Anti-tuberculosis chemotherapy alters TNFR2 expression on CD4+ lymphocytes in both drug-sensitive and -resistant tuberculosis: however, only drug-resistant tuberculosis maintains a pro-inflammatory profile after a long time.

BACKGROUND: Tuberculosis (TB) is an infectious disease. During TB, regulatory T cells (Treg) are related to poor prognosis. However, information about conventional and unconventional Treg (cTreg and uTreg, respectively) is limited. The tumour necrosis factor (TNF) and its receptors (TNFR1 and TNFR2) are necessary for mycobacterial infection, and TNFR2 signalling is required to maintain Treg. METHODS: A blood sample of drug-susceptible (DS-TB) and drug-resistant tuberculosis (DR-TB) patients was obtained before (basal) and after 2 and 6 months of anti-TB therapy. Expression of TNF, TNFR1, and TNFR2 (transmembrane form, tm) on cTreg, uTreg, activated CD4+ (actCD4+), and CD4+ CD25- (CD4+) T cell subpopulations were evaluated. The main objective was to identify immunological changes associated with sensitive/resistant Mtb strains and with the use of anti-TB therapy. RESULTS: We found that after 6 months of anti-TB therapy, both DS- and DR-TB patients have decreased the frequency of cTreg tmTNF+, CD4+ tmTNFR1+ and CD4+ tmTNFR2+. Nevertheless, after 6 months of therapy, only DR-TB patients decreased the frequency of actCD4+ tmTNF+ and actCD4+ tmTNFR2+, exhibited a systemic inflammatory status (high levels of TNF, IFN-γ and IL-12), and their purified CD4+ T cells showed that TNF and TNFR2 are up-regulated at the transcriptional level. Moreover, DS- and DR-TB down-regulated TNFR1 and other proteins associated with Treg (FOXP3 and TGFß1) in response to the anti-TB therapy. CONCLUSION: These results partially explain the differences in the immune response of DS-TB vs DR-TB. The frequency of actCD4+ tmTNFR2+ cells and inflammatory status should be considered in the follow-up of therapy in DR-TB patients.

Social determinants of multidrug-resistant tuberculosis: A scoping review and research gaps.

Tuberculosis is a prime example of a social disease that requires social, economic and environmental interventions. However, research on social determinants of Multidrug-Resistant (MDR-TB) is limited. The five-stage scoping review showed the most common association of MDR-TB with multidimensional poverty (income, nutrition, education and social support) both as a contributing factor and a consequence of it. The review also found that physical environment (inadequate housing, overcrowding, poor physical environment, and smoking), health care needs, cultural determinants (race, ethnicity and gender), comorbidities had a strong influence on the development and transmission of MDR-TB. Since, epidemiology and care for MDR-TB are greatly influenced by socioeconomic factors, social, environmental and economic actions are needed in addition to the implementation of novel diagnostic techniques and treatments.

Multidrug-resistant Disseminated Tuberculosis Related to Infliximab in a Patient with Ulcerative Colitis and Negative Evaluation for Latent Tuberculosis.

Anti-tumor necrosis factor (anti-TNF) is an effective biological agent for the treatment of moderate-to-severe active ulcerative colitis (UC) refractory to conventional therapy. On the other hand, anti-TNF therapy is strongly associated with a potential risk of tuberculosis (TB). Active TB is a critical complication that makes it difficult to treat patients who require anti-TNF for the treatment of UC refractory to conventional therapy. Based on the clinical guidelines, patients with inflammatory bowel disease (IBD) are strongly recommended to screen for latent TB before anti-TNF administration. Considering the possibility of active or reactivated TB related to anti-TNF therapy, all patients with IBD should be monitored closely for TB during anti-TNF therapy, irrespective of the screening results for latent TB. In particular, the risk of anti-TNF-related multidrug-resistant TB (MDR-TB) in patients with IBD has not been elucidated. This paper reports the first case of disseminated MDR-TB that developed in a UC patient receiving infliximab despite the negative evaluation for latent TB screening.

