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The role of microbial factors in outcomes of tuberculosis treatment has not been well studied. We performed a case-control study to evaluate the association between a Beijing strain and tuberculosis treatment outcomes. Isolates from patients with culture-positive treatment failure (n = 8) or relapse (n = 54) were compared with isolates from randomly selected controls (n = 296) by using spoligotyping. Patients with Beijing strains had a higher risk for relapse (odds ratio [OR] 2.0, 95% confidence interval [CI] 1.0-4.0, p = 0.04) but not for treatment failure. Adjustment for factors previously associated with relapse had little effect on the association between Beijing strains and relapse. Beijing strains were strongly associated with relapse among Asian-Pacific Islanders (OR 11, 95% CI 1.1-108, p = 0.04). Active disease caused by a Beijing strain was associated with increased risk for relapse, particularly among Asian-Pacific Islanders. [ABSTRACT FROM AUTHOR]

Rationale: Moxifloxacin has promising preclinical activity against Mycobacterium tuberculosis, but has not been evaluated in multidrug treatment of tuberculosis in humans. Objective: To compare the impact of moxifloxacin versus ethambutol, both in combination with isoniazid, rifampin, and pyrazinamide, on sputum culture conversion at 2 mo as a measure of the potential sterilizing activity of alternate induction regimens. Methods: Adults with smear-positive pulmonary tuberculosis were randomized in a factorial design to receive moxifloxacin (400 mg) versus ethambutol given 5 d/wk versus 3 d/wk (after 2 wk of daily therapy). All doses were directly observed. Measurements: The primary endpoint was sputum culture status at 2 mo of treatment. Results: Of 336 patients enrolled, 277 (82%) were eligible for the efficacy analysis, 186 (67%) were male, 175 (63%) were enrolled at African sites, 206 (74%) had cavitation on chest radiograph, and 60 (22%) had HIV infection. Two-month cultures were negative in 71% of patients (99 of 139) treated with moxifloxacin versus 71% (98 of 138) treated with ethambutol (p = 0.97). Patients receiving moxifloxacin, however, more often had negative cultures after 4 wk of treatment. Patients treated with moxifloxacin more often reported nausea (22 vs. 9%, p = 0.002), but similar proportions completed study treatment (88 vs. 89%). Dosing frequency had little effect on 2-mo culture status or tolerability of therapy. Conclusions: The addition of moxifloxacin to isoniazid, rifampin, and pyrazinamide did not affect 2-mo sputum culture status but did show increased activity at earlier time points. [ABSTRACT FROM AUTHOR]

Recurrence of active tuberculosis after treatment can be due to relapse of infection with the same strain or reinfection with a new strain of Mycobacterium tuberculosis. The proportion of recurrent tuberculosis cases caused by reinfection has varied widely in previous studies. We evaluated cases of recurrent tuberculosis in two prospective clinical trials: a randomized study of two regimens for the last 4 months of treatment (n = 1,075) and a study of a twice-weekly rifabutin-containing regimen for human immunodeficiency virus-infected tuberculosis (n = 169). Isolates at diagnosis and from positive cultures after treatment completion underwent genotyping using IS6110 (with secondary genotyping for isolates with less than six copies of IS6110). Of 85 patients having a positive culture after completing treatment, 6 (7.1%) were classified as false-positive cultures by a review committee blinded to treatment assignment. Of the remaining 75 cases with recurrent tuberculosis and genotyping data available, 72 (96%; 95% confidence interval, 88.8-99.2%) paired isolates had the same genotype; only 3 (4%; 95% confidence interval, 0.8-11.2%) had a different genotype and were categorized as reinfection. We conclude that recurrent tuberculosis in the United States and Canada, countries with low rates of tuberculosis, is rarely due to reinfection with a new strain of M. tuberculosis. [ABSTRACT FROM AUTHOR]

The pharmacokinetics of rifapentine at 600, 900, and 1,200 mg were studied during once-weekly continuation phase therapy in 35 patients with tuberculosis. Mean area under the plasma concentration-time curve (AUC(0-infinity)) increased significantly with dose (rifapentine AUC(0- infinity): 296, 410, and 477 microg.hour/ml at 600, 900, and 1,200 mg, respectively; p = 0.02 by linear regression). In multivariate stepwise regression analyses, AUC(0-infinity) values for rifapentine and the active 25-desacetyl metabolite were associated with drug dose and plasma albumin concentration, and were lower among men and among white individuals. Fifty-four percent of patients had total (free and protein-bound) plasma concentrations of rifapentine and of desacetyl rifapentine detected for more than 36 hours after clearance of concurrently administered isoniazid. Serious adverse effects of therapy in these study patients were infrequent (1 of 35 cases; 3%) and not linked with higher rifapentine AUC(0-infinity) or peak concentration. The present pharmacokinetic study supports further trials to determine the optimal rifapentine dose for treatment of tuberculosis. [ABSTRACT FROM AUTHOR]

Background: Several agents are effective in preventing Mycobacterium avium complex disease in patients with advanced human immunodeficiency virus (HIV) infection. However, there is uncertainty about whether prophylaxis should be continued in patients whose CD4+ cell counts have increased substantially with antiviral therapy.Methods: We conducted a multicenter, double-blind, randomized trial of treatment with azithromycin (1200 mg weekly) as compared with placebo in HIV-infected patients whose CD4+ cell counts had increased from less than 50 to more than 100 per cubic millimeter in response to antiretroviral therapy. The primary end point was M. avium complex disease or bacterial pneumonia.Results: A total of 520 patients entered the study; the median CD4+ cell count at entry was 230 per cubic millimeter. In 48 percent of the patients, the HIV RNA value was below the level of quantification. The median prior nadir CD4+ cell count was 23 per cubic millimeter, and 65 percent of the patients had had an acquired immunodeficiency syndrome-defining illness. During follow-up over a median period of 12 months, there were no episodes of confirmed M. avium complex disease in either group (95 percent confidence interval for the rate of disease in each group, 0 to 1.5 episodes per 100 person-years). Three patients in the azithromycin group (1.2 percent) and five in the placebo group (1.9 percent) had bacterial pneumonia (relative risk in the azithromycin group, 0.60; 95 percent confidence interval, 0.14 to 2.50; P=0.48). Neither the rate of progression of HIV disease nor the mortality rate differed significantly between the two groups. Adverse effects led to discontinuation of the study drug in 19 patients assigned to receive azithromycin (7.4 percent) and in 3 assigned to receive placebo (1.1 percent; relative risk, 6.6; P=0.002).Conclusions: Azithromycin prophylaxis can safely be withheld in HIV-infected patients whose CD4+ cell counts have increased to more than 100 cells per cubic millimeter in response to antiretroviral therapy. [ABSTRACT FROM AUTHOR]

