Drug-resistant Tuberculosis Cases Research Articles

Atspari vaistams vaikų tuberkuliozė

Tuberkuliozė tebėra didžiulė žmonijos problema. Netinkamai gydant ligonius, skiriant per trumpą gydymo kursą, per mažas dozes, nutraukiant gydymą, tuberkuliozės mikobakterijos tampa atsparios vaistams nuo tuberkuliozės. Straipsnyje aptariama mikobakterijų atsparumo priežastys bei profilaktikos galimybės, vaikų atsparios vaistams tuberkuliozės diagnostikos kriterijai, gydymo rekomendacijos. Kauno 2-oje klinikinėje ligoninėje vaikų sergančių atsparia vaistams tuberkulioze padaugėjo nuo 1 iki 5 atvejų per pastaruosius metus. Aprašome du klinikinius vaikų tuberkuliozės atvejus, kai vaistams atsparia tuberkulioze sergantys suaugusieji apkrėtė vaikus. Ar gali tik DOTS metodikos taikymas išspręsti šią problemą? Mūsų nuomone, reikalingas priverstinis gydymas suaugusiems ligoniams, kurie nesigydo ir užkrečia aplinkinius.

Epidemiological features of drug resistant tuberculosis in Harare, 1994 to 1996.

To characterise the prevalence, clinical and radiological features of drug resistant tuberculosis in selected patients with pulmonary tuberculosis in Harare between 1994 and 1996. A retrospective review of medical and microbiological records. Beatrice Road Infectious Diseases Hospital, Harare, Zimbabwe. 381 smear-positive tuberculosis patients who had samples submitted to the National Tuberculosis Reference Laboratory for culture and susceptibility testing. Prevalence of resistance of isolated cultures of Mycobacterium tuberculosis to anti-tuberculosis drugs; clinical, radiological and microbiological response to treatment with recommended anti-tuberculosis regimens. Resistance to one or more drugs was detected in 16 isolates (16/165, 9.7%), single drug resistance in five (3.0%) and resistance to two or more drugs in 11 (6.7%). There were no distinctive clinical or radiological features of drug-resistant tuberculosis, although a higher percent of drug resistant cases had evidence of pleural disease (25% vs 2.5%, p = 0.005). Neither past history of tuberculosis or known or suspected HIV infection was associated with the presence of drug resistance. In spite of the resurgence of tuberculosis and the high prevalence of HIV infection in Zimbabwe, the rates of drug resistance have remained relatively low, even among a selected population at high risk of resistance. A significant proportion of cases of drug-resistant tuberculosis appear to be due to new transmission of drug resistant strains, which reinforces the importance of maintaining a surveillance system for the monitoring of drug susceptibility. Ongoing prospective studies should provide more reliable estimates of the prevalence and determinants of drug resistance in Zimbabwe.

Drug-Resistant TB

The World Health Organization (WHO) has launched an initiative to prevent hundreds of thousands of cases of drug-resistant tuberculosis (TB) and save as many as 134 000 lives by 2008 (http://www.who.int/tb/publications/2007/global_response_plan.pdf).

Mechanism of thioamide drug action against tuberculosis and leprosy.

Thioamide drugs, ethionamide (ETH) and prothionamide (PTH), are clinically effective in the treatment of Mycobacterium tuberculosis, M. leprae, and M. avium complex infections. Although generally considered second-line drugs for tuberculosis, their use has increased considerably as the number of multidrug resistant and extensively drug resistant tuberculosis cases continues to rise. Despite the widespread use of thioamide drugs to treat tuberculosis and leprosy, their precise mechanisms of action remain unknown. Using a cell-based activation method, we now have definitive evidence that both thioamides form covalent adducts with nicotinamide adenine dinucleotide (NAD) and that these adducts are tight-binding inhibitors of M. tuberculosis and M. leprae InhA. The crystal structures of the inhibited M. leprae and M. tuberculosis InhA complexes provide the molecular details of target–drug interactions. The purified ETH-NAD and PTH-NAD adducts both showed nanomolar Kis against M. tuberculosis and M. leprae InhA. Knowledge of the precise structures and mechanisms of action of these drugs provides insights into designing new drugs that can overcome drug resistance.

