The respiratory microbiome and nontuberculous mycobacteria: an emerging concern in human health.

Nontuberculous mycobacteria (NTM) are diverse microbial species encompassing commensals and pathogens with the ability to cause pulmonary disease in both immunocompetent and immunocompromised individuals. In contrast to Mycobacterium tuberculosis, which has seen a reduction in disease rates in developed countries, the incidence and prevalence of NTM disease is increasing. NTM are difficult to treat with standard antimicrobial regimens and may contain both virulence and antibiotic-resistance genes with potential for pathogenicity. With the advent of molecular techniques, it has been elucidated that these organisms do not reside in isolation and are rather part of a complex milieu of microorganisms within the host lung microbiome. Over the last decade, studies have highlighted the impact of the microbiome on host immunity, metabolism and cell-cell communication. This recognition of a broader community raises the possibility that the microbiome may disrupt the balance between infection and disease. Additionally, NTM disease progression and antimicrobial therapy may affect the healthy steady state of the host and function of the microbiome, contributing to further dysbiosis and clinical deterioration. There have been limited studies assessing how NTM may influence the relationship between microbiome and host. In this review, we highlight available studies about NTM and the microbiome, postulate on virulence mechanisms by which these microorganisms communicate and discuss implications for treatment.

Management of Drug Toxicity in Mycobacterium avium Complex Pulmonary Disease: An Expert Panel Survey.

Adverse events are frequent in nontuberculous mycobacteria pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus, and gastrointestinal upset. These opinions can provide assistance in individual patient management decisions.

Program-wide review and follow-up of erythema Induratum of Bazin and tuberculosis-associated ocular inflammation management in a TB low-incidence setting: need for improved treatment candidate selection, therapy standardization, and care collaboration.

BACKGROUND: Erythema induratum of Bazin (EIB) - nodular vasculitis associated with Mycobacterium tuberculosis (TB) - and Tuberculosis-Associated Ocular Inflammation (TB-AOI) represent uncommon manifestations of TB. There is limited data and a lack of diagnostic and treatment standards for these conditions. METHODS: Eleven-year retrospective review of EIB and TB-AOI cases managed in a provincial TB program with prospective phone-based follow-up of anti-tubercular therapy (ATT) recipients. Presumptive TB-AOI and EIB diagnoses were determined by ophthalmologist or dermatologist assessments correlated with positive tuberculin skin test and/or QuantiFERON-TB Gold, along with pathologic criteria in EIB cases. RESULTS: Of 21 EIB and 20 TB-AOI cases that received ATT, 13 and 11, respectively, were reached for follow-up. The majority of EIB and TB-AOI cases were female and immigrated from TB high-burden countries. Median durations of pre-diagnosis symptoms were 2 and 0.8 years (IQR 2.5 & 1.1) for EIB and TB-AOI cases, respectively. Overall, 14 different ATT regimens were used for a median duration of 6 months (range 5-9). ATT related adverse events resulting in treatment discontinuation occurred in 14% of EIB and 10% of TB-AOI cases. On last follow-up, 76% of EIB and 42% of TB-AOI had improvement or resolution of disease. CONCLUSION: EIB and TB-AOI were uncommon presentations receiving variable therapy. While treatment response was modest for EIB cases, TB-AOI cases had sub-optimal treatment outcomes. The unique diagnostic and management challenges presented by these conditions in TB low-incidence settings highlight a need for improved treatment candidate selection, therapy standardization, and cross-specialty medical collaboration.

Is Universal Screening Necessary? Incidence of Tuberculosis among Tibetan Refugees Arriving in Calgary, Alberta.