Tuberculosis drugs' distribution and emergence of resistance in patient's lung lesions: A mechanistic model and tool for regimen and dose optimization.

BACKGROUND: The sites of mycobacterial infection in the lungs of tuberculosis (TB) patients have complex structures and poor vascularization, which obstructs drug distribution to these hard-to-reach and hard-to-treat disease sites, further leading to suboptimal drug concentrations, resulting in compromised TB treatment response and resistance development. Quantifying lesion-specific drug uptake and pharmacokinetics (PKs) in TB patients is necessary to optimize treatment regimens at all infection sites, to identify patients at risk, to improve existing regimens, and to advance development of novel regimens. Using drug-level data in plasma and from 9 distinct pulmonary lesion types (vascular, avascular, and mixed) obtained from 15 hard-to-treat TB patients who failed TB treatments and therefore underwent lung resection surgery, we quantified the distribution and the penetration of 7 major TB drugs at these sites, and we provide novel tools for treatment optimization. METHODS AND FINDINGS: A total of 329 plasma- and 1,362 tissue-specific drug concentrations from 9 distinct lung lesion types were obtained according to optimal PK sampling schema from 15 patients (10 men, 5 women, aged 23 to 58) undergoing lung resection surgery (clinical study NCT00816426 performed in South Korea between 9 June 2010 and 24 June 2014). Seven major TB drugs (rifampin [RIF], isoniazid [INH], linezolid [LZD], moxifloxacin [MFX], clofazimine [CFZ], pyrazinamide [PZA], and kanamycin [KAN]) were quantified. We developed and evaluated a site-of-action mechanistic PK model using nonlinear mixed effects methodology. We quantified population- and patient-specific lesion/plasma ratios (RPLs), dynamics, and variability of drug uptake into each lesion for each drug. CFZ and MFX had higher drug exposures in lesions compared to plasma (median RPL 2.37, range across lesions 1.26-22.03); RIF, PZA, and LZD showed moderate yet suboptimal lesion penetration (median RPL 0.61, range 0.21-2.4), while INH and KAN showed poor tissue penetration (median RPL 0.4, range 0.03-0.73). Stochastic PK/pharmacodynamic (PD) simulations were carried out to evaluate current regimen combinations and dosing guidelines in distinct patient strata. Patients receiving standard doses of RIF and INH, who are of the lower range of exposure distribution, spent substantial periods (>12 h/d) below effective concentrations in hard-to-treat lesions, such as caseous lesions and cavities. Standard doses of INH (300 mg) and KAN (1,000 mg) did not reach therapeutic thresholds in most lesions for a majority of the population. Drugs and doses that did reach target exposure in most subjects include 400 mg MFX and 100 mg CFZ. Patients with cavitary lesions, irrespective of drug choice, have an increased likelihood of subtherapeutic concentrations, leading to a higher risk of resistance acquisition while on treatment. A limitation of this study was the small sample size of 15 patients, performed in a unique study population of TB patients who failed treatment and underwent lung resection surgery. These results still need further exploration and validation in larger and more diverse cohorts. CONCLUSIONS: Our results suggest that the ability to reach and maintain therapeutic concentrations is both lesion and drug specific, indicating that stratifying patients based on disease extent, lesion types, and individual drug-susceptibility profiles may eventually be useful for guiding the selection of patient-tailored drug regimens and may lead to improved TB treatment outcomes. We provide a web-based tool to further explore this model and results at http://saviclab.org/tb-lesion/.

