Outbreaks Of Multidrug-resistant Tuberculosis Research Articles

Genotypic assessment of isoniazid and rifampin resistance in Mycobacterium tuberculosis: a blind study at reference laboratory level.

Progress in understanding the basis of resistance to isoniazid (INH) and rifampin (RMP) has allowed molecular tests for the detection of drug-resistant tuberculosis to be developed. Consecutive isolates (n = 95) of Mycobacterium tuberculosis, from a Spanish reference laboratory investigating outbreaks of multidrug-resistant tuberculosis, were coded and sent to two external laboratories for genotypic analysis of INH and RMP resistance by PCR-single-strand conformation polymorphism (SSCP) analysis of specific regions of four genes: part of the coding sequence of katG and the promoter regions of inhA and ahpC for INH and the RMP resistance region of rpoB. After correction for the presence of outbreak strains and multiple isolates from single patients, RMP resistance was detected successfully by PCR-SSCP in > 96% of the RMP-resistant strains. PCR-SSCP had a sensitivity of 87% for INH resistance detection, and mutations in katG, inhA, katG-inhA, ahpC, and katG-ahpC were identified in 36.8, 31.6, 2.6, 13.2, and 2.6%, respectively, of the unique strains. Specificity was 100%. Molecular detection of resistance to the two main antituberculous drugs, INH and RMP, can be accomplished accurately by using a strategy which limits analysis to four genetic regions. This may allow the expedient analysis of drug resistance by reference laboratories.

Tuberculosis then and now: a personal perspective on the last 50 years.

Rates of death from tuberculosis in the United States decreased from 194 per 100,000 persons in 1900 to 40 per 100,000 persons in 1945, in part because the epidemic of tuberculosis in the western world was running its course and in part because of public health initiatives and improved socioeconomic conditions. In 1945, 63,000 persons died of tuberculosis and 115,000 new cases of the disease emerged. Streptomycin and para-aminosalicylic acid had just been discovered; the discovery of isoniazid followed, in 1952. Sanitarium care, nonsurgical and surgical collapse therapy, and resectional surgery were in widespread use. By the middle of the 1950s, it was evident that bedrest did not add to the benefit produced by effective chemotherapy, and sanitariums began to close, a process that was completed by the 1970s. As mortality and morbidity due to tuberculosis rapidly decreased, the U.S. government decreased funding for tuberculosis and many states and cities downgraded their tuberculosis control programs. After 1984, the rate of new cases of tuberculosis, which had decreased to 9.4 per 100,000, began to increase and focal outbreaks of multidrug-resistant tuberculosis were reported. Noncompliance with drug therapy, homelessness, immigration to the United States from developing countries, and human immunodeficiency virus (HIV) infection were invoked as explanations. With the reinstitution of federal funding, improved case-finding and surveillance, and the practice of having patients receive therapy while under direct observation, the rate of new cases of tuberculosis decreased to 8.7 per 100,000 in 1995, the lowest rate since national surveillance was begun in 1953. However, at the end of the 20th century, the worldwide burden of tuberculosis, which is engrafted onto the pandemic of HIV infection, is enormous: an estimated 7.6 million new cases in developing countries and 400,000 new cases in industrial nations.

Combined effect of pyrazinamide and ofloxacin within the human macrophage

Setting: Recent reports of outbreaks of multidrug resistant tuberculosis have raised questions as to the most appropriate therapeutic response for those exposed to such organisms. A recent Centers for Disease Control National Action Plan suggests the combination of pyrazinamide (PZA) and a quinolone as a potential preventive therapy regimen. Objective: Prior studies in the ex-vivo human macrophage model have shown PZA to have only a bacteriostatic effect and, in addition, to diminish the bactericidal effect of rifampin. This study was designed to quantify the intramacrophage antimycobacterial effect of PZA when combined with a quinolone (ofloxacin). Design: Forty μg/ml of PZA was combined with varying concentrations of ofloxacin and administered to human macrophages infected with virulent tubercle bacilli; drug sequencing was also studied. Results: A clinically achievable level of PZA enhances the antimycobacterial effect of low, non-bactericidal levels of ofloxacin and does not impede the bactericidal effect of a higher clinically effective level of ofloxacin. Unlike the combination of PZA and rifampin, these interactive effects are not affected by the sequence of drug administration. Conclusions: Findings support the use of these agents as a potentially effective preventive therapy combination for individuals exposed to multidrug resistant tuberculous organisms.

