Elizabeth Clara Barroso

Fatores de risco para tuberculose multirresistente adquirida

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 Ceara, 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.

Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis

Low antimycobacterial drug concentrations have been observed in tuberculosis (TB) patients under treatment. The lactulose/mannitol urinary excretion test (L/M), normally used to measure intestinal permeability, may be useful to assess drug absorption. The objective of this research was to study intestinal absorptive function and bioavailability of rifampin and isoniazid in TB patients. A cross sectional study was done with 41 patients and 28 healthy controls, using the L/M test. The bioavailabilities of rifampin (R) and isoniazid (H) were evaluated in 18 patients receiving full doses. Urinary excretion of mannitol and lactulose, measured by HPLC, was significantly lower in TB patients. The serum concentrations of the drugs were below the expected range for R (8-24 mcg/mL) or H (3-6 mcg/mL) in 16/18 patients. Analyzing the drugs individually, 12/18 patients had low serum concentrations of R, 13/18 for H and 8/18 for both drugs. We suggest that there is a decrease in the functional absorptive area of the intestine in TB patients, which would explain the reduced serum concentrations of antituberculosis drugs. There is a need for new approaches to improve drug bioavailability in TB patients.

Prevalência da tuberculose multirresistente no Estado do Ceará, 1990-1999

Multidrug-resistant tuberculosis (MDR-TB) is a worldwide concern but its magnitude in the state of Ceara - Northeastern Brazil has been so far unknown. Objectives: To determine the prevalence of MDR-TB among us as well as the sesceptibility of Mycobacterium tuberculosis> to antituberculosis drugs. Methods: A retrospective study was conducted using 1,500 susceptibility tests (ST) for rifampin (RFM), isoniazid (INH), streptomycin (SM), pyrazinamide (PYZ), ethambutol (ETM) and ethionamide (ETH) that were performed at the Central Laboratory of the State of Ceara (LACEN) between 1990 and 1999. The proportion method test was used. Results: Of the 1,500 stains studied, 404 (27%) were resistant to at least one drug, including both primary and acquired resistance. MDR-TB, defined as resistance to at least rifampin and isoniazid was observed in 266 (17.7%) patients. During the study period, there were 41,073 TB cases and MDR-TB prevalence was 0.65% in our state. Among the patients studied, 62.3% were men and mean age was 40.17 ± 14.62. Overall prevalence for single-drug resistance was 8.1% (INH = 5.7%; SM = 1.5%; and RFP = 0.9%). Resistance to 2, 3, 4, 5 and 6 drugs was, respectively, 10.8%; 3.1%; 0.9%; 1.5%; and 2.9%. HIV testing was performed in all inpatients and some outpatients (total of 86 patients) and revealed that they were all HIV negative. The probability of 5-year survival (138 patients assessed) was greater in the MDR-TB group treated with alternative drugs, including the patients of the failure group. Conclusion: The MDR-TB prevalence rate found in this study is intermediate in comparison with those reported in Brazil and the other parts of the world. Preventive approaches, early diagnosis and the development of effective, safe and relatively inexpensive new drugs should be stimulated.

Fatores associados aos tratamentos inadequados em grupo de portadores de tuberculose multirresistente