Background. Canadian policy requires refugees with a history of tuberculosis (TB) or abnormal chest radiograph to be screened after arrival for TB. However, Tibetan refugees are indiscriminately screened, regardless of preimmigration assessment. We sought to determine the incidence of latent (LTBI) and active TB, as well as treatment-related outcomes and associations between preimmigration factors and TB infection among Tibetan refugees arriving in Calgary, Alberta. Design. Retrospective cohort study including Tibetan refugees arriving between 2014 and 2016. Associations between preimmigration factors and incidence of latent and active TB were determined using Chi-square tests. Results. Out of 180 subjects, 49 percent had LTBI. LTBI was more common in migrants 30 years of age or older (P = 0.009). Treatment initiation and completion rates were high at 90 percent and 76 percent, respectively. No associations between preimmigration factors and treatment completion were found. A case of active TB was detected and treated. Conclusion. Within this cohort, the case of active TB would have been detected through the usual postsurveillance process due to a history of TB and abnormal chest radiograph. Forty-nine percent had LTBI, compared to previously quoted rates of 97 percent. Tibetan refugees should be screened for TB in a similar manner to other refugees resettling in Canada.

Long-term Follow-up of Mycobacterium avium Complex Lung Disease in Patients Treated With Regimens Including Clofazimine and/or Rifampin.

BACKGROUND: Mycobacterium avium complex (MAC) lung disease requires prolonged treatment with multiple antibiotics. Drug intolerances and interactions are common with the current recommended treatment. There is limited information on outcomes with alternative medications. METHODS: Retrospective review including adult patients with MAC lung disease who were treated and monitored for at least 6 months posttreatment. The aim was to evaluate the clinical and microbiologic outcomes in patients treated with regimens including clofazimine and/or rifampin. RESULTS: One hundred and seven patients were included (79% were female; mean age, 67 years). Sputum samples were smear positive in 54% of patients. The majority (84%) were treated with clofazimine in combination with a macrolide and ethambutol. Fourteen patients (13%) were treated with rifampin, macrolide, and ethambutol. Most patients (95%) converted from positive to negative sputum culture results in an average of 4.5 ± 4.2 months (range, 0-30 months). A significantly greater proportion of patients treated with clofazimine converted to negative culture results compared with those treated with rifampin (100% vs 71%; P = .0002). Microbiologic relapse occurred in 52 of 107 patients (49%). Thirty-six percent of patients required retreatment. There was no difference in microbiologic relapse or re-treatment rates between the two treatment groups. CONCLUSIONS: The majority of patients with MAC lung disease achieve negative sputum culture results. Re-treatment is needed in approximately one-third of patients. In this cohort, both initial outcomes and re-treatment rates were at least as good in patients treated with clofazimine-containing regimens as in patients receiving rifampin-containing regimens. Clofazimine should be considered as an alternative drug for the treatment of MAC lung disease.

New treatment options for multidrug-resistant tuberculosis.

Despite the development of effective treatments, tuberculosis (TB) remains a major health problem. TB continues to infect new victims and kills nearly 2 million people annually. The problem is much greater in resource-limited countries but is present worldwide. Inadequate public health resources, cost, the obligatory long treatment period, and adverse drug effects contribute to treatment failures and relapses. Drug-resistant Mycobacterium tuberculosis (MTB) strains arise spontaneously and are propagated by inadequate treatment. According to World Health Organization global data, 17% of MTB strains in new, previously untreated cases are resistant to at least one drug. Approximately, 3.3% of new MTB cases are resistant to both isoniazid and rifampin, also called multidrug resistant (MDR), and rates of MDR-TB are greater than 60% in previously treated patients in some countries. Approximately 5% of cases of MDR-TB are also resistant to fluoroquinolones and to injectable drugs, and are called extensively drug resistant (XDR). Recently, XDR strains have been isolated that are also resistant to all standard second-line anti-TB medications. Successful drug treatment of TB with complex resistance profiles is virtually impossible with currently available drugs. There is a desperate need for new compounds that cure strains resistant to currently available drugs and for drugs that are better tolerated and will shorten treatment regimens. In the short term, new strategies for the management of drug-resistant TB with currently available drugs are being explored. These include the use of high-dose isoniazid, substitution of rifabutin in a small proportion of rifampin-resistant cases, linezolid, fluoroquinolones, and phenothiazines. A number of novel drugs are undergoing clinical testing and will hopefully be available in the near future. These include the newer oxazolidinones, diarylquinolines, nitroimidazopyrans, ethenylenediamines, pyrroles, and benzothiazinones.