We reviewed prominent national and international guidelines to compare recommendations for laboratory monitoring for persons on antiretroviral therapy. The United States Department of Health and Human Services guidelines recommend more frequent CD4 count, viral load, hematologic, renal, and liver tests than other guidelines. To evaluate the evidence base for these recommendations, we reviewed phase 3 trials of currently recommended antiretroviral regimens and large cohort studies. Cohort studies have consistently shown that persons with sustained viral suppression have stable or increasing CD cell counts, so it is not clear how continued CD4 count monitoring contributes to clinical care. Long-term safety data from trials and observational cohorts show little evidence to support hematologic, hepatic, or renal monitoring (apart from persons on tenofovir disoproxil fumarate). It is time to use the available data from clinical trials and cohort studies to develop evidence-based recommendations for laboratory monitoring tests for persons with viral suppression., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: A better understanding of the risk for coronavirus disease 2019 (COVID-19) that people experiencing homelessness (PEH) face in congregate shelters versus unsheltered encampments is critical for an effective pandemic response., Methods: We analyzed factors associated with current and past severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection among PEH in day and overnight shelters and encampments in Denver, Colorado, during June 2-July 28, 2020, and constructed multivariable logistic regression models to examine risk factors for SARS-CoV-2 RNA and seropositivity with age, race/ethnicity, testing location, testing month, and symptom status as predictor variables., Results: A total of 823 participants were tested for SARS-CoV-2 RNA, and 276 individuals were tested for SARS-CoV-2 antibodies. A greater percentage of PEH at overnight shelters tested positive for SARS-CoV-2 RNA (8.6% vs 2.5%, P < .01) and antibodies (21.5% vs 8.7%, P = .03) compared with encampments. In regression models, testing at an overnight shelter compared with testing at encampments (odds ratio [OR] = 3.03, 95% confidence interval [CI]: 1.16-9.02) had increased odds of a positive SARS-CoV-2 RNA result. Age >60 years compared with age <40 years (OR = 5.92; 95% CI: 1.83-20.3), Hispanic ethnicity (OR = 3.43; 95% CI: 1.36-8.95), and non-Hispanic Black race compared with non-Hispanic White race (OR = 3.07; 95% CI: 1.16-8.26), and testing at an overnight shelter compared to testing at encampments (OR = 2.45; 95% CI: 1.04-6.17) had increased odds of a positive antibody result., Conclusions: Our findings support the need for continuing assessment of mitigation strategies in shelters, increasing access to individual rooms and linkage to housing options for PEH, and supporting people to remain in encampments when these options are not available., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Objective: The aim of this report is to investigate the nature of the relationship between depression and condomless sex (CLS) among gay, bisexual and other men who have sex with men (GBMSM)., Methods: Data are from the Antiretrovirals, Sexual Transmission Risk and Attitude (ASTRA) study of people living with HIV and attending one of eight HIV outpatient clinics in England (2011-2012) and the Attitudes to and Understanding of Risk of Acquisition of HIV (AURAH) study of HIV-negative/unknown status individuals attending one of 20 genitourinary medicine clinics in England (2013-2014). This analysis included GBMSM only. For each study, the prevalence of depressive symptoms (Patient Health Questionnaire-9 score ≥10) was presented according to three categories of sex in the past 3 months (considering anal/vaginal sex with men/women and anal sex with men in separate definitions): (1) no sex, (2) condom-protected sex only and (3) CLS. Multinomial logistic regression with 'condom-protected sex only' as the reference group was used to adjust for age and (for ASTRA participants) time since HIV diagnosis., Results: There were opposing associations of depression with recent sexual behaviour: the prevalence of depression was higher among those who reported no sex and those who reported CLS, compared with those who reported condom-protected sex only. Among the 2170 HIV-positive GBMSM in ASTRA, considering anal/vaginal sex with men/women, the prevalence of depressive symptoms was 32%, 20% and 28%, respectively, among men reporting no sex (n=783), condom-protected sex only (n=551) and CLS (n=836) (global p<0.001). Among the 1477 HIV-negative GBMSM in AURAH, the prevalence of depressive symptoms was 12%, 8% and 13%, respectively, for no sex (n=137), condom-protected sex only (n=487) and CLS (n=853) (global p=0.017). Patterns were similar after adjustment and when only considering anal sex between men., Conclusions: Depression may be linked both to lack of sexual activity and to sexual risk taking. When investigating associations between depression and CLS, it is important to separate out individuals reporting condom-protected sex only from those reporting no sex., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

We assessed attitudes to disclosure to new sexual partners and association with sexual behaviours among HIV-diagnosed gay, bisexual, and other men who have sex with men (GBMSM) in the UK Antiretrovirals, Sexual Transmission Risk and Attitudes (ASTRA) study in 2011-12. Among 1373 GBMSM diagnosed with HIV for ≥3 months and reporting sex in the past three months (84% on antiretroviral therapy (ART), 75% viral load (VL) ≤50c/mL), 56.3% reported higher sexual disclosure ("agree" or "tend to agree" with "I'd expect to tell a new partner I'm HIV-positive before we have sex"). GBMSM on ART with self-reported undetectable VL had lower disclosure than those on ART without self-reported undetectable VL and those not on ART. Higher sexual disclosure was associated with higher prevalence of CLS in the past three months; this was due to its association with CLS with other HIV-positive partners. Higher sexual disclosure was more common among GBMSM who had CLS with other HIV-positive partners only (72.1%) compared to those who had higher-risk CLS with HIV-serodifferent partners (55.6%), other CLS with HIV-serodifferent partners (45.9%), or condom-protected sex only (47.6%). Findings suggest mutual HIV-disclosure and HIV-serosorting were occurring in this population. Knowledge of VL status may have impacted on disclosure to sexual partners.

Introduction: Phase 2 clinical trials of tuberculosis treatment have shown that once-daily regimens in which rifampin is replaced by high dose rifapentine have potent antimicrobial activity that may be sufficient to shorten overall treatment duration. Herein we describe the design of an ongoing phase 3 clinical trial testing the hypothesis that once-daily regimens containing high dose rifapentine in combination with other anti-tuberculosis drugs administered for four months can achieve cure rates not worse than the conventional six-month treatment regimen., Methods/design: S31/A5349 is a multicenter randomized controlled phase 3 non-inferiority trial that compares two four-month regimens with the standard six-month regimen for treating drug-susceptible pulmonary tuberculosis in HIV-negative and HIV-positive patients. Both of the four-month regimens contain high-dose rifapentine instead of rifampin, with ethambutol replaced by moxifloxacin in one regimen. All drugs are administered seven days per week, and under direct observation at least five days per week. The primary outcome is tuberculosis disease-free survival at twelve months after study treatment assignment. A total of 2500 participants will be randomized; this gives 90% power to show non-inferiority with a 6.6% margin of non-inferiority., Discussion: This phase 3 trial formally tests the hypothesis that augmentation of rifamycin exposures can shorten tuberculosis treatment to four months. Trial design and standardized implementation optimize the likelihood of obtaining valid results. Results of this trial may have important implications for clinical management of tuberculosis at both individual and programmatic levels., Trial Registration: NCT02410772. Registered 8 April 2015,https://www.clinicaltrials.gov/ct2/show/NCT02410772?term=02410772&rank=1., Competing Interests: Declaration of Competing Interest The authorship team members have declared any potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Sanofi commercial interests did not influence the study design; the collection, analysis, or interpretation of data; the preparation of this manuscript; or the decision to submit this manuscript for publication. A Sanofi technical expert served on the protocol team., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In a pilot study of 22 patients with an acute bacterial skin infection, serum levels of C-reactive protein and procalcitonin tended to be elevated at presentation and declined within 3-5 days of treatment. Further study of a biomarker-guided treatment strategy to reduce antibiotic overuse in skin infections is warranted.