BACKGROUND: Multidrug resistant tuberculosis is a threat to tuberculosis control worldwide. In many studies, it has been suggested that inadequate treatment is a risk factor for the development of multidrug resistent tuberculosis. OBJECTIVE: To identify the factors associated with inadequate treatment in a group of patients with multidrug resistent tuberculosis. METHOD: The authors identified all drug sensitivity test for tuberculosis performed at the Central Laboratory of the state of Ceara from 1990 to 1999. Retrospective and prospective analysis was performed, comparing the characteristics of adequately treated patients with those of inadequately treated patients. Multidrug resistance was defined as resistance to 2 drugs (rifampin and isoniazid) or more, using the Cox proportional hazards model. RESULTS: Of the 1,500 sensitivity test performed at the Central Laboratory of Public Health of the state of Ceara, 266 revealed multidrug-resistant strains. Of those 266 patients, the authors were able to identify only 153, of whom 19 were excluded. Thus, our sampling consisted of 134 patients. Univariate analysis demonstrated that the significant factors associated with inadequate treatment were: noncompliance with the treatment, extreme poverty, drug intolerance, mistakes in the management of the patients, lack of medication being supplied by the health service, two or more previous treatments, pronounced lung cavities and bilateral lesions on chest X-rays. They found a further association (p < 0.0010) between alcoholism or smoking and noncompliance with the treatment. In the multivariate analysis, the factors associated with an outcome of inadequate treatment were: two or more previous treatments (p < 0.0001, OR = 5.9; CI 95%: 2.5-13.7), pronounced cavitation (p < 0.0217, OR = 2.7; CI 95%: 1.2-6.1) and bilateral chest X-ray lesions (p < 0.0226, OR = 3.2; CI 95%: 1.4-7.4) CONCLUSION: In the study, the authors observed that factors related to inadequate treatment are wide-ranging. An attempt at better control of the disease is warranted, especially in those patients with pronounced cavitation or bilateral lesions in chest X-rays. And those with 2 or more previous treatments.

Mycobacterium fragae sp. nov., a non-chromogenic species isolated from human respiratory specimens

Three isolates of a slow-growing, non-chromogenic mycobacterium were grown from three sputum samples of a patient from the north-eastern Ceará state in Brazil. Identification at species level could not be obtained with PCR restriction analysis of the hsp65 gene. In order to characterize the isolates we carried out phenotypic and genotypic tests. We sequenced the nearly complete 16S rRNA gene and obtained partial sequences of the hsp65 (encoding the hypervariable region of the 65 kDa heat-shock protein) and rpoB (encoding the beta-subunit of RNA polymerase) genes. The three isolates turned out to be identical and most closely related to the species Mycobacterium celatum and Mycobacterium kyorinense. The results, however, showed significant differences between these species and the isolates studied, which led us to consider them members of a novel species for which we propose the name Mycobacterium fragae. The type strain is HF8705(T) ( = Fiocruz-INCQS/CMRVS P4051(T) = DSM 45731(T)).

Ocorrência de tuberculose doença entre contatos de tuberculose sensível e multirresistente

INTRODUCAO: Desde os primeiros anos da quimioterapia anti-tuberculose, existe polemica a respeito da transmissibilidade, infectividade, virulencia e patogenicidade de bacilos sensiveis e resistentes a quimioterapia. OBJETIVO: Determinar a ocorrencia de casos de tuberculose doenca entre contatos intra-domiciliares de tuberculose multirresistente e tuberculose sensivel. METODO: Foi realizado um estudo caso-controle, sendo considerado tuberculose multirresistente o caso de portador de bacilo resistente a pelo menos rifampicina e isoniazida, e tuberculose sensivel o caso que tivesse feito o primeiro tratamento num periodo semelhante ao primeiro tratamento do caso de tuberculose multirresistente, estando o paciente curado no momento da entrevista. Contato foi definido como o residente no domicilio do caso indice. Os casos foram selecionados a partir dos resultados dos testes de sensibilidade obtidos pelo metodo das proporcoes no Laboratorio Central do Estado do Ceara, e os controles constituidos por pacientes baciliferos registrados no Programa de Controle da Tuberculose, entre 1.990 e 1.999. RESULTADOS: Foram avaliados 126 portadores de tuberculose multirresistente e 176 de tuberculose sensivel. O numero de contatos foi de 557 no grupo dos casos, 752 no grupo controle e a media de contatos por caso indice foi de 4,42 e 4,27 respectivamente. Entre os casos, 4,49% dos contatos (25/557) fizeram tratamento para tuberculose apos os casos indices. Esse percentual foi de 5,45% (41/752) entre os controles (p = 0,4468). Ocorreu micro-epidemia de tuberculose multirresistente confirmada por teste de sensibilidade em oito familias. CONCLUSAO: Os resultados deste estudo sugerem que a ocorrencia de tratamentos de tuberculose gerados entre contatos intra-domiciliares de tuberculose sensivel e tuberculose multirresistente e semelhante.

