Spread of Strain W, a Highly Drug-Resistant Strain of Mycobacterium tuberculosis, Across the United States

Transcription

1 85 Spread of Strain W, a Highly Drug-Resistant Strain of Mycobacterium tuberculosis, Across the United States Tracy B. Agerton, Sarah E. Valway, Richard J. Blinkhorn, Kenneth L. Shilkret, Randall Reves, W. William Schluter, Betty Gore, Carol J. Pozsik, Bonnie B. Plikaytis, Charles Woodley, and Ida M. Onorato From the Epidemic Intelligence Service, Epidemiology Program Office, and Epidemiology and Surveillance Branch and Field Services Branch, Division of Tuberculosis Elimination, and the Division of AIDS, STD, and Tuberculosis Laboratory Research, National Center for HIV, STD and Tuberculosis Prevention, Centers for Disease Control and Prevention, Atlanta, Georgia; Cuyahoga County Tuberculosis Program, Division of Infectious Diseases, Department of Internal Medicine, Metrohealth Medical Center, Cleveland, Ohio; Tuberculosis Program, New Jersey Department of Health and Senior Services, Trenton, New Jersey; Denver Metro Tuberculosis Clinic, Department of Health and Hospitals, and Department of Preventive Medicine and Biometrics, University of Colorado Health Sciences Center, Denver, Colorado; and the Tuberculosis Control Program, South Carolina Department of Health and Environmental Control, Columbia, South Carolina Strain W, a highly drug-resistant strain of Mycobacterium tuberculosis, was responsible for large nosocomial outbreaks in New York in the early 1990s. To describe the spread of strain W outside New York, we reviewed data from epidemiologic investigations, national tuberculosis surveillance, regional DNA fingerprint laboratories, and the Centers for Disease Control and Prevention Mycobacteriology Laboratory to identify potential cases of tuberculosis due to strain W. From January 1992 through February 1997, 23 cases were diagnosed in nine states and Puerto Rico; 8 were exposed to strain W in New York before their diagnosis; 4 of the 23 transmitted disease to 10 others. Eighty-six contacts of the 23 cases are presumed to be infected with strain W; 11 completed alternative preventive therapy. Strain W tuberculosis cases will occur throughout the United States as persons infected in New York move elsewhere. To help track and contain this strain, health departments should notify the Centers for Disease Control and Prevention of cases of tuberculosis resistant to isoniazid, rifampin, streptomycin, and kanamycin. Since the early 1990s, the Division of Tuberculosis Elimination at the Centers for Disease Control and Prevention (CDC) has been tracking a unique strain of multidrug-resistant (MDR) Mycobacterium tuberculosis and its closely related variants across the United States. This strain, designated W, is defined by a unique multiband restriction fragment length polymorphism (RFLP) pattern [1, 2] (figure 1). Several variants (e.g., W1 in figure 1) with closely related RFLP patterns have been identified and, together with strain W, define the strain W family. A multiplex PCR has been developed that identifies See editorial response by Salomon and Perlman on pages Received 12 August 1998; revised 15 December Reprints or correspondence: Tracy Agerton, Division of TB Elimination, Mailstop E-10, Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA Clinical Infectious Diseases 1999;29: by the Infectious Diseases Society of America. All rights reserved /99/ $03.00 members of this family [3]. The MDR variants in the strain W family are typically resistant to isoniazid, rifampin, streptomycin, ethambutol, ethionamide, rifabutin, and kanamycin. Strain W was responsible for several large hospital and prison outbreaks in New York in the early 1990s involving several hundred cases [1, 4 9]. Most of the patients in these outbreaks were severely immunocompromised because of HIV infection, and mortality rates exceeded 80%. Because of their resistance to all first-line and many second-line antituberculosis medications, these strains are difficult to treat, and early detection and treatment are essential for preventing transmission [8]. This strain is now endemic in New York State and New York City. Methods Cases with strain W were defined as any patient diagnosed with tuberculosis in the United States (excluding New York City and New York State) or Puerto Rico with an M. tuberculosis isolate resistant to at least isoniazid, rifampin, and streptomycin and with a W family DNA fingerprint and/or positive result by the W family specific PCR [3]. Those without an isolate available for DNA testing were defined as a case of strain W if they had strong epidemiologic links to a known strain W case while that case was infectious. Cases were identified through epidemiologic investigations and by surveillance data obtained from CDC-funded RFLP testing laborato-