Multidrug-Resistant Tuberculosis Outbreak on an HIV Ward—Madrid, Spain, 1991–1995

Beginning in 1990, outbreaks of multidrug-resistant tuberculosis (MDR-TB) have been reported in hospitals and prisons in the eastern United States (1). During June 1991-January 1995, MDR-TB was diagnosed in 47 patients and one health-care worker at a 120-bed, infectious disease referral hospital in urban Madrid; on April 19, 1995, the Spanish Field Epidemiology Training Program was asked to investigate this outbreak. This report summarizes the findings of this investigation, which suggested that nosocomial transmission of MDR-TB occurred on a hospital ward for patients with human immunodeficiency virus (HIV) infection.

Infectious Diseases in an Age of Chance: The Impact of Human Ecology and Behavior on Disease Transmission

The decade of the 1990s has been marked by an unprecedented array of highly visible infectious diseases. These have included the appearance of cholera in Latin America for the first time this century, outbreaks of multidrug-resistant tuberculosis, upsurges of diphtheria in the former Soviet Union, the discovery of hantavirus-associated disease in the southwestern United States, plague in India, the reawakening of Ebola hemorrhagic fever in Africa, and now the possible link between bovine spongiform encephalopathy and a variant of human Creutzfeldt-Jakob disease in Great Britain. This seemingly endless string of episodes has served as a reminder that infectious diseases are far from vanquished, and that today this subject is in as great a state of dynamic flux as at any time in its history. Along with these episodes has come a veritable explosion of interest in the subject of emerging infectious diseases by scientists, the print and visual media, and the public, seeking to explain the underlying reasons for the phenomena in order to predict the future course of events.

Preventing Multidrug-Resistant Tuberculosis

In the 5 years since the first major outbreaks of multidrug-resistant tuberculosis (MDR TB) in the United States were reported, the epidemiology of MDR TB has become clearer.1,2Clinically, the course of illness can be devastating for both human immunodeficiency virus (HIV)—infected and noninfected persons, especially when diagnosis and adequate therapy are delayed.1,3However, prompt diagnosis and appropriate therapy can improve the likelihood of a successful outcome.4-6Directly observed therapy (DOT) has increasingly become the standard of care7and has been accompanied by dramatic reductions in morbidity and drug resistance, including MDR TB.8,9Evidence supports DOT as the adherence-promoting strategy of choice par excellence. Reflecting an improvement in control efforts is the increase in the proportion of patients completing therapy. In 1993,82% of patients in the United States completed therapy within 12 months, compared with 77% in 1992 (Centers for Disease Control and Prevention [CDC],

Tuberculosis control: the relevance of classic principles in an era of acquired immunodeficiency syndrome and multidrug resistance.

The estimated 64,000 excess cases of tuberculosis which occurred in the United States between 1985 and 1993 (1) are part of a global pandemic (2). Years before industrialized countries started to experience a resurgence in tuberculosis, the had persisted in neglected groups within their own borders and in developing nations (3). With outbreaks of multidrugresistant tuberculosis in the United States, the threat of casual transmission of a highly fatal disease (4, p. 648) led to a renaissance of interest in, and expansion of funding for, tuberculosis epidemiology, studies on the emergence of multidrug-resistant strains, and control programs in the United States. Global tuberculosis control programs, however, remain woefully underfunded (5) and are often poorly structured.

Institutional Control Measures for Tuberculosis in the Era of Multiple Drug Resistance: ACCP/ATS Consensus Conference

Institutional Control Measures for Tuberculosis in the Era of Multiple Drug Resistance: ACCP/ATS Consensus Conference

Multidrug-resistant tuberculosis in patients without HIV infection.