Mutations Prevalent among Rifampin- and Isoniazid-Resistant Mycobacterium tuberculosis Isolates from a Hospital in Vietnam

Vietnam is ranked 13th among the WHO list of 22 high-burden countries, based upon estimated total number of tuberculosis cases. Despite having a model national tuberculosis program, consistently achieving and exceeding WHO targets for detection and cure, drug-resistant and multidrug-resistant tuberculosis cases continue to rise. Rapid multidrug-resistant tests applicable in this setting, coupled with effective treatment regimens, would be a useful tool in reversing this trend, allowing early identification of patients with multidrug-resistant tuberculosis and avoiding resistance-amplifying regimens. Sequencing of consecutive isolates identified by the National Tuberculosis Program showed 89% of isoniazid-resistant isolates could be detected by targeting just 2 codons, katG 315 and -15C-->T in the inhA promoter, while rifampin resistance will be more complex to detect, with many different mutation and insertion events in rpoB. The most prevalent rifampin resistance-conferring mutations, as in other countries, were in rpoB codons 531 (43%), 526 (31%), and 516 (15%). However, a hybridization-based resistance test with probes targeting the 5 most common mutations would only detect 78% of rifampin-resistant isolates. Overall, these data suggest that rifampin resistance may be used as a surrogate marker for multidrug-resistant tuberculosis and that a sensitivity of between 70 to 80% may be possible for rapid molecular detection of multidrug-resistant tuberculosis in this setting.

Drug-resistant tuberculosis: A disease of target populations in Houston, Texas

To analyse the traditional and molecular epidemiology of drug-resistant tuberculosis (DRTB) in Houston and Harris County, Texas in the setting of decreasing disease incidence. Case-control study of 193 patients with DRTB and 1977 patients with drug-susceptible TB (DSTB) identified from a population-based surveillance, 1995-2001. In a multivariate logistic regression, the following risk factors were found to be predictors of having DRTB (P< or =0.05): human immunodeficiency virus (HIV) seropositivity, Hispanic ethnicity, Asian ethnicity, history of past TB; whereas being foreign born, having a history of past TB, and younger age were predictors of MDRTB. There were 15 patients who acquired drug resistance while on therapy, and they were significantly more likely than controls to be HIV-seropositive, be of Asian ethnicity, have smear-positive pulmonary disease and present with pleural effusion on chest radiograph. No difference in 6-month mortality between DRTB and DSTB cases was found. During the study period, the incidence of DRTB remained constant. In Houston, there is a steady, low-level, incidence of DRTB which disproportionately affects specific subpopulations, with no evidence of increased mortality at 6 months.

Risk factors for drug resistant tuberculosis in Leicestershire--poor adherence to treatment remains an important cause of resistance.

In the light of rising numbers of tuberculosis (TB) cases in the United Kingdom, the problem of anti-tubercular drug resistance remains a significant concern. Drug resistant TB cases are more difficult and costly to treat, and require appropriate treatment and control mechanisms. This matched case control study aimed to investigate risk factors for resistance in Leicestershire, using data for laboratory isolates of Mycobacterium tuberculosis identified from 1993 to 1998. Each case, defined as culture positive laboratory isolates resistant to at least one first-line drug, was matched to four fully sensitive controls on age, sex and ethnic group. Twenty-three cases and 81 controls were included in the analysis. Drug resistance in Leicestershire was found to be associated with poor adherence to treatment (OR 4.8, 95% CI 1.6-14.4, P=0.005) and with previous TB (OR 3.7, 95% CI 1.2-11.8, P=0.022). These findings emphasize the need to provide support to patients taking treatment in order to maximize adherence.

Antibiotic resistant tuberculosis in the United Kingdom: 1993–1999

Background: The re-emergence of tuberculosis as a global health problem over the past two decades, accompanied by an increase in tuberculosis drug resistance, prompted the development of a comprehensive national...

Issues in the treatment of Mycobacterium tuberculosis in patients with human immunodeficiency virus infection.

The HIV/AIDS pandemic has led to a rise in the incidence of tuberculosis and an epidemic of co-infection in many developing countries. Treatment of Mycobacterium tuberculosis in persons with HIV infection presents several challenges to the clinician particularly in resource-poor countries. As will be discussed in this paper diagnosis of latent tuberculosis relies on tuberculin skin testing which has poor sensitivity and reproducibility in immunocompromised patients. The World Health Organization (WHO) recommends treatment of active tuberculosis as the primary means of global tuberculosis control. In practice treatment of active tuberculosis typically requires that a symptomatic patient self-report to a health service for evaluation and management. Even if this approach to tuberculosis control were sufficient many logistic and clinical problems remain involving tuberculosis diagnosis and therapy in the patient with HIV/AIDS. Recognizing the significant clinical and public health challenges surrounding the treatment of tuberculosis in patients with HIV infection this paper will address a number of issues relevant to the care of co-infected patients. These include current guidelines for the treatment of active tuberculosis as well as the diagnosis and treatment of latent tuberculosis in HIV-positive patients. The paper concludes with a discussion of promising new drugs for tuberculosis treatment. (excerpt)