2 86 Agerton et al. CID 1999;29 (July) Figure 1. DNA fingerprints of Mycobacterium tuberculosis strains W and W1. The figure shows Southern blots of PvuII-digested genomic DNAs from strain W (lane 1) and W1 (lane 2) hybridized with a probe specific for IS6110. ries for isolates whose drug susceptibility patterns and/or DNA fingerprint matched that of strain W or its variants for the period January 1992 through February Cases were also identified from the national tuberculosis surveillance database by use of resistance to isoniazid, rifampin, and streptomycin and lack of susceptibility to kanamycin (isolates either not tested against kanamycin or with missing results) as indicating a possible case. Medical charts of possible cases were reviewed, and DNA fingerprint analysis was done on all available isolates. Results From January 1992 to February 1997, a total of 104,549 cases of tuberculosis were reported to the CDC from the United States (excluding New York City and New York State) and Puerto Rico. Of these, 23 met the case definition for strain W tuberculosis: 13 were primary cases (cases diagnosed outside of New York with no identified source of infection in their state of residence) and 10 were secondary cases (those infected from one of the primary cases). These 23 cases were diagnosed in nine states (California, Colorado, Georgia, Florida, Maryland, New Jersey, Ohio, Pennsylvania, and South Carolina) and Puerto Rico. Isolates were available for DNA fingerprint analysis from 20 cases, cases 1 8 and cases All had fingerprints matching that of the strain W family. Cases 9 11 met the case definition by having a strong epidemiologic link (family and household) to case 8. Table 1 describes characteristics of the tuberculosis cases caused by the strain W family. Cases 2 6 were briefly described by Bifani et al. in 1996 [1]. Of the 23 cases described in table 1, 13 were HIV-positive. Of the 10 HIV-negative cases, 8 were known to have immunocompromising conditions, which included old age, diabetes, high-dose steroid therapy for chronic obstructive pulmonary disease, immunosuppressive treatment following renal transplant, cancer, or long-standing history of alcohol abuse. Of the 23 cases, 5 (3 who were HIV-positive) died before positive culture results were reported and therefore never received treatment for MDR tuberculosis. The remaining 18 all received some length of adequate therapy for strain W M. tuberculosis. Ten were reported as receiving only directly observed therapy (DOT); six received some DOT; and for two, all therapy was self-administered. The median duration of treatment was 6.5 months (range, 4 days to 33 months). Of the 18 cases who received treatment for strain W M. tuberculosis, 5 received appropriate therapy immediately after diagnosis (before culture and susceptibility results were available) because of a known connection to a strain W case. The other 13 began receiving adequate treatment once drug susceptibility test results were reported. For these 13 cases, the median length of time between diagnosis and the start of appropriate therapy was 3 months (range, 1 6 months). Of the 18 cases who received appropriate therapy, 11 (8 HIV-positive) died during treatment; 2 of them died within 1 week of receiving appropriate therapy. Two cases were lost to follow-up within the first 4 months after receiving appropriate treatment; both reportedly returned to their respective countries of birth. As of November 1998, two cases were still receiving therapy. The remaining three all completed at least 18 months of therapy after cultures began yielding negative results for M. tuberculosis. However, one (HIV-negative) of these three cases relapsed within 2 months of completing therapy and died of strain W tuberculosis 3 months later. Overall, 17 (74%) of the 23 cases are known to have died: 11 (85%) of 13 HIV-positive and 6 (60%) of 10 HIV-negative cases. Six HIV-positive and 4 HIV-negative cases died of MDR tuberculosis; the rest died of other causes.

