Gisela F. Schecter

An outbreak of tuberculosis with accelerated progression among persons infected with the human immunodeficiency virus. An analysis using restriction-fragment-length polymorphisms.

BACKGROUND Tuberculosis typically develops from a reactivation of latent infection. Clinical tuberculosis may also arise from a primary infection, and this is thought to be more likely in persons infected with the human immunodeficiency virus (HIV). However, the relative importance of these two pathogenetic mechanisms in this population is unclear. METHODS Between December 1990 and April 1991, tuberculosis was diagnosed in 12 residents of a housing facility for HIV-infected persons. In the preceding six months, two patients being treated for tuberculosis had been admitted to the facility. We investigated this outbreak using standard procedures plus analysis of the cultured organisms with restriction-fragment-length polymorphisms (RFLPs). RESULTS Organisms isolated from all 11 of the culture-positive residents had similar RFLP patterns, whereas the isolates from the 2 patients treated for tuberculosis in the previous six months were different strains. This implicated the first of the 12 patients with tuberculosis as the source of this outbreak. Among the 30 residents exposed to possible infection, active tuberculosis developed in 11 (37 percent), and 4 others (13 percent) had newly positive tuberculin skin tests. Of 28 staff members with possible exposure, at least 6 had positive tuberculin-test reactions, but none had tuberculosis. CONCLUSIONS Newly acquired tuberculous infection in HIV-infected patients can spread readily and progress rapidly to active disease. There should be heightened surveillance for tuberculosis in facilities where HIV-infected persons live, and investigation of contacts must be undertaken promptly and be focused more broadly than is usual.

Treatment of Tuberculosis in Patients with Advanced Human Immunodeficiency Virus Infection

BACKGROUND AND METHODS Infection with the human immunodeficiency virus (HIV) increases the risk of tuberculosis and may interfere with the effectiveness of antituberculosis chemotherapy. To examine the outcomes in patients with both diagnoses, we conducted a retrospective study of all 132 patients listed in both the acquired immunodeficiency syndrome (AIDS) and tuberculosis case registries in San Francisco from 1981 through 1988. RESULTS At the time of the diagnosis of tuberculosis, 78 patients (59 percent) did not yet have a diagnosis of AIDS, 18 patients (14 percent) were given a concomitant diagnosis of AIDS (as determined by the presence of an AIDS-defining disease other than tuberculosis), and the remaining 36 patients (27 percent) already had AIDS. The manifestations of tuberculosis were entirely pulmonary in 50 patients (38 percent), entirely extrapulmonary in 40 patients (30 percent), and both pulmonary and extrapulmonary in 42 patients (32 percent). The treatment regimens were as follows: isoniazid and rifampin supplemented by ethambutol for the first two months, 52 patients; isoniazid and rifampin supplemented by pyrazinamide and ethambutol for the first two months, 39 patients; isoniazid and rifampin, 13 patients; isoniazid and rifampin supplemented by pyrazinamide for the first two months, 4 patients; and other drug regimens, 17 patients. The intended duration of treatment for patients whose regimen included pyrazinamide was six months, and for patients who did not receive pyrazinamide, nine months. Seven patients received no treatment because tuberculosis was first diagnosed after death. Sputum samples became clear of acid-fast organisms after a median of 10 weeks of therapy. Abnormalities on all chest radiographs taken after three months of treatment were stable or improved except for those of patients who had new nontuberculous infections. The only treatment failure occurred in a man infected with multiple drug-resistant organisms who did not comply with therapy. Adverse drug reactions occurred in 23 patients (18 percent). For all 125 treated patients, median survival was 16 months from the diagnosis of tuberculosis. Tuberculosis was a major contributor to death in 5 of the 7 untreated patients and 8 of the 125 treated patients. Three of 58 patients who completed therapy had a relapse (5 percent); compliance was poor in all 3. CONCLUSIONS Tuberculosis causes substantial mortality in patients with advanced HIV infection. In patients who comply with the regimen, conventional therapy results in rapid sterilization of sputum, radiographic improvement, and low rates of relapse.