Primary bacillary resistance in multidrug-resistant tuberculosis and predictive factors associated with cure at a referral center in São Paulo, Brazil / Resistência bacilar primária em tuberculose multidrogarresistente e fatores preditivos associados à cura, em um centro de referência da cidade de São Paulo

ABSTRACT Objective: To identify transmitted or primary resistance among cases of multidrug-resistant tuberculosis and predictive factors for cure in multidrug-resistant tuberculosis after the first treatment. Method: Descriptive study of a cohort from 2006 to 2010, in a reference unit of tuberculosis in São Paulo, Brazil. The data were obtained by the revision of medical records. Clinical criteria were used to classify transmitted and acquired resistance. Extended primary resistance was also defined, in this study, as cases initially treated with a standardized scheme, but with no therapeutic success, and the pre-treatment drug susceptibility test (DST) showed presence of resistance. Results: 156 patients with multidrug-resistant tuberculosis and their respective sputum samples were eligible for the study. Only 7% of the patients were positive for the human immunodeficiency virus (HIV). Previous treatment occurred in 95% of the sample. The cure rate after the first treatment was 54%. The median bacteriological conversion time of those who healed was one month. Bacillary resistance was considered acquired resistance in 100 (64%) and transmitted resistance in 56 (36%). By logistic regression, patients who presented primary multidrug-resistant tuberculosis (odds ratio-OR = 6,29), without comorbidity (OR = 3,37) and with higher initial weight (OR = 1.04) were associated with cure after the first treatment. Conclusion: The early detection of bacillary resistance and appropriate treatment are in favor of healing. Thus, it is crucial to know exactly the primary resistance rate avoiding the use of inadequate treatments, amplification of bacillary resistance and its transmission.

RESUMO Objetivo: Identificar resistência transmitida ou primária entre casos de tuberculose multidrogarresistente e fatores preditivos associados à cura da tuberculose multidrogarresistente após o primeiro tratamento. Método: Estudo descritivo de uma coorte de 2006 a 2010, em uma unidade de referência em tuberculose no estado de São Paulo, Brasil. Os dados foram obtidos por meio de revisão de prontuários médicos. Critérios clínicos e laboratoriais foram utilizados para classificar resistência transmitida e adquirida. Resistência primária estendida por definição, neste estudo, abrange também casos inicialmente tratados com esquema padrão, porém sem sucesso terapêutico, e teste de sensibilidade colhido pré-tratamento demonstrou presença de resistência. Resultados: Foram elegíveis para o estudo 156 doentes com tuberculose multidrogarresistente e suas respectivas amostras de escarro. Apenas 7% dos doentes eram positivos ao vírus da imunodeficiência humana (HIV). Tratamento prévio aconteceu em 95% da amostra. A taxa de cura após o primeiro tratamento foi de 54%. A mediana do tempo de conversão bacteriológica dos que se curaram foi de um mês. Dos 156 doentes, 100 (64%) e 56 (36%) foram classificados como resistência adquirida e resistência transmitida, respectivamente. Pela regressão logística, os doentes que se apresentaram com tuberculose multidrogarresistente primária (razão de chance - RC = 6,29), sem comorbidade (RC = 3,37) e com maior peso inicial (RC = 1,04) foram associados ao desfecho cura ao final do primeiro tratamento. Conclusão: A detecção precoce da resistência bacilar e o tratamento adequado favorecem a cura. Dessa forma, é indispensável conhecer com exatidão a taxa de resistência primária evitando o uso de tratamentos inadequados, a ampliação da resistência bacilar e a sua transmissão.

The value of initial cavitation to predict re-treatment with pulmonary tuberculosis.

