Implementation contexts of a Tuberculosis Control Program in Brazilian prisons

OBJECTIVE To analyze the influence from context characteristics in the control of tuberculosis in prisons, and the influence from the program implementation degrees in observed effects.METHODS A multiple case study, with a qualitative approach, conducted in the prison systems of two Brazilian states in 2011 and 2012. Two prisons were analyzed in each state, and a prison hospital was analyzed in one of them. The data were submitted to a content analysis, which was based on external, political-organizational, implementation, and effect dimensions. Contextual factors and the ones in the program organization were correlated. The independent variable was the program implementation degree and the dependent one, the effects from the Tuberculosis Control Program in prisons.RESULTS The context with the highest sociodemographic vulnerability, the highest incidence rate of tuberculosis, and the smallest amount of available resources were associated with the low implementation degree of the program. The results from tuberculosis treatment in the prison system were better where the program had already been partially implemented than in the case with low implementation degree in both cases.CONCLUSIONS The implementation degree and its contexts – external and political-organizational dimensions – simultaneously contribute to the effects that are observed in the control of tuberculosis in analyzed prisons.

Spatial analysis of avoidable hospitalizations due to tuberculosis in Ribeirao Preto, SP, Brazil (2006-2012)

ABSTRACT OBJECTIVE To describe the spatial distribution of avoidable hospitalizations due to tuberculosis in the municipality of Ribeirao Preto, SP, Brazil, and to identify spatial and space-time clusters for the risk of occurrence of these events. METHODS This is a descriptive, ecological study that considered the hospitalizations records of the Hospital Information System of residents of Ribeirao Preto, SP, Southeastern Brazil, from 2006 to 2012. Only the cases with recorded addresses were considered for the spatial analyses, and they were also geocoded. We resorted to Kernel density estimation to identify the densest areas, local empirical Bayes rate as the method for smoothing the incidence rates of hospital admissions, and scan statistic for identifying clusters of risk. Softwares ArcGis 10.2, TerraView 4.2.2, and SaTScanTM were used in the analysis. RESULTS We identified 169 hospitalizations due to tuberculosis. Most were of men (n = 134; 79.2%), averagely aged 48 years (SD = 16.2). The predominant clinical form was the pulmonary one, which was confirmed through a microscopic examination of expectorated sputum (n = 66; 39.0%). We geocoded 159 cases (94.0%). We observed a non-random spatial distribution of avoidable hospitalizations due to tuberculosis concentrated in the northern and western regions of the municipality. Through the scan statistic, three spatial clusters for risk of hospitalizations due to tuberculosis were identified, one of them in the northern region of the municipality (relative risk [RR] = 3.4; 95%CI 2.7–4,4); the second in the central region, where there is a prison unit (RR = 28.6; 95%CI 22.4–36.6); and the last one in the southern region, and area of protection for hospitalizations (RR = 0.2; 95%CI 0.2–0.3). We did not identify any space-time clusters. CONCLUSIONS The investigation showed priority areas for the control and surveillance of tuberculosis, as well as the profile of the affected population, which shows important aspects to be considered in terms of management and organization of health care services targeting effectiveness in primary health care.

Acute renal failure after rifampicin

A patient with miliary tuberculosis and a chronic urogenital focus is described, who had a borderline renal function at diagnosis and developed overt renal failure upon daily treatment with rifampin (RMP), isoniazid (INH) and ethambutol (EMB). This is the first Brazilian report of BMP induced renal damage. A renal biopsy taken on the third day of oliguria showed recent tubular necrosis with acute interstitial inflammation and granuloma formation. The aspect of the granulomatous lesion hightly suggested drug etiology because of the lack of palisading, high incidence of neutrophils and absence of facid-fast bacilli. This is the first presentation of an acute granulomatous interstitial nephritis probably due to RMP. Furthermore the pathogenesis of the renal damage caused by tuberculosis and RMP are discussed.