3 CID 1999;29 (July) U.S. Spread of Strain W M. tuberculosis 87 Table 1. Characteristics of cases of tuberculosis due to strain W Mycobacterium tuberculosis. Case State Year of diagnosis Race/sex/age Birth country Exposure risk HIV status Site of disease Sputum Sputum smear culture TST Cavitary lesions Initial drug resistance pattern 1 CA 1996 H/M/43 y US Unk Pos Both Neg Pos Unk No INH-Rif-Stm-Emb-Ethi-Km-Rib 2 CO 1994 B/F/38 y US Inmate/NYC Neg Pulmonary Pos Pos 27 mm Yes INH-Rif-Stm-Emb-PZA-Km-Amik 3 CO 1994 B/M/37 y US Household Pos Pulmonary Pos Pos Neg No INH-Rif-Stm-Emb-PZA-Km-Amik 4 FL 1994 H/F/53 y PR Inpatient/NYC Pos Extrapul None None Unk No INH-Rif-Stm-Emb-Km 5 FL 1995 H/F/34 y DR HCW/NYC Neg Pulmonary Neg Pos 10 mm No INH-Rif-Stm-Emb-Km-Rib 6 GA 1993 W/M/35 y US HCW/NYC Pos Pulmonary Pos Pos Pos Unk INH-Rif-Stm-Emb-Ethi-Km-Rib 7 MD 1994 B/M/38 y US Inmate/NYC Pos Pulmonary Neg Pos Neg No INH-Rif-Stm-Emb-Ethi-Km-Rib 8 NJ 1992 B/F/34 y Haiti Unk Pos Pulmonary Pos Pos Neg Yes INH-Rif-Stm-Emb-Km-Rib 9 NJ 1992 B/F/3 mo Haiti Household Pos Both Pos Pos Neg No INH-Rif-Stm-Emb 10 NJ 1992 B/M/13 mo Haiti Household Pos Pulmonary None None 15 mm No INH-Rif-Stm-Emb-Km-Rib 11 NJ 1995 B/M/41 y Haiti Household Pos Pulmonary Pos Pos Old pos No INH-Rif-Stm-Emb-Km-Rib 12 NJ 1997 W/M/60 y US Unk Neg Pulmonary Neg Pos Neg No INH-Rif-Stm-Emb-Ethi-Km-Rib 13 OH 1992 H/F/25 y PR Inpatient/NYC Pos Both Pos Pos Unk No INH-Rif-Stm-Emb-Ethi-Km-Amik-Cyse 14 OH 1995 W/M/42 y US HCW Neg Pulmonary Pos Pos 23 mm Yes INH-Rif-Stm-Emb-Km-Amik 15 PA 1992 H/M/53 y US Inpatient/NYC Pos Both Neg Pos Neg No INH-Rif-Stm-Emb-Ethi-Km-Rib 16 PA 1995 W/M/47 y US Unk Neg Pulmonary None None Neg No INH-Rif-Stm-Emb-Ethi-Km-Rib 17 PR 1994 H/M/49 y US Unk Neg Pulmonary Pos Pos Unk No INH-Rif-Stm-Emb-Ethi-Cyse-Rib 18 SC 1995 W/M/42 y US Inpatient/NYC Pos Pulmonary Pos Pos 18 mm Yes INH-Rif-Stm-Emb-Ethi-Km-Rib 19 SC 1995 B/M/32 y US Friend Pos Pulmonary Pos Pos Neg Yes INH-Rif-Stm-Emb-Ethi-Km-Rib 20 SC 1995 W/M/54 y US Household Neg Pulmonary Neg Pos Neg Yes INH-Rif-Stm-Emb-Ethi-Km-Rib 21 SC 1995 W/F/82 y US Household Neg Pulmonary Neg Pos 35 mm No INH-Rif-Stm-Emb-Ethi-Km-Rib 22 SC 1995 W/M/60 y US Family Neg Pulmonary Pos Pos Neg Yes INH-Rif-Stm-Emb-Ethi-Km-Rib 23 SC 1995 W/M/78 y US Contact/hospital Neg Pulmonary Pos Pos Neg Yes INH-Rif-Stm-Emb-Ethi-Km-Rib NOTE. Amik amikacin; B Black; Both pulmonary and extrapulmonary; CA California; CO Colorado; Cyse cycloserine; DR Dominican Republic; Emb ethambutol; Ethi ethionamide; Extrapul extrapulmonary; FL Florida; GA Georgia; H Hispanic; HCW health care worker; INH isoniazid; Km kanamycin; MD Maryland; Neg Negative; NJ New Jersey; NYC New York City; OH Ohio; PA Pennsylvania; Pos Positive (but no value available); PR Puerto Rico; PZA pyrazinamide; Rib rifabutin; Rif rifampin; SC South Carolina; Stm streptomycin; TST tuberculin skin test; Unk Unknown; US United States; W White. Five cases, all health care workers (HCWs), had documented skin test conversions before their diagnosis with tuberculosis. Three received preventive therapy at the time of their skin test conversions. One HCW received isoniazid, ethambutol, and pyrazinamide for 12 months, because he was aware that he was exposed to cases of both fully susceptible and strain W tuberculosis at work. The two other HCWs were not aware at the time of their tuberculin skin test conversions that they were infected with strain W M. tuberculosis, and they both received only isoniazid for 6 months. No information was available as to why the remaining two HCWs did not receive preventive therapy. Of the 13 primary cases, 8 are known to have had exposure to strain W in New York City before being diagnosed; 2 were HCWs at hospitals with outbreaks, 4 were inpatients in New York City hospitals that experienced outbreaks of strain W tuberculosis, and 2 others were inmates in New York City jails where strain W tuberculosis outbreaks occurred. Five had no definitive exposure identified. However, two of the five were HIV-positive, had relatives or friends in New York City, and reported visiting them within 2 years before their diagnosis. One HIV-negative primary case was a patient who had no identified risk factor but had cared for an HIV-positive relative in New York City who died of AIDS-related illness. This relative was not known to have tuberculosis, but he had been an HCW in a New York City hospital that had strain W outbreaks (there was no autopsy). Another case was a patient who denies visiting New York City; however, he was an HCW in an urban area adjacent to New York City before his diagnosis. The fifth case with no definitive exposure identified was a patient who denies having been in New York