The impact of smoking on tuberculosis treatment outcomes: a meta-analysis.

BACKGROUND: Cigarette smoking contributes to tuberculosis (TB) epidemiology. However, limited evidence exists on how smoking impacts TB treatment outcomes such as treatment loss to follow-up and culture conversion.METHODS: This meta-analysis assessed current evidence of the impact of active cigarette smoking on TB treatment outcomes. PubMed, Scopus, Embase, and the Cochrane Library were searched for English-language articles published from database inception through 2017. Articles addressing active pulmonary TB and cigarette smoking were identified and data abstracted. Smokers were defined as those who smoked every day or some days at the time of interview/diagnosis. Non-smokers did not smoke at the time of interview/diagnosis. Unfavorable outcomes included any outcome other than cure or completion of TB treatment. Three different data sets were examined: 8 articles addressing unfavorable treatment outcomes, 9 analyzing only treatment loss to follow-up, and 5 addressing delayed smear or culture conversion. Studies that had <20 subjects or that addressed only populations with comorbidities were excluded.RESULTS: We identified 1030 studies; 21 studies fulfilled the inclusion/exclusion criteria. Smokers had greater odds of unfavorable outcomes (pooled odds ratio [pOR] 1.23, 95%CI 1.14-1.33), delayed smear or culture conversion (pOR 1.55, 95%CI 1.04-2.07), and treatment loss to follow-up (pOR 1.35, 95%CI 1.21-1.50).CONCLUSION: Cigarette smoking is associated with negative treatment results and delayed conversion to negative smear or culture, suggesting smoking is an important factor for consideration in TB elimination efforts.

Extensively drug-resistant tuberculosis 'hotspots' and sociodemographic associations in Durban, South Africa.

In KwaZulu-Natal, South Africa, the incidence of extensively drug-resistant tuberculosis (XDR-TB) is driven by the transmission of resistant strains. As data suggest that cases may be spatially clustered, we sought to identify 'hotspots' and describe these communities. We enrolled XDR-TB patients diagnosed from 2011 to 2014 in eThekwini. Global positioning system (GPS) coordinates for participant homes were collected and hotspots were identified based on population-adjusted XDR-TB incidence. The sociodemographic features of hotspots were characterised using census data. For a subset of participants, we mapped non-home XDR-TB congregate locations and compared these with results including only homes. Among 132 participants, 75 (57%) were female and 87 (66%) lived in urban or suburban locations. Fifteen of 197 census tracts were identified as XDR-TB hotspots with ≥95% confidence. Four spatial mapping methods identified one large hotspot in northeastern eThekwini. Hotspot communities had higher proportions of low educational attainment (12% vs. 9%) and unemployment (29.3% vs. 20.4%), and lower proportion of homes with flush toilets (36.4% vs. 68.9%). The case density shifted towards downtown Durban when congregate locations (e.g., workplaces) for 43 (33%) participants were mapped. In eThekwini, XDR-TB case homes were clustered into hotspots with more poverty indicators than non-hotspots. Prevention efforts targeting hotspot communities and congregate settings may be effective in reducing community transmission. .

Dual ß-Lactam Combinations Highly Active against Mycobacterium abscessus Complex In Vitro.

As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual ß-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain ß-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual ß-lactam treatment regimen.IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual ß-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual ß-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of ß-lactam drugs.

Impact of gyrB and eis Mutations in Improving Detection of Second-Line-Drug Resistance among Mycobacterium tuberculosis Isolates from Georgia.

