RATIONALE Treatment of latent tuberculosis (TB) infection with weekly rifapentine and isoniazid is a potentially effective alternative to current therapies. OBJECTIVES To compare the efficacy of weekly rifapentine/isoniazid to daily rifampin/pyrazinamide in preventing TB in household contacts of patients with pulmonary TB in Brazil. METHODS Contacts of patients with TB were randomized to rifapentine 900 mg/isoniazid 900 mg once weekly for 12 wk or rifampin 450-600 mg/pyrazinamide 750-1,500 mg daily for 8 wk and followed for at least 2 yr. MEASUREMENTS TB rates, adverse events, and adherence to therapy. MAIN RESULTS A total of 399 household contacts were enrolled, 206 in the rifapentine/isoniazid arm and 193 in the rifampin/pyrazinamide arm. The median age was 34 yr, median weight was 63 kg, 60% of participants were female, and only one patient was HIV infected. Rifapentine/isoniazid was well tolerated, but the trial was halted by the investigators before completion because of unanticipated hepatotoxicity in the rifampin/pyrazinamide arm. Twenty of 193 participants (10%) receiving rifampin/pyrazinamide experienced grade 3 or 4 hepatotoxicity, compared with 2 of 206 participants (1%) on rifapentine/isoniazid (p<0.001). There were no hospitalizations or deaths due to hepatotoxicity, and all participants' liver enzyme levels returned to normal during follow-up. During follow-up, four cases of active TB developed, three in the rifapentine/isoniazid group and one in the rifampin/pyrazinamide group (1.46 vs. 0.52%; difference, 0.94%; 95% confidence interval, -1.6 to 3.7%). CONCLUSIONS Rifapentine/isoniazid was better tolerated than rifampin/pyrazinamide and was associated with good protection against TB. Rifapentine/isoniazid weekly for 12 wk is likely a promising therapy for latent TB infection.

As Maria Jose Miguez-Burbano and colleagues point out, numerous non-tuberculous mycobacteria may cause disease in people with HIV infection. Our review was intentionally limited to a discussion of Mycobacterium avium complex infection in HIV-infected individuals, since this is by far the most common clinically relevant non-tuberculous mycobacteria, as well as the most common bacterial opportunistic infection in people with AIDS in the developed world. 1 Karakousis PC Moore RD Chaisson RE Mycobacterium avium complex in patients with HIV infection in the era of highly active antiretroviral therapy. Lancet Infect Dis. 2004; 4: 557-65 Summary Full Text Full Text PDF PubMed Scopus (169) Google Scholar Non-tuberculous mycobacteria in HIV-infected patients: geographic, behavioural, and immunological factorsWe read, with great interest, the article by Petros Karakousis and colleagues1 regarding non-tuberculous mycobacteria in HIV-infected individuals, and wish to draw attention to certain aspects overlooked by this review. Although comprehensive, the focus on Mycobacterium avium complex fails to consider that there are about 77 other mycobacterial species.2 Aside from Mycobacterium avium complex, Mycobacterium fortuitum, Mycobacterium kansasii, Mycobacterium xenopi, Mycobacterium chelonae, and Mycobacterium gordonae are among many other mycobacterial species responsible for a third of non-tuberculous mycobacterial diseases. Full-Text PDF

A whole-blood interferon-gamma release assay (IGRA) is being evaluated for its potential to replace the tuberculin skin test (TST) for detecting Mycobacterium tuberculosis infection. To test the assay in a population in which tuberculosis is highly endemic and in another population that is representative of an urban United States population, 253 volunteers from Ethiopia and 175 volunteers from Baltimore were studied for responsiveness on IGRA compared with a simultaneously performed TST. The agreement between the 2 tests, beyond that due to chance, was 68% among subjects from Baltimore and only 35% among those from Ethiopia. IGRA had a sensitivity of 71%, compared with 95% sensitivity for the TST, among 21 subjects who had undergone treatment for culture-confirmed tuberculosis. The specificity was 85% for IGRA and 96% for TST among 52 subjects with no known history of exposure to tuberculosis. In its current form, with purified protein derivative used as the stimulation antigen, the IGRA was found to perform poorly in comparison to the TST in diagnosing M. tuberculosis infection.