A Molecular Epidemiologic Analysis of Tuberculosis Trends in San Francisco, 1991–1997

During the late 1980s and early 1990s, when tuberculosis case rates were increasing in many parts of the United States, it became apparent that considerable transmission of Mycobacterium tuberculosis was occurring and that the infection often progressed rapidly to tuberculosis (1-4). Transmission of M. tuberculosis followed by rapid progression to clinical disease was directly shown by many instances of institutional transmission and was indirectly shown by population-based studies using genotyping of the organism to infer epidemiologic links among patients with tuberculosis (5-14). Case rates are again decreasing in many urban areas and in the United States as a whole (15, 16). In New York City, the reduction in the tuberculosis case rate has been attributed mainly to the use of directly observed therapy, but other control measures have also been instituted (15). Many of the control interventions focused on preventing transmission of M. tuberculosis in high-risk groups and in such settings as hospitals, prisons, and shelters. Prevention of M. tuberculosis transmission would decrease the rate of tuberculosis cases that result from recent infection followed by a short latency period and rapid progression to clinical disease. Other measures, such as increased use of isoniazid preventive therapy, would decrease tuberculosis cases caused by reactivation of latent infection. In San Francisco, California, we identified a high proportion of clustered cases by using both conventional and molecular epidemiologic methods (9, 12); cases were considered to be clustered if the isolates had identical DNA fingerprints. These findings indicated that considerable transmission of M. tuberculosis was occurring within the population. On the basis of these observations, tuberculosis control measures directed toward reducing transmission of M. tuberculosis in high-risk groups were instituted beginning in early 1991. We hypothesized that these measures would reduce the frequency of tuberculosis resulting from recent transmission (clustering) as well as decrease the overall incidence of the disease. In this observational study, we describe the trends in tuberculosis incidence and the molecular epidemiologic pattern of the disease in San Francisco from 1 January 1991 through 31 December 1997. Methods Study Sample Tuberculosis was diagnosed in 2051 persons in San Francisco between 1 January 1991 and 31 December 1997. Of these cases, 1761 (86%) were confirmed by isolation of M. tuberculosis. Deoxyribonucleic acid fingerprinting using IS6110-based restriction fragment length polymorphism analysis was done on isolates from 1548 (88%) of the 1761 culture-positive cases. Six or more IS6110 hybridizing bands were found in 1238 (80%) of the tested isolates, and the remaining 310 isolates had five or fewer IS6110 bands. We excluded isolates from 25 cases (1.6% of cases for which DNA fingerprinting was done) that met criteria for laboratory cross-contamination. Polymorphic guanine-cytosine-rich sequence (PGRS)-based restriction fragment length polymorphism analysis was done on 257 of the 310 (83%) non-laboratory contaminant isolates with five or fewer IS6110 bands. Thus, 1495 of 1761 patients (85% of all culture-positive cases) had isolates with complete DNA fingerprinting data. No significant year-to-year differences were seen in the percentage of isolates for which IS6110-based and PGRS-based DNA fingerprinting was done. At the time of diagnosis, tuberculosis control personnel entered standard demographic information into the Centers for Disease Control and Preventions Report of a Verified Case of Tuberculosis form. Annual case rates of tuberculosis in San Francisco were calculated per 100 000 persons by using 1990 U.S. Census data on the population of San Francisco residents according to age, sex, place of birth, and race or ethnicity (17). The prevalence of HIV infection in San Francisco was obtained by using data from the 1997 Consensus Report on HIV Prevalence and Incidence in San Francisco (18). DNA Fingerprinting Methods IS6110-based DNA fingerprinting was performed by using the internationally standardized method, and the resulting patterns were compared by using BioImage Whole Band Analyzer software (version 3.3, BioImage Corp., Ann Arbor, Michigan) (19, 20). Isolates that had identical IS6110 fingerprints that contained five or fewer hybridizing bands were further analyzed with PGRS-based fingerprinting (21-24). Genomic DNA was digested with Sma1 and was probed by using a consensus sequence of the PGRS (22). The resulting patterns were examined visually and were defined as matching if the number, relative intensity, and molecular weights of the bands were identical. Definition of Laboratory Cross-Contamination Laboratory cross-contamination was considered to be the cause of a positive culture when all of the following criteria were met: 1) A patient had only one positive culture and that