Classification of drug-resistant tuberculosis in an epidemic area

Traditionally, patients with drug-resistant tuberculosis are classified as having acquired drug-resistant or primary drug-resistant disease on the basis of a history of previous tuberculosis treatment. Only cases of primary drug resistance are assumed to be due to transmission of drug-resistant strains. This descriptive study of 63 patients with drug-resistant tuberculosis assessed the relative contribution of transmission of drug-resistant strains in a high-incidence community of Cape Town, South Africa, by restriction-fragment length polymorphism (RFLP). The RFLP results were compared with the results obtained by traditional classification methods. According to RFLP definitions, 52% (33 cases) of drug-resistant tuberculosis was caused by transmission of a drug-resistant strain. The proportion of cases due to transmission was higher for multidrug-resistant (64%; 29 cases) than for single-drug-resistant (no cases) tuberculosis. By the clinical classification, only 18 (29%) patients were classified as having primary drug-resistant tuberculosis (implying transmission). The clinical classification was thus misleading in 25 patients. The term acquired drug resistance includes patients infected with strains that truly acquired drug resistance during treatment and patients who were initially infected with or reinfected with a drug-resistant strain. This definition could lead to misinterpretation of surveillance studies, incorrect evaluation of tuberculosis programmes, and delayed diagnosis and treatment of patients with multidrug-resistant disease. The clinical term acquired drug resistance should be replaced with the term "drug resistance in previously treated cases", which includes cases with drug resistance due to true acquisition as well as that due to transmitted drug-resistant strains.

Evidence from molecular fingerprinting of limited spread of drug-resistant tuberculosis in Texas.

To determine the contribution of recent transmission to spread of drug-resistant tuberculosis in Texas, we performed IS6110-based and pTBN12-based restriction fragment length polymorphism (RFLP) analyses on Mycobacterium tuberculosis isolates. Isolates collected from 201 patients in Texas between 1992 and 1994 were studied. The distribution of cases was strikingly focal. All cases were reported from 35 of the 254 counties in Texas, and 74% (148 of 201) were reported from only 9 counties. One hundred sixty-one (80%) of the patients had M. tuberculosis isolates with unique RFLP patterns, and 41 (20%) patients were in 20 clusters, each comprising 2 to 3 patients. The largest number of cases of drug-resistant tuberculosis were reported in counties bordering Mexico, but the percentage of clustered cases was highest in northeast Texas and in counties that included the cities of Dallas, Fort Worth, and Houston. Compared to nonclustered patients, clustered patients were more likely to be African American and to have been born in the United States. Clustered patients were significantly more likely to be from the same geographic area, and clustered patients from the same geographic area were more likely to have isolates with identical drug susceptibility patterns, suggesting that they were linked by recent transmission. In 11 of 20 clusters, clustered patients were from geographically separate regions, and most isolates did not have identical drug susceptibility patterns, suggesting that tuberculosis was contracted from a common source in the remote past. Based on the low percentage of clustered cases and the small cluster size, we conclude that there is no evidence for the extensive transmission of drug-resistant tuberculosis in Texas.

Drug resistant tuberculosis in sub-Saharan Africa: An estimation of incidence and cost for the year 2000

Setting: Rwanda Objectives: To evaluate the tuberculosis (TB) drug resistance in Rwanda on smear positive sputa, collected prospectively at the start of the National TB programme, before the start of any treatment or retreatment. To adapt the scenarios of Schulzer et al (1992) to the data from Rwanda, in order to obtain an estimation of the number of drug resistant and multi-drug resistant (MDR) TB cases expected by the year 2000. Design: A total of 298 specimens (236 randomly selected new cases and 62 retreated cases), collected between January 1991 and June 1993, were sent to Belgium in 1% cetylpyridinium chloride. Drug resistance was determined using the proportion method. Results: MDR, i.e. resistance to at least rifampicin (R) and isoniazid (H), was observed in 3 (1.3%) out of 236 new cases and in 4 (6.5%) out of 62 retreated cases. For new cases, single drug resistance to H, R and ethambutol (E) was 3%, 0.4% and 4.2% respectively; for retreated cases it was 14.5%, 1.6% and 6.5% respectively. Based on the estimate of the size of the TB problem in sub-Saharan Africa by the year 2000 (Schulzer), we calculated that the region should expect between 15 543 and 223 417 cases of MDR, all forms combined (between 2.3 and 32.7 per 100 000 inhabitants), by the end of the century. Conclusion: The results from Rwanda during the period studied do not appear dramatic. However, for some other developing countries, they may just represent the tip of the iceberg. Rapid recognition of resistance to the major antituberculosis agents is essential for control of TB. Integration of an MDR increase factor into the TB budget would not dramatically increase the total TB budget. Our data urgently point to the need for drug resistance surveys, followed by continuous drug resistance monitoring in high TB prevalence areas.