OBJECTIVE:To compare the effectiveness of initial highly active antiretroviral therapy with either: a single protease inhibitor (PI); ritonavir (RTV)/saquinavir (SQV); or efavirenz (EFV) plus nucleoside reverse transcriptase inhibitors. DESIGN:Cohort study. SETTING:Urban HIV clinic. PATIENTS:Five-hundred and forty-five HIV-1-infected individuals with minimal antiretroviral exposure who started combination therapy with > or = 3 antiretroviral drugs and > or = 1 NRTI to which they had not previously been exposed (single PI, 416; RTV/SQV, 68; EFV, 61). MAIN OUTCOME MEASURES:HIV-1 RNA < 400 copies/ml within 8 months of starting therapy; time to HIV-1 RNA rebound to > 1000 copies/ml in the subset of patients achieving initial viral suppression; change in CD4 cell count from baseline within 12 months of starting therapy. RESULTS:By intent-to-treat analysis, initial viral suppression was achieved by 72% of patients in the EFV group, compared to 49% in the single PI group (P = 0.001) and 51% in the RTV/SQV group (P = 0.019). Among patients who achieved initial viral suppression, time to viral rebound was similar in the three groups. Durable viral suppression (> or = 3 consecutive HIV-1 RNA levels < 400 copies/ml for > 6 months) was achieved by 53% of patients in the EFV group, 26% in the single PI group, and 29% in the RTV/SQV group (P < 0.05 for both comparisons with EFV). The median CD4 cell count increase was 139 x 10(6) cells/l, and was similar in the three groups. CONCLUSIONS:In agreement with a recent clinical trial, use of initial EFV-based combination antiretroviral therapy was associated with higher rates of viral suppression than PI-based therapy in a clinical cohort.

Guidelines for the treatment of community-acquired pneumonia (CAP) have been issued by various institutions. These therapeutic recommendations, culled from available medical literature, can be conflicting and confusing. The following factors further complicate clinical management: Accurate diagnosis is sometimes challenging, therapeutic options are abundant and aggressively marketed, and drug resistance is an increasing concern. Moreover, costs of care and clinical outcomes can vary significantly with therapeutic approaches. All of these factors point to a critical need for more consistent medical guidelines for treating CAP.

Opportunistic infections (OIs) are well recognized to produce substantial morbidity and mortality among patients with HIV infection. Since measures are available for reducing the incidence and the impact of these processes for patients, the United States Public Health Service and the Infectious Diseases Society of America, with endorsing professional societies, have developed guidelines for implementing a comprehensive strategy to prevent these OIs. These guidelines have been developed by a diverse working group of expert health care providers and patient representatives in order to synthesize available data and to provide practical advice for health care practitioners and patients.

This statement provides new recommendations for targeted tuberculin testing and treatment regimens for persons with latent tuberculosis infection (LTBI) and updates previously published guidelines (1, 2). This statement is issued in recognition of the importance of these activities as an essential component of the TB Elimination Strategy promoted by the U.S. Public Health Service Advisory Council on the Elimination of Tuberculosis, and reports the deliberations of expert consultants convened by the American-Thoracic Society (ATS) and Centers for Disease Control and Prevention (CDC).Isoniazid for 6-12 mo has been the mainstay of treatment for LTBI in the United States for more than 30 yr. However, the application of isoniazid for LTBI has been limited because of poor adherence, due to the relatively long duration of treatment required, and because of concerns about toxicity. Therefore, there has been interest in the development of shorter, rifampin-based regimens as alternatives to isoniazid for the treatment of LTBI, During the past decade, a series of studies of "short-course" treatment of LTBI in persons with human immunodeficiency virus (HIV) infection has been undertaken. The results of these trials have recently become available, and the in-depth analyses of these and prior studies of isoniazid form the scientific basis of the treatment guidelines presented in this report. In addition, many changes to previous recommendations regarding testing for and treatment of LTBI are presented (Table 1).

Upper respiratory infections comprise a large percentage of visits to primary care physicians and often are treated with antibiotics. Streptococcus pneumoniae is a leading cause of invasive disease and is a common cause of lower respiratory infections, but it is also frequently found colonizing and producing disease in the upper respiratory tract. Over the past decade, increased rates of antimicrobial resistance have been documented among S. pneumoniae isolates. Other upper respiratory pathogens, including Haemophilus influenzae, Streptococcus pyogenes, and Bordetella pertussis, are also associated with drug resistance. The trends in antimicrobial susceptibility patterns among upper respiratory pathogens, mechanisms of resistance to antimicrobial agents, the question of whether drug resistance correlates with clinical treatment failure, and implications drug resistance has for currently available treatment of upper respiratory infections are discussed.