specimen tested negative on microscopic examination for acid-fast bacilli; 2) the specimen had been processed in the laboratory within 28 days of a specimen from another patient who had a positive result on microscopic examination for acid-fast bacilli; and 3) the microscopically positive specimen had the same DNA fingerprint as the putative contaminated specimen (25). Definition of Clustering Clustering was defined as the occurrence, within 1 year, of two or more isolates from different patients that contained 1) six or more IS6110 bands in an identical pattern or 2) five or fewer IS6110 bands that matched identically and had an identical PGRS pattern. A 1-year period for defining clustering was used because we were especially interested in assessing transmission of M. tuberculosis that resulted in rapid progression to disease. Clustered cases were identified as follows. For every initial isolate of M. tuberculosis from an incident case of tuberculosis, the database of IS6110 fingerprints was searched to identify any matching patterns within the previous year. If a match was found in the previous year, the case was counted as being in a cluster. For example, if the fingerprint from a case diagnosed in March matched the fingerprint from a case diagnosed the previous August, the case diagnosed in March was counted as clustered. Because no match preceding the first case identified with a particular fingerprint (index cases) will be found, these cases were counted as not clustered. Data from the 1990 U.S. Census from California (17) and the 1997 Consensus Report on HIV Prevalence and Incidence in San Francisco (18) were used to calculate annual rates of clustered cases per 100 000 persons for each year from 1992 to 1997, both for the population as a whole and according to place of birth (United States or outside of the United States) and presence of HIV infection. Because we did not begin performing comprehensive DNA fingerprinting until 1 January 1991, we could not compare isolates from patients in whom tuberculosis was diagnosed in the first 1-year period (1 January 1991 through 31 December 1991) with isolates from previous cases. Thus, the comparison of strains began with isolates obtained after 1 January 1992. Of the 1495 cases with isolates that had complete DNA fingerprinting data, 225 were from patients whose diagnosis was established between 1 January 1991 and 31 December 1991, and 1270 were from patients whose diagnosis was established between 1 January 1992 and 31 December 1997. These 1270 patients made up the final study sample for the analysis of clustering over time. Intensification of Tuberculosis Control Measures Tuberculosis control measures were intensified in five areas beginning in 1991, partly on the basis of findings from our earlier molecular epidemiologic studies (12, 26). 1. Improved contact investigations. Disease control investigators were trained to improve communication with specific populations at risk, including homeless persons and persons with a history of substance abuse. In addition, the assessment of what constitutes significant contact was broadened. The median number of contacts per new case increased from 1 in 1991 to 4 in 1995 and was 3 in 1996 and 1997 (P<0.001; chi-square test). The percentage of cases with no contacts identified decreased from 25% in 1990 to 3% in 1997 (Table 1). The total number of contacts identified each year increased between 1991 (approximately 1100) and 1992 and continued to range from approximately 2000 to 3000 from 1993 through 1997. The number of contacts infected with M. tuberculosis identified through these investigations increased from 498 in 1991 to 956 in 1997, and approximately 80% of the contacts completed a course of isoniazid preventive therapy in each of these years. The number of cases of active tuberculosis found through contact investigations ranged from 19 to 25 per year during the study period. Table 1. Data on Contacts of Tuberculosis Cases and Number of Case-Patients with Tuberculosis Receiving Directly Observed Therapy per Year in San Francisco, California, 1991-1997 2. Expanded use of directly observed therapy. Overall, 28% (541 of 1958) of all patients with incident cases received directly observed therapy as part of their treatment during the study period (Table 1). The proportion of patients receiving directly observed therapy increased from 22% in 1991 to a peak of 35% in 1996; in 1997, the percentage was 22%. The percentage of all patients who had documented negative sputum cultures within 3 months of the initiation of therapy increased slightly, from 65% in 1990 to 68% in 1997. 3. Development of an HIV-related tuberculosis prevention program. Persons seen at any of six city-based HIV primary care and methadone maintenance clinics underwent tuberculin skin testing and were evaluated clinically for tuberculosis. Depending on HIV status, tuberculin reactors were treated with a 12- or 6-month course of isoniazid preventive therapy after exclusion of active tubercu

