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Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide. Analysis of tuberculosis drug trials identifies features to stratify patients for longer or shorter treatment duration than the standard of care, in order to improve therapeutic outcomes.

Abstract Rationale Levofloxacin (LFX) and moxifloxacin (MXF) are the two most frequently recommended fluoroquinolones for treatment of patients with multidrug-resistant tuberculosis (MDR-TB). However, studies comparing the effectiveness of LFX and MXF among patients with MDR-TB are lacking. Objectives To compare the effectiveness of LFX and MXF in terms of culture conversion after 3 months of treatment for MDR-TB. Methods In this prospective multicenter randomized open label trial, we randomly assigned 182 patients with MDR-TB (sensitive to LFX and MXF) to receive either LFX (750 mg/day; 90 patients) or MXF (400 mg/day; 92 patients) with a background drug regimen. The primary outcome was the proportion of patients who achieved sputum culture conversion at 3 months of treatment. Secondary outcomes were time to culture conversion and time to smear conversion, with data censored at 3 months, and the proportions of adverse drug reactions. Measurements and Main Results At 3 months of treatment, 68 (88.3%) of the 77 patients in the LFX group and 67 (90.5%) of the 74 in the MXF group showed conversion to negative sputum cultures (odds ratio for LFX compared with MXF, 0.78; 95% confidence interval, 0.27–2.20). Adverse drug reactions were reported in six patients (7.7%) in the LFX group and four (5.2%) in the MXF group (P = 0.75). Conclusions The choice of LFX or MXF for treatment of patients with MDR-TB may not affect sputum culture conversion at 3 months of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01055145).

For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis. We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points. Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy. Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).

In this phase 2 study, the addition of bedaquiline to routine therapy for multidrug-resistant tuberculosis showed significant efficacy, with accelerated sputum-culture conversion and increased culture conversion at 24 and 120 weeks. The World Health Organization (WHO) estimates that the global incidence of tuberculosis in 2012 was 8.6 million cases, with 1.3 million deaths, predominantly occurring in developing countries. 1 Although there has been some progress in reducing tuberculosis cases and deaths in the past 20 years, multidrug-resistant tuberculosis (i.e., with resistance to at least isoniazid and rifampin) remains a major challenge. The 2012 global incidence of multidrug-resistant tuberculosis was 450,000 cases. 1 Therapy for multidrug-resistant tuberculosis is a long, arduous regimen of antiquated drugs that are mainly bacteriostatic and have an unfavorable side-effect profile. 2 The WHO reports that major efforts are needed to . . .

Abstract Rationale The macrolide antibiotic azithromycin reduces exacerbations in adults with persistent symptomatic asthma. However, owing to the pleotropic properties of macrolides, unintended bacteriological consequences such as augmented pathogen colonization or dissemination of antibiotic-resistant organisms can occur, calling into question the long-term safety of azithromycin maintenance therapy. Objectives To assess the effects of azithromycin on the airway microbiota, pathogen abundance, and carriage of antibiotic resistance genes. Methods 16S rRNA sequencing and quantitative PCR were performed to assess the effect of azithromycin on sputum microbiology from participants of the AMAZES (Asthma and Macrolides: The Azithromycin Efficacy and Safety) trial: a 48-week, double-blind, placebo-controlled trial of thrice-weekly 500 mg oral azithromycin in adults with persistent uncontrolled asthma. Pooled-template shotgun metagenomic sequencing, quantitative PCR, and isolate whole-genome sequencing were performed to assess antibiotic resistance. Measurements and Main Results Paired sputum samples were available from 61 patients (n = 34 placebo, n = 27 azithromycin). Azithromycin did not affect bacterial load (P = 0.37) but did significantly decrease Faith’s phylogenetic diversity (P = 0.026) and Haemophilus influenzae load (P < 0.0001). Azithromycin did not significantly affect levels of Streptococcus pneumoniae, Staphylococcus aureus, Pseudomonas aeruginosa, or Moraxella catarrhalis. Of the 89 antibiotic resistance genes detected, five macrolide resistance genes and two tetracycline resistance genes were increased significantly. Conclusions In patients with persistent uncontrolled asthma, azithromycin reduced airway H. influenzae load compared with placebo but did not change total bacterial load. Macrolide resistance increased, reflecting previous studies. These results highlight the need for studies assessing the efficacy of nonantibiotic macrolides as a long-term therapy for patients with persistent uncontrolled asthma.