The country of Georgia has a high burden of multi- and extensively drug-resistant tuberculosis (XDR-TB). To evaluate whether mutations in gyrB and eis genes increased the sensitivity of detection of phenotypic resistance to ofloxacin and kanamycin or capreomycin compared to use of the first-generation MTBDRsl assay alone, which tests for mutations in gyrA and rrs genes, a retrospective study of stored Mycobacterium tuberculosis isolates was performed. All isolates underwent DNA sequencing of resistance-determining regions. Among 112 M. tuberculosis isolates with DNA extraction data, targeted sequencing was successfully performed for each gene as follows: for gyrA, 98% sensitivity; for gyrB, 96%; for rrs, 93%; for the eis gene and its promoter, 93%. The specificity and hence the positive predictive value of gyrA and gyrB mutations for detecting ofloxacin resistance were 100%. The addition of gyrB mutations increased the sensitivity of phenotypic ofloxacin resistance detection by 13% (75% to 88%). All rrs resistance-conferring mutations were A1401G, and this mutation had low sensitivity (40% and 18%) and high specificity (95% and 100%) in predicting phenotypic capreomycin and kanamycin resistance, respectively. The eis C-14T mutation increased the sensitivity of phenotypic kanamycin resistance detection by 9% (18% to 27%) and was found solely in kanamycin phenotypic resistance isolates. Our data showed that the inclusion of eis C-14T and gyrB mutations in addition to rrs and gyrA mutations improves the sensitivity of detection of phenotypic ofloxacin and kanamycin resistance, respectively.

Acquisition of second-line drug resistance and extensive drug resistance during recent transmission of Mycobacterium tuberculosis in rural China.

Multidrug-resistant tuberculosis (MDR-TB) is prevalent in countries with a high TB burden, like China. As little is known about the emergence and spread of second-line drug (SLD) -resistant TB, we investigate the emergence and transmission of SLD-resistant Mycobacterium tuberculosis in rural China. In a multi-centre population-based study, we described the bacterial population structure and the transmission characteristics of SLD-resistant TB using Spoligotyping in combination with genotyping based on 24-locus MIRU-VNTR (mycobacterial interspersed repetitive unit-variable-number tandem repeat) plus four highly variable loci for the Beijing family, in four rural Chinese regions with diverse geographic and socio-demographic characteristics. Transmission networks among genotypically clustered patients were constructed using social network analysis. Of 1332 M. tuberculosis patient isolates recovered, the Beijing family represented 74.8% of all isolates and an association with MDR and simultaneous resistance between first-line drugs and SLDs. The genotyping analysis revealed that 189 isolates shared MIRU-VNTR patterns in 78 clusters with clustering rate and recent transmission rate of 14.2% and 8.3%, respectively. Fifty-three SLD-resistant isolates were observed in 31 clusters, 30 of which contained the strains with different drug susceptibility profiles and genetic mutations. In conjunction with molecular data, socio-network analysis indicated a key role of Central Township in the transmission across a highly interconnected network where SLD resistance accumulation occurred during transmission. SLD-resistant M. tuberculosis has been spreading in rural China with Beijing family being the dominant strains. Primary transmission of SLD-resistant strains in the population highlights the importance of routine drug susceptibility testing and effective anti-tuberculosis regimens for drug-resistant TB.

Role of casual contacts in the recent transmission of tuberculosis in settings with high disease burden.

Tuberculosis (TB) remains a major cause of morbidity and mortality worldwide. It is expected that combining multiple molecular methods will further help in focusing contact investigations. We performed a population-based molecular epidemiological study in six sites in China between 1 June 2009 and 31 December 2010. A genotyping method combining 7-loci MIRU-VNTR and IS6110-based RFLP was employed to determine predictors of recent transmission. A second interview was performed with the clustered patients to identify potential epidemiological links. The molecular clustering analysis revealed that 187 isolates (15.3%) were clustered by sharing identical VNTR-IS6110 combined patterns, with an estimated recent transmission index being 8.9%. None of these patients reported having contacts with other members within the same cluster. Nineteen of 121 reported having a history of contact with a TB case within 2 years before the current TB diagnosis. Additionally, geographical correlation was established for 19 cases in nine clusters, while only one possible epidemiological link was established in secondary interview. The results underscore the role of casual contact or reactivation of latent TB as a driving factor maintaining the current endemicity in rural China, with high disease burdens of tuberculosis.