Radiometric studies of mycobacterium tuberculosis

An in vitro assay system that included automated radiometric quantification of 14CO2 released as a result of oxidation of 14C- substrates was applied for studying the metabolic activity of M. tuberculosis under various experimental conditions. These experiments included the study of a) mtabolic pathways, b) detection times for various inoculum sizes, c) effect of filtration on reproducibility of results, d) influence of stress environment e) minimal inhibitory concentrations for isoniazid, streptomycin, ethambutol and rifampin, and f) generation times of M. tuberculosis and M. bovis. These organisms were found to metabolize 14C-for-mate, (U-14C) acetate, (U-14C) glycerol, (1-14C) palmitic acid, 1-14C) lauric acid, (U-14C) L-malic acid, (U-14C) D-glucose, and (U-14C) D-glucose, but not (1-14C) L-glucose, (U-14C) glycine, or (U-14C) pyruvate to 14CO2. By using either 14C-for-mate, (1-14C) palmitic acid, or (1-14C) lauric acid, 10(7) organisms/vial could be detected within 24 48 hours and as few as 10 organisms/vial within 16-20 days. Reproducible results could be obtained without filtering the bacterial suspension, provided that the organisms were grown in liquid 7H9 medium with 0.05% polysorbate 80 and homogenized prior to the study. Drugs that block protein synthesis were found to have lower minimal inhibitory concentrations with the radiometric method when compared to the conventional agar dilution method. The mean generation time obtained for M. bovis and different strains of M. tuberculosis with various substrates was 9 ± 1 hours.

Tuberculosis in patients with chronic renal failure

Nine cases of tuberculosis (TB) were diagnosed among 800 uremic patients, followed-up during 11 years, a prevalence of 1125%, 2.5 times higher than that in the general population. Six patients (66.7%) had lymph node involvement (4 cervical and 2 mediastinal). Three patients (33.3%) had pulmonary involvement (2 pleuro-pulmonary and 1 bilateral apical pulmonary). Eight patients were undergoing dialysis and 1 was pre-dialytic. The duration of dialysis ranged from 1 to 60 months. Three patients had previously received immunosuppressive drugs for unsuccessful renal transplantation. Daily fever was present in all but one patient; he was asymptomatic and TB was suspected after routine chest radiography. Biopsy was the diagnostic procedure in 7 patients (77.8%), four by direct cervical lymph node biopsy, 2 by mediastinal, performed by mediastinoscopy and 1 by pleural biopsy. In 2 other patients TB was confirmed by the presence of tubercle bacilli; in sputum (1 patient) and in a bronchial flushing specimen (the other patient). Triple therapy was used in all patients (isoniazid and ethambutol in all), plus rifampicin in 8 and streptomycin in 1. One patient had jaundice and another had optical neuritis. Five patients were cured. The other four died during treatment of causes unrelated to TB or its treatment.

Tuberculosis in renal transplant patients

Tuberculosis (TB) was diagnosed in 25 of 466 patients who underwent renal transplant over a period of 15 years. TB developed from 1 month to 9 years post-transplant. In 56% of the cases the onset was within the first post-transplant year. TB affected several isolated or combined organs. Pulmonary involvement was present in 76% of cases, either as isolated pleuro-pulmonary (56%) or associated with other sites (20%). The non-pulmonary sites were: skin, joints, tests, urinary tract, central nervous system and lymphonodules. The diagnosis was confirmed by biopsy in 64% of the cases, by identification of tubercle bacilli in 24% and only at necropsy in 12% Biopsy specimens could be classified in three histological forms: exudative, that occurred in early onset and more severe cases granulomatous in late onset and benign cases; and mixed in intermediate cases. Azathioprine dosages were similar along post-transplant time periods in TB patients and in the control groups; and in TB patients who were cured and who died. The number of steroid treated rejection crises was greater in TB than in the control group. Prednisone doses were higher and the number of rejection crises was greater in TB patients who died than in those who were cured. Fifteen patients were cured and ten died, two of them of causes unrelated to TB. Six of the eight TB-related deaths occurred in the first 6 post-transplant months. The outcome was poor in patients in whom TB arose early in post-transplant period and where the exudative or mixed forms were present; whereas the prognosis was good in patients with late onset and granulomatous form of TB. In one patient TB was transmitted by the allograft.

Approaches to tuberculosis mucosal vaccine development using nanoparticles and microparticles: a review

Next-generation vaccines for tuberculosis should be designed to prevent the infection and to achieve sterile eradication of Mycobacterium tuberculosis. Mucosal vaccination is a needle-free vaccine strategy that provides protective immunity against pathogenic bacteria and viruses in both mucosal and systemic compartments, being a promising alternative to current tuberculosis vaccines. Micro and nanoparticles have shown great potential as delivery systems for mucosal vaccines. In this review, the immunological principles underlying mucosal vaccine development will be discussed, and the application of mucosal adjuvants and delivery systems to the enhancement of protective immune responses at mucosal surfaces will be reviewed, in particular those envisioned for oral and nasal routes of administration. An overview of the essential vaccine candidates for tuberculosis in clinical trials will be provided, with special emphasis on the potential different antigens and immunization regimens.

