Will tuberculosis become resistant to all antibiotics?

The discovery of high prevalences of antibiotic resistance in some pathogens, in some parts of the world, has provoked fears of a widespread loss of drug efficacy. Here, we use a mathematical model to investigate the evolution of resistance to four major anti-tuberculosis drugs (isoniazid, rifampicin, ethambutol and streptomycin) in 47 sites around the world. The model provides a new method of estimating the relative risk of treatment failure for patients carrying drug-resistant strains and the proportion of patients who develop resistance after failing treatment. Using estimates of these two quantities together with other published data, we reconstructed the epidemic spread of isoniazid resistance over the past 50 years. The predicted median prevalence of resistance among new cases today was 7.0% (range 0.9-64.3%), close to the 6.3% (range 0-28.1%) observed. Predicted and observed prevalences of resistance to isoniazid plus rifampicin (multidrug-resistant or MDR-TB) after 30 years of combined drug use were also similar, 0.9% (0.1-5.9%) and 1.0% (range 0-14.1%), respectively. With current data, and under prevailing treatment practices, it appears that MDR-TB will remain a localized problem, rather than becoming a global obstacle to tuberculosis control. To substantiate this result, further measurements are needed of the relative fitness of drug-resistant strains.

The burden of drug-resistant tuberculosis and mechanisms for its control.

Drug resistance in tuberculosis is largely a man-made phenomenon caused by erroneous prescribing practices on the part of physicians and noncompliance on the part of patients. The global epidemiology of drug-resistant TB, the impact of standardized short-course chemotherapy (SSC), and the potential future evolution of MDR TB are discussed in this chapter.

Drug-resistant tuberculosis in the Dominican Republic: results of a nationwide survey.

SETTING: The Dominican Republic. OBJECTIVE: To assess the extent of drug-resistant tuberculosis (TB) following the guidelines of the World Health Organization (WHO)/International Union Against Tuberculosis and Lung Disease (IUATLD) new global surveillance project on drug resistance in TB. METHODS: Using a multi-step proportional weighted approach, a sample of 688 sequential cases of smear positive pulmonary TB diagnosed between April 1994 and April 1995 was studied in six of the country's eight health regions. Pre-treatment sputum samples were cultured on Loewenstein-Jensen medium and drug susceptibility tests were performed using the economic variant of the proportion method. RESULTS: Of 420 cases with drug susceptibility results, resistance to one or more drugs was observed in 43.8%; resistance was found in 52.1% of 117 TB cases with a history of previous antituberculosis treatment and in 40.6% of 303 new TB cases. In five of the six health regions surveyed, > or = 41% of strains were resistant to one or more drugs. Multidrug resistance (MDR) to isoniazid and rifampicin with or without resistance to other drugs was found in 43 (10.2%) of 420 cases, including 6.6% of new TB cases. In five of the six health regions > or = 8% of strains were classified as MDR. Independent predictors of MDR-TB included being in the age group 25 to 44 years (odds ratio [OR] = 4.2, 95% confidence interval [Cl] 1.5, 11.6; P = 0.005), being aged 45 years and over (OR = 4.5, 95% CI 1.4, 14.4; P = 0.009), and having a prior history of TB (OR = 3.7, 95% CI 1.9, 7.4; P = 0.0001). CONCLUSION: The proportion of Mycobacterium tuberculosis strains resistant to one or more anti-TB drugs in the Dominican Republic is among the highest observed world-wide. The severity of the problem urgently requires the full implementation of TB control strategies endorsed by the WHO and the IUATID, which include political commitment to a National TB Program, case detection utilizing sputum-smear microscopy, directly observed treatment, regular drug supply, and standardised recording and reporting systems. Also, the sale of TB drugs in the private market should be controlled.

Adverse events in the treatment of multidrug-resistant tuberculosis: results from the DOTS-Plus initiative.

Adverse events associated with second-line drugs have been mentioned as obstacles in the management of multidrug-resistant tuberculosis (MDR-TB). Data on adverse events were collected from five DOTS-Plus sites in Estonia, Latvia, Peru (Lima), the Philippines (Manila) and the Russian Federation (Tomsk Oblast). The results show that among 818 patients enrolled on MDR-TB treatment only 2% of patients stopped treatment, but 30% required removal of the suspected drug(s) from the regimen due to adverse events. The study shows that adverse events are manageable in the treatment of MDR-TB in resource-limited settings provided that standard management strategies are applied.

Childhood tuberculosis: clinical research needs.