OBJECTIVE: Pulmonary cavitation is the classic hallmark of pulmonary tuberculosis (PTB) and is the site of very high mycobacterial burden associated with antimycobacterial drug resistance and treatment failure. The objective of this study was to investigate the relationship between re-treatment PTB and initial pulmonary cavitation coordinated with other clinical factors. METHODS: We conducted a case-control study of 291 newly diagnosed cases of pulmonary TB in The Infectious Hospital of Wuxi from Dec 2009 to Dec 2011 with complete follow-up information until December 31st of 2014. 68 patients were followed-up with PTB re-treatment; the rest of the PTB patients (n = 223) had completed anti-TB treatment, and cured without re-treatment were selected as controls. RESULTS: The univariate analysis [hazard ratio (HR) 1.885, 95 % CI 1.170-3.035, P = 0.009] and the multivariable analysis (HR 2.242, 95 % CI 1.294-3.882, P = 0.004) demonstrated that the initial pulmonary cavitation was a prognostic predictor for TB re-treatment. Additionally, the re-treatment rates in PTB patients with cavitation and no-cavitation were 27.1 and 15.5 %, respectively, with significant difference (log-rank test; P = 0.010). Other factors, age of ≥60 and history of smoking, were also prognostic variables. CONCLUSION: Initial pulmonary cavitation of chest X-ray was a significant predictor for PTB re-treatment.

Factores asociados a tuberculosis multidrogorresistente primaria en pacientes de Callao, Peru / Factors associated with primary multidrug-resistant tuberculosis in patients from Callao, Peru

Introducción:En el Perú, Lima y Callao constituyen regiones con riesgo alto de transmisión activa de tuberculosis. La tuberculosismultidrogorresistente se presenta en el 5,54% de los casos nuevos de tuberculosis pulmonar (TB MDR primaria) en Lima y Callao. Susfactores de riesgo no han sido estudiados en pacientes del Callao.Objetivos:Determinar los factores de riesgo para TB MDR primariaen pacientes atendidos en centros de salud de Callao, durante los años 2009- 2010.Diseño:Estudio caso control.Lugar:Centros deSalud de Callao.Participantes:Participaron 29 pacientes con TB MDR primaria y 37 con tuberculosis sensible, según los registros delPrograma de Control de Tuberculosis y las historias clínicas ubicadas en los centros de salud.Intervenciones:Toda la información fueobtenida de fuentes secundarias. En el análisis bivariado se calculó el OR de cada covariable. Para el cálculo de los OR multivariadosse utilizó modelos de regresión logística.Principales medidas de resultados:Factores de riesgo para TB MDR.Resultados:En elanálisis bivariado, el haber tenido contacto con pacientes TB MDR o XDR fue un factor de riesgo significativo (OR: 5,56; IC95%: 1,05a 29,27); lo mismo se demostró en el análisis multivariado (OR: 14,56; IC95%: 1,52 a 139,54). Además, en el análisis multivariado, lavariable edad≥40 años mostró ser un factor protector significativo (OR: 0,94; IC95%: 0,90 a 0,99).Conclusiones:El tener contactocon pacientes TB MDR/XDR fue factor de riesgo y una edad menor a 40 años un factor protector para contraer TB MDR primaria enlos pacientes del Callao estudiados.

Introduction: Lima and Callao are high risk areas for tuberculosis active transmission in Peru. Multidrug-resistant tuberculosis represents 5.54 per cent of the new cases of pulmonary tuberculosis (primary MDR-TB) in Lima and Callao. Involved risk factors have not been studied in patients from Callao. Objectives: To determine risk factors for primary MDR-TB in patients attending health care facilities in Callao during 2009-2010. Design: Case-control study. Setting: Health care facilities from Callao. Participants: Twenty nine primary MDR-TB patients and 37 drug-sensitive TB patients were studied through assessment of the Tuberculosis Control Program Registries and healthcare facilities’ clinical records. Interventions: Information was obtained from secondary sources. Odds-ratios were calculated by bivariate analysis. Logistic regression models were used to calculate multivariate odd-ratios. Main outcome measures: Risk factors for primary MDR-TB. Results: Prior contact with a MDR-TB or XDR-TB patient was a significant risk factor (OR: 5.56; 95 per cent CI: 1.05-29.27) in bivariate analysis; the same was found in multivariate analysis (OR: 14.56; 95 per cent CI: 1.52–139.54). Being 40 or more years old was a significant protective factor in multivariate analysis (OR: 0.94; 95 per cent CI: 0.90–0.99). Conclusions: Previous contact with a MDR-TB or XDR-TB patient was a risk factor, and being 40 or more years old was a protective factor for primary MDR-TB in Callao patients studied.