Linezolid in the Treatment of Multidrug-Resistant Tuberculosis

BACKGROUND Linezolid is a new antibiotic with activity against Mycobacterium tuberculosis in vitro and in animal studies. Several small case series suggest that linezolid is poorly tolerated because of the side effects of anemia/thrombocytopenia and peripheral neuropathy. To characterize our clinical experience with linezolid, the California Department of Public Health Tuberculosis Control Branchs Multidrug-Resistant Tuberculosis (MDR-TB) Service reviewed cases in which the MDR-TB treatment regimens included linezolid therapy. METHODS Record review was performed for 30 patients treated with linezolid as part of an MDR-TB regimen. Data were collected on clinical and microbiological characteristics, linezolid tolerability, and treatment outcomes. The dosage of linezolid was 600 mg daily. Vitamin B6 at a dosage of 50-100 mg daily was used to mitigate hematologic toxicity. RESULTS During 2003-2007, 30 patients received linezolid for the treatment of MDR-TB. Patients had isolates resistant to a median of 5 drugs (range, 2-13 drugs). Of the 30 cases, 29 (97%) were pulmonary; of these 29, 21 (72%) had positive results of acid-fast bacilli smear, and 16 (55%) were cavitary. Culture conversion occurred in all pulmonary cases at a median of 7 weeks. At data censure (31 December 2008), 22 (73%) of 30 patients had successfully completed treatment. Five continued to receive treatment. There were no deaths. Three patients had a poor outcome, including 2 defaults and 1 treatment failure. Side effects occurred in 9 patients, including peripheral and optic neuropathy, anemia/thrombocytopenia, rash, and diarrhea. However, only 3 patients stopped linezolid treatment because of side effects. CONCLUSIONS Linezolid was well tolerated, had low rates of discontinuation, and may have efficacy in the treatment of MDR-TB.

Imipenem for treatment of tuberculosis in mice and humans.

ABSTRACT Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against Mycobacterium tuberculosis in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with M. tuberculosis strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first- or second-line agents; elimination of M. tuberculosis from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of M. tuberculosis organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log10 CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with M. tuberculosis. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.

The changing epidemiology of acquired drug-resistant tuberculosis in San Francisco, USA

BACKGROUND The increasing incidence of tuberculosis caused by drug-resistant Mycobacterium tuberculosis is thought in part to reflect inadequate implementation of standard tuberculosis control measures. However, in San Francisco, USA, which has an effective tuberculosis control programme, we have recently observed an increase in cases of acquired drug-resistance. METHODS To explore further this observation, we analysed the secular trend of acquired drug-resistance and conducted a population-based case-control study of all reported tuberculosis cases in the city of San Francisco between 1985 and 1994. FINDINGS We identified 14 patients with tuberculosis caused by fully susceptible M tuberculosis who subsequently developed drug-resistance. Of these acquired drug-resistance cases, two occurred between 1985 and 1989, whereas 12 occurred between 1990 and 1994 (p = 0.028). In the case-control study, AIDS (odds ratio 20.2, 95% CI 1.12-363.6), non-compliance with therapy (19.7, 1.66-234.4), and gastrointestinal symptoms (11.5, 1.23-107.0) were independently associated with acquired drug-resistance. Between 1990 and 1994, one in 16 tuberculosis patients with AIDS and either gastrointestinal symptoms or non-compliance developed acquired drug- resistance. INTERPRETATION The substantial increase in acquired drug- resistance in San Francisco seems to be a product of the increasing prevalence of HIV/M tuberculosis coinfection. Our data suggest that the interface of the HIV and tuberculosis epidemics fosters acquired drug-resistance, and that traditional tuberculosis control measures may not be sufficient in communities with high rates of HIV infection.