City in the past 10 years, and no potential exposure has been identified. Four of the 13 primary cases who were diagnosed in four different states transmitted strain W to 10 other patients (figure 2) and are described below. Colorado. A strain W variant, W1, was isolated from two patients who were diagnosed as having MDR tuberculosis in 1994 in Colorado. The source case (case 2; table 1), a nursing home employee, had moved in 1993 to Colorado from New York City, where she had been an inmate in a jail experiencing a strain W outbreak. She had a positive tuberculin skin test result (27 mm) in the winter of 1994 on initial employee evaluation at the nursing home, where she worked in the laundry room and did not engage in direct patient care. She received 1 month of preventive therapy with isoniazid, and did not return for follow-up appointments but continued working at the nursing home. She was diagnosed with tuberculosis in the summer of 1994 with sputa positive by smear and culture. The

4 88 Agerton et al. CID 1999;29 (July) Figure 2. Transmission from four cases of tuberculosis due to strain W Mycobacterium tuberculosis diagnosed outside New York. NYC New York City. DNA fingerprint of her isolate matched that of the strain W variant W1. She was successfully treated with a combination of surgical resection and 30 months of DOT with ethionamide, capreomycin, ofloxacin, and para-amino salicylate. The secondary case (case 3; table 1) was a patient who was a household contact of the source case and was identified during the contact investigation of the source case, which began as soon as sputum specimens positive for acid-fast bacilli were reported. An isolate from case 3 also had a DNA fingerprint matching that of variant W1. Case 3 received DOT with ethionamide, capreomycin, ofloxacin, and para-amino salicylate. However, he died 17 months later from causes other than MDR tuberculosis while still receiving treatment for tuberculosis. An extensive investigation was conducted in the nursing home in which case 2 was employed. Seventy-eight coworkers and 98 residents had skin tests placed. Twenty-five of these (6 coworkers and 19 residents) had initial positive skin test results, and 5 (1 coworker and 4 residents) had skin test conversions. Four of these contacts completed 12 months of alternative preventive therapy with ofloxacin. Three household members were also screened around case 2; one had a skin test conversion and received 6 months of ofloxacin. Another was identified as case 3 at the 12-week follow up screening. No additional contacts were screened around case 3, because cases 2 and 3 shared a household and case 2 s investigation was considered to be adequate for both. New Jersey. In June 1992, three cases of strain W were diagnosed in New Jersey. The source case (case 8; table 1) was a woman who had relatives in New York City but did not report a definite exposure to a case of tuberculosis. She was positive for acid-fast bacilli by smear and culture and died 2 years after diagnosis while still receiving DOT with ethionamide, capreomycin, cycloserine, ofloxacin, and para-amino salicylate. Her isolate had the DNA fingerprint pattern W. The other two cases in 1992 were her children, both 2 years old. Both died of MDR tuberculosis caused by strain W within 6 months of diagnosis despite DOT with ethionamide, cycloserine, and ciprofloxacin. No DNA fingerprint testing was done on their isolates. A fourth case (case 11; table 1), a household member of cases 8 10, was diagnosed with MDR tuberculosis caused by strain W in March He began self-administering treatment with isoniazid, rifampin, ethambutol, pyrazinamide, cycloserine, and para-amino salicylate and moved out of the country 3 months after diagnosis while still receiving treatment. The contact investigation around case 8 (which began as soon as sputum smears positive for acid-fast bacilli were reported) identified cases 9 and 10, a family member with a prior positive skin test (case 11), and a fourth household contact (3 years old) who had an initial positive tuberculin skin test. Case 11 had been previously diagnosed in 1989 with culture-positive pleural tuberculosis that was fully susceptible to all tuberculosis medications. He received 12 months of treatment with isoniazid, rifampin, and ethambutol. Since case 11 had a documented history of prior infection with M. tuberculosis, preventive therapy was not offered when the 1992 cases were diagnosed. Despite negative sputum smears and cultures and a normal chest radiograph, the child with a positive skin test was treated for 9 months with a regimen of isoniazid, pyrazinamide, rifampin, and ethambutol. Cases 9 and 10 were in children 2 years old, and since the source case (case 8) for both children