Investigations of outbreaks of multidrug-resistant tuberculosis have found low rates of treatment response and very high mortality, and they have mainly involved patients with advanced human immunodeficiency virus (HIV) infection. For patients without HIV infection, one study reported an overall rate of response to treatment of 56 percent, and the mortality from tuberculosis was 22 percent. We investigated treatment response and mortality rates in 26 HIV-negative patients in New York with multidrug-resistant tuberculosis. We obtained detailed data from seven teaching hospitals in New York City on patients with multidrug-resistant tuberculosis--defined as tuberculosis resistant at least to isoniazid and rifampin--who were HIV-negative on serologic testing. Lengths of times from diagnosis to the initiation of appropriate therapy and from the initiation of appropriate therapy to conversion to negative cultures were assessed. Therapeutic responses were evaluated by both microbiologic and clinical criteria. Between March 1991 and September 1994, 26 HIV-negative patients were identified and treated. Of the 25 patients for whom adequate data were available for analysis, 24 (96 percent) had clinical responses; all 17 patients for whom data on microbiologic response were available had such a response. The median times from diagnosis to the initiation of appropriate therapy and from the initiation of therapy to culture conversion were 44 days (range, 0 to 181) and 69 days (range, 2 to 705), respectively. Side effects requiring the discontinuation of medication occurred in 4 of 23 patients (17 percent) who were treated with second-line antituberculosis medications. The median follow-up for the 23 patients who responded and who received appropriate therapy was 91 weeks (range, 41 to 225). In this report from New York City, HIV-negative patients with multidrug-resistant tuberculosis, contrary to previous reports, responded well to appropriate chemotherapy, both clinically and microbiologically.

095-PA11 DNA fingerprinting of a multidrug resistant tuberculosis outbreak in Buenos Aires

095-PA11 DNA fingerprinting of a multidrug resistant tuberculosis outbreak in Buenos Aires

Tuberculosis in health care workers at a hospital with an outbreak of multidrug-resistant Mycobacterium tuberculosis

<h3>Objective:</h3> Investigate reports of tuberculosis in health care workers employed at a hospital with an outbreak of multidrug-resistant<i>Mycobacterium tuberculosis</i>. <h3>Design:</h3> Case series of tuberculosis in health care workers, January 1, 1989, through May 31, 1992. Antimicrobial susceptibility testing and restriction fragment length polymorphism analysis of<i>M tuberculosis</i>isolates. Longitudinal analysis of cumulative tuberculin skin test surveillance data. Assessment of infection control. The patients consisted of 361 health care workers who had either serial tuberculin skin tests or tuberculosis. <h3>Results:</h3> Six health care workers, the largest number linked to one multidrug-resistant tuberculosis outbreak, had disease due to<i>M tuberculosis</i>that matched the outbreak strain from hospitalized patients. The two who were seropositive for human immunodeficiency virus died, one of tuberculous meningitis and the other of multiple causes including tuberculosis. The estimated risk of a skin test conversion was positively associated with time and increased by a factor of 8.3 (1979 to 1992). In 1992 the annual risk for workers in the lowest exposure occupational group was 2.4%. In comparison, nurses and housekeepers had relative risks of 8.0 (95% confidence interval, 3.2 to 20.3) and 9.4 (95% confidence interval, 2.7 to 32.3), respectively. Laboratory workers had a relative risk of 4.2 (95% confidence interval, 1.1 to 15.5). Tuberculosis admissions increased, but the hospital had inadequate ventilation to isolate tuberculosis patients effectively. There were lapses in infection control practices. <h3>Conclusions:</h3> Health care workers who were exposed during a hospital outbreak of multidrug-resistant tuberculosis had occupationally acquired active disease. The human immunodeficiency virus—infected health care workers with tuberculosis had severe disease and died. The risk of skin test conversion increased during the study period, and higher exposure occupations had elevated risk. Effective infection control is essential to prevent the transmission of tuberculosis to health care workers. (Arch Intern Med. 1995;155:854-859)

Tuberculosis in Health Care Workers at a Hospital With an Outbreak of Multidrug-Resistant Mycobacterium tuberculosis