Clinical and microbiologic outcomes in patients receiving treatment for Mycobacterium abscessus pulmonary disease.

BACKGROUND: Mycobacterium abscessus can produce a chronic pulmonary infection for which little is known regarding optimal treatment and long-term outcomes. METHODS: We performed a retrospective observational study (2001-2008) including all patients who met American Thoracic Society criteria for M. abscessus pulmonary disease. Our aim was the evaluation of clinical and microbiologic outcomes in patients treated with combined antibiotic and surgical therapy, compared with antibiotic therapy alone. RESULTS: A total of 107 patients were included in the analysis. Patients were predominantly female (83%) and never-smokers (60%), with a mean age of 60 years. Fifty-nine (55%) of 107 patients had coexistent or previous history of Mycobacterium avium complex pulmonary infection. High-resolution chest CT showed bronchiectasis and nodular opacities in 98% of patients and cavities in 44%. Sixty-nine (46 medical, 23 surgical) patients were followed up for a mean duration of 34 months (standard deviation, 21.1 months, range, 2-82 months). Cough, sputum production, and fatigue remained stable, improved, or resolved in 80%, 69%, and 59% of patients, respectively. Twenty (29%) of 69 patients remained culture positive, 16 (23%) converted but experienced relapse, 33 (48%) converted to negative and did not experience relapse, and 17 (16%) died during the study period. There were significantly more surgical patients than medical patients whose culture converted and remained negative for at least 1 year (57% vs 28%; P = .022). CONCLUSIONS: Patients with M. abscessus pulmonary disease who are treated with multidrug antibiotic therapy and surgery or antibiotic therapy alone had similar clinical outcomes. However, surgical resection, in addition to antibiotics, may offer a prolonged microbiologic response.

High incidence of hospital admissions with multidrug-resistant and extensively drug-resistant tuberculosis among South African health care workers.

BACKGROUND: Nosocomial transmission has been described in extensively drug-resistant tuberculosis (XDR-TB) and HIV co-infected patients in South Africa. However, little is known about the rates of drug-resistant tuberculosis among health care workers in countries with high tuberculosis and HIV burden. OBJECTIVE: To estimate rates of multidrug-resistant tuberculosis (MDR-TB) and XDR-TB hospitalizations among health care workers in KwaZulu-Natal, South Africa. DESIGN: Retrospective study of patients with drug-resistant tuberculosis who were admitted from 2003 to 2008 for the initiation of drug-resistant tuberculosis therapy. SETTING: A public tuberculosis referral hospital in KwaZulu-Natal, South Africa. PARTICIPANTS: 231 health care workers and 4151 non-health care workers admitted for initiation of MDR-TB or XDR-TB treatment. MEASUREMENTS: Hospital admission rates and hospital admission incidence rate ratios. RESULTS: Estimated incidence of MDR-TB hospitalization was 64.8 per 100,000 health care workers versus 11.9 per 100,000 non-health care workers (incidence rate ratio, 5.46 [95% CI, 4.75 to 6.28]). Estimated incidence of XDR-TB hospitalizations was 7.2 per 100,000 health care workers versus 1.1 per 100,000 non-health care workers (incidence rate ratio, 6.69 [CI, 4.38 to 10.20]). A higher percentage of health care workers than non-health care workers with MDR-TB or XDR-TB were women (78% vs. 47%; P < 0.001), and health care workers were less likely to report previous tuberculosis treatment (41% vs. 92%; P < 0.001). HIV infection did not differ between health care workers and non-health care workers (55% vs. 57%); however, among HIV-infected patients, a higher percentage of health care workers were receiving antiretroviral medications (63% vs. 47%; P < 0.001). LIMITATION: The study had an observational retrospective design, is subject to referral bias, and had no information on type of health care work or duration of occupational exposure to tuberculosis. CONCLUSION: Health care workers in this HIV-endemic area were substantially more likely to be hospitalized with either MDR-TB or XDR-TB than were non-health care workers. The increased risk may be explained by occupational exposure, underlining the urgent need for tuberculosis infection-control programs.

