Limited Transmission of Multidrug-Resistant Tuberculosis Despite a High Proportion of Infectious Cases in Los Angeles County, California ANNETTE T. NITTA, LAURA S. KNOWLES, JAIMIN KIM, ELEANOR L. LEHNKERING, LEE A. BORENSTEIN, PAUL T. DAVIDSON, SYDNEY M. HARVEY, and MURIEL L. DE KONING Tuberculosis Control Program, Public Health, Los Angeles County Department of Health Services; University of California, Los Angeles, School of Medicine or Public Health; Public Health Laboratory, Los Angeles County Department of Health Services; and University of Southern California, School of Medicine, Los Angeles, California
Preventing transmission of multidrug-resistant tuberculosis is critical because of treatment toxicity, cost, and the lack of effective therapy for latent infection. We attempted to determine the extent of transmission in Los Angeles County by comparing relatedness of multidrug-resistant tuberculosis cases using restriction fragment length polymorphism and by cross-matching contact information to the Tuberculosis Registry. Strain typing was done on isolates of 102 pulmonary multidrug-resistant cases identified between August 1993 and 1998. Seventy-one (70%) of the cases had cavitary lesions on chest radiograph, and 94 (92%) had sputa smear-positive for acid fast bacilli. Fifteen (15%) of the cases were known to be infected with human immunodeficiency virus. Four molecular clusters of two cases each and one closely related pair were identified among the 102 cases; contact investigation successfully identified all clusters but one. Among 946 contacts identified and cross-matched with the county’s Tuberculosis Registry, one secondary case due to drug-resistant Mycobacterium bovis was found. To summarize, a very high proportion of pulmonary multidrug-resistant tuberculosis cases in Los Angeles County were infectious. Molecular strain typing indicated limited spread of disease, although it underestimated transmission compared with contact investigation. We believe aggressive surveillance and case management were critical to limiting the spread of multidrugresistant tuberculosis. Keywords: tuberculosis; multidrug-resistant; transmission
Outbreaks of multidrug-resistant tuberculosis (MDR-TB) prior to 1986 were sporadic and rare (1,2), but recent outbreaks of MDR-TB occurred in hospitals and correctional institutions and involved many persons with human immunodeficiency virus (HIV) whose mortality rates were high (3). Immigration, the decline of tuberculosis (TB) control programs, the concurrent HIV epidemic, and socioeconomic problems converged in New York City (NYC), which reported 62% of the nation’s MDR-TB cases in 1991 (4–7). Nosocomial clustering of MDR-TB cases in NYC was demonstrated (8). Los Angeles County (LAC) reported the second highest number of TB cases among all metropolitan areas between 1993 and 1997, and a third of California’s cases (9, 10). Despite evidence of recent TB transmission in LAC (11), an MDR-TB outbreak in an adjacent county (12), and social factors similar to those in NYC, the proportion of MDR-TB cases in LAC between 1993 and 1997 remained low (0.7–2.3%) compared
(Received in original form March 26, 2001; accepted in final form November 29, 2001) Correspondence and requests for reprints should be addressed to Annette T. Nitta, M.D., Assistant Director, TB Control Program, 2615 South Grand Avenue, Room 507, Los Angeles, CA 90007. E-mail:
[email protected] Am J Respir Crit Care Med Vol 165. pp 812–817, 2002 DOI: 10.1164/rccm.2103109 Internet address: www.atsjournals.org
with NYC (19%, April 1991) (5). Given the limitations of conventional contact investigation (CI) (13–15), investigating the undetected transmission of MDR-TB was vital because there is no therapy with proven efficacy for latent MDR-TB (16) and treatment of MDR-TB disease requires extended use of toxic, less effective drugs given by daily directly observed therapy (DOT) (17). Because MDR-TB always originates from mismanagement (18), it is an indicator of public health program failure (19). We describe our epidemiologic analysis of the MDR-TB cases in LAC, our use of molecular typing to identify undetected transmission, and the interventions we believe prevented local outbreaks of MDR-TB.