Objective: HIV transmission is ongoing among men who have sex with men (MSM) in the UK. Sex without a condom (condomless sex, CLS) is the main risk factor. We investigated the prevalence of and factors associated with types of CLS., Methods: Cross-sectional questionnaire study in UK HIV clinics in 2011/2012 (ASTRA). MSM diagnosed with HIV for ≥3 months reported on anal and vaginal sex, CLS with HIV-serodifferent partners (CLS-D) and CLS with HIV-seroconcordant (CLS-C) partners in the previous 3 months. Mutually exclusive sexual behaviours were as follows: (1) Higher HIV risk CLS-D (not on antiretroviral therapy (ART) or clinic-recorded viral load(VL) >50 c/mL), (2) Other CLS-D, (3) CLS-C without CLS-D, (4) Condom-protected sex only and (5) No anal or vaginal sex. Associations were examined of sociodemographic, HIV-related, lifestyle, and other sexual measures with the five categories of sexual behaviour. We examined the prevalence of higher HIV risk CLS-D incorporating (in addition to ART and VL) time on ART, ART non-adherence, and recent sexually transmitted infections (STIs)., Results: Among 2189 HIV-diagnosed MSM (87% on ART), prevalence of any CLS in the past 3 months was 38.2% (95% CI 36.2% to 40.4%) and that of any CLS-D was 16.3% (14.8%-17.9%). The five-category classification was as follows: (1) Higher HIV risk CLS-D: 4.2% (3.5% to 5.2%), (2) Other CLS-D: 12.1% (10.8% to 13.5%), (3) CLS-C without CLS-D: 21.9% (20.2% to 23.7%), (4) Condom-protected sex only: 25.4% (23.6% to 27.3%) and (5) No anal or vaginal sex: 36.4% (34.3% to 38.4%). Compared with men who reported condom-protected sex only, MSM who reported any CLS in the past 3 months had higher prevalence of STIs, chemsex-associated drug use, group sex, higher partner numbers, and lifetime hepatitis C. Prevalence of higher HIV risk CLS-D ranged from 4.2% to 7.5% according to criteria included., Conclusion: CLS was prevalent among HIV-diagnosed MSM, but CLS-D with higher HIV transmission risk was overall low. CLS-D is no longer the most appropriate measure of HIV transmission risk behaviour among people with diagnosed HIV; accounting for VL is important., Competing Interests: Competing interests: AMJ is Governor of the Wellcome Trust. ANP received speaker fees for talks at conferences sponsored by Gilead. MD, AJR, LS, JE, JM, SE, NP, EW, SC, WJB, AS, FCL declare no conflicts of interest., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

OBJECTIVE For most common infections requiring hospitalization, antibiotic treatment is completed after hospital discharge. Postdischarge therapy is often unnecessarily broad spectrum and prolonged. We developed an intervention to improve antibiotic selection and shorten treatment durations. DESIGN Single center, quasi-experimental retrospective cohort study METHODS Patients prescribed oral antibiotics at hospital discharge before (July 2012-June 2013) and after (October 2014-February 2015) an intervention consisting of (1) institutional guidance for oral step-down antibiotic selection and duration of therapy and (2) pharmacy audit of discharge prescriptions with real-time prescribing recommendations to providers. The primary outcomes measured were total prescribed duration of therapy and use of antibiotics with broad gram-negative activity (ie, fluoroquinolones or amoxicillin-clavulanate). RESULTS Overall, 300 cases from the preintervention period and 200 cases from the intervention period were included. Compared with the preintervention period, the use of antibiotics with broad gram-negative activity decreased during the intervention (51% vs 40%; P=.02), particularly fluoroquinolones (38% vs 25%; P=.002). The total duration of therapy decreased from a median of 10 days (interquartile range [IQR], 7-13 days) to 9 days (IQR, 6-13 days) but did not reach statistical significance (P=.13). However, the duration prescribed at discharge declined from 6 days (IQR, 4-10 days) to 5 days (IQR, 3-7 days) (P=.003). During the intervention, there was a nonsignificant increase in the overall appropriateness of discharge prescriptions from 52% to 66% (P=.15). CONCLUSIONS A multifaceted intervention to optimize antibiotic prescribing at hospital discharge was associated with less frequent use of antibiotics with broad gram-negative activity and shorter postdischarge treatment durations. Infect Control Hosp Epidemiol 2017;38:534-541.

OBJECTIVES To evaluate changes in outpatient fluoroquinolone (FQ) and nitrofurantoin (NFT) use and resistance among E. coli isolates after a change in institutional guidance to use NFT over FQs for acute uncomplicated cystitis. DESIGN Retrospective preintervention-postintervention study. SETTING Urban, integrated healthcare system. PATIENTS Adult outpatients treated for acute cystitis. METHODS We compared 2 time periods: January 2003-June 2007 when FQs were recommended as first-line therapy, and July 2007-December 2012, when NFT was recommended. The main outcomes were changes in FQ and NFT use and FQ- and NFT-resistant E. coli by time-series analysis. RESULTS Overall, 5,714 adults treated for acute cystitis and 11,367 outpatient E. coli isolates were included in the analysis. After the change in prescribing guidance, there was an immediate 26% (95% CI, 20%-32%) decrease in FQ use (P<.001), and a nonsignificant 6% (95% CI, -2% to 15%) increase in NFT use (P=.12); these changes were sustained over the postintervention period. Oral cephalosporin use also increased during the postintervention period. There was a significant decrease in FQ-resistant E. coli of -0.4% per quarter (95% CI, -0.6% to -0.1%; P=.004) between the pre- and postintervention periods; however, a change in the trend of NFT-resistant E. coli was not observed. CONCLUSIONS In an integrated healthcare system, a change in institutional guidance for acute uncomplicated cystitis was associated with a reduction in FQ use, which may have contributed to a stabilization in FQ-resistant E. coli. Increased nitrofurantoin use was not associated with a change in NFT resistance. Infect Control Hosp Epidemiol 2017;38:461-468.

Background.  Syndrome-specific interventions are a recommended approach to antibiotic stewardship, but additional data are needed to understand their potential impact. We implemented an intervention to improve the management of inpatient community-acquired pneumonia (CAP) and evaluated its effects on antibiotic and resource utilization. Methods.  A stakeholder group developed and implemented a clinical practice guideline and order set for inpatient, non-intensive care unit CAP recommending a short course (5 days) of a fluoroquinolone-sparing antibiotic regimen in uncomplicated cases. Unless there was suspicion for complications or resistant pathogens, chest computed tomography (CT) and sputum cultures were discouraged. This was a retrospective preintervention postintervention study of patients hospitalized for CAP before (April 15, 2008-May 31, 2009) and after (July 1, 2011-July 31, 2012) implementation of the guideline. The primary comparison was the difference in duration of therapy during the baseline and intervention periods. Secondary outcomes included changes in use of levofloxacin, CT scans, and sputum culture. Results.  One hundred sixty-six and 84 cases during the baseline and intervention periods, respectively, were included. From the baseline to intervention period, the median duration of therapy decreased from 10 to 7 days ( P < .0001). Prescription of levofloxacin at discharge decreased from 60% to 27% of cases ( P < .0001). Use of chest CT and sputum culture decreased from 47% to 32% of cases ( P = .02) and 51% to 31% of cases ( P = .03), respectively. The frequency of clinical failure between the 2 periods was similar. Conclusions.  A syndrome-specific intervention for inpatient CAP was associated with shorter treatment durations and reductions in use of fluoroquinolones and low-yield diagnostic tests.

Background: The epidemiology and management of skin infections in nursing homes has not been adequately described. We reviewed the characteristics, diagnosis, and treatment of skin infections among residents of nursing homes to identify opportunities to improve antibiotic use., Methods: This was a retrospective study involving 12 nursing homes in the Denver metropolitan area. For residents at participating nursing homes diagnosed with a skin infection between July 1, 2013 and June 30, 2014, clinical and demographic information was collected through manual chart review., Results: Of 100 cases included in the study, the most common infections were non-purulent cellulitis (n = 55), wound infection (n = 27), infected ulcer (n = 8), and cutaneous abscess (n = 7). In 26 cases, previously published minimum clinical criteria for initiating antibiotics (Loeb criteria) were not met. Most antibiotics (n = 52) were initiated as a telephone order following a call from a nurse, and 41 patients were not evaluated by a provider within 48 h after initiation of antibiotics. Nearly all patients (n = 95) were treated with oral antibiotics alone. The median treatment duration was 7 days (interquartile range 7-10); 43 patients received treatment courses of ≥10 days., Conclusion: Most newly diagnosed skin infections in nursing homes were non-purulent infections treated with oral antibiotics. Antibiotics were initiated by telephone in over half of cases, and lack of a clinical evaluation within 48 h after starting antibiotics was common. Improved diagnosis through more timely clinical evaluations and decreasing length of therapy are important opportunities for antibiotic stewardship in nursing homes.