5 CID 1999;29 (July) U.S. Spread of Strain W M. tuberculosis 89 was known, no contact investigations were done around the children. Case 11 left the country soon after his diagnosis, and no contact investigation was conducted around him. Ohio. The source patient (case 13; table 1) had lived in New York City and been seen multiple times in hospital HIV clinics and as an inpatient at a New York City hospital that experienced a strain W outbreak. She often traveled between New York City and Ohio. In August 1992, she was admitted to a hospital in Ohio with fever and a right lower lobe infiltrate seen on chest radiography. After admission, she developed an enlarging supraclavicular node that spontaneously opened. Sputa for testing for acid-fast bacilli were also obtained. The node drainage and sputum specimens were highly positive by smear and culture for acid-fast bacilli and had a DNA fingerprint matching that of strain W. Despite treatment with ciprofloxacin, ethambutol, pyrazinamide, amikacin, ethionamide, and rifabutin, the patient died 1 month after diagnosis. The secondary case (case 14; table 1) was an HCW infected during the autopsy done on the source case. His skin test converted to positive (23 mm) in January 1994 during annual employment skin test evaluation (he had had negative skin tests [0 mm] in April 1991 and November 1992). In January 1994, he began receiving preventive therapy with isoniazid because the source of his infection was not identified as a strain W case. Isoniazid was discontinued after a short time because of side effects. He was diagnosed with tuberculosis in May The DNA fingerprint of his isolate matched that of strain W. He was treated with ethionamide, ciprofloxacin, capreomycin, and cycloserine after susceptibility results were reported. Two months later, cycloserine was discontinued because of changes in his mental status, and ethambutol was added (the isolate was 20% resistant). Four months after beginning therapy, the patient was readmitted to the hospital because of shortness of breath. He had a new consolidation in the right lower lobe and went into respiratory failure 1 day later and was intubated. Sputum specimens were highly positive by smear and culture for acid-fast bacilli. He was treated with IL-2, steroids, ethambutol, pyrazinamide, capreomycin, ofloxacin, cycloserine, ethionamide, and paraamino salicylate. After 2 months, he was discharged from the hospital. Cultures continued to be positive, and the patient s chest radiographs showed his condition to be worsening during the next year. Two years after diagnosis, the patient began to receive total parental nutrition and complained of nausea and vomiting. A regimen of intravenous ampicillin/sulbactam, capreomycin, and ofloxacin was begun, along with ethionamide and IFN-. Two years after his first admission, he was again admitted because of respiratory failure and a consolidation in his left lower lobe and was intubated and treated with steroids, imipenem, ofloxacin, and capreomycin. He was discharged home on this regimen while receiving oxygen. A culture obtained during this admission showed additional resistance to all fluoroquinolones. The patient was treated with DOT with capreomycin, metronidazole, ampicillin/sulbactam, ciprofloxacin, para-amino salicylate, IFN-, and cycloserine until his death in March 1998 from an exsanguinating hemoptysis. Both cases 13 and 14 had smear-positive sputa and were considered infectious. Extensive contact investigations were conducted in the hospitals where these patients were admitted during the course of their illnesses as soon as sputum specimens positive for acid-fast bacilli were reported. A total of 231 HCWs were screened around cases 13 and 14. One HCW who had direct contact with case 13 had a tuberculin skin test conversion and completed 9 months of alternative preventive therapy with pyrazinamide and ciprofloxacin. One hundred thirty-three coworkers of case 14 were screened as contacts. Two had skin test conversions because of direct contact with case 14 during the patient s infectious period. One completed 9 months of alternative preventive therapy with pyrazinamide and ofloxacin; the other began alternative preventive therapy, but it was discontinued because of side effects. No additional contacts of case 13 were investigated. However, 27 friends and relatives and two household members of case 14 were screened. Four of the 27 friends and relatives and both of the household members had initial positive skin tests (none had subsequent conversion). None of these contacts have received alternative preventive therapy, but all are being monitored closely by the