Despite aggressive antibiotic therapy, bronchopulmonary colonization by Pseudomonas aeruginosa causes persistent morbidity and mortality in cystic fibrosis (CF). Chronic P. aeruginosa infection in the CF lung is associated with structured, antibiotic-tolerant bacterial aggregates known as biofilms. We have demonstrated the effects of non-bactericidal, low-dose nitric oxide (NO), a signaling molecule that induces biofilm dispersal, as a novel adjunctive therapy for P. aeruginosa biofilm infection in CF in an ex vivo model and a proof-of-concept double-blind clinical trial. Submicromolar NO concentrations alone caused disruption of biofilms within ex vivo CF sputum and a statistically significant decrease in ex vivo biofilm tolerance to tobramycin and tobramycin combined with ceftazidime. In the 12-patient randomized clinical trial, 10 ppm NO inhalation caused significant reduction in P. aeruginosa biofilm aggregates compared with placebo across 7 days of treatment. Our results suggest a benefit of using low-dose NO as adjunctive therapy to enhance the efficacy of antibiotics used to treat acute P. aeruginosa exacerbations in CF. Strategies to induce the disruption of biofilms have the potential to overcome biofilm-associated antibiotic tolerance in CF and other biofilm-related diseases. This paper reports the first example of targeted anti-biofilm therapy in human disease. We have demonstrated that using low-dose nitric oxide as a non-bactericidal signaling molecule to induce biofilm dispersal may be useful as a novel adjunctive therapy to treat chronic pseudomonal biofilm infection in cystic fibrosis.

Tuberculosis transmission continues to be a major public health challenge. In this cluster-randomized, controlled trial conducted in Vietnam, active community-wide screening for tuberculosis over 4 years is shown to decrease the prevalence of tuberculosis.

We assessed whether multiplex real-time PCR plus conventional microbiological testing is safe and more effective than conventional microbiological testing alone for reducing antibiotic use in community-acquired pneumonia (CAP). In this randomised trial, we recruited adults hospitalised with CAP at four Spanish hospitals. Patients were randomly assigned (1:1) to undergo either multiplex real-time PCR in non-invasive respiratory samples plus conventional microbiological testing or conventional microbiological testing alone. The primary endpoint was antibiotic use measured by days of antibiotic therapy (DOT). Between February 20, 2020, and April 24, 2023, 242 patients were enrolled; 119 were randomly assigned to multiplex real-time PCR plus conventional microbiological testing and 123 to conventional microbiological testing alone. All but one of the patients allocated to multiplex real-time PCR plus conventional microbiological testing underwent PCR, which was performed in sputum samples in 77 patients (65.2%) and in nasopharyngeal swabs in 41 (34.7%). The median DOT was 10.04 (IQR 7.98, 12.94) in the multiplex PCR plus conventional microbiological testing group and 11.33 (IQR 8.15, 16.16) in the conventional microbiological testing alone group (difference −1.04; 95% CI, −2.42 to 0.17; p  = 0.093). No differences were observed in adverse events and 30-day mortality. Our findings do not support the routine implementation of multiplex real-time PCR in the initial microbiological testing in hospitalised patients with CAP. Clinicaltrials.gov registration: NCT04158492. Here, the authors report the results of a randomised trial assessing whether adding multiplex real-time PCR to conventional testing reduces antibiotic use in community-acquired pneumonia and observe no significant reduction in days of antibiotic therapy or in 30-day mortality.

Abstract Rationale The principal underlying inhaled antibiotic treatment in bronchiectasis is that airway bacterial load drives inflammation, and therefore antibiotic treatment will reduce symptoms. Objectives To determine the relationship between bacterial load and clinical outcomes, assess the stability of bacterial load over time, and test the hypothesis that response to inhaled antibiotics would be predicted by baseline bacterial load. Methods We performed three studies. Studies 1 and 2 were prospective studies including adults with bronchiectasis. Study 3 was a post hoc analysis of a randomized trial of inhaled aztreonam. A priori patients were divided into low (<105 cfu/g), moderate (105–106 cfu/g), and high bacterial load (≥107 cfu/g) using quantitative sputum culture. Measurements and Main Results Bacterial load was a stable trait associated with worse quality of life and more airway inflammation in studies 1, 2, and 3. In study 3, patients with high bacterial load showed an improvement in the primary endpoint (Quality of Life–Bronchiectasis–Respiratory Symptoms Score at Week 4) in favor of aztreonam (mean difference of 9.7 points; 95% confidence interval, 3.4–16.0; P = 0.003). The proportion of patients who achieved an increase above the minimum clinically important difference was higher in the aztreonam group at Week 4 (63% vs. 37%; P = 0.01) and at Week 12 (62% vs. 38%; P = 0.01) only in high bacterial load patients. Conclusions Improvement of quality of life with inhaled aztreonam was only evident in patients with high bacterial load. Bacterial load may be a useful biomarker of severity of disease and treatment response.

In this report on the treatment of multidrug-resistant (MDR) tuberculosis, the authors found that delamanid, a novel anti-TB medication, led to more rapid sputum culture conversion to negative when added to a background regimen than the background regimen alone. The emergence over the past two decades of multidrug-resistant tuberculosis, or tuberculosis caused by strains of Mycobacterium tuberculosis that are resistant to isoniazid and rifampin, with or without resistance to other agents, has greatly complicated efforts to control the global tuberculosis epidemic. Approximately 440,000 cases of multidrug-resistant tuberculosis occur worldwide annually, accounting for nearly 5% of the global burden of tuberculosis. 1 Multidrug-resistant tuberculosis requires treatment with combination therapy consisting of four to six medications, including the more toxic and less potent second-line drugs, administered for up to 2 years. Cure rates are lower and mortality is higher with multidrug-resistant tuberculosis . . .