Background: Infectious Diseases Society of America guidelines recommend that patients hospitalized for acute bacterial skin infections after failure of outpatient antibiotic therapy be managed as "severe" infections; however, the clinical relevance of apparent failure of outpatient therapy is not clear., Methods: This was a secondary analysis of a multicenter, retrospective cohort of adults and children hospitalized for cellulitis, abscess, or wound infection. We compared clinical features, laboratory and microbiology findings, antibiotic treatment, and outcomes among patients who received outpatient antibiotics prior to admission and those who did not., Results: Of 533 patients, 179 (34%) received outpatient antibiotics prior to admission. Compared with those who did not, patients who received antibiotics prior to admission less frequently had fever (18% vs 26%, P=.04) and leukocytosis (33% vs 51%, P<.001). In the 202 cases where a microorganism was identified, Staphylococcus aureus was more common among those who received antibiotics prior to admission (75% vs 58%, P=.02), particularly methicillin-resistant S aureus (41% vs 27%, P=.049), whereas aerobic gram-negative bacilli were less common (3% vs 13%, P=.03). After hospitalization, clinical failure occurred with similar frequency between the 2 groups (12% vs 11%, P=.73)., Conclusions: Patients hospitalized with skin infections after apparently failing outpatient therapy had clinical features suggestive of less severe infection and similar outcomes compared with patients who did not receive antibiotics prior to admission. Our results suggest that inpatient treatment for patients not responding to outpatient therapy should focus on methicillin-resistant S aureus, not gram-negative pathogens., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: The incidence of cutaneous abscesses has increased markedly since the emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Injection drug use is a risk factor for abscesses and may affect the microbiology and treatment of these infections. In a cohort of patients hospitalized with cutaneous abscesses in the era of CA-MRSA, the objectives were to compare the microbiology of abscesses between injection drug users and non-injection drug users and evaluate antibiotic therapy started in the emergency department (ED) in relation to microbiologic findings and national guideline treatment recommendations., Methods: This was a secondary analysis of two published retrospective cohorts of patients requiring hospitalization for acute bacterial skin infections between January 1, 2007, and May 31, 2012, in seven academic and community hospitals in Colorado. In the subgroup of patients with cutaneous abscesses, microbiologic findings and the antibiotic regimens started in the ED were compared between injection drug users and non-injection drug users. Antibiotic regimens involving multiple agents, lack of activity against MRSA, or an agent with broad Gram-negative activity were classified as discordant with Infectious Diseases Society of America (IDSA) guideline treatment recommendations., Results: Of 323 patients with cutaneous abscesses, 104 (32%) occurred in injection drug users. Among the 235 cases where at least one microorganism was identified by culture, S. aureus was identified less commonly among injection drug users compared with non-injection drug users (55% vs. 75%, p = 0.003), with similar patterns observed for MRSA (33% vs. 47%, p = 0.054) and methicillin-susceptible S. aureus (17% vs. 26%, p = 0.11). In contrast to S. aureus, streptococcal species (53% vs. 25%, p < 0.001) and anaerobic organisms (29% vs. 10%, p < 0.001) were identified more commonly among injection drug users. Of 88 injection drug users and 186 non-injection drug users for whom antibiotics were started in the ED, the antibiotic regimens were discordant with IDSA guideline recommendations in 47 (53%) and 101 (54%), respectively (p = 0.89). In cases where MRSA was ultimately identified, the antibiotic regimen started in the ED lacked activity against this pathogen in 14% of cases., Conclusions: Compared with non-injection drug users, cutaneous abscesses in injection drug users were less likely to involve S. aureus, including MRSA, and more likely to involve streptococci and anaerobes; however, MRSA was common in both groups. Antibiotic regimens started in the ED were discordant with national guidelines in over half of cases and often lacked activity against MRSA when this pathogen was present., (© 2015 by the Society for Academic Emergency Medicine.)

Objective: To evaluate the long-term outcomes of an antimicrobial stewardship program (ASP) implemented in a hospital with low baseline antibiotic use., Design: Quasi-experimental, interrupted time-series study., Setting: Public safety net hospital with 525 beds., Intervention: Implementation of a formal ASP in July 2008., Methods: We conducted a time-series analysis to evaluate the impact of the ASP over a 6.25-year period (July 1, 2008-September 30, 2014) while controlling for trends during a 3-year preintervention period (July 1, 2005-June 30, 2008). The primary outcome measures were total antibacterial and antipseudomonal use in days of therapy (DOT) per 1,000 patient-days (PD). Secondary outcomes included antimicrobial costs and resistance, hospital-onset Clostridium difficile infection, and other patient-centered measures., Results: During the preintervention period, total antibacterial and antipseudomonal use were declining (-9.2 and -5.5 DOT/1,000 PD per quarter, respectively). During the stewardship period, both continued to decline, although at lower rates (-3.7 and -2.2 DOT/1,000 PD, respectively), resulting in a slope change of 5.5 DOT/1,000 PD per quarter for total antibacterial use (P=.10) and 3.3 DOT/1,000 PD per quarter for antipseudomonal use (P=.01). Antibiotic expenditures declined markedly during the stewardship period (-$295.42/1,000 PD per quarter, P=.002). There were variable changes in antimicrobial resistance and few apparent changes in C. difficile infection and other patient-centered outcomes., Conclusion: In a hospital with low baseline antibiotic use, implementation of an ASP was associated with sustained reductions in total antibacterial and antipseudomonal use and declining antibiotic expenditures. Common ASP outcome measures have limitations.

Of 300 patients prescribed oral antibiotics at the time of hospital discharge, urinary tract infection, community-acquired pneumonia, and skin infections accounted for 181 of the treatment indications (60%). Half of the prescriptions were antibiotics with broad Gram-negative activity. Discharge prescriptions were inappropriate in 79 of 150 cases reviewed (53%).

Background: Among diabetics, complicated skin infections may involve gram-negative pathogens; however, the microbiology of cellulitis and cutaneous abscess is not well established., Objective: To compare the microbiology and prescribing patterns between diabetics and nondiabetics hospitalized for cellulitis or abscess., Design: Secondary analysis of 2 published retrospective cohorts., Setting/patients: Adults hospitalized for cellulitis or abscess, excluding infected ulcers or deep tissue infections, at 7 academic and community facilities., Methods: Microbiological findings and antibiotic use were compared among diabetics and nondiabetics. Multivariable logistic regression was performed to identify factors associated with exposure to broad gram-negative therapy, defined as receipt of at least 2 calendar days of β-lactamase inhibitors, second- to fifth-generation cephalosporins, fluoroquinolones, carbapenems, tigecycline, aminoglycosides, or colistin., Results: Of 770 total patients with cellulitis or abscess, 167 (22%) had diabetes mellitus. Among the 38% of cases with a positive culture, an aerobic gram-positive organism was isolated in 90% of diabetics and 92% of nondiabetics (P = 0.59); aerobic gram-negative organisms were isolated in 7% and 12%, respectively (P = 0.28). Overall, diabetics were more likely than nondiabetics to be exposed to broad gram-negative therapy (54% vs 44% of cases, P = 0.02). By logistic regression, diabetes mellitus was independently associated with exposure to broad gram-negative therapy (odds ratio: 1.66, 95% confidence interval: 1.15-2.40)., Conclusion: In cases of cellulitis or abscess associated with a positive culture, gram-negative pathogens were not more common among diabetics compared with nondiabetics. However, diabetics were overall more likely to be exposed to broad gram-negative therapy suggesting this prescribing practice may not be not warranted., (© 2014 Society of Hospital Medicine.)