Associations between national tuberculosis program budgets and tuberculosis outcomes: an ecological study.

INTRODUCTION: The objective of this study is to explore the associations between national tuberculosis program (NTP) budget allocation and tuberculosis related outcomes in the World Health Organization's 22 high burden countries from 2007-2009. METHODS: This ecological study used mixed effects and generalized estimating equation models to identify independent associations between NTP budget allocations and various tuberculosis related outcomes. Models were adjusted for a number of independent variables previously noted to be associated with tuberculosis incidence. RESULTS: Increasing the percent of the NTP budget for advocacy, communication and social mobilization was associated with an increase in the case detection rate. Increasing TB-HIV funding was associated with an increase in HIV testing among TB patients. Increasing the percent of the population covered by the Directly Observed Therapy (DOT) program was associated with an increase in drug susceptibility testing. Laboratory funding was positively associated with tuberculosis notification. Increasing the budgets for first line drugs, management and multi-drug resistant tuberculosis (MDR-TB) was associated with a decrease in smear positive deaths. CONCLUSION: Effective TB control is a complex and multifaceted challenge. This study revealed a number of budget allocation related factors associated with improved TB outcome parameters. If confirmed with future longitudinal studies, these findings could help guide NTP managers with allocation decisions.

Likelihood of generating MDR-TB and XDR-TB under adequate National Tuberculosis Control Programme implementation.

The most frequent factors associated with selection of resistance at the community level and the generation of multidrug-resistant tuberculosis (MDR-TB) under epidemic conditions have been described in the last decades. These factors are multiple, and it is often a combination of these that has been implicated in the origin of MDR-TB epidemics in specific zones or countries. The analysis of and correct approach to the causes should be the first and most important step in the fight against this critical problem. However, it has never been investigated whether specific circumstances, even under adequate implementation of a National TB Control Programme (NTP), could lead to selection or amplification of resistance. The NTP should consider explanations for when there is no decline in MDR-TB rates even after appropriate control measures have been implemented. Under the special circumstances analysed in this article, the World Health Organization (WHO) Category I regimen can amplify resistance to rifampicin (in initial isoniazid-resistant cases) or ethambutol (EMB) + pyrazinamide (in initial MDR-TB cases). The WHO Category II regimen can also amplify resistance to EMB or streptomycin. The subsequent addition of the only second-line drugs available in many countries (fluoroquinolones and/or injectables) can worsen the situation and generate extensively drug-resistant TB. Strategies for minimising these risks of amplifying resistance are discussed in this article.

Multidrug-resistant tuberculosis: a menace that threatens to destabilize tuberculosis control.

Multidrug-resistant tuberculosis (MDR-TB), caused by Mycobacterium tuberculosis that is resistant to both isoniazid and rifampicin with or without resistance to other drugs, is a phenomenon that is threatening to destabilize global tuberculosis (TB) control. MDR-TB is a worldwide problem, being present virtually in all countries that were surveyed. According to current World Health Organization and the International Union Against Tuberculosis and Lung Disease estimates, the median prevalence of MDR-TB has been 1.1% in newly diagnosed patients. The proportion, however, is considerably higher (median prevalence, 7%) in patients who have previously received anti-TB treatment. While host genetic factors may contribute to the development of MDR-TB, incomplete and inadequate treatment is the most important factor leading to its development, suggesting that it is often a man made tragedy. Efficiently run TB control programs based on a policy of directly observed treatment, short course (DOTS), are essential for preventing the emergence of MDR-TB. The management of MDR-TB is a challenge that should be undertaken by experienced clinicians at centers equipped with reliable laboratory services for mycobacterial cultures and in vitro sensitivity testing as it the requires prolonged use of costly second-line drugs with a significant potential for toxicity. The judicious use of drugs; supervised standardized treatment; focused clinical, radiologic, and bacteriologic follow-up; and surgery at the appropriate juncture are key factors in the successful management of these patients. With newer effective anti-TB drugs still a distant dream, innovative approaches such as DOTS-Plus are showing promise for the management of patients with MDR-TB under program conditions and appear to be a hope for future.