Genotyping and drug resistance patterns of Mycobacterium tuberculosis strains observed in a tuberculosis high-burden municipality in Northeast, Brazil

OBJECTIVES This study has used a combination of clinical information, spoligotyping, and georeferencing system to elucidate the genetic diversity of the Mycobacterium tuberculosis isolates circulating in a TB-prevalent municipality of Northeast Brazil. METHODS A total of 115 M. tuberculosis strains were isolated from pulmonary tuberculosis patients from January 2007 to March 2008 in Fortaleza. Drug susceptibility and spoligotyping assays were performed and place of residence of the patients were georeferenced. RESULTS Of the M. tuberculosis strains studied, 51 (44.3%) isolates were resistant to at least one drug (R-TB) and 64 (55.7%) were sensitive to all the drugs tested (S-TB). A high frequency of resistance was found in previously treated cases (84%) and among new cases (16%; p<0.001). A total of 74 (64%) isolates were grouped into 22 spoligotyped lineages, while 41 (36%) isolates were identified as new. Among the predominant genotypes, 33% were Latim American Mediterranean (LAM), 12% Haarlem (H), and 5% U. There was no association of geographic distribution of RT-TB patients as compared to the controls and also the geographic location to the spoligotype patterns. The geospatial analysis revealed that 24 (23%) patients (hot spot zones) either shared the same residence or lived in a close neighborhood of a case. Among these concentration zones, the patients lived in the same residence and shared a common genotype pattern and resistance pattern. DISCUSSION It was observed that the spoligopatterns family distribution was similar to that reported for South America, prevailing the LAM and H lineages. A high rate-case among the resistant TB group occurs as a result of transmitted and acquired resistance. A more effective surveillance program is needed in order to succeed in reducing tuberculosis in Northeast Brazil.

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide in patients with pulmonary tuberculosis

Intestinal barrier function and serum concentrations of rifampin, isoniazid and pyrazinamide were studied in healthy controls and patients with active pulmonary tuberculosis. A case-control study of 29 controls and 30 cases attending at the Health Center, July, 2004 to December, 2005 was conducted. The body mass index was significantly reduced in cases compared to controls (p < 0.001). The intestinal paracellular transport of lactulose was significantly (p = 0.019) reduced in cases compared to controls. The transcellular transport of mannitol and the lactulose:mannitol ratio were not significantly (p = 0.0698) reduced in cases compared to controls. Low serum concentrations of rifampin, isoniazid and pyrazinamide were observed in 81% (48/59), 92% (54/59) and 28% (12/59), respectively, in all individuals. The results demonstrated a marked decrease on intestinal paracellular transport in patients with active pulmonary tuberculosis and reduced serum concentrations of rifampin and isoniazid in both groups.

Papel da tuberculose domiciliar no surgimento da tuberculose multirresistente

BACKGROUND: Multidrug-Resistant tuberculosis (MDR-TB) is a matter of worldwide concern. Identify associated risk factors may contribute to its control. OBJECTIVES: To assess if household tuberculosis (TB) cases would is a risk factor for MDR-TB. METHOD: A population-based case-control study was conducted in a retrospective way. Multidrug resistance was defined as resistance to at least Rifampin (RFM) and Isoniazid (INH), and susceptible TB (the case when first treatment had been made in a period similar to the first treatment of the MDR-TB cases, but disease free at the time of the interview). Selection of cases was made based upon the list of Susceptibility Tests (ST) carried out at the Central Laboratory of Public Health of the State of Ceara, from, 1990 to 1999. The proportion method was used. Controls were selected from among the records of the TB Control Program. The history of TB in the family was investigated. These cases were divided into three groups: cured TB, non adherence TB and MDR-TB. RESULTS: During the study period, 266 cases of MSR TB were diagnosed. We identified only 153 patients. Of these, 19 were excluded. The group of cases was comprised of 134 patients and that of controls by 185. Fisher exact test disclosed no association between MDR-TB and household contacts with TB cases (p=0.119). Studying the subgroups we found that contact with cured TB patients was associated with susceptible TB (p<0.0001) whereas household non-adherence TB and in the family MDR-TB were associated with MDR-TB, p<0.016 and p<0.03 respectively. CONCLUSION: In the family cases of MDR-TB and cases of nonadherence to treatment are risk factors for MDR-TB and therefore represent a public health problem.