Objective: Hospitalizations for acute bacterial skin and skin structure infection (ABSSSI) are common. Optimizing antibiotic use for ABSSSIs requires an understanding of current management. The objective of this study was to evaluate antibiotic prescribing practices and factors affecting prescribing in a diverse group of hospitals., Design: Multicenter, retrospective cohort study., Setting: Seven community and academic hospitals., Methods: Children and adults hospitalized between June 2010 and May 2012 for cellulitis, wound infection, or cutaneous abscess were eligible. The primary endpoint was a composite of 2 prescribing practices representing potentially avoidable antibiotic exposure: (1) use of antibiotics with a broad spectrum of activity against gram-negative bacteria or (2) treatment duration greater than 10 days., Results: A total of 533 cases were included: 320 with nonpurulent cellulitis, 44 with wound infection or purulent cellulitis, and 169 with abscess. Of 492 cases with complete prescribing data, the primary endpoint occurred in 394 (80%) cases and varied significantly across hospitals (64%-97%; P < .001). By logistic regression, independent predictors of the primary endpoint included wound infection or purulent cellulitis (odds ratio [OR], 5.12 [95% confidence interval (CI)], 1.46-17.88), head or neck involvement (OR, 2.83 [95% CI, 1.17-6.82]), adult cases (OR, 2.20 [95% CI, 1.18-4.11]), and admission to a community hospital (OR, 1.90 [95% CI, 1.05-3.44])., Conclusions: Among patients hospitalized for ABSSSI, use of antibiotics with broad gram-negative activity or treatment courses longer than 10 days were common. There may be substantial opportunity to reduce antibiotic exposure through shorter courses of therapy targeting gram-positive bacteria.

Background: Recreational drug use in men who have sex with men (MSM) is of concern because it might be linked to the transmission of HIV and other sexually transmitted infections. Evidence about drug use in HIV-diagnosed MSM in the UK is limited by representativeness of the study populations. We describe patterns of drug use and associations with sexual behaviours in HIV-diagnosed MSM in the UK., Methods: We used data from the cross-sectional ASTRA study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. We examined data for MSM, assessing the prevalence of recreational drug use and polydrug use in the previous 3 months and associations with sociodemographic and HIV-related factors. We examined the association of polydrug use with measures of condomless sex in the previous 3 months and with other sexual behaviours., Findings: Our analysis included data for 2248 MSM: 2136 (95%) were gay, 1973 (89%) were white, 1904 (85%) were on antiretroviral treatment (ART), and 1682 (76%) had a viral load of 50 copies per mL or lower. 1138 (51%) used recreational drugs in the previous 3 months; 608 (27%) used nitrites, 477 (21%) used cannabis, 460 (21%) used erectile dysfunction drugs, 453 (20%) used cocaine, 280 (13%) used ketamine, 258 (12%) used 3,4-methylenedioxy-N-methylamphetamine (MDMA), 221 (10%) used gamma-hydroxybutyrate or gamma-butyrolactone, 175 (8%) used methamphetamine, and 162 (7%) used mephedrone. In the 1138 individuals who used drugs, 529 (47%) used three or more drugs and 241 (21%) used five or more. Prevalence of injection drug use was 3% (n = 68). Drug use was independently associated with younger age (p < 0·0001), not being religious (p = 0·001), having an HIV-positive stable partner (p = 0·0008), HIV-serostatus disclosure (p = 0·009), smoking (p < 0·0001), evidence of harmful alcohol drinking (p = 0·0001), and ART non-adherence (p < 0·0001). Increasing polydrug use was associated with increasing prevalence of condomless sex (prevalence range from no drug use to use of five or more drugs was 24% to 78%), condomless sex with HIV-seroconcordant partners (17% to 69%), condomless sex with HIV-serodiscordant partners (10% to 25%), and higher-HIV-risk condomless sex after taking viral load into account (4% to 16%; p ≤ 0·005 for all). Associations were similar after adjustment for sociodemographic and HIV-related factors. Methamphetamine was more strongly associated with higher-HIV-risk condomless sex than were other commonly used drugs., Interpretation: Polydrug use is prevalent in HIV-diagnosed MSM and is strongly associated with condomless sex. Specialist support services for MSM with HIV who use recreational drugs might be beneficial in the reduction of harm and prevention of ongoing transmission of HIV and other sexually transmitted infections., Funding: National Institute for Health Research., (Copyright © 2014 Daskalopoulou et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

Initial descriptions of the HIV engagement continuum are limited by short-term follow-up and incomplete data. We evaluated engagement in a newly HIV-diagnosed cohort. Our goals were to assess long-term engagement-in-care, evaluate the effects of out-of-state migration on engagement estimates, and determine whether engagement has improved in more recently diagnosed individuals. This is a retrospective cohort study of individuals newly HIV-diagnosed at two large HIV care centers in the Denver metropolitan area from 2005 to 2009. Clinical data were obtained from three public HIV providers and two clinical trial groups. For statewide evaluation, we used mandated laboratory reporting databases for CD4 lymphocyte counts and HIV-1 RNA levels. From 2005 to 2009, 615 individuals were diagnosed with HIV. By 18 months after HIV diagnosis, 84% of the cohort had linked to care, 73% were retained in care, 49% were prescribed antiretroviral therapy, and 36% had viral suppression. By 5 years after HIV diagnosis, 55% of the cohort were retained in care, 37% had viral suppression, 15% had moved out of state, and 3% were deceased. When censoring for outmigration and death, 66% of the cohort were retained in care and 45% of the cohort had viral suppression 5 years after HIV diagnosis. Engagement-in-care 18 months after diagnosis was better in individuals diagnosed more recently. Retention in care declined while viral suppression increased over time after HIV diagnosis. Accounting for outmigration and death significantly increased estimates of engagement-in-care. Performance in the engagement continuum 18 months after diagnosis improved significantly in individuals more recently diagnosed with HIV.

Background: Hospitalizations for acute bacterial skin and skin structure infection (ABSSSI) in children are increasingly frequent, but little is known about antibiotic utilization. In adults, recent studies suggest substantial opportunity to reduce broad-spectrum antibiotic use and shorten therapy. We sought to determine whether similar opportunity exists in children., Methods: This was a planned secondary analysis of a pediatric cohort taken from a multicenter, retrospective cohort of patients hospitalized for ABSSSI between June 1, 2010, and May 31, 2012. The prespecified primary endpoint was a composite of 2 prescribing practices: (1) use of antibiotics with broad Gram-negative activity or (2) treatment duration >10 days., Results: One-hundred and two patients ≤ 18 years old were included: 43 had non-purulent cellulitis, 19 had wound infection or purulent cellulitis and 40 had cutaneous abscess. The median age was 5 years (range 45 days to 18 years). Clindamycin was the most frequently prescribed antibiotic during hospitalization (67% of cases) and at discharge (66% of cases). The median duration of therapy was 11 days (interquartile range 10-12) and was similar for all 3 types of ABSSSI. The primary endpoint occurred in 67% of cases, including broad Gram-negative therapy in 25% and treatment duration >10 days in 61%. By multivariate logistic regression, admission through an emergency department and management by a medical (vs. surgical) service were independently associated with the primary endpoint., Conclusions: Children hospitalized for ABSSSI are frequently exposed to antibiotics with broad Gram-negative activity or treated longer than 10 days suggesting opportunity to reduce antibiotic use.

Background: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults., Methods: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME)., Results: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed., Conclusions: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults., (Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society 2014. This work is written by US Government employees and is in the public domain in the US.)