Objective. To determine the effect of contemporary clinical care on the natural history of opportunistic disease in an urban population infected with the human immunodeficiency virus (HIV). Setting. Urban university HIV clinic. Design. Retrospective and prospective observational study. Patients. One thousand two hundred forty-six HIV-infected patients with CD4(+) counts of 300 cells/mm(3) or less. Measurements. Incidence rates and Kaplan-Meier estimates of the probability of developing opportunistic disease, and the association between preventive drug therapies and the occurrence of opportunistic infection. Results. The most common opportunistic disease was Candida esophagitis, which had an incidence of 13.3 events per 100 person-years and a 3-year Kaplan-Meier probability of 0.30. Pneumocystis carinii pneumonia. Mycobacterium avium complex bacteremia, cytomegalovirus, and the acquired immunodeficiency syndrome dementia complex occurred at rates of 5 to 9 events per 100 person-years and 3-year Kaplan-Meier probabilities of 0.15 to 0.22. Non-Hodgkin lymphoma, M. tuberculosis infection, progressive multifocal leukoencephalopathy, and cryptosporidiosis were the least common disorders, with an incidence of about 1 to 2 events per 100 person-years and a 3-year pneumonia, and herpes zoster decreased (p < 0.05) between 1989-1992 and 1993-1995. Fluconazole use was associated with a decreased relative rate of 0.49 (p = 0.06) for cryptococcal meningitis and a decreased relative rate of 0.61 (p = 0.005) for esophageal candidiasis. Rifabutin use was associated with a decreased relative rate of 0.37 (p = 0.002) for M. avium complex bacteremia, and trimethoprim-sulfamethoxazole use was associated with decreased relative rates of 0.33 (p = 0.02) for secondary P. carinii pneumonia and 0.55 (p = 0.08) for primary P. carinii pneumonia. Candidiasis, herpes zoster, and M. tuberculosis infection first occurred at a median CD4(+) count greater than 100 cells/mm(3), but all other opportunistic diseases first occurred at a median CD4(+) count less than 50 cells/mm(3). Median survival after diagnosis varied from 35 days for non-Hodgkin lymphoma to 680 days for herpes zoster. Conclusions. In the patients studied, the incidences of secondary P. carinii pneumonia, cryptococcal meningitis, and herpes zoster have declined in the past 5 years. The incidences of primary P. carinii pneumonia and Kaposi sarcoma appear to be declining compared with historical estimates. However, although these and other opportunistic diseases continue to be relatively frequent complications of HIV infection, they are first occurring at more advanced immunosuppression than in the past. Continued efforts are needed to develop effective strategies for preventing opportunistic disease in very advanced HIV infection.

Recent technologic developments have introduced a number of improvements in the ability of clinical laboratories to cultivate and identify Mycobacterium tuberculosis complex more quickly than previously. These developments include more rapid detection of growth and tests to identify RNA or DNA of M. tuberculosis complex directly in clinical samples. United States Food and Drug Administration (FDA) panels have recently recommended approval of two direct amplification tests (DAT), the Gen-Probe(R) MTD (San Diego, CA) and the AMPLICOR(R) M. tuberculosis test (Roche Diagnostic Systems, Inc., Branchburg, NJ). The FDA has approved the MTD for identification of M. tuberculosis complex in respiratory specimens that are smear-positive for acid-fast bacilli (AFB). In addition, the specimen must be from a patient who has not received antituberculous medication for seven or more days or within the last 12 months. From the data reviewed by the FDA, the specificity (100%) and sensitivity (95%/96% in the two studies) of these two tests in AFB smear-positive specimens were found to be comparable to the Accuprobe (Cen-Probe) for identification of M. tuberculosis complex in culture, with the advantage that the DAT results are available much sooner. The DAT are significantly more sensitive than the AFB smear. However, in AFB smear-negative samples, the specificity, sensitivity, and positive predictive value were 96/99%, 48/53% and 24/58%, respectively, in the two studies. For some results, the Cen-Probe assay had the higher value and for others, the Roche assay was higher. The DAT result, particularly when discordant with the AFB smear, must be used in conjunction with clinical assessment. While both the MTD and the AMPLlCOR(R) M. tuberculosis test have undergone extensive testing in clinical laboratories, neither test has been examined for its utility in routine clinical use or public health settings in the United States. An American Thoracic Society Workshop was convened to examine the data and technology available to date, to develop a consensus addressing the appropriate use of the rapid diagnostic tests (in particular, DAT's) for tuberculosis, and to identify future research needs and directions. The consensus among three focus groups, clinical, laboratory, and public health, was that, while these tests are a major improvement over standard techniques, there is currently insufficient information on their clinical and public health utility. When the AFB smear and DAT are both positive, the diagnosis of tuberculosis can be considered to be established. Furthermore, when the AFB smear is negative and the DAT is also negative, it is unlikely that M. tuberculosis will be grown from that sample. When there is discordance between the AFB smear and the DAT, additional consideration must be given to the overall clinical picture and repeat testing should be done. It is recommended that the currently available DAT's always be performed in conjunction with microscopy and culture, and each test result must be interpreted within the overall clinical setting in which it is used.