Extensively drug-resistant tuberculosis (XDR-TB) among health care workers in South Africa.

SUMMARY OBJECTIVE: To determine the clinical profile and outcomes of health care workers (HCWs) with extensively drug resistant tuberculosis (XDR-TB) in the Eastern and Western Cape Provinces of South Africa. METHOD: Retrospective case record review of 334 patients with XDR-TB reported during the period 1996-2008 from Western and Eastern Cape Province, Cape Town, South Africa. Case records of HCWs with XDR-TB were analysed for clinical and microbiological features, and treatment outcomes. RESULTS: From 334 case records of patients with XDR-TB, 10 HCWs were identified. Eight of ten were HIV-uninfected, and four of 10 had died of XDR-TB despite treatment. All 10 HCWs had received an average of 2.4 courses of TB treatment before being diagnosed as XDR-TB. CONCLUSIONS: In the Eastern and Western Cape provinces of South Africa XDR-TB affects HCWs, is diagnosed rather late, does not appear to be related to HIV status and carries a high mortality. There is an urgent need for the South African government to implement WHO infection control recommendations and make available rapid drug susceptibility testing for HCWs with suspected multidrug-resistant (MDR)/XDR-TB. Further studies to establish the actual risk and sources of infection (nosocomial or community) are required.

Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study.

BACKGROUND: Data from Kwazulu Natal, South Africa, suggest that almost all patients with extensively drug-resistant (XDR) tuberculosis are HIV-positive, with a fatal outcome. Since, there are few data for the treatment-related outcomes of XDR tuberculosis in settings with a high HIV prevalence, we investigated the associations of these diseases in such settings to formulate recommendations for control programmes. METHODS: In a retrospective cohort study, we analysed the case records of patients (>16 years old) with XDR tuberculosis (culture-proven at diagnosis) between August, 2002, and February, 2008, at four designated provincial treatment facilities in South Africa. We used Cox proportional hazards regression models to assess risk factors associated with the outcomes-mortality and culture conversion. FINDINGS: 195 of 227 patients were analysed. 21 died before initiation of any treatment, and 174 patients (82 with HIV infection) were treated. 62 (36%) of these patients died during follow-up. The number of deaths was not significantly different in patients with or without HIV infection: 34 (41%) of 82 versus 28 (30%) of 92 (p=0.13). Treatment with moxifloxacin (hazard ratio 0.11, 95% CI 0.01-0.82; p=0.03), previous culture-proven multidrug-resistant tuberculosis (5.21, 1.93-14.1; p=0.001), and number of drugs used in a regimen (0.59, 0.45-0.78, p<0.0001) were independent predictors of death. Fewer deaths occurred in patients with HIV infection given highly active antiretroviral therapy than in those who were not (0.38, 0.18-0.80; p=0.01). 33 (19%) of 174 patients showed culture conversion, of which 23 (70%) converted within 6 months of initiation of treatment. INTERPRETATION: In South Africa, patients with XDR tuberculosis, a substantial proportion of whom are not infected with HIV, have poor management outcomes. Nevertheless, survival in patients with HIV infection is better than previously reported. The priorities for the country are still prevention of XDR tuberculosis, and early detection and management of multidrug-resistant and XDR tuberculosis through strengthened programmes and laboratory capacity. FUNDING: South African Medical Research Council, European Union Framework 7 program, and European Developing Countries Clinical Trials Partnership.

Neurological complications of infliximab.

The use of anti-tumor necrosis factor-a (TNF-a) therapies has led to improved outcomes in the treatment of rheumatoid arthritis (RA). However, the use of these new therapeutic agents requires careful monitoring for adverse effects. We describe 3 patients who developed neurological disease closely associated with the use of infliximab, a monoclonal antibody that binds to and inactivates TNF-a. All had evidence of polyneuropathy, demyelinating in one and axonal in 2. One patient had a central nervous system syndrome. Physicians should be aware of these potential adverse effects when treating patients with infliximab.