Childhood tuberculosis (TB) is common in the developing world, where over 90% of global TB cases occur, and has increased in human immunodeficiency virus (HIV) endemic regions. Most children with TB are not infectious, and so, from a public health perspective, are not afforded the same priority by TB control programmes as older age groups in settings of limited resources. In addition, the diagnosis of pulmonary TB is particularly difficult in young children. This has resulted in TB being a neglected disease in children, although it causes substantial morbidity and mortality. This review summarises the current knowledge of clinical aspects of childhood TB management, and aims to identify priority areas for future research. The most critical need is for improved capability to confirm diagnosis. This would lead to better management of childhood TB and would greatly enhance our ability to conduct meaningful research in many related areas, including immunological studies which could lead to a more effective vaccine. Also important are a better understanding of risk factors for infection and disease, including the impact of HIV, and operational research to improve treatment outcomes and management of well childhood contacts.

Determinants of drug-resistant tuberculosis: analysis of 11 countries.

SETTING: Eleven countries/territories. OBJECTIVES: Global information on the determinants of drug-resistant tuberculosis (TB) based on representative data is not available. We therefore studied the relationship between demographic characteristics, prior TB treatment, and human immunodeficiency virus (HIV) infection with anti-tuberculosis drug resistance. METHODS: Population-based representative data on new and previously treated patients with TB collected within an international drug resistance surveillance network. RESULTS: Of 9,615 patients, 8,222 (85.5%) were new cases of TB and 1,393 (14.5%) were previously treated cases. Compared with new cases, previously treated cases were significantly more likely to have resistance to one (OR = 2.5,95% CI 2.1-3.0; P < 0.001), two (OR = 4.6, 95%CI 3.7-5.6; P < 0.001), three (OR = 11.5, 95%CI 8.6-15.3; P < 0.001), and four (OR = 18.5, 95% CI 12.0-28.5; P < 0.001) drugs. An approximately linear increase in the likelihood of having multidrug-resistant tuberculosis (MDR-TB) was observed as the total time (measured in months) of prior anti-tuberculosis treatment increased (P < 0.001, chi2 for trend). In multivariate analysis, prior TB treatment for 6-11 months (OR = 7.6, 95% CI 2.6, 22.4; P < 0.001) and > or = 12 months (OR 13.7, 95% CI 4.5-41.6; P < 0.001), but not HIV positivity, was associated with MDR-TB. CONCLUSION: This study shows that prior but ineffective treatment is a strong predictor of drug resistance, and that HIV is not an independent risk factor for MDR-TB. The association between length of treatment and drug resistance may reflect longer treatment as a result of treatment failure in patients with drug resistance; it may also reflect irregular prior treatment for TB, leading to drug resistance.

Towards optimization of surveillance resistance to antituberculosis drug resistance.

In the past decade, strengthening tuberculosis (TB) surveillance has become a public health priority in Europe. In western Europe, TB case rates slowed their previous decline, but in eastern Europe dramatic increases, often with doubling of rates, were re

Effect of pregnancy on the risk of developing active tuberculosis.

In a case-control study, the effect of recent pregnancy on the risk of developing active tuberculosis among women of reproductive age was investigated in Santo Domingo. Human immunodeficiency virus (HIV)-positive and HIV-negative women diagnosed with new-onset tuberculosis (TB) were compared, respectively, with HIV-positive and HIV-negative women without TB with regard to reproductive history, demographic characteristics, and risk factors for HIV infection. In neither HIV-positive nor HIV-negative women was recent pregnancy or childbirth associated with an increased risk of developing active TB. These results fail to confirm earlier suggestions that pregnancy increases the risk that a woman of child-bearing age infected with Mycobacterium tuberculosis will develop active TB.

Screening for active tuberculosis in HIV testing centre.

In industrialised nations HIV-seropositive individuals can be offered skin testing for tuberculosis (TB) and isoniazid prophylaxis, but this approach is neither practicable nor affordable in most developing countries. In Santo Domingo, Dominican Republic, we offered skin testing and a brief clinical examination for active TB to people requesting HIV testing at one centre. 200 newly detected HIV-positive individuals and 200 age and sex-matched HIV-negative ones were compared. 39 (9.7%) of the 400 individuals seeking HIV testing had active TB; 29 were HIV positive and 10 were HIV negative (adjusted odds ratio 3.3, 95% CI 1.3-8.7; p = 0.01). In multivariate analysis, the strongest independent predictors of active TB were 10 mm or more of induration on skin testing, a history of chronic cough, lymphadenopathy, and HIV infection. Of the patients diagnosed with TB, 85% had one or more symptoms readily ascertainable in a brief screening questionnaire. Screening for TB at HIV-testing sites could be an effective approach to early detection of active TB among not just HIV-positive but also HIV-negative people. Integrating screening for TB into HIV testing schemes could help to reduce the spread of TB and allow patients with TB to be diagnosed and treated earlier.