TB tools to tell the tale-molecular genetic methods for mycobacterial research.

In spite of the availability of drugs and a vaccine, tuberculosis--one of man's medical nemeses--remains a formidable public health problem, particularly in the developing world. The persistent nature of the tubercle bacillus, with one third of the world's population is estimated to be infected, combined with the emergence of multi drug-resistant strains and the exquisite susceptibility of HIV-positive individuals, has underscored the urgent need for in-depth study of the biology of Mycobacterium tuberculosis address the resurgence of TB. In aiming to understand the mechanisms by which mycobacteria react to their immediate environments, molecular genetic tools have been developed from naturally occurring genetic elements. These include protein expressing genes, and episomal and integrating elements, which have been derived mainly from prokaryotic but also from eukaryotic organisms. Molecular genetic tools that had been established as routine procedures in other prokaryotic genera were thus mimicked. Knowledge of the underlying mechanisms greatly expedited the harnessing of these elements for mycobacteriological research and has brought us to a point where these molecular genetic tools are now employed routinely in laboratories worldwide.

Cutaneous tuberculosis in Indian children: the importance of screening for involvement of internal organs.

AIMS AND OBJECTIVES: Resurgence of skin tuberculosis especially with drug-resistant strains has been well documented in recent years, but this problem has not received much attention in the paediatric age group. Hence, we carried out the present study to analyse the clinical and therapeutic aspects of cutaneous tuberculosis in children. MATERIALS AND METHODS: A detailed clinical examination, investigations, such as haemogram, serology for HIV, Mantoux test, chest X-ray, cytology, culture and histopathology were carried out in all children. They were treated with antitubercular therapy (WHO regimen), and the clinical response was followed up. RESULTS: Of 142 patients with cutaneous tuberculosis, 68 were children (40 females, 28 males). These children were aged from 9 months to 14 years. The duration of the disease varied from 1 month to 6 years. Family history of tuberculosis was present in 28 (41.2%) of the patients. Scrofuloderma was the most common presentation encountered in 30 (44.1%) patients with preferential involvement of the cervical (56.2%) and inguinal (20%) regions. Fifteen (22.1%) patients had lupus vulgaris, of which the keratotic type was the most common (46.7%), 16 had lichen scrofulosorum, three had tuberculosis verrucosa cutis, and four had more than one type of tuberculosis. Involvement of the lung in 14 (20.6%), bone in seven (10.2%), and both in four (5.9%) was found. Histopathology corroborated the clinical diagnosis in 54 (80.6%), culture was positive in six (8.8%). Fifty (73.5%) patients completed the treatment with an excellent response, no multidrug resistant cases were seen. CONCLUSIONS: Cutaneous tuberculosis in children continues to be an important cause of morbidity, there is a high likelihood of internal involvement, especially in patients with scrofuloderma. A search is required for more sensitive, economic diagnostic tools. Response to treatment at 4 weeks often helps in substantiating the diagnosis of tuberculosis in doubtful cases.

