibiogram among physicians in family medicine, internal medicine, and surgery residency programs at a Midwest Academic Healthcare institution. Through simple, inexpensive measures the comfort with, access to, and utilization of the antibiogram can be improved.