PIP: A relation between tuberculosis (TB) and HIV infection is well established. 20-60% of AIDS patients in developing countries have been found to have or to develop TB. The combined effects of HIV and TB epidemics on the health systems of developing countries is frightening. To check the growing numbers of HIV-associated TB cases, the US Centers for Disease Control and Prevention and the World Health Organization recommended TB skin testing of HIV-positive people. Those found to be dually infected would be offered prophylactic isoniazid. Most developing countries, however, cannot afford such preventive therapy. The authors investigated whether screening for TB infection and disease at HIV-testing sites is an useful approach to TB control in developing countries. The authors offered skin testing and a brief clinical exam for active TB to people requesting HIV testing at one center in Santo Domingo, Dominican Republic. 200 newly detected HIV-positive individuals were subsequently compared against 200 age and sex-matched HIV-negative individuals. 9.7% of the people seeking HIV testing had active TB; 29 were HIV-positive and 10 HIV-negative. Multivariate analysis found the strongest independent predictors of active TB to be 10 mm or more of induration on skin testing, an history of chronic cough, lymphadenopathy, and HIV infection. Of the patients diagnosed with TB, 85% had one or more symptoms readily ascertainable in a brief screening questionnaire. These findings lead the authors to conclude that screening for TB at HIV-testing sites could be an effective approach to early detection of active TB among both HIV-seropositive and HIV-seronegative people. Integrating screening for TB into HIV testing schemes could help reduce the spread of TB and allow patients with TB to be diagnosed and treated earlier.

A hospital-based survey of BCG coverage in Santo Domingo, the Dominican Republic.

A cross-sectional study was conducted in April-June 1992 at the outpatient clinic of the Robert Reid Children's Hospital in Santo Domingo to assess BCG vaccination coverage and factors affecting BCG vaccination of children. A consecutive sample of 2,000 patients under 18 years of age was included in the study. The person accompanying the patient to the hospital was interviewed, using a standardized questionnaire, and both of the patient's arms were examined for the presence of a BCG scar. Overall, 67.7% of the participants were found to have the scar and 68.3% were said to have received a BCG vaccination. However, only 80.8% of those with the scar were said to have been vaccinated. Multivariate logistic regression analysis found that residence in Santo Domingo, the subject's age, and the education of the subject's legal guardian were all significant predictors of the scar's presence, but that the strongest predictor was a history of immunization (OR = 6.29, 95% CI = 5.01, 7.89). Despite various limitations of this study, the results support other data indicating that the BCG vaccination program in the Dominican Republic needs to be strengthened. While the situation may be no worse than that found in a number of other Latin American countries, it appears that many Dominican children are not benefiting from the preventive effect of BCG vaccination and are therefore running an unnecessarily high risk of contracting tuberculosis.

Human immunodeficiency virus infection in children with tuberculosis in Santo Domingo, Dominican Republic: prevalence, clinical findings, and response to antituberculosis treatment.

We studied human immunodeficiency virus (HIV)-seroprevalence among children with clinically diagnosed tuberculosis (TB) and compared the clinical features and response to short-term anti-TB therapy of children with and without HIV infection in Santo Domingo, Dominican Republic. Children aged 18-59 months with new-onset, clinically diagnosed TB were tested for HIV antibodies, their clinical features were recorded and their response to a standard 6-month regimen of daily isoniazid and rifampicin with daily streptomycin and pyrazinamide for the first 2 months was assessed. To increase the number of HIV-infected children with TB available for study, we also included children previously known to be HIV infected who developed new-onset TB. Eleven (5.8%) of 189 consecutively enrolled children with clinically diagnosed TB were HIV infected. Fifteen other children with previously documented HIV infection and new-onset TB were available for study, yielding 26 HIV-positive and 178 HIV-negative children with TB. Of these 204 children with clinically diagnosed TB, 25 HIV-positive and 156 HIV-negative children were successfully followed for 6 months or until death. The proportion of HIV-positive children who failed treatment was 6 (29%) of 21 as compared with only 5 (3%) of 156 HIV-negative children [relative risk = 8.9; 95% confidence interval (CI) 2.9, 26.6; p = 0.0004]. HIV-infected children with clinically diagnosed TB are substantially more likely to fail standard treatment for TB than are HIV-uninfected children. If standard treatment regimens are used in such children, response to treatment must be monitored very closely and appropriate changes in the regimen must be made expeditiously.