The role of the efflux mechanisms in multidrug resistance in Mycobacterium tuberculosis

Abstract The emergence of multi and extensively drug resistant tuberculosis (MDRTB and XDRTB) has increased the concern of public health authorities around the world. The World Health Organization has defined MDRTB as tuberculosis (TB) caused by organisms resistant to at least isoniazid and rifampicin, the main first-line drugs used in TB therapy, whereas XDRTB refers to TB resistant not only to isoniazid and rifampicin, but also to a fluoroquinolone and to at least one of the three injectable second-line drugs, kanamycin, amikacin and capreomycin. Resistance in Mycobacterium tuberculosis is mainly due to the occurrence of spontaneous mutations and followed by selection of mutants by subsequent treatment. However, some resistant clinical isolates do not present mutations in any genes associated with resistance to a given antibiotic, which suggests that other mechanism(s) are involved in the development of drug resistance, namely the presence of efflux pump systems that extrude the drug to the exterior of the cell, preventing access to its target. Increased efflux activity can occur in response to prolonged exposure to subinhibitory concentrations of anti-TB drugs, a situation that may result from inadequate TB therapy. The inhibition of efflux activity with a non-antibiotic inhibitor may restore activity of an antibiotic subject to efflux and thus provide a way to enhance the activity of current anti-TB drugs. The work described in this thesis foccus on the study of efflux mechanisms in the development of multidrug resistance in M. tuberculosis and how phenotypic resistance, mediated by efflux pumps, correlates with genetic resistance. In order to accomplish this goal, several experimental protocols were developed using biological models such as Escherichia coli, the fast growing mycobacteria Mycobacterium smegmatis, and Mycobacterium avium, before their application to M. tuberculosis. This approach allowed the study of the mechanisms that result in the physiological adaptation of E. coli to subinhibitory concentrations of tetracycline (Chapter II), the development of a fluorometric method that allows the detection and quantification of efflux of ethidium bromide (Chapter III), the characterization of the ethidium bromide transport in M. smegmatis (Chapter IV) and the contribution of efflux activity to macrolide resistance in Mycobacterium avium complex (Chapter V). Finally, the methods developed allowed the study of the role of efflux pumps in M. tuberculosis strains induced to isoniazid resistance (Chapter VI). By this manner, in Chapter II it was possible to observe that the physiological adaptation of E. coli to tetracycline results from an interplay between events at the genetic level and protein folding that decrease permeability of the cell envelope and increase efflux pump activity. Furthermore, Chapter III describes the development of a semi-automated fluorometric method that allowed the correlation of this efflux activity with the transport kinetics of ethidium bromide (a known efflux pump substrate) in E. coli and the identification of efflux inhibitors. Concerning M. smegmatis, we have compared the wild-type M. smegmatis mc2155 with knockout mutants for LfrA and MspA for their ability to transport ethidium bromide. The results presented in Chapter IV showed that MspA, the major porin in M. smegmatis, plays an important role in the entrance of ethidium bromide and antibiotics into the cell and that efflux via the LfrA pump is involved in low-level resistance to these compounds in M. smegmatis. Chapter V describes the study of the contribution of efflux pumps to macrolide resistance in clinical M. avium complex isolates. It was demonstrated that resistance to clarithromycin was significantly reduced in the presence of efflux inhibitors such as thioridazine, chlorpromazine and verapamil. These same inhibitors decreased efflux of ethidium bromide and increased the retention of [14C]-erythromycin in these isolates. Finaly, the methods developed with the experimental models mentioned above allowed the study of the role of efflux pumps on M. tuberculosis strains induced to isoniazid resistance. This is described in Chapter VI of this Thesis, where it is demonstrated that induced resistance to isoniazid does not involve mutations in any of the genes known to be associated with isoniazid resistance, but an efflux system that is sensitive to efflux inhibitors. These inhibitors decreased the efflux of ethidium bromide and also reduced the minimum inhibitory concentration of isoniazid in these strains. Moreover, expression analysis showed overexpression of genes that code for efflux pumps in the induced strains relatively to the non-induced parental strains. In conclusion, the work described in this thesis demonstrates that efflux pumps play an important role in the development of drug resistance, namely in mycobacteria. A strategy to overcome efflux-mediated resistance may consist on the use of compounds that inhibit efflux activity, restoring the activity of antimicrobials that are efflux pump substrates, a useful approach particularly in TB where the most effective treatment regimens are becoming uneffective due to the increase of MDRTB/XDRTB.