Investigate reports of tuberculosis in health care workers employed at a hospital with an outbreak of multidrug-resistant Mycobacterium tuberculosis. Case series of tuberculosis in health care workers, January 1, 1989, through May 31, 1992. Antimicrobial susceptibility testing and restriction fragment length polymorphism analysis of M tuberculosis isolates. Longitudinal analysis of cumulative tuberculin skin test surveillance data. Assessment of infection control. The patients consisted of 361 health care workers who had either serial tuberculin skin tests or tuberculosis. Six health care workers, the largest number linked to one multidrug-resistant tuberculosis outbreak, had disease due to M tuberculosis that matched the outbreak strain from hospitalized patients. The two who were seropositive for human immunodeficiency virus died, one of tuberculous meningitis and the other of multiple causes including tuberculosis. The estimated risk of a skin test conversion was positively associated with time and increased by a factor of 8.3 (1979 to 1992). In 1992 the annual risk for workers in the lowest exposure occupational group was 2.4%. In comparison, nurses and housekeepers had relative risks of 8.0 (95% confidence interval, 3.2 to 20.3) and 9.4 (95% confidence interval, 2.7 to 32.3), respectively. Laboratory workers had a relative risk of 4.2 (95% confidence interval, 1.1 to 15.5). Tuberculosis admissions increased, but the hospital had inadequate ventilation to isolate tuberculosis patients effectively. There were lapses in infection control practices. Health care workers who were exposed during a hospital outbreak of multidrug-resistant tuberculosis had occupationally acquired active disease. The human immunodeficiency virus-infected health care workers with tuberculosis had severe disease and died. The risk of skin test conversion increased during the study period, and higher exposure occupations had elevated risk. Effective infection control is essential to prevent the transmission of tuberculosis to health care workers.

Control of nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis among healthcare workers and HIV-infected patients.

From 1988 to 1990, an outbreak of multidrug-resistant tuberculosis (MDR-TB) among patients, and an increased number of tuberculin-skin-test conversions among healthcare workers, occurred on the HIV ward of Jackson Memorial Hospital, Miami, Florida, USA. Measures similar to those subsequently recommended in the 1990 Centers for Disease Control and Prevention guidelines were implemented on the HIV ward by June, 1990, and in September, 1992, we evaluated the efficacy of these control measures. Among MDR-TB patients and healthcare workers with tuberculin-skin-test conversions on the HIV ward, we looked for evidence of exposure to HIV ward MDR-TB patients positive for acid-fast bacilli in sputum during initial (January-May, 1990) and follow-up (June, 1990-June, 1992) periods. Exposure before implementation of control measures to an infectious MDR-TB patient on the HIV ward was recorded in 12 of 15 (80%) MDR-TB patients during the initial period and 5 of 11 (45%) MDR-TB patients during follow-up. After implementation of control measures, no episodes of MDR-TB could be traced to contact with infectious MDR-TB patients on the HIV ward. Skin-test conversions among workers on the HIV ward declined from 7 of 25 (28%) during the initial period to 3 of 17 (18%) in the early (June, 1990-February, 1991) and 0 of 23 in the late (March, 1991-June, 1992) follow-up periods (p < 0.01). Skin-test conversions among healthcare workers were not associated with increased exposure to MDR-TB patients, and were not significantly higher among workers on the HIV ward than on a control ward without tuberculosis patients (3/27 vs 0/16). These data demonstrate that implementation of measures similar to the Centers for Disease Control and Prevention 1990 tuberculosis-control guidelines were effective in halting transmission of MDR-TB to healthcare workers and HIV-infected patients.

Preventive Therapy for Contacts of Multidrug-Resistant Tuberculosis: A Delphi Survey

Several outbreaks of multidrug resistant tuberculosis (MDR-TB) have recently occurred in which healthcare workers and others have become infected. Given the lack of clinical data to guide preventive therapy for such contacts, a Delphi survey of a panel of 31 TB therapy experts was undertaken to identify a consensus regimen. An initial questionnaire presented three scenarios describing persons with significant exposure to MDR-TB and with new tuberculin skin test reactions > 15 mm (except one anergic patient) without evidence of disease. Panelists were asked to suggest possible preventive therapy regimens. During a second round survey, the panel members were asked to review the suggested regimens provided for each scenario and to rank them from one to nine as extremely inappropriate to extremely appropriate. Results of this second survey were tabulated and shared with the members of the panel who were then asked to rerank each regimen in light of the previous cumulative panel responses. No specific regimen achieved initial positive consensus by predefined criteria. In two of the three scenarios the no treatment option, however, was deemed clearly inappropriate. The data were also analyzed by what percentage of respondents who ranked a regimen as at all appropriate (ie, six or more on the nine point scale). For scenarios involving a nurse, an HIV-positive tuberculin reactor, and a patient who was anergic HIV-positive, treatment with pyrazinamide 1,500 mg daily with ciprofloxacin 750 mg twice a day for 4 months received a somewhat appropriate rating from more than 50 percent of respondents. The management of persons exposed to and infected by patients with MDR-TB has become a serious problem in the context of MDR-TB outbreaks. This panel of experts agreed that some form of preventive therapy was warranted; however, they were not able to reach defined consensus on what regimen should be used, although a regimen of pyrazinamide 1,500 mg daily with ciprofloxacin 750 mg twice a day for 4 months was considered somewhat appropriate. Clinical data on the efficacy of alternative preventive therapy regimens for such contacts are urgently needed.