Background: Uncomplicated skin and soft tissue infections are among the most frequent indications for outpatient antibiotics. A detailed understanding of current prescribing practices is necessary to optimize antibiotic use for these conditions., Methods: This was a retrospective cohort study of children and adults treated in the ambulatory care setting for uncomplicated cellulitis, wound infection, or cutaneous abscess between March 1, 2010 and February 28, 2011. We assessed the frequency of avoidable antibiotic exposure, defined as the use of antibiotics with broad gram-negative activity, combination antibiotic therapy, or treatment for 10 or more days. Total antibiotic-days prescribed for the cohort were compared with antibiotic-days in 4 hypothetical short-course (5-7 days), single-antibiotic treatment models consistent with national guidelines., Results: A total of 364 cases were included for analysis (155 cellulitis, 41 wound infection, and 168 abscess). Antibiotics active against methicillin-resistant Staphylococcus aureus were prescribed in 61% of cases of cellulitis. Of 139 cases of abscess where drainage was performed, antibiotics were prescribed in 80% for a median of 10 (interquartile range, 7-10) days. Of 292 total cases where complete prescribing data were available, avoidable antibiotic exposure occurred in 46%. This included use of antibiotics with broad gram-negative activity in 4%, combination therapy in 12%, and treatment for 10 or more days in 42%. Use of the short-course, single-antibiotic treatment strategies would have reduced prescribed antibiotic-days by 19% to 55%., Conclusions: Approximately half of uncomplicated skin infections involved avoidable antibiotic exposure. Antibiotic use could be reduced through treatment approaches using short courses of a single antibiotic., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This is a retrospective cohort study of 352 newly diagnosed HIV-infected individuals in Denver, from 2005 to 2007. Utilizing data from 3 health care systems, 2 clinical trials units, and statewide Colorado HIV laboratory reporting databases, we tracked initial linkage to HIV care, retention in care, loss to follow-up, and transitions between HIV care providers. After more than 2.6 years of follow-up, 256 (73%) individuals linked to HIV care within 180 days. Of the 301 individuals who eventually linked to care, 168 (56%) had at least one 180-day gap in care, while 49 (16%) had a 360-day gap. Transitions in care were common, with 131 (37%) individuals accessing care from 2 different providers and 15% having evidence of living outside of Colorado. In this newly diagnosed HIV-infected cohort, linkage to care was slow and long-term retention in care was poor. Transitions between HIV care providers were common and may impair engagement in care over time. Out-of-state migration was frequent and may cause an underestimation of engagement in care.

Life expectancy for people diagnosed with HIV has improved dramatically however the number of new infections in the UK remains high. Understanding patterns of sexual behaviour among people living with diagnosed HIV, and the factors associated with having condom-less sex, is important for informing HIV prevention strategies and clinical care. In addition, in view of the current interest in a policy of early antiretroviral treatment (ART) for all people diagnosed with HIV in the UK, it is of particular importance to assess whether ART use is associated with increased levels of condom-less sex. In this context the ASTRA study was designed to investigate current sexual activity, and attitudes to HIV transmission risk, in a large unselected sample of HIV-infected patients under care in the UK. The study also gathered background information on demographic, socio-economic, lifestyle and disease-related characteristics, and physical and psychological symptoms, in order to identify other key factors impacting on HIV patients and the behaviours which underpin transmission. In this paper we describe the study rationale, design, methods, response rate and the demographic characteristics of the participants. People diagnosed with HIV infection attending 8 UK HIV out-patient clinics in 2011-2012 were invited to participate in the study. Those who agreed to participate completed a confidential, self-administered pen-and-paper questionnaire, and their latest CD4 count and viral load test results were recorded. During the study period, 5112 eligible patients were invited to take part in the study and 3258 completed questionnaires were obtained, representing a response rate of 64% of eligible patients. The study includes 2248 men who have sex with men (MSM), 373 heterosexual men and 637 women. Future results from ASTRA will be a key resource for understanding HIV transmission within the UK, targeting prevention efforts, and informing clinical care of individuals living with HIV.

Macrophage migration inhibitory factor (MIF), an innate cytokine encoded in a functionally polymorphic genetic locus, contributes to detrimental inflammation but may be crucial for controlling infection. We explored the role of variant MIF alleles in tuberculosis. In a Ugandan cohort, genetic low expressers of MIF were 2.4-times more frequently identified among patients with Mycobacterium tuberculosis (TB) bacteremia than those without. We also found mycobacteria-stimulated transcription of MIF and serum MIF levels to be correlated with MIF genotype in human macrophages and in a separate cohort of US TB patients, respectively. To determine mechanisms for MIF's protective role, we studied both aerosolized and i.v. models of mycobacterial infection and observed MIF-deficient mice to succumb more quickly with higher organism burden, increased lung pathology, and decreased innate cytokine production (TNF-α, IL-12, IL-10). MIF-deficient animals showed increased pulmonary neutrophil accumulation but preserved adaptive immune response. MIF-deficient macrophages demonstrated decreased cytokine and reactive oxygen production and impaired mycobacterial killing. Transcriptional investigation of MIF-deficient macrophages revealed reduced expression of the pattern recognition receptor dectin-1; restoration of dectin-1 expression recovered innate cytokine production and mycobacterial killing. Our data place MIF in a crucial upstream position in the innate immune response to mycobacteria and suggest that commonly occurring low expression MIF alleles confer an increased risk of TB disease in some populations.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Rationale: The lack of consistent associations between clinical outcomes and microbiological responses to therapy for some infectious diseases has raised questions about the adequacy of microbiological endpoints for tuberculosis treatment trials., Objectives: To evaluate the association between symptoms and microbiological response to tuberculosis treatment., Methods: We performed a retrospective analysis of four clinical trials in which participants had culture-positive tuberculosis, standardized symptom assessment, and follow-up mycobacterial cultures. Two trials (studies 22 and 23) followed participants to identify recurrent tuberculosis; participants in studies 27 and 28 were only followed to treatment completion., Measurements and Main Results: This analysis included 1,978 participants; 39 (2.0%) had culture-confirmed treatment failure, and 75 (3.9%) had culture-confirmed recurrence. Productive cough was associated with indices of increased mycobacterial burden at diagnosis (acid-fast smear grade, severity of radiographic abnormalities). Fever and sweats improved rapidly with treatment, whereas productive cough decreased more slowly and was present in 20% of visits after treatment completion. During treatment, study participants with productive cough more often had concurrent culture positivity compared with those without productive cough (studies 22 and 23: adjusted odds ratio, 1.80; 95% confidence interval [CI], 1.33-2.44). Finally, symptoms during the latter part of treatment and follow-up were associated with culture-confirmed treatment failure and recurrence in studies 22 and 23 (for cough: adjusted hazard ratio, 2.07; 95% CI, 1.23-3.49; for fever: adjusted hazard ratio, 5.05; 95% CI, 2.76-9.19)., Conclusions: There are consistent relationships between symptoms and microbiological indices of tuberculosis, including measures of mycobacterial burden at baseline, culture positivity during treatment, and time to culture-confirmed treatment failure and recurrence.