Papel da tuberculose domiciliar no surgimento da tuberculose multirresistente / The role of household contact in the appearance of multidrug-resistant tuberculosis

INTRODUÇAO: A tuberculose multirresistente é uma preocupação em todo o mundo. A identificação de fatores de risco associados pode contribuir para o seu controle. OBJETIVO: Avaliar se o contato com tuberculose domiciliar é fator de risco para tuberculose multirresistente. MÉTODO: Estudo caso-controle de base populacional de modo retrospectivo. Foi considerado multirresistente o bacilo resistente a pelo menos rifampicina+isoniazida, e tuberculose sensível o caso no qual houvesse sido feito o primeiro tratamento num período semelhante ao primeiro tratamento do caso com tuberculose multirresistente, mas que estivesse curado no momento da entrevista. Os casos foram selecionados através dos testes de sensibilidade realizados no Laboratório Central do Estado do Ceará de 1990 a 1999, pelo método das proporções. Os controles foram selecionados entre os bacilíferos do livro de registro do Programa de Controle da Tuberculose, em período semelhante. Foi pesquisada a história de tuberculose na família. Os casos de Tuberculose na família foram divididos em 03 subgrupos: tuberculose curada, tuberculose abandonada e tuberculose multirresistente. RESULTADOS: 266 casos de tuberculose multirresistente foram diagnosticados. Identificamos 153 pacientes, dos quais, 19 foram excluídos. O grupo de casos e controle foi de 134 e 185 pacientes, respectivamente. Através do teste exato de Fisher não foi encontrada associação entre tuberculose multirresistente e contato com tuberculose na família (p=0,1190). Estudando os subgrupos, encontramos que o contato com pacientes curados de tuberculose estava associado com tuberculose sensível (p<0,0001), enquanto que o abandono do tratamento da tuberculose na família e a tuberculose multirresistente na família estavam associados com a tuberculose multirresistente, p<0,0160 e p<0,0300 respectivamente. CONCLUSAO: A existência na família de casos de tuberculose multirresistente e de casos de tuberculose com abandono de tratamento é fator de risco para tuberculose multirresistente e, portanto, constitui problema de saúde pública.

Fatores associados aos tratamentos inadequados em grupo de portadores de tuberculose multirresistente / Factors associated with inadequate treatment in a group of patients with multidrug-resistant tuberculosis

INTRODUÇAO: A tuberculose multirresistente é uma ameaça ao controle da tuberculose em todo o mundo. Tratamento inadequado é freqüentemente apontado como fator de risco para tuberculose multirresistente. OBJETIVO: Identificar fatores associados ao tratamento inadequado em portadores de tuberculose multirresistente. MÉTODO: Foram levantados e identificados os testes de sensibilidade para tuberculose, realizados no Laboratório Central do Estado do Ceará de 1990 a 1999. Foi realizado um estudo retrospectivo e prospectivo, em grupo de portadores de tuberculose multirresistente, comparando as características dos pacientes com tratamento adequado com as dos com tratamentos inadequados. Foi considerado multirresistente o bacilo resistente a pelo menos rifampicina + isoniazida e utilizado o método das proporções. RESULTADOS: Dos 1.500 testes de sensibilidade realizados, 266 eram multirresistentes. Destes, identificaram-se apenas 153 pacientes, dos quais 19 foram excluídos, restando, no estudo, 134 pacientes. Pela análise univariada os fatores associados significativamente ao tratamento inadequado foram: não-adesão ao tratamento, pobreza extrema, intolerância medicamentosa, falha no atendimento, falta de medicação, dois ou mais tratamentos anteriores, lesões radiológicas bilaterais e grandes cavidades pulmonares. Foi encontrada ainda associação (p < 0,001) de alcoolismo e/ou tabagismo com a não-adesão. Na análise multivariada, permaneceram associados ao tratamento inadequado: dois ou mais tratamentos anteriores (p < 0,0001, OR = 5,9; IC 95 por cento: 2,5-13,7), grandes cavidades pulmonares (p < 0,0217, OR = 2,7; IC 95 por cento: 1,2-6,1) e lesões radiológicas bilaterais (p < 0,0226, OR = 3,2; IC 95 por cento: 1,4-7,4). CONCLUSAO: Neste estudo, observou-se que os fatores associados aos tratamentos inadequados são de grande abrangência. Deve existir uma tentativa para controlar melhor a doença, principalmente nos pacientes em retratamento e nos portadores de grandes cavidades e/ou lesões bilaterais na radiografia torácica.