health department. None have developed active tuberculosis to date. South Carolina. This 1995 outbreak involved a source case and, after two generations of transmission, five secondary cases [10]. The initial isolate from the source case (case 18; table 1) was resistant to isoniazid, rifampin, streptomycin, ethambutol, ethionamide, rifabutin, and kanamycin and had a DNA fingerprint matching that of strain W1. Case 18 was treated initially with isoniazid, rifampin, pyrazinamide, and ethambutol. Three months later, when susceptibility test results for first-line drugs only were reported, the patient s treatment regimen was altered to ethionamide, cycloserine, and ofloxacin. An isolate collected 3 months after his diagnosis was reported as additionally resistant to pyrazinamide. He has completed 2 years of DOT with this regimen and remains alive and well. The five secondary cases (cases 19 23) have died. Cases 22 and 23 died from MDR tuberculosis before culture results were reported and therefore never received treatment for MDR tuberculosis. Cases 20 and 21 died from other causes, after receiving DOT with ethionamide, cycloserine, and ofloxacin for 3 and 8 months, respectively. Case 19 also died from causes other than MDR tuberculosis after receiving 4 months of DOT with pyrazinamide, capreomycin, ofloxacin, and para-amino salicylate. Four of the secondary cases were in household members and/or relatives of the source case. Case 22 was hospitalized during the course of his illness and transmitted MDR tuberculosis to another hospital patient, case 23, via a contaminated bronchoscope [10].

6 90 Agerton et al. CID 1999;29 (July) None of the five secondary cases had any opportunity to receive alternative preventive therapy. Three of the secondary cases (cases 19 21) were diagnosed within 1 month of the diagnosis of the source case, and two (cases 22 and 23) were not identified as contacts to strain W cases until after their death. Cases 18, 19, 22, and 23 had sputa positive for acid-fast bacilli by smear, and contact investigations were started as soon as positive smear results were reported. There were 89 contacts identified around these cases who completed screening at the time of this investigation. Of these contacts, 10 were household members, 37 were friends or relatives, and 42 were HCWs. Thirty-one contacts (35%) had initial positive or converted tuberculin skin test results (9 household members, 16 friends or relatives, and 6 HCWs). Two of case 18 s household members, cases 20 and 21, developed tuberculosis. The same list of contacts used for case 18 was used for cases 20 and 21 because they were all in the same household. No additional contacts were elicited from cases 20 and 21, both of whom had sputum specimens negative by smear. Of the 31 contacts who had positive or converted skin tests, two were identified as cases (cases 20 and 21) during the contact investigation and were treated for tuberculosis caused by strain W1. Of the remaining 29 contacts, 5 refused any preventive therapy and 5 completed 6 months of preventive therapy with isoniazid. Nineteen contacts were offered alternative preventive therapy with pyrazinamide and ethambutol; most were offered this regimen 6 months after exposure. Six of these contacts were HCWs who had direct contact with case 22 and documented skin test conversions. These six HCWs were not identified as contacts and offered alternative preventive therapy until this outbreak was investigated, 1 year after exposure occurred. Only three contacts completed alternative preventive therapy; however, all known contacts are being closely monitored by the health department. Other contact investigations. Of the remaining nine primary cases with no secondary cases, one (case 4; table 1) was a patient who had only extrapulmonary disease and was not considered infectious. For two others (cases 7 and 15; table 1), information regarding contacts was not known because one patient died before contacts could be elicited and the other was in and out of corrections facilities in more than one state, and information from contact investigations in the prisons was not available. Three cases (cases 1, 5, and 16; table 1) had pulmonary disease but negative results on smear testing of sputum. Twenty-eight contacts (24 HCWs and 4 household members) were identified and screened around these cases after positive culture results were reported. All had negative tuberculin skin tests when screened 12 weeks after exposure to a case. The remaining three cases (cases 1, 6, and 12; table 1) had pulmonary disease and sputum smears positive for acid-fast bacilli, and contact investigations began as soon as the positive results were reported. Eight