Purpose: Community-acquired pneumonia (CAP) is the most common infection leading to hospitalization in the USA. The objective of this study was to evaluate management practices for inpatient CAP in relation to Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines to identify opportunities for antibiotic and health care resource stewardship., Methods: This was a retrospective cohort study of adults hospitalized for CAP at a single institution from 15 April 2008 to 31 May 2009., Results: Of the 209 patients with CAP who presented to Denver Health Medical Center during the study period and were hospitalized, 166 (79 %) and 43 (21 %) were admitted to a medical ward and the intensive care unit (ICU), respectively. Sixty-one (29 %) patients were candidates for outpatient therapy per IDSA/ATS guidance with a CURB-65 score of 0 or 1 and absence of hypoxemia. Sputum cultures were ordered for 110 specimens; however, an evaluable sample was obtained in only 49 (45 %) cases. Median time from antibiotic initiation to specimen collection was 11 [interquartile range (IQR) 6-19] h, and a potential pathogen was identified in only 18 (16 %) cultures. Blood cultures were routinely obtained for both non-ICU (81 %) and ICU (95 %) cases, but 15 of 36 (42 %) positive cultures were false-positive results. The most common antibiotic regimen was ceftriaxone + azithromycin (182, 87 % cases). Discordant with IDSA/ATS recommendations, oral step-down therapy consisted of a new antibiotic class in 120 (66 %), most commonly levofloxacin (101, 55 %). Treatment durations were typically longer than suggested with a median of 10 (IQR 8-12) days., Conclusions: In this cohort of patients hospitalized for CAP, management was frequently inconsistent with IDSA/ATS guideline recommendations, revealing potential targets to reduce unnecessary antibiotic and healthcare resource utilization.

Objectives: Due to antimicrobial resistance in Streptococcus pneumoniae, national guidelines recommend a respiratory fluoroquinolone or combination antimicrobial therapy for outpatient treatment of community-acquired pneumonia (CAP) associated with risk factors for drug-resistant S. pneumoniae (DRSP). The objectives of this study were to assess the prevalence of these risk factors and antibiotic prescribing practices in cases of outpatient CAP treated in the acute care setting., Methods: This was a retrospective cohort study of adult outpatients treated for CAP in the emergency department (ED) or urgent care center of an urban, academic medical center from May 1, 2009, through October 31, 2009, and comparison of antibiotic therapy in cases with and without DRSP risk factors., Results: Of 175 patients, 90 (51%) had at least one DRSP risk factor, most commonly asthma (n = 28, 16%), alcohol abuse (n = 24, 14%), diabetes mellitus (n = 18, 10%), chronic obstructive pulmonary disease (n = 16, 9%), age > 65 years (n = 16, 9%), and use of antibiotics within 3 months (15, 9%). Antibiotic prescriptions were similar among cases with and without DRSP risk factors: a macrolide (62% vs. 59%, respectively, p = 0.65), doxycycline (27% vs. 28%, p = 0.82), or a respiratory fluoroquinolone (9% vs. 9%, p = 0.90). Concordance with national guideline treatment recommendations was significantly lower in cases with DRSP risk factors (9% vs. 87%, p < 0.0001)., Conclusions: DRSP risk factors were present in approximately half of outpatient CAP cases treated in the acute care setting; however, guideline-concordant antibiotic therapy was infrequent. Strict adherence to current guidelines would substantially increase use of fluoroquinolones or combination therapy. Whether the potential risks associated with these broad-spectrum regimens are justified by improved clinical outcomes requires further study., (© 2012 by the Society for Academic Emergency Medicine.)

Rifapentine (RP T) is an antituberculosis drug that may shorten treatment duration when substituted for rifampin (RI F).The maximal tolerated daily dose of RP T and its potential for cytochrome 3A4 induction and autoinduction at clinically relevant doses are unknown. In this phase I, dose-escalation study among healthy volunteers, daily doses as high asa prespecified maximum of 20 mg/kg/day were well tolerated. Steady-state RP T concentrations increased with dose from 5 to 15 mg/kg, but area under the plasma concentration–time curve (AU C0–24) and maximum concentration (Cmax)were similar in the 15- and 20-mg/kg cohorts. Although RP T pharmacokinetics (PK) appeared to be time-dependent,accumulation occurred with daily dosing. The mean AU C0–12 of oral midazolam (MDZ), a cytochrome 3A (CYP 3A) probe drug, was reduced by 93% with the coadministration of RPT and by 74% with the coadministration of RIF (P < 0.01).Changes in the oral clearance of MDZ did not vary by RP T dose. In conclusion, RP T was tolerated at doses as high as20 mg/kg/day, its PK were less than dose-proportional, and its CYP 3A induction was robust.

Setting: Two international, multicenter Phase 2 clinical trials examining fluoroquinolone-containing regimens in adults with smear-positive pulmonary tuberculosis (TB), conducted from July 2003 to March 2007. Both trials enrolled human immunodeficiency virus (HIV) infected participants who were not receiving antiretroviral therapy (ART) at TB treatment initiation., Objective: To assess the impact of HIV infection on TB treatment outcomes in Phase 2 clinical trials., Design: Cross-protocol analysis comparing the safety, tolerability and outcomes of anti-tuberculosis treatment by HIV status., Results: Of 750 participants who received at least one dose of study treatment, 123 (16%) were HIV-infected. Treatment completion rates were similar by HIV status (81% infected vs. 85% non-infected), as were rates of week 8 culture conversion (66% infected vs. 63% non-infected), and treatment failure (5% infected vs. 3% non-infected). Among HIV-infected participants, treatment failure detected using liquid media was more frequent in those treated thrice weekly (14% thrice weekly vs. 2% daily, P = 0.03). HIV-infected participants more frequently experienced an adverse event during the intensive phase treatment than non-HIV-infected participants (30% vs. 15%, P < 0.01)., Conclusion: HIV-infected persons not receiving ART had more adverse events during the intensive phase of anti-tuberculosis treatment, but tolerated treatment well. Failure rates were higher among HIV-infected persons treated with thrice-weekly intensive phase therapy.

Background: Cellulitis and cutaneous abscess are among the most common infections leading to hospitalization, yet optimal management strategies have not been adequately studied. We hypothesized that implementation of an institutional guideline to standardize and streamline the evaluation and treatment of inpatient cellulitis and abscess would decrease antibiotic and health care resource utilization., Methods: A retrospective preintervention-postintervention study was performed to compare management before and after implementation of the guideline (January 1, 2007-December 31, 2007, and July 9, 2009-July 8, 2010)., Results: A total of 169 patients (66 with cellulitis, 103 with abscess) were included in the baseline cohort, and 175 (82 with cellulitis, 93 with abscess) were included in the intervention cohort. The intervention led to a significant decrease in use of microbiological cultures (80% vs 66%; P = .003) and fewer requests for inpatient consultations (46% vs 30%; P = .004). The median duration of antibiotic therapy decreased from 13 days (interquartile range [IQR], 10-15 days) to 10 days (IQR, 9-12 days) (P < .001). Fewer patients received antimicrobial agents with broad aerobic gram-negative activity (66% vs 36%; P < .001), antipseudomonal activity (28% vs 18%; P = .02), or broad anaerobic activity (76% vs 49%; P < .001). Clinical failure occurred in 7.7% and 7.4% of cases (P = .93), respectively., Conclusion: Implementation of a guideline for the management of inpatient cellulitis and cutaneous abscess led to shorter durations of more targeted antibiotic therapy and decreased use of resources without adversely affecting clinical outcomes.

For individuals with human immunodeficiency virus (HIV) infection to fully benefit from potent combination antiretroviral therapy, they need to know that they are HIV infected, be engaged in regular HIV care, and receive and adhere to effective antiretroviral therapy. Test-and-treat strategies for HIV prevention posit that expanded testing and earlier treatment of HIV infection could markedly decrease ongoing HIV transmission, stemming the HIV epidemic. However, poor engagement in care for HIV-infected individuals will substantially limit the effectiveness of test-and-treat strategies. We review the spectrum of engagement in care for HIV-infected individuals in the United States and apply this information to help understand the magnitude of the challenges that poor engagement in care will pose to test-and-treat strategies for HIV prevention.

