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Background: Nontuberculous mycobacteria are environmental organisms that cause infections leading to chronic, debilitating pulmonary disease, among which Mycobacterium avium complex (MAC) is the most common species., Methods: We described patterns of macrolide-based multidrug antibiotic therapies for MAC pulmonary disease (MAC-PD) in US Medicare beneficiaries with bronchiectasis between January 2006 and December 2014. MAC therapy was defined as a multidrug regimen containing a macrolide plus ≥1 other drug targeting MAC-PD (rifamycin, ethambutol, fluoroquinolone, or amikacin) prescribed concomitantly for >28 days., Results: We identified 9189 new MAC therapy users, with a mean age (standard deviation) of 74 (6 years) at the start of therapy; 75% female and 87% non-Hispanic white. A guideline-based regimen (a macrolide, ethambutol, and rifamycin, with or without amikacin) was prescribed for 51% of new MAC therapy users at treatment start, of whom 41% were continuing guideline-based therapy at 6 months, and only 18% at 12 months. Of all new MAC therapy users, by 18 months only 11% were still receiving MAC treatment, 55% had discontinued therapy, and 34% were censored owing to death or the end of the study period., Conclusions: Overall, nearly half of new MAC therapy users were prescribed a non-guideline-recommended macrolide-based therapy, including regimens commonly associated with promoting macrolide resistance. Treatment discontinuation was common, and once discontinued, only a few beneficiaries resumed therapy at a later time. Our study adds important data to the current literature on treatment patterns for MAC-PD among older US populations. Future research should examine treatment patterns using more contemporary data sources., Competing Interests: Potential conflicts of interest. J. H. K. has received research grants from Moderna and GlaxoSmithKline, paid to the institution. E. H. has served on advisory board for AN2 Pharmaceuticals and received consulting fees. S. K. B. reports grants or contracts from Insmed, outside the submitted work and paid to the institution, as site subinvestigator for a clinical trial in nontuberculous mycobacteria (NTM) lung disease; payment or honoraria paid to institution from Boehringer Ingelheim; and membership on the executive committee for The Union–North American Region. T. K. M. has received grants or contracts from the Ontario Thoracic Society/Lung Foundation for a study on preventing the recurrence of Mycobacterium avium (MAC) lung disease, from Insmed as site investigator for a clinical trial on MAC lung disease, and from the Oregon Health & Science University/Patient Centered Outcomes Research Institute as site investigator for clinical trial of MAC lung disease, all paid to the institution, and from the Lung Health Foundation. T. K. M. has received consulting fees from Insmed, RedHill Biopharma, and Spero, including for MAC lung disease study design, paid to the institution; payment or honoraria from Astra Zeneca and Novartis for CME in NTM lung disease, paid to the institution; and support for attending meetings and/or travel from NTM Info & Research (NTMir) and hotel accommodation for presentation at the NTMir annual meeting for patients and providers associated with the American Thoracic Society Annual Conference in May 2019. T. K. M. has also served as chair of the data safety monitoring board for clofazimine monotherapy in MAC lung disease and has a leadership/fiduciary role as an advisor to the Toronto NTM lung disease patient support group. K. L. W. has grants or contracts and consulting fees from Paratek, AN2 Pharmaceuticals, Insmed, and Red Hill Biopharma and consulting fees from Spero Therapeutics. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: This double-blind, placebo-controlled study was conducted to assess the efficacy of the nonabsorbed oral antibiotic rifaximin to prevent shigellosis in volunteers challenged with Shigella flexneri., Methods: Volunteers were randomized to receive either prophylactic rifaximin (200 mg 3 times daily for 3 days; n = 15) or placebo (n = 10) on days 0, 1, and 2. On day 1, volunteers were challenged with approximately 1500 colony-forming units of S. flexneri 2a strain 2457T given orally in sodium bicarbonate buffer., Results: The incidence of diarrhea was 0 with rifaximin, compared with 60% with placebo (P = .001). The median time to onset of diarrhea was 78.5 h with placebo (P < .001). The incidence of dysentery was 0 for rifaximin and 10% for placebo (P = .4). The incidence of colonization with Shigella was 0 with rifaximin, compared with 50% with placebo (P < .005). A significant serum or mucosal immune response after challenge by at least 1 indicator (immunoglobulin A titer, immunoglobulin G titer, and immunoglobulin A antibody-secreting cell count) was 0 with rifaximin and 80% with placebo (P < .001)., Conclusions: Rifaximin was effective and well tolerated, compared with placebo, in preventing shigellosis in this double-blind study of volunteers challenged with S. flexneri 2a.