Screening for tuberculosis in Jail and clinic follow-up after release

OBJECTIVES The purpose of this study was to describe tuberculosis (TB) screening and preventive therapy in the San Francisco County Jail and to measure the follow-up rate at the public health department TB clinic. METHODS The records of male inmates screened for 6 months in 1994 were reviewed. Those prescribed isoniazid and released before therapy ended were matched with TB clinic records. Inmates were considered to have followed up if they came to the TB clinic within 1 month of release. RESULTS Of 3352 inmates screened, 553 (16.5%) reported a prior positive skin test, and 330 (26.9%) of 1229 tests placed and read were positive. Of those with positive tests, 151 (45.8%) began isoniazid. Most of the inmates were foreign-born Hispanics (80.8%). Ninety-three (61.6%) inmates were released before completion, after an average of 68.5 days. Three (3.2%) went to the TB clinic within a month. CONCLUSIONS Jail represents an important screening site for TB, but care is not continued after release. Strategies are needed to enhance the continuity of isoniazid preventive care.

Contemporary management of cervical tuberculosis

Although excisional biopsy has traditionally been required to diagnose cervical tuberculosis (TB), fine needle aspiration biopsy (FNAB) has also been found to be useful. The presentation and management of 47 patients diagnosed with cervical TB between 1984 and 1988 were retrospectively reviewed. Chest x‐rays were normal in 58% of the patients, and purified protein derivative (PPD) skin testing was positive in 96%. When FNAB was used, TB could be suspected in 83% of cases and definitively established in 62%. Open biopsy correctly diagnosed cervical TB in all masses excised. Medical therapy alone resulted in resolution of disease in 94% of patients diagnosed by FNAB, and subsequent excisional biopsy was necessary in only one patient. The results suggest that FNAB is a useful initial procedure in the diagnosis of cervical TB. Excisional biopsy should be reserved for cases where no diagnosis by FNAB can be made, or for persistent cervical disease despite full‐course antituberculous chemotherapy.

Treatment of Multidrug-Resistant Tuberculosis in San Francisco: An Outpatient-Based Approach

BACKGROUND Treatment of patients with multidrug-resistant tuberculosis requires prolonged therapy, often involving long hospital stays. Despite intensive and costly therapy, cure rates are relatively low. METHODS We reviewed the outcomes for all patients with multidrug-resistant tuberculosis treated in San Francisco, California, during 1982-2000 and identified billing charges for patients treated during 1995-2000. Mycobacterium tuberculosis isolates were genotyped by IS6110-based restriction fragment-length polymorphism analysis. RESULTS Forty-eight cases were identified with resistance to a median of 3 drugs (range, 2-9 drugs). The median age of the patients was 49.5 years (range, 22-78 years); 36 (75%) of 48 patients were foreign born, 11 (23%) were human immunodeficiency virus (HIV) seropositive, and 45 (94%) had pulmonary tuberculosis. Thirty-two (97%) of the 33 HIV-seronegative patients were cured, with only 1 relapse occurring 5 years after treatment. All 11 HIV-seropositive patients died during observation. Twenty-one patients (44%) required hospitalization, with a median duration of stay of 14 days (range, 3-74 days). The estimated inpatient and outpatient aggregate cost for the 11 patients treated after 1994 was

Extensively drug-resistant tuberculosis: New strains, new challenges

519,928, with a median cost of