contacts two household members, two HCWs, and four friends or family members were screened around these cases. Two household members, two HCWs, and two friends had initial positive tuberculin skin test results or skin test conversions when screened, giving transmission rates of 100% for both household and HCW contacts and 50% for friends and family members. Only one of these contacts underwent 6 months of alternative preventive therapy with pyrazinamide and ofloxacin. Discussion Before 1992, the only cases of tuberculosis due to strain W were reported in New York City and New York State. Since then, 23 cases have been diagnosed in nine other states and Puerto Rico. Secondary cases have been documented in four states. The fact that 86 contacts of these 23 cases of tuberculosis appear to be infected by strain W illustrates the magnitude of transmission of this strain outside New York State. Among the 23 cases discussed herein, evidence of transmission of M. tuberculosis caused by strain W was seen only among the cases of pulmonary disease with sputum smears positive for acid-fast bacilli. Of the 17 cases with positive smear results for whom contact investigation information was available, transmission rates ranged from 90% among household members to 4% among HCWs who were screened around these cases. Of the 18 household members of these patients, 6 who had positive tuberculin skin tests or skin test conversions became secondary cases. The contact investigations conducted around these cases varied widely in terms of number of persons screened. There were extensive investigations around cases who were hospitalized, and many HCWs with minimal contact to the case, including the entire worksite staff around one case, were screened because of hospital policy or to address the concerns of the workers. Not all of these persons had direct contact with an infectious case; therefore, the inclusion of them in the denominator for conversion rates undoubtedly underestimates these rates. The purpose of contact investigations around tuberculosis cases is to identify infected persons and administer preventive therapy to reduce the risk of disease for these contacts. Recommendations for preventive therapy for those infected with M. tuberculosis strains resistant to both isoniazid and rifampin include a regimen of pyrazinamide and ethambutol [11]. However, members of the strain W family are typically resistant to ethambutol; therefore, pyrazinamide and a quinolone are recommended for preventive therapy for those infected with strain W [11]. However, many strain W M. tuberculosis isolates are also resistant to pyrazinamide, and thus no potential alternative preventive therapy is available when this situation occurs. When alternative preventive therapy is possible, it should be offered to infected contacts of cases with strain W, with the advisement that the protective gains are unknown and may be outweighed by the potential side effects of the drugs. Two

7 CID 1999;29 (July) U.S. Spread of Strain W M. tuberculosis 91 studies demonstrated high rates of intolerance (including elevated aminotransferase levels) to preventive therapy with ofloxacin and pyrazinamide [12, 13]. In both studies, adverse effects due to alternative preventive therapy caused the regimen to be discontinued within the first 6 months in the majority of the participants. Also, one study that involved HCWs infected with MDR tuberculosis reported a very low acceptance rate (56%) of the alternative preventive therapy [13]. The CDC has been collecting information from multiple sources about the rates of completion of therapy associated with alternative preventive therapy [14, 15]. These sources reported completion rates as low as 65%. Low acceptance rates for alternative preventive therapy are most likely due to the known increased risk of adverse effects and to the lack of efficacy studies available for this regimen. However, it will be years before the efficacy of this regimen is known in persons known to be infected with MDR tuberculosis, if efficacy is established. With declining rates in MDR tuberculosis in this country combined with low acceptance and completion rates associated with this regimen, conducting such efficacy studies would be difficult [14]. Table 1 illustrates the varying drug resistance patterns seen in strain W cases; some isolates were initially resistant to pyrazinamide. One patient (case 18) received initial therapy with isoniazid, rifampin, ethambutol, and pyrazinamide before drug susceptibility results were known; since this particular strain of M. tuberculosis is resistant to isoniazid, rifampin, and ethambutol, it is likely that acquired resistance to pyrazinamide developed