Recent transmission of W-Beijing family Mycobacterium tuberculosis in rural eastern China.

OBJECTIVE: To understand the degree of recent transmission of tuberculosis (TB) and determine the risk factors associated with recent transmission stratified by W-Beijing genotype in rural China. DESIGN: A cross-sectional study of bacteriologically confirmed TB patients registered in two rural counties of eastern China over a 1-year period. RESULTS: Of 351 patient isolates, spoligotyping identified 243 (69.2%) as W-Beijing family strains, and 53 (15.1%) and 15 (4.3%) as members of T1 Family and Family 33, respectively. Insertion sequence (IS) 6110 based restriction fragment length polymorphism typing revealed that 31 clusters together accounted for 80 of the 351 isolates. Strains with the W-Beijing genotype were more likely to be clustered than non-Beijing strains (42.3% vs. 8.3%, P < 0.001). The proportion of cases due to recent transmission was estimated at 23.1% (32.1% W-Beijing genotype vs. 2.8% non-W-Beijing genotype). Multivariate analysis showed that bacille Calmette-Guérin (BCG) vaccination (aOR 2.97), multidrug resistance (aOR 5.45) and body mass index (aOR 1.13) were independent predictors for clustering among W-Beijing isolates. CONCLUSIONS: The low clustering proportions highlight the role of endogenous reactivation of TB as a main concern in rural eastern China. Our findings also suggest that W-Beijing strains were associated with recent transmission in this population, where multidrug resistance and BCG vaccination may play an important role in the mechanism of TB transmission.

Prevalence of agr specificity groups among Staphylococcus aureus strains colonizing children and their guardians.

PCR-based assays were used to evaluate agr locus nucleotide polymorphism for the identification of agr autoinducer receptor specificity groups within a population of Staphylococcus aureus isolates colonizing children and their guardians. All isolates could be assigned to one of three major agr groups that had similar prevalences, regardless of whether isolates were implicated in transmission of S. aureus within families. Among healthy carriers, agr groups I to III appear to be equally fit, which may reflect selection for the coexistence of S. aureus strains in a population.

Molecular identification of streptomycin monoresistant Mycobacterium tuberculosis related to multidrug-resistant W strain.

A distinct branch of the Mycobacterium tuberculosis W phylogenetic lineage (W14 group) has been identified and characterized by various genotyping techniques. The W14 group comprises three strain variants: W14, W23, and W26, which accounted for 26 clinical isolates from the New York City metropolitan area. The W14 group shares a unique IS6110 hybridizing banding motif as well as distinct polymorphic GC-rich repetitive sequence and variable number tandem repeat patterns. All W14 group members have high levels of streptomycin resistance. When the streptomycin resistance rpsL target gene was sequenced, all members of this strain family had an identical mutation in codon 43. Patients infected with the W14 group were primarily of non- Hispanic black origin (77%); all were US-born. Including HIV positivity, 84% of the patients had at least one known risk factor for tuberculosis.

Molecular epidemiology of tuberculosis among eight hospitals in New York City, 1996-1997.

OBJECTIVE: To determine the molecular epidemiology of tuberculosis isolated from patients cared for at eight hospitals scattered throughout New York City. MATERIALS AND METHODS: Cases of tuberculosis occurring in 1996 and 1997 at collaborating hospitals were identified, and demographic data were extracted from patient charts. All available isolates were analyzed by IS6110 for genetic relatedness. The molecular fingerprints were compared both to each other and to the larger repository of strains from New York City developed and maintained at the Public Health Research Institute. RESULTS: One hundred and eighty cases were fully characterized. Compared with New York City cases, study patients were more likely to be Asian and less likely to be non-Hispanic blacks. Overall, 97 (54%) of the cases were clustered with respect to other study strains or with respect to the other New York City isolates. Clustered strains were significantly more likely to be from non-Hispanic blacks or patients born in the United States. The largest cluster (n = 17) was the "W" strain previously associated with an outbreak of multidrug-resistant tuberculosis in New York City. In the current study, the majority of W strain isolates were fully drug-susceptible. CONCLUSIONS: High rates of genetically related tuberculosis continue to occur among patients in New York City, in spite of improved control of nosocomial outbreaks and dramatic decreases in the overall case rates. The use of molecular techniques to suggest patterns of transmission has become essential in developing and assessing routine tuberculosis control strategies.