Background: Although complicated skin and soft-tissue infections (SSTIs) are among the most common infections requiring hospitalization, their clinical spectrum, management, and outcomes have not been well described., Methods: We report a cohort of consecutive adult patients hospitalized for SSTI from 1 January through 31 December 2007 at an academic medical center. Cases meeting inclusion criteria were reviewed and classified as cellulitis, cutaneous abscess, or SSTI with additional complicating factors., Results: In total, 322 patients were included; 66 (20%) had cellulitis, 103 (32%) had cutaneous abscess, and 153 (48%) had SSTI with additional complicating factors. Injection drug use, diabetes mellitus, and alcohol abuse were common comorbidities. Serum inflammatory markers were routinely measured and blood cultures and imaging studies were routinely performed in each group. Of 150 patients with a positive culture result for an abscess, deep tissue, or blood, Staphylococcus aureus or streptococci were identified in 145 (97%). Use of antibiotics with broad aerobic gram-negative activity (61%-80% of patients) or anaerobic activity (73%-83% of patients) was frequent in each group. The median duration of therapy for cellulitis, cutaneous abscess, and SSTI with additional complicating factors was 13 (interquartile range [IQR], 10-14), 13 (IQR, 10-16), and 14 (IQR, 11-17) days, respectively. Treatment failure, recurrence, or rehospitalization due to SSTI within 30 days occurred in 12.1%, 4.9%, and 9.2% of patients, respectively., Conclusions: Hospitalizations for SSTI were common; more than half were due to cellulitis or cutaneous abscess. Frequent use of potentially unnecessary diagnostic studies, broad-spectrum antibiotic therapy, and prolonged treatment courses in these patients suggest targets for antimicrobial stewardship programs.

The increase in drug-resistant tuberculosis and the global pandemic of human immunodeficiency virus infection-related tuberculosis threaten global tuberculosis control. There are needs for improved therapy in all aspects of tuberculosis treatment: treatment of latent infection, active drug-susceptible disease, and particularly, drug-resistant disease. Fortunately, at this time of great need, the field of tuberculosis drug development has reemerged after >30 years of inactivity. I review the specific needs for new treatment regimens, the pathways of tuberculosis drug development, and the agents that are currently in clinical development. There is renewed interest in the rifamycin class; studies in the mouse model suggest that higher doses of rifampin or rifapentine may markedly improve the treatment of drug-susceptible disease. Fluoroquinolones may allow shorter treatment durations for drug-susceptible disease, though initial phase 2B trials have shown inconsistent activity. Novel drugs, such as TMC207, OPC-67683, PA824, SQ109, and PNU-100480, may improve the treatment of drug-resistant and drug-susceptible tuberculosis.

Objective: To assess the association between adherence to antiretroviral therapy and the presence of class-specific antiretroviral medication resistance., Design: Secondary analysis of prospective clinical trial data., Methods: Participants randomized to the protease inhibitor or nonnucleoside reverse transcriptase inhibitor (NNRTI) strategies of the Community Programs for Clinical Research on AIDS (CPCRA) Flexible Initial Retrovirus Suppressive Therapies (FIRST) Study were included. Adherence was measured by 7-day self-report. Virological failure was defined as an HIV-RNA more than 1000 at or after 4 months. The association between cumulative adherence and the development of class-specific genotypic resistance was assessed by Cox regression analysis., Results: Included were 457 and 446 antiretroviral-naive participants on the protease inhibitor and NNRTI strategies, respectively. The median time to initial virological failure in the protease inhibitor strategy was 1.2 years; 135 (30%) individuals failed with resistance. The median time to initial virological failure in the NNRTI strategy was 3.0 years; 127 (28%) failed with resistance. No association was found between cumulative adherence and protease inhibitor resistance [hazard ratio 1.1, 95% confidence interval (CI) 0.9-1.4 per 10% lower adherence]. However, lower cumulative adherence was associated with an increased risk of NNRTI resistance at initial virological failure (hazard ratio 1.2, 95% CI 1.1-1.3 per 10% lower adherence). In both strategies, lower cumulative adherence was associated with an increased risk of nucleoside reverse transcriptase inhibitor (NRTI) resistance at initial virological failure., Conclusion: Adherence-resistance relationships are class-specific. For NRTIs and NNRTIs, initial virological failure with resistance is more likely at lower levels of cumulative adherence.

Objective: To describe the epidemiology of bloodstream infection caused by USA300 strains of methicillin-resistant Staphylococcus aureus (MRSA), which are traditionally associated with cases of community-acquired infection, in the healthcare setting., Design: Retrospective cohort study., Setting: Three academically affiliated hospitals in Denver, Colorado., Methods: Review of cases of S. aureus bloodstream infection during the period from 2003 through 2007. Polymerase chain reaction was used to identify MRSA USA300 isolates., Results: A total of 330 cases of MRSA bloodstream infection occurred during the study period, of which 286 (87%) were healthcare-associated. The rates of methicillin resistance among the S. aureus isolates recovered did not vary during the study period and were similar among the 3 hospitals. However, the percentages of cases of healthcare-associated MRSA bloodstream infection due to USA300 strains varied substantially among the 3 hospitals: 62%, 19%, and 36% (P<.001) for community-onset cases and 33%, 3%, and 33% (P=.005) for hospital-onset cases, in hospitals A, B, and C, respectively. In addition, the number of cases of healthcare-associated MRSA bloodstream infection caused by USA300 strains increased during the study period at 2 of the 3 hospitals. At each hospital, USA300 strains were most common among cases of community-associated infection and were least common among cases of hospital-onset infection. Admission to hospital A (a safety-net hospital), injection drug use, and human immunodeficiency virus infection were independent risk factors for healthcare-associated MRSA bloodstream infection due to USA300 strains., Conclusions: The prevalence of USA300 strains among cases of healthcare-associated MRSA bloodstream infection varied dramatically among geographically clustered hospitals. USA300 strains are replacing traditional healthcare-related strains of MRSA in some healthcare settings. Our data suggest that the prevalence of USA300 strains in the community is the dominant factor affecting the prevalence of this strain type in the healthcare setting.

Background: Because of high rates of trimethoprim-sulfamethoxazole resistance in Escherichia coli, Denver Health switched to levofloxacin as the initial therapy for urinary tract infections (UTIs) in 1999. We evaluated the effects of that switch 6 years later., Methods: Levofloxacin prescriptions per 1000 outpatient visits and levofloxacin resistance in outpatient E. coli were evaluated over time. E. coli isolated in 2005 were further characterized by specimen source and antimicrobial susceptibilities. Risk factors for levofloxacin-resistant E. coli UTI among nonpregnant adult outpatients were evaluated in a case-control study., Results: Between 1998 and 2005, levofloxacin use increased from 3.1 to 12.7 prescriptions per 1000 visits (P<.01) and resistance in outpatients increased from 1% to 9% (P<.01). Although prescriptions for sulfonamide antibiotics decreased by half during the same period, E. coli resistance to trimethoprim-sulfamethoxazole increased from 26.1% to 29.6%. Levofloxacin-resistant E. coli were more likely resistant to other antibiotics than levofloxacin-susceptible isolates (90% vs 43%, P<.0001). Risk factors for levofloxacin-resistant E. coli UTI were hospitalization (odds ratio for each week of hospitalization, 2.0; 95% confidence interval, 1.0-3.9) and use of levofloxacin (odds ratio, 5.6; 95% confidence interval, 2.1-27.5) within the previous year., Conclusion: Fluoroquinolone prescriptions increased markedly after an institutional policy change for empiric treatment of UTI, and a rapid increase in fluoroquinolone resistance among outpatient E. coli followed. Risk factors for infection with resistant E. coli were recent hospitalization and levofloxacin use. Risk factors should be considered before initiating empiric treatment with a fluoroquinolone.