Epidemiology of An Outbreak of Drug-Resistant Tuberculosis in the U.K. Using Restriction Fragment Length Polymorphism

1. Drug-resistant tuberculosis is a growing health care problem. When a series of cases occur, it is essential to know if patients with multidrug-resistant disease represent one or a number of separate outbreaks. 2. The epidemiology of an outbreak of isoniazid- and streptomycin-resistant tuberculosis in Blackburn was studied by restriction fragment length polymorphism using a probe for the IS6110 DNA sequence. 3. Mycobacterium tuberculosis from four cases of isoniazid- and streptomycin-resistant disease had an identical restriction fragment length polymorphism pattern. This pattern was not shared by drug-sensitive isolates of M. tuberculosis obtained from Blackburn (n = 8) or London (n = 13) or a M. tuberculosis isolate from a fifth Blackburn case which was resistant to isoniazid alone. 4. This methodology confirmed that all four cases of isoniazid- and streptomycin-resistant disease were part of a single epidemiologically related outbreak of drug-resistant disease. This study demonstrates how the epidemiology of an outbreak of multidrug-resistant tuberculosis in the U.K. can be confirmed by restriction fragment length polymorphism.

Multidrug-Resistant Tuberculosis

The incidence of tuberculosis, especially multidrug-resistant tuberculosis (MDR-TB), has increased significantly in recent years. Outbreaks of MDR-TB have occurred in hospitals, homeless shelters, and correctional institutions. MDR-TB is frequently associated with human immunodeficiency virus infection and prior antituberculous therapy. To minimize emergence of resistance, a four-drug regimen for initial, empiric treatment of tuberculosis is recommended. Susceptibility testing should be performed on all isolates to guide further therapy and define local resistance patterns. Directly observed therapy administered twice or thrice weekly can be used to ensure compliance. For resistant organisms, treatment with at least two drugs to which the organism is sensitive is recommended. Cure of MDR-TB is difficult to achieve and mortality is high. Surgery may provide a useful adjunctive therapy in advanced cases. The optimal prophylactic regimen for exposure to MDR-TB and/or skin test conversion remains to be determined. Current efforts to control intra-institutional transmission of tuberculosis have focused on prompt case identification, use of disposable particulate respirator masks, and negative air flow ventilation (when available). Ultraviolet germicidal irradiation has been advocated as an effective and economical means of reducing institutional transmission.

Molecular genetics of drug resistance in Mycobacterium tuberculosis.

Tuberculosis (TB) is the single largest killer among infectious diseases. The recent resurgence of TB together with outbreaks of multidrug resistant tuberculosis has focused attention on understanding the mechanisms of such drug resistance. Because of the relative neglect of TB research in the past and late arrival of mycobacterial genetic tools, the molecular mechanisms of drug resistance in TB remained largely unknown until very recently. In this paper we review recent progress on the mechanisms of resistance to three major anti-TB drugs; isoniazid, rifampicin and streptomycin. While the resistance mechanisms for rifampicin and streptomycin are similar to those found in other bacteria, isoniazid susceptibility and resistance is unique to Mycobacterium tuberculosis. So far, mutations in two chromosomal loci, katG and inhA have been found to be involved in isoniazid resistance in TB. Identification and characterization of mutations responsible for resistance opens up new possibilities for rapid detection of drug resistant strains. Molecular understanding of drug resistance and drug action in M. tuberculosis may eventually lead to rational design of new anti-TB drugs.