Rifaximin, a virtually nonabsorbed (<0.4%) rifamycin drug, has in vitro activity against aerobic and anaerobic gram-positive and gram-negative microorganisms. Because rifaximin is nonabsorbed, systemic adverse effects are unusual, and after 3 days of therapy, the fecal level of the drug reaches 8000 microg/g. Moreover, the important selection of resistant mutants by the related drug, rifampin, has not yet been observed for rifaximin. Rifaximin has been demonstrated to reduce the duration of traveler's diarrhea secondary to noninvasive bacterial pathogens and recently has been shown to reduce the occurrence of the disease when used for chemoprophylaxis. Preliminary studies have demonstrated its potential for the treatment of other gastrointestinal disorders, such as hepatic encephalopathy. Additional studies should be performed to further define the role of rifaximin in the treatment of gastrointestinal diseases in adults and children.

The use of antibacterial drugs was first shown to effectively reduce the occurrence of traveler's diarrhea nearly 50 years ago. The approach was not encouraged for general use by a Consensus Development Conference in 1985 because of concerns about adverse effects of the drugs and the possible development of resistance against systemically absorbed drugs. When therapy with poorly absorbed rifaximin was shown to be as effective as therapy with systemically absorbed drugs in shortening the duration of traveler's diarrhea, without the development of resistant coliform flora, the use of rifaximin for the prevention of traveler's diarrhea was studied. In the present study, rifaximin provided 72% protection against the development of diarrhea and 77% protection against active or treated diarrhea during 2 weeks of drug administration to United States students in Mexico. Rifaximin offers a potentially useful approach for preventing traveler's diarrhea. Potential areas of future study include use of the drug to prevent diarrhea due to mucosally invasive bacteria, including ciprofloxacin-resistant Campylobacter species, and to reduce the occurrence of postinfectious irritable bowel syndrome.

We sought to determine the risk of acquired rifamycin resistant (ARR) tuberculosis associated with rifampin- versus rifabutin-based directly observed therapy and to assess the risk factors for relapse of tuberculosis. This observational cohort study included patients with culture-confirmed rifamycin-susceptible tuberculosis reported to the Baltimore City Health Department (Baltimore, MD) during the period of January 1993 through December 2001. Of the 407 patients, 108 (27%) were human immunodeficiency virus (HIV) seropositive, 161 (40%) were HIV seronegative, and 138 (34%) had an unknown serostatus. Three (2.8%) of 108 HIV-seropositive persons had ARR tuberculosis, compared with 0 of 299 persons with negative or unknown HIV serostatus (P=.02). Among HIV-seropositive patients, 3 (3.7%) of 81 who were treated with rifampin and 0 of 27 who were treated with rifabutin had ARR tuberculosis (P=.57). Among HIV-seropositive patients, the only risk factor for recurrent tuberculosis was a low median initial CD4+ T lymphocyte count (51 vs. 138 cells/mm3; P=.02). The median CD4+ T lymphocyte count among patients with ARR tuberculosis was 51 cells/mm3. ARR tuberculosis can occur with rifampin-based regimens, but in this study, the risk was not significantly higher than that for a rifabutin-based regimen.

Rifaximin is a poorly absorbed rifamycin derivative under investigation for treatment of infectious diarrhea. Adult students from the United States in Mexico and international tourists in Jamaica were randomized to receive either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for 3 days, following a double-blinded model, from June 1997 to September 1998. A total of 187 subjects with diarrhea were studied. Time from initiation of therapy to passage of last unformed stool was comparable for those receiving rifaximin or ciprofloxacin (median, 25.7 hours versus 25.0 hours, respectively). There was no significant difference in the proportion of subjects in the 2 groups with respect to clinical improvement during the first 24 hours (P=.199), failure to respond to treatment (P=.411), or microbiological cure (P=.222). The incidence of adverse events was low and similar in each group. Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of traveler's diarrhea.

Rifalazil (formerly known as KRM-1648) in combination with isoniazid has been found to be more active than rifampin/isoniazid. Administration of rifalazil/isoniazid for 12 weeks resulted in continued apparent sterilization of organs 6 months after cessation of therapy. In this study we evaluated the durability of rifalazil/isoniazid treatment. Female CD-1 mice were infected with Mycobacterium tuberculosis ATCC 35801 (strain Erdman). Rifalazil and isoniazid were given in combination for 6 and 12 weeks; no mycobacteria could be cultured from spleens and lungs at both the 6-week and 12-week time points. After completing treatment, groups of mice treated with rifalazil/isoniazid for 6 or 12 weeks were observed without any additional treatment. These observation groups were compared to groups of rifalazil/isoniazid-treated mice (6 and 12 weeks) given dexamethasone for 7 and 8 weeks, respectively. Modest regrowth was noted in the spleens and lungs of the group treated with rifalazil/isoniazid for 6 weeks. Regrowth in the 6-weeks group was enhanced slightly by treatment with dexamethasone. In contrast, no regrowth was noted in the 12-weeks rifalazil/isoniazid group, and treatment with dexamethasone did not result in any regrowth.