CONTEXT:An ongoing restriction fragment length polymorphism (RFLP) study of Mycobacterium tuberculosis isolates from tuberculosis (TB) cases revealed an identical 10-banded IS6110 RFLP pattern unique to 2 patients diagnosed as having TB 6 months apart. Their only identifiable link was care at the same hospital.OBJECTIVE:To determine if nosocomial transmission had occurred.DESIGN:Traditional and molecular epidemiologic investigation.MEASUREMENTS:We reviewed medical charts and bronchoscopic records, examined hospital locations visited by both patients, evaluated hospital ventilation systems, and observed cleaning and disinfection of bronchoscopes.RESULTS:A patient with cough, hoarseness, and fever underwent bronchoscopy and was diagnosed as having TB. A second patient with a mediastinal mass underwent bronchoscopy 2 days later and was diagnosed as having small cell carcinoma. Following 6 months of chemotherapy and radiation therapy, the second patient developed fever and an infiltrate of the right upper lobe of the lung. Bronchoscopic washings revealed acid-fast bacilli and were culture positive for M tuberculosis. Both patients had undergone bronchoscopy with the same instrument in the same operating room with no intervening bronchoscopies. Bronchoscope cleaning and disinfection procedures were inconsistent with national guidelines.CONCLUSIONS:A contaminated bronchoscope was the most likely source of M tuberculosis transmission between these 2 patients. The RFLP analysis of M tuberculosis isolates was responsible for detecting this nosocomial source of transmission and led to the implementation of public health measures to prevent further spread of infection and disease. This study emphasizes the need for continued vigilance in endoscope cleaning techniques.

The report by Moore et al1that appeared in the October 9, 1995, issue of theARCHIVESraises some points that reinforce our experience concerning the association between various degrees of severity of human immunodeficiency virus (HIV) infection, neutropenia, and onset of bacterial infection. The authors are to be congratulated for their study, since direct cause-effect relationships between these clinicopathological processes are notoriously difficult to establish. This difficulty is primarily due to the many variables that can interact in a complex manner to establish and permit progression of pneumonia, septicemia, and endocarditis, the bacterial infections that are most frequently encountered in HIV-infected patients.2 Moore and colleagues1were careful to adjust their analysis to accommodate the use of antibacterial agents or HIV-inhibitory drugs; the former suppress bacterial infection in the neutropenic patients, while the latter may induce iatrogenic neutropenia. Sixteen percent of patients were undergoing sulfamethoxazole-trimethoprim therapy at

We appreciate the comments of Dr. Ewig, who has reiterated what we stated (CHEST 1995; 107:1018-23) in our discussion: that differences in the severity of Pneumocystis carinii pneumonia (PCP) and the mortality between groups taking and not taking prophylaxis may have been the result of access to health care, rather than to the effect of prophylaxis itself. Our study was a retrospective study, so patients not taking prophylaxis may have differed in many other ways from those receiving prophylaxis. Therefore, we are unable to conclude that the improved outcome of patients receiving prophylaxis was a result of the drugs themselves. Such a causal relationship, however, is plausible. The purpose of our study was not to determine the biologic effect of prophylaxis on the severity of PCP, which would not have been possible in a retrospective study, but to determine why HIV-infected individuals continue to develop PCP despite the known efficacy of prophylaxis and to assess the impact of the failure to prevent PCP on morbidity, mortality, and health-care costs. We found that the majority of cases of PCP at our institution was the result of “failure” of the health-care system (to provide adequate access to medical care), of health-care providers (to test patients for HIV and to provide prophylaxis when indicated), and of patients themselves (to continue medical follow-up for HIV infection and to take prescribed prophylaxis). In contrast, failure of prophylaxis itself was less important as a cause of PCP. Thus, over three quarters of the cases of PCP at our institution were potentially preventable, and hospitalization, hospital charges, and deaths were disproportionately high in this group. The conclusions that should be drawn from our study are not that prophylaxis decreases the severity of PCP, although that may be the case, but that most PCP today is preventable through early diagnosis of HIV infection, provision of primary medical care for infected individuals, institution of prophylaxis, and efforts to improve patient compliance. The differences in the efficacy of currently recommended prophylactic regimens, while important, play a smaller role in explaining the high incidence of PCP in the era of prophylaxis.