Risk factors for acquired multidrug-resistant tuberculosis

Multidrug-resistant tuberculosis (MDR-TB) is a severe and feared problem, that is difficult to control and has shown a tendency to increase worldwide. OBJECTIVE: To analyze the risk factors for acquired MDR-TB. CASUISTIC AND METHODS: A retrospective population-based case-control study was conducted. A bacillus was considered multidrug-resistant whenever it was resistant at least to rifampin (RFP) + isoniazid (INH), and a case was considered as sensitive tuberculosis (TB) if it had undergone the first treatment during a similar period as the first treatment of an MDR-TB case, but was cured at the time of the interview. Case selection was made based on the list of Sensitivity Tests (ST) performed at the Central Public Health Laboratory of the State of Ceará, from 1990 through 1999. The Proportion Method was used to investigate resistance to the six antituberculosis drugs (isoniazid, rifampin, pyrazinamide, ethambutol, ethionamide, streptomycin) used as the standard treatment in Brazil. Controls were selected from the registry of the TB Control Program. Univariate and multivariate analysis were performed, with p < 0.05 considered significant. RESULTS: Out of the 1,500 STs performed during the studied period, 266 strains were multidrug-resistant; 153 patients were identified, 19 of which were excluded. The Group of Cases comprised 134 patients, and the Group of Controls comprised 185. Multivariate analysis helped to detect the following risk factors: lack of home sewer system, alcoholism + smoking, number of previous treatments, irregular treatment, and lung cavities. CONCLUSION: These five factors are important for the development of acquired MDR-TB, and an attempt to neutralize them might contribute to control TB.

Clinical and programmatic mismanagement rather than community outbreak as the cause of chronic, drug-resistant tuberculosis in Buenaventura, Colombia, 1998.

SETTING: Buenaventura, Colombia. OBJECTIVE: To assess whether antituberculosis drug resistance was generated by poor management or community transmission. DESIGN: Treatment-failure and new tuberculosis (TB) patients identified between May 1997 and June 1998 were interviewed and their treatment histories reviewed. Bacteriologic testing, including drug susceptibility profiles (DSP) and DNA fingerprinting by restriction fragment length polymorphism (RFLP), was performed and human immunodeficiency virus (HIV) testing was offered. RESULTS: DSP and RFLP fingerprints were obtained for isolates from 34 of 64 treatment-failure patients; 25 (74%) were resistant to > or = one drug. Fifteen of the 25 patients consented to HIV testing; none were positive. An average of 2.8 major treatment errors per patient was identified. RFLP from the treatment-failure patients revealed 20 unique isolates and six clusters (isolates with identical RFLP); 4/6 clusters contained isolates with different DSP. Analysis of the RFLP from both treatment-failure and new patients revealed that 44/111 (40%) isolates formed 18 clusters. Four of 47 (9%) new patients had multidrug-resistant TB (MDR-TB). Eleven isolates belonged to the Beijing family, related to the MDR strain W. CONCLUSION: Drug resistance in Buenaventura results from both poor management and community transmission. Dependence on DSP to identify TB transmission is inadequate when programmatic mismanagement is common.

Infection control. A long time coming.

This article presents the case of a doctor who developed multidrug-resistant tuberculosis in his right lung. Development of the disease was attributed to treatment errors and resulted in surgical intervention to effect a cure. The isolation and management of this patient spanned a total of 12 months. Infection control interventions to minimise the effects of sensory deprivation, given the length of stay of the patient, appear to have been satisfactory, with no treatment for any clinical depression required. The availability of negative pressure ventilation and the then controversial use of masks prevented any nosocomial transmission of MDR TB. Use of masks resulted in a two-tier system of infection control. It was difficult to make such a decision in the absence of any published UK guidelines. Guidelines have subsequently been published.