The purpose of this study was to determine the role of enteroaggregative Escherichia coli (EAEC) in the development of traveler's diarrhea and the clinical response of patients with EAEC diarrhea following treatment with ciprofloxacin. Sixty-four travelers with diarrhea and no other recognized enteropathogen were enrolled in treatment studies in Jamaica and Mexico from July 1997 to July 1998. EAEC was isolated from 29 travelers (45.3%). There was a significant reduction in the duration of posttreatment diarrhea in the 16 patients treated with ciprofloxacin, as compared with that in the 13 patients who received placebo (mean of 35.3 versus 55.5 hours; P = .049). There was a nonsignificant reduction in the mean number of unformed stools passed during the 72 hours after enrollment in the ciprofloxacin-treated group (5.6), as compared with that in the placebo group (7.5) (P = .128). This study provides additional evidence that EAEC should be considered as a cause of antibiotic-responsive traveler's diarrhea.

Most HIV-infected patients with tuberculosis can be treated satisfactorily with standard regimens with expectations of good results. Treatment of tuberculosis in these patients has been complicated by the introduction of HAART, which relies on drugs that interfere with the most potent class of antituberculous medications. Rifampin-free regimens or regimens that employ rifabutin may be acceptable strategies for patients who are receiving protease inhibitors, although these regimens have not been rigorously evaluated in patients with AIDS. At present, there is good reason to believe that a 6-month course of a rifabutin-containing regimen or a 9-12-month course of a regimen of streptomycin, isoniazid, and pyrazinamide should be adequate therapy for most patients with drug-susceptible disease. As the treatment of HIV infection with antiretroviral agents evolves, the treatment of tuberculosis in patients with AIDS is likely to evolve as well. This will require careful coordination of antituberculosis and antiretroviral therapies.

The incidence of tuberculosis (TB) in patients with human immunodeficiency virus (HIV) infection has increased in recent years, raising issues regarding preventive therapy for TB in this high-risk patient population. To determine if an HIV-positive individual is at risk for reactivation of latent infection, testing with purified protein derivative (PPD) is recommended; however, many people with impaired cell-mediated immunity due to HIV are anergic. Strategies regarding PPD testing and criteria for HIV-positive patients are presented. Isoniazid has been the accepted drug for use as prophylaxis for TB in immunocompetent patients, and there is evidence that isoniazid is also effective in HIV-positive, PPD-positive patients. Data from efficacy and feasibility trials and the risks and benefits of preventive therapy with isoniazid are discussed. Because of toxicity and compliance problems with isoniazid, there is a continuing need for development of alternative therapies. The results of some preliminary studies of newer therapies are presented here.

Tuberculosis due to Mycobacterium tuberculosis and other mycobacteria should be considered in the diagnostic approach to febrile immunocompromised patients. In patients with AIDS, organisms of the Mycobacterium avium complex (MAC) are the most common bacterial causes of disseminated infection. Effective means of both treating and preventing disseminated MAC infections have been developed that use regimens including the new macrolides, aminoglycosides, and rifamycins. Antimicrobial agents active against M. tuberculosis are not usually active against MAC organisms, and the converse may also be true. With the advent of more cases of drug-resistant tuberculosis, however, the urgency regarding development of new therapeutic approaches for tuberculosis is widely appreciated. Research into the pathogenesis and treatment of infections due to M. tuberculosis and MAC, which has been much neglected, is likely to provide new knowledge that will benefit the clinical approach to all mycobacterial diseases.

Mycobacterium malmoense is a potentially pathogenic species that was first described in 1977. During the past decade M. malmoense has been recognized with increasing frequency as a pulmonary pathogen. More than 180 cases of M. malmoense infection have been reported. Most of these infections affected a previously damaged lung. Other infection sites included the skin, lymph nodes, and bursae. Five cases of disseminated infection have been reported. The antituberculous drugs associated with the most favorable susceptibility patterns are rifampin and ethambutol. Because of the slow growth of M. malmoense on conventional, egg-based bacteriologic media, the incubation time should be > 6 weeks; special solid and liquid media are recommended. We report a case of disseminated pulmonary and gastrointestinal infection due to M. malmoense in a patient with AIDS, who was treated successfully with a combination of rifabutin (ansamycin), clofazimine, and isoniazid. In addition, we review the characteristics of extrapulmonary and disseminated infections due to M. malmoense.