Tuberculosis treatment in nepal: a rapid assessment of government centers using different types of patient supervision.

SETTING: Urban and periurban government tuberculosis (TB) treatment clinics in Nepal. OBJECTIVE: To assess TB treatment supervision strategies and outcomes. DESIGN: Three types of treatment centers were selected according to intensity of treatment supervision: Group A-all patients supervised by directly observed therapy (DOT) at the treatment center during the intensive phase; Group B-flexible DOT where patient-nominated treatment supervisors include community or family members; Group C-drugs dispensed monthly and no supervised treatment. The cohort studied comprised all new patients starting treatment during a 5-month period in 1996 (n = 759). RESULTS: At group A treatment centers, 100% of patients had daily DOT supervised by treatment center staff during the intensive phase. At group B sites, 75% of nominated supervisors were family or community members and 13% of patients had no supervisor. At group C sites 93% of patients were unsupervised. Bacteriologically confirmed cure rates for smear-positive patients were 91% (95%CI 80.3-97.2) for A sites, 57% (95%CI 48.8-64.0) for B, and 34% (95%CI 25.1-40.4) for C. Treatment centers with the best results had good access to laboratory facilities, uninterrupted drug supply, longer clinic hours, standardized TB case management, and support from a non-governmental organization. CONCLUSION: At government facilities in Nepal, only group A treatment centers achieved World Health Organization global targets for cure. Group B treatment centers showed better outcomes than unsupervised therapy but did not achieve cure targets. Rapid low-cost assessments to collect data that are not routinely reported can improve the evaluation of program aspects such as supervision strategies.

Prevalence of vaginal colonization by drug-resistant Candida species in college-age women with previous exposure to over-the-counter azole antifungals.

We enrolled 382 college-age women in a cross-sectional survey to investigate the relationship between use of over-the-counter (OTC) azole-based antifungal drugs and vaginal colonization by drug-resistant Candida. This study showed no correlation (P=.506) between previous OTC exposure and colonization of drug-resistant Candida in vaginal flora. However, a small number of resistant Candida species isolates were obtained from women with a history of multiple exposures to OTC antifungals; given the widespread use of these products, this may be an emerging concern.

Rising number of tuberculosis cases among Tibetans in New York City.

Tuberculosis among Tibetans increased in New York City between 1995 and 1999. We examined characteristics of 68 Tibetan patients compared to 702 non-Tibetan patients from Nepal, India, or China, diagnosed between January 1995 and December 1999. The number of Tibetan patients increased each year after 1995 whereas non-Tibetans remained stable during the same period. Tibetans were younger (27 vs. 44 years), more likely to be infectious (63% vs. 46%), have multidrug resistance (7% vs. 2%) and shorter time to diagnosis after arrival (9 vs. 79 months, p < 0.01). For Tibetan patients, 68% of identified contacts were evaluated. The prevalence of tuberculosis infection was 65%. In contrast, among non-Tibetan patients 88.8% of contacts were evaluated and 45.2% were infected. Outreach efforts with community leaders and educational presentations at community events have been implemented in an effort to ensure continuity of care and completion of treatment.

Prevalence of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in the community.