Transesophageal echocardiographic assessment of papillary muscle rupture.

BACKGROUND: In some patients with papillary muscle rupture, the ruptured head may not prolapse into the left atrium, which makes diagnosis by transthoracic or transesophageal echocardiography difficult. METHODS AND RESULTS: In an attempt to find additional or more definite diagnostic echocardiographic features, we analyzed intraoperative transesophageal echocardiograms of 21 consecutive patients with papillary muscle rupture (20 involved the left ventricle and 1 involved the right ventricle) confirmed at surgery. In 7 (35%) of 20 patients with left ventricular papillary muscle rupture, the ruptured head was not seen to prolapse into the left atrium. In these patients, examination of the left ventricle proved most useful. Abnormal, large-amplitude erratic motion (1 to 5 cm in 17 patients; 0.5 cm in 1 patient) of a large echo density in the left ventricle consistent with the ruptured head was noted in 18 (90%) of these 20 patients. This included all 7 patients with non-prolapse of the ruptured papillary muscle head into the left atrium. Less prominent erratic motion or flutter of the papillary muscle still attached to the left ventricular wall was also noted but was less sensitive in the diagnosis of papillary muscle rupture. The single patient with right ventricular papillary muscle rupture showed erratic motion as well as prolapse of the ruptured head into the right atrium. CONCLUSIONS: Transesophageal echocardiographic examination of the left ventricle is useful in the diagnosis of papillary muscle rupture, especially in those patients in whom the ruptured head does not prolapse into the left atrium. The left ventricle should be scrutinized thoroughly during transesophageal echocardiographic examination for erratic papillary muscle motion in all patients with suspected rupture.

Infectiousness of Mycobacterium tuberculosis in HIV-1-infected patients with tuberculosis: a prospective study.

BACKGROUND: Previous studies concerning the relative infectiousness of HIV-1-positive individuals with pulmonary tuberculosis have produced conflicting results. Thus, we assessed the effect of HIV-1 on the infectiousness of Mycobacterium tuberculosis in a prospective study. METHODS: We organised in Santo Domingo, Dominican Republic, a cohort study of household contacts of HIV-1-positive and HIV-1-negative individuals with newly diagnosed pulmonary tuberculosis. Household contacts were assessed at their houses at baseline and followed up for 14 months for evidence of M tuberculosis infection and tuberculosis with a multi-step tuberculin skin test, anergy skin test, physical examinations, chest radiographs, and sputum smears. FINDINGS: Tuberculin induration of 5 mm or greater was seen in 153 (61%) of 252 household contacts of HIV-1-positive index cases and in 418 (76%) of 551 household contacts of HIV-1-negative index cases (odds ratio 0.49 [95% CI 0.35-0.67], p=0.00001). In multivariate logistic-regression analysis after allowance for between-household variation in tuberculin response, HIV-1 infection of the index case remained inversely associated with the tuberculin response of the household contacts (0.52 [0.29-0.93], p=0.02). When the analysis was restricted to household contacts aged between 2 years and 15 years the adjusted association remained significant (0.37 [0.14-0.98], p=0.04). Among household contacts who had a negative tuberculin skin test at baseline, conversion to tuberculin skin test positivity was less frequent among household contacts of HIV-1-positive index cases (cut-off > or =5 mm: 32/131 [24%] vs 71/204 [35%], p=0.05; cut-off > or =10 mm: 23/153 [15%] vs 55/245 [22%], p=0.07). INTERPRETATION: These data suggest that HIV-1-positive individuals with tuberculosis are less likely than HIV-1-negative individuals with tuberculosis to transmit M tuberculosis to their close contacts. No changes in the current policy regarding tuberculosis contact tracing are needed in the presence of HIV-1.

The dynamics of tuberculosis in response to 10 years of intensive control effort in Peru.

Improved tuberculosis (TB) case detection and cure rates are expected to accelerate the decline in incidence of TB and to reduce TB-associated deaths. Time series analyses of case reports in Peru showed that the per capita TB incidence rate was probably steady before 1991. Case reports increased between 1990 and 1992 as a result of improved case detection. Although diagnostic efforts have continued to increase since 1993, the incidence of new pulmonary TB cases has declined in every department of the country, with a national rate of decline > or =5.8% per year (range, 1.9%-9.7%). This elevated rate of decline suggests that 27% (19%-34%) of cases (158,000) and 70% (63%-77%) of deaths (91,000) among smear-positive patients were averted between 1991 and 2000. This is the first demonstration that a significant number of TB cases can be prevented through intensive short-course chemotherapy in a high-burden country.