Escalating threat from tuberculosis: the third epidemic.

A 1994 study reported on cases of drug-resistant tuberculosis (TB) at the Chest Service at Bellevue Hospital, in New York City. 20 years of TB laboratory susceptibility tests were reviewed in 4681 cases. Combined resistance to isoniazid and rifampicin rose from 2.5% in 1971 to 16% in 1991. Over 75% of these cases in 1991 were resistant to rifampicin, isoniazid, streptomycin, and ethambutol. Most of the patients belonged to one or more of the following groups: young, Black or Hispanic, unemployed, homeless, male, HIV-infected, and drug abuser. Clinical characteristics were: anergy, fever, cough, night sweats, weight loss, radiograph bilateral infiltrates, adenopathy, cavities, miliary shadowing, and normal chest radiograph. Overall, in 1993 in the US, 3% of all new cases and 6.9% of recurrent cases were resistant to both rifampicin and isoniazid. This resurgence of TB in industrialized countries has been ascribed to: 1) immigration of foreign populations at high risk of developing TB, 2) coinfection with HIV, and 3) an increase in high risk groups. The WHO stresses the importance of identifying meaningful denominators when discussing both primary and acquired drug resistance rates. Restriction fragment length polymorphism (RFLP) is the molecular technique that differentiates individual strains of Mycobacterium tuberculosis. Three recent studies from New York used RFLP to demonstrate the clustering of multidrug-resistant TB. Solutions to the problem consist of adequate infrastructure, i.e., a national TB program; prescription of combined preparations; inducement or enforcement of compliance using directly observed therapy (DOT) (a DOT protocol employed in Denver, Colorado, used 2 weeks of therapy followed by 24 weeks of twice weekly intermittent therapy); prevention of nosocomial spread by isolation of smear-positive cases during the first 2 weeks of treatment; rapid diagnosis of TB and drug susceptibility (within 10-21 days using radiometric culture, nucleic acid probes, and high performance liquid chromatography of mycolic acids); and treatment by five or six drugs.

Appearance of drug-resistant tuberculosis in rural Tennessee.

Drug-resistant tuberculosis (DRTB) is a growing national health concern in both urban populations and rural areas and is exacerbated by the growing epidemic of human immunodeficiency virus (HIV) infection. Between 1989 and 1992, 7 cases of DRTB (5 with multidrug-resistance) were diagnosed in an eight-county region of East Tennessee. During 1990 and 1991 alone, 5 of 100 patients with tuberculosis had drug-resistant strains (5%). All 7 patients with DRTB had 100% resistance to isoniazid; 5 also had resistance to streptomycin, 2 to rifampin, and 1 to pyrazinamide and ethambutol. All patients were white, U.S.-born, and without evidence of HIV infection. Contact investigation revealed that more contacts of patients with DRTB (13 of 74, 18%) were infected than were contacts of patients with drug-sensitive tuberculosis (46 of 290, 16%). Our study demonstrates that DRTB is not confined to geographically distinct areas, but may be a subtle and easily missed diagnosis in presumably low-risk rural populations.

Mycobacterial diseases and the compromised host.

Tuberculosis due to Mycobacterium tuberculosis and other mycobacteria should be considered in the diagnostic approach to febrile immunocompromised patients. In patients with AIDS, organisms of the Mycobacterium avium complex (MAC) are the most common bacterial causes of disseminated infection. Effective means of both treating and preventing disseminated MAC infections have been developed that use regimens including the new macrolides, aminoglycosides, and rifamycins. Antimicrobial agents active against M. tuberculosis are not usually active against MAC organisms, and the converse may also be true. With the advent of more cases of drug-resistant tuberculosis, however, the urgency regarding development of new therapeutic approaches for tuberculosis is widely appreciated. Research into the pathogenesis and treatment of infections due to M. tuberculosis and MAC, which has been much neglected, is likely to provide new knowledge that will benefit the clinical approach to all mycobacterial diseases.