in his strain W isolate. For the infected contacts of cases whose isolates are also resistant to pyrazinamide, there is no recommended preventive therapy regimen. This was the situation for some of the infected contacts identified in the contact investigations presented herein. The CDC received information that some clinicians have used ofloxacin alone, but there are no data available on the ability of this drug to prevent disease in infected contacts. All infected contacts and their physicians should be educated about the strain of M. tuberculosis with which they are infected. In addition, all contacts who are ineligible for or decline alternative preventive therapy should be closely monitored, with symptom checks and chest radiographs every 6 months, for the 2 years after the contact has been identified as likely infected with strain W M. tuberculosis the time period when contacts are at the greatest risk for progressing from infection to active disease [11]. Although strain W is typically resistant to isoniazid, rifampin, streptomycin, ethambutol, ethionamide, rifabutin, and kanamycin, the resistance patterns outlined in table 1 illustrate that the drug resistance patterns of strain W isolates can vary. For example, in case 17, the isolate was resistant to cycloserine but not to kanamycin, a resistance pattern not seen in any of the other 22 strain W cases discussed. Because of these variations, it is important that susceptibility testing for all available second-line drugs (including ethionamide, kanamycin, cycloserine, capreomycin, para-amino salicylic acid, amikacin, rifabutin, ciprofloxacin, and ofloxacin) should be done for all isolates that show resistance to first-line drugs [16 18]. This information is necessary to determine adequate treatment for tuberculosis cases and appropriate preventive therapy for contacts. Additionally, susceptibility testing should be done for isolates collected during the course of therapy if the patient is still culture-positive 2 3 months after treatment started, since it is possible to acquire additional drug resistance [16 18]. The tuberculosis outbreaks caused by strain W in New York involved hundreds of patients, most of whom were HIVinfected and severely immunocompromised from AIDS [1, 4 9]. The mortality rates in these outbreaks were as high as 80% [1, 4 9]. Mortality for the 23 cases outlined above was also very high, 74% overall (85% for HIV-positive and 60% for HIV-negative patients). Ten of the 17 deaths were attributed to MDR tuberculosis. Of the six HIV-negative patients who died, five had other immunocompromising conditions that undoubtedly adversely affected their outcome. This demonstrates that when other immunocompromising conditions (e.g., old age, diabetes, cancer) are present, MDR tuberculosis caused by strain W can be particularly deadly for HIV-negative persons. Early clinical suspicion and detection of MDR tuberculosis as well as prompt initiation of appropriate DOT are critical for successful treatment of this strain [8]. MDR tuberculosis is spreading to areas that have rarely experienced MDR tuberculosis because of the mobility of the U.S. population. Also, there is a reservoir of persons who became infected with strain W during the large nosocomial outbreaks in New York City in the late 1980s and early 1990s. Because preventive therapy for these persons has no proven efficacy, many of these infected persons may become strain W tuberculosis cases in the future. We do not know exactly how many strain W cases would be expected outside of New York over this 5-year period. We did extensive searches through multiple data sources to identify the cases outlined herein and feel confident that we have identified all cases known to state and local health departments. However, since some of the 23 patients outlined in this paper have no identified contact to a known strain W case and reportedly spent little or no time in New York, there are probably unidentified cases outside New York who served as their source. Thus, we think that these 23 cases are a minimal estimate of the strain W cases outside New York. Therefore, it is important for state and local health departments to increase their vigilance and surveillance for MDR tuberculosis. Health care providers should be educated about these issues and informed if MDR tuberculosis is in the community. The Division of Tuberculosis Elimination at the CDC should be notified (phone: [404] ; fax: [404] ) if a case of MDR tuberculosis shows resistance to isoniazid, rifampin, streptomycin, and kanamycin; if the case is suspected to be due to strain W; or if the isolate has a DNA fingerprint matching

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