Recent reports indicate that community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections are increasing and may now involve persons without risk factors predisposing for acquisition. To estimate the extent of community MRSA in New York City, the prevalence of S. aureus and MRSA nasal colonization in a well-patient population of 500 children and guardians was determined. The prevalence of S. aureus nasal carriage was 35% for children and 28% for guardians. One person with predisposing risk factors was colonized with an MRSA, which was identified as the predominant clone found in New York City hospitals. A high degree of methicillin-susceptible S. aureus strain diversity was noted, with no apparent selection for specific clonal types. Thus, MRSA colonization is not ubiquitous in persons without predisposing risk outside of the health care environment. Bacterial competition and a lack of strong selection may limit the community spread of MRSA and can account for its sporadic distribution.

Resistance rather than virulence selects for the clonal spread of methicillin-resistant Staphylococcus aureus: implications for MRSA transmission.

The population structure of methicillin-resistant Staphylococcus aureus (MRSA) is predominantly clonal, which may be related to the fitness of the genetic background of the methicillin-susceptible S. aureus (MSSA) into which the mecA chromosomal resistant determinant has inserted. To test this idea, we assessed whether the genotypes of New York MRSA are present in MSSA populations by using a combination of protein A gene sequence typing (spa typing) and pulsed-field gel electrophoresis (PFGE). Although about 16% of colonizing MSSA isolated from community subjects were related to MRSA, only one of the five predominant New York MRSA clonal types was found among the MSSA isolates. Similarly, among nosocomial MSSA, only four MRSA homologues were observed, two of which may have arisen through deletion of the mec element. Thus, MRSA clonal types represent a limited spectrum of the diversity seen in community and hospital S. aureus populations. The data are best explained by antibiotic selection pressure, as opposed to increased transmissibility or virulence, being responsible for the clonal dissemination of the resistance phenotype in MRSA genetic backgrounds, an in turn, the limited spread of these strains outside of the hospital environment.

Identification of a W variant outbreak of Mycobacterium tuberculosis via population-based molecular epidemiology.

CONTEXT: Typing of Mycobacterium tuberculosis could provide a more sensitive means of identifying outbreaks than use of conventional surveillance techniques alone. Variants of the New York City W strain of M tuberculosis were identified in New Jersey. OBJECTIVE: To describe the spread of the W family of M tuberculosis strains in New Jersey identified by molecular typing and surveillance data. DESIGN: Population-based cross-sectional study. SETTING AND SUBJECTS: All incident culture-positive tuberculosis cases reported in New Jersey from January 1996 to September 1998, for which the W family was defined by insertion sequence (IS) IS6110 DNA fingerprinting, polymorphic GC-rich repetitive sequence (PGRS) typing, spacer oligotyping (spoligotyping), and variable number tandem repeat (VNTR) analysis. MAIN OUTCOME MEASURE: Identification and characterization of W family clones supplemented by surveillance data. RESULTS: Isolates from 1207 cases were analyzed, of which 68 isolates (6%) belonged to the W family based on IS6110 and spoligotype hybridization patterns. The IS6110 hybridization patterns or fingerprints revealed that43 patients (designated group A) shared a unique banding motif not present in other W family isolates. Strains collected from the remaining 25 patients (designated group B), while related to W, displayed a variety of IS6110 patterns and did not share this motif. The PGRS and VNTR typing confirmed the division of the W family into groups A and B and again showed group A strains to be closely related and group B strains to be more diverse. The demographic characteristics of individuals from groups A and B were specific and defined. Group A patients were more likely than group B patients to be US born (91 % vs 24%, P<.001), black (76% vs 16%, P<.001), human immunodeficiency virus positive (40% vs 0%, P = .007), and residents of urban northeast New Jersey counties (P<.001). Patients with group B strains were primarily non-US born, of Asian descent, and more dispersed throughout New Jersey. No outbreak had been detected using conventional surveillance alone. CONCLUSIONS: The implementation of multiple molecular techniques in conjunction with surveillance data enabled us to identify a previously undetected outbreak in a defined geographical setting. The outbreak isolates comprise members of a distinct branch of the W family phylogenetic lineage. The use of molecular strain typing provides a proactive approach that may be used to initiate, and not just augment, traditional surveillance outbreak investigations.