Initial Therapy for Tuberculosis in the Era of Multidrug Resistance: Recommendations of the Advisory Council for the Elimination of Tuberculosis

These recommendations update previous CDC/American Thoracic Society (ATS) recommendations for the treatment of tuberculosis (TB) among adults and children. The most notable changes are in response to the increasing prevalence of drug-resistant TB in the United States. These recommendations include the need for a) in vitro drug susceptibility testing of Mycobacterium tuberculosis isolates from all patients and reporting of these results to the health department, b) initial four-drug regiments for the treatment of TB, and c) initial directly observed therapy for persons with TB. Adherence to these recommendations will help prevent the occurrence of more cases of drug-resistant TB, reduce the occurrence of treatment failure, and reduce the transmission of TB in the United States.

From the Centers for Disease Control and Prevention. Initial therapy for tuberculosis in the era of multidrug resistance: recommendations of the Advisory Council for the Elimination of Tuberculosis

These recommendations update previous CDC/American Thoracic Society (ATS) recommendations for the treatment of tuberculosis (TB) among adults and children. The most notable changes are in response to the increasing prevalence of drug-resistant TB in the United States. These recommendations include the need for a) in vitro drug susceptibility testing of Mycobacterium tuberculosis isolates from all patients and reporting of these results to the health department, b) initial four-drug regimens for the treatment of TB, and c) initial directly observed therapy for persons with TB. Adherence to these recommendations will help prevent the occurrence of more cases of drug-resistant TB, reduce the occurrence of treatment failure, and reduce the transmission of TB in the United States.

The Epidemiologic Patterns of Drug-resistantMycobacterium tuberculosisInfections: A Community-based Study

A community-based study of tuberculosis in Santa Clara County, California was conducted in order to identify community-specific determinants of drug-resistant Mycobacterium tuberculosis infections. From January 1984 through December 1986, 517 verified cases of tuberculosis were reported from the county. Drug susceptibility test results to isoniazid, streptomycin, ethambutol, and rifampin were available for 256 of the 517 cases. The frequency of resistance of M. tuberculosis isolates to one or more drugs was 27% for all cases and 25% for those who had had no previous antituberculosis treatment. Isolates from Asian immigrants had the highest frequencies of resistance (33 to 45%), and the Southeast Asian immigrants had a drug-resistant tuberculosis case rate greater than 30/100,000 population per year. In patients who had cavitary lung disease and who had a previous history of tuberculosis, drug-resistant tuberculosis was 3.5 times as likely to occur than in persons who had neither of these characteristics (p less than 0.001). For such patients, the positive predictive value of isolating resistant M. tuberculosis approached 90%. We believe these community-based findings will guide clinical and public health interventions specifically appropriate for the community.

Primary drug-resistant tuberculosis in Vietnam veterans.

Five cases of primary drug-resistant pulmonary tuberculosis acquired in Vietnam are presented. The exposure of large numbers of American military personnel to areas of the world with high incidence...

The Rehabilitation of Chronic, Drug Resistant Cases of Tuberculosis with Cycloserine, and Successful Treatment of Virgin Cases

1.Data are presented on 397 cases of tuberculosis treated with cycloserine (CS) alone, or in combination with INH. The original purpose of combining CS and INH was to obtain a CS dose which would enhance the antituberculosis effects of INH, while keeping the toxicity at a minimum. 2.Our data show that the therapeutic efficacy of CS, alone or combined with INH, depends upon the attainment and maintenance of CS plasma levels above 20 mcg./ml. 3.The toxicity of CS has been reduced, a)by the concomitant administration of pyridoxine hydrochloride, which also protects against INH in combination therapy; b)by spreading the daily dose as widely as possible, and c)by insuring that the plasma levels of CS are kept well below 50 mcg./ml. Under this regimen, very few cases had to be discontinued because of toxicity. 4.Cycloserine alone in doses which maintain the plasma level at about 30 mcg./ml. has been shown to induce prompt clinical and roentgenographic improvement, a gain in weight, and rapid reversal of infectiousness, in a large proportion of both resistant and virgin cases of tuberculosis. 5.Bacillary resistance to CS developed but rarely, and in our experience has never been complete, even after continuous administration over several years.