Drug resistance of M. Tuberculosis isolated from patients with HIV infection seen at an AIDS Reference Center in São Paulo, Brazil

M. tuberculosis-positive cultures were obtained from 228 patients seen in our service and drug sensitivity assays were carried out from January 1992 to December 1994. A survey of the medical records of these patients showed resistance to one or more drugs in 47 (20.6%), 25 of whom (10.9%), who reported previous treatment, were considered to have acquired resistance. Among the antecedents investigated, only previous treatment and alcoholism were the factors independently associated with the occurrence of resistance. The survival of patients with resistant strains was lower than that of patients attacked by non-resistant M. tuberculosis. We conclude that in the present series M. tuberculosis resistance to tuberculostatic agents was predominantly of the acquired type.

Au-nanossondas aplicação na detecção de Mycobacterium tuberculosis e plasmodium berghei

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para a obtenção do grau de Mestre em Biotecnologia

A case report of vascular catheter-associated bacteremia caused by Mycobacterium tuberculosis in a non-immunosuppressed patient

Mycobacterium tuberculosis was isolated from a central venous catheter in a non-immunosuppressed patient with systemic tuberculosis. This case report represents a very uncommon form of isolation of Mycobacterium tuberculosis. A total improvement was obtained after treatment.

The use of cyclosporine modifies the clinical and histopathological presentation of tuberculosis after renal transplantation

Tuberculosis is one of the most frequent opportunistic infections after renal transplantation and occurred in 30 of 1264 patients transplanted between 1976 and 1996 at Hospital São Paulo - UNIFESP and Hospital Dom Silvério, Brazil. The incidence of 2.4% is five times higher than the Brazilian general population. The disease occurred between 50 days to 18 years after the transplant, and had an earlier and worse development in patients receiving azathioprine, prednisone and cyclosporine, with 35% presenting as a disseminated disease, while all patients receiving azathioprine and prednisone had exclusively pulmonary disease. Ninety percent of those patients had fever as the major initial clinical manifestation. Diagnosis was made by biopsy of the lesion (50%), positivity to M. tuberculosis in the sputum (30%) and spinal cerebral fluid analysis (7%). Duration of treatment ranged from 6 to 13 months and hepatotoxicity occurred in 3 patients. The patients who died had a significant greater number of rejection episodes and received higher doses of corticosteroid. In conclusion, the administration of cyclosporine changed the clinical and histopathological pattern of tuberculosis occurring after renal transplantation.

A retrospective evaluation of a score system adopted by the Ministry of Health, Brazil in the diagnosis of pulmonary tuberculosis in childhood: a case control study

Based on a retrospective case-control study we evaluated the score system adopted by the Ministry of Health of Brazil (Ministério da Saúde - MS), to diagnose pulmonary tuberculosis (PTB) in childhood. This system is independent of bacteriological or histopathological data to define a very likely (> or = 40 points), possible (30-35 points) or unlikely (< or = 25 points) diagnosis of tuberculosis. Records of hospitalized non-infected HIV children at the Instituto de Puericultura e Pediatria Martagão Gesteira of Federal University of Rio de Janeiro (IPPMG-UFRJ), were reviewed. Patients were adjusted for age and divided in two different groups: 45 subjects in the case group (culture-positive) [mean of age = 10.64 mo; SD 9.66]; and 96 in the control group (culture-negative and clinic criteria that dismissed the disease) [mean of age = 11.79 mo.; SD 11.31]. Among the variables analyzed, the radiological status had the greater impact into the diagnosis (OR = 25.39), followed by exposure to adult with tuberculosis (OR = 10.67), tuberculin skin test >10mm (OR = 8.23). The best cut-off point to the diagnosis of PTB was 30 points, where the score system was more accurate, with sensitivity of 88.9% and specificity of 86.5%.