Exogenous reinfection with multidrug-resistant Mycobacterium tuberculosis in patients with advanced HIV infection.

In the United States there have been recent outbreaks of multidrug-resistant tuberculosis. These outbreaks have primarily involved persons infected with the human immunodeficiency virus (HIV). We collected clinical information on 17 patients seen at a New York City hospital who had repeatedly positive cultures for Mycobacterium tuberculosis. Analysis of restriction-fragment--length polymorphisms (RFLPs) was performed on serial isolates of M. tuberculosis obtained from these patients. Six patients had isolates that remained drug-susceptible, and the RFLP patterns of these isolates did not change over time. Eleven patients had isolates that became resistant to antimicrobial agents. The RFLP patterns of the isolates from six of these patients remained essentially unchanged (two strains showed one additional band) despite the development of drug resistance. In five other patients, however, the RFLP patterns of the isolates changed dramatically at the time that drug resistance was detected. The change in the RFLP pattern of the isolate from one patient appeared to be the result of contamination during processing in the laboratory. In the remaining four patients, all of whom had advanced HIV disease, the clinical and microbiologic evidence was consistent with the presence of active tuberculosis caused by a new strain of M. tuberculosis. Resistance to antituberculous drugs can develop not only in the strain that caused the initial disease, but also as a result of reinfection with a new strain of M. tuberculosis that is drug-resistant. Exogenous reinfection with multidrug-resistant M. tuberculosis can occur either during therapy for the original infection or after therapy has been completed.

The emergence of drug-resistant tuberculosis in New York City.

In the past decade the incidence of tuberculosis has increased nationwide and more than doubled in New York City, where there have been recent nosocomial outbreaks of multidrug-resistant tuberculosis. We collected information on every patient in New York City with a positive culture for Mycobacterium tuberculosis during April 1991. Drug-susceptibility testing was performed at the Centers for Disease Control and Prevention. Of the 518 patients with positive cultures, 466 (90 percent) had isolates available for testing. Overall, 33 percent of these patients had isolates resistant to one or more antituberculosis drugs, 26 percent had isolates resistant to at least isoniazid, and 19 percent had isolates resistant to both isoniazid and rifampin. Of the 239 patients who had received antituberculosis therapy, 44 percent had isolates resistant to one or more drugs and 30 percent had isolates resistant to both isoniazid and rifampin. Among the patients who had never been treated, the proportion with resistance to one or more drugs increased from 10 percent in 1982 through 1984 to 23 percent in 1991 (P = 0.003). Patients who had never been treated and who were infected with the human immunodeficiency virus (HIV) or reported injection-drug use were more likely to have resistant isolates. Among patients with the acquired immunodeficiency syndrome, those with resistant isolates were more likely to die during follow-up through January 1992 (80 percent vs. 47 percent, P = 0.02). A history of antituberculosis therapy was the strongest predictor of the presence of resistant organisms (odds ratio, 2.7; P < 0.001). There has been a marked increase in drug-resistant tuberculosis in New York City. Previously treated patients, those infected with HIV, and injection-drug users are at increased risk for drug resistance. Measures to control and prevent drug-resistant tuberculosis are urgently needed.

Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis

Concomitant with the resurgence of tuberculosis in the United States have been increasing reports of nosocomial transmission of TB. From January 1990 through September 1992, the Centers for Disease Control (CDC) investigated eight nosocomial outbreaks of multidrug-resistant tuberculosis (MDR-TB). Over 200 patients were infected; approximately 75% of these patients died. Risk factors for infection included human immunodeficiency virus infection or acquired immunodeficiency syndrome and recent hospitalization on the same ward as other MDR-TB patients. Restriction fragment length polymorphism (RFLP) analysis of M. tuberculosis isolates revealed unique strains were transmitted in each hospital. In three hospitals, health care workers (HCW) assigned to wards with MDR-TB patients were shown to be more likely to have tuberculin skin test (TST) conversions than HCW assigned to wards without MDR-TB patients. These outbreaks demonstrate the serious morbidity and mortality associated with nosocomial MDR-TB and emphasize the importance of adhering to current CDC guidelines for preventing the transmission of tuberculosis in healthcare settings, with special focus on HIV-related issues.