METHODS Patient Identification and Data Collection Between August 1993 and 1998, susceptibility reports were reviewed to identify new cases of MDR-TB (defined as Mycobacterium tuberculosis complex resistant to at least isoniazid and rifampin). Cases from Pasadena and Long Beach (independent reporting jurisdictions) were excluded. A case was defined as someone whose clinical data supported the diagnosis of pulmonary MDR-TB, and who submitted specimen(s) that grew MDR-TB. The MDR-TB Unit consulted on and assisted with comanaging all MDR-TB cases. Under the authority of the California Health and Safety Code (20), medical records were reviewed to collect data including birthdate, address, sex, birth country, ethnicity, disease site(s), microbiologic results, radiographic findings, treatment history, and HIV risk factors. Initial MDR-TB was defined as disease in someone whose treatment history was unclear; primary MDR-TB was disease in someone with no prior TB treatment; acquired MDR-TB was disease in someone previously treated for at least 1 mo with at least two antituberculosis drugs to which resistance was later documented. Demographic traits of the MDR-TB cases were compared with pulmonary nonmultidrug-resistant TB cases confirmed during the same time period.
Contact Investigation Contacts of MDR-TB cases were identified and tested by the health department or private health care providers according to previously described methods (21). Contact information was cross-matched with the county’s Tuberculosis Registry to identify secondary cases among contacts. Data collected included birthdate, all documented tuberculin skin test (TST) dates and results, and chest radiograph results. If a contact developed MDR-TB disease, data on the index case were recorded. Because the majority of contacts were foreign born and previously immunized with bacillus Calmette–Guérin (BCG), induration on skin testing could represent boosted or cross reaction to BCG rather than true infection (22). Therefore, TST conversion was defined as a baseline TST of 5 mm followed by an increase of 10 mm of induration between TSTs done within 2 yr. For contacts less than 4 yr old, we defined conversion as an initial TST 10 mm in a foreign-born child or 5 mm in a U.S.-born contact because it indicated recent infection.
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Figure 1. Geographic distribution of pulmonary MDR-TB cases, Los Angeles County, California, August 1993–1998 (n 102).
Restriction Fragment Length Polymorphism (RFLP) Analysis RFLP was performed on all available isolates from pulmonary MDR-TB cases and secondary cases. Strain typing using IS6110 was performed according to methods described by van Embden and coworkers (23). Analysis with pTBN12 using methods described by Chaves and coworkers (24) was done to provide greater strain discrimination on isolates with less than six IS6110 bands and on isolates of secondary cases whose IS6110 fingerprint patterns differed by only one band compared with those of the index cases. A molecular cluster was defined as two or more persons whose organisms (1) had identical IS6110 patterns containing six or more IS6110 fragments or (2) had identical IS6110 and pTBN12 patterns, if fewer than six IS6110 fragments were present.
Statistical and Epidemiologic Analyses Descriptive analyses were performed using SAS 8 (SAS Institute, Cary, NC). Univariate analyses were conducted using 2 test for categorical variables and Student’s t test for continuous variables. An value of 0.05 defined significance. Spatial distribution of the MDR-TB cases was evaluated to elucidate further epidemiologic relationships using MapInfo 3.0 (MapInfo Corp., Troy, NY).
RESULTS Between August 1993 and 1998, 149 culture-positive cases of active pulmonary MDR-TB were identified by the LAC Tuberculosis Control Program. Based on our past experience (25), we ultimately excluded 14 cases (9%) because the diagnosis of MDR-TB did not fit the clinical picture for the following nonexclusive reasons: a single positive culture with no clinical evidence of TB (six cases), cure achieved using drugs showing in vitro resistance (six cases), no resistance on repeat testing (two cases), no evidence of TB at autopsy (one case), and specimen mislabeling (one case). (In the same period, four extrapulmonary MDR-TB cases were reported but were excluded from
our series because their risk to transmit was low.) Of the 135 verified cases of pulmonary MDR-TB, 102 (76%) had viable cultures for RFLP analysis. The age range of the 102 cases was from 15 to 79 yr with a median age of 43 yr. Seventy-one (70%) of the 102 cases had cavitary lesions on chest radiograph, and 94 (92%) submitted sputa that were smear-positive for acid fast bacilli (AFB). One hundred (98%) of the 102 MDR-TB cases with viable cultures had disease due to M. tuberculosis; two (2%) had disease due to M. bovis. Of the 33 patients whose isolates were not fingerprinted, isolates of 31 cases were unavailable and two were nonviable. The following factors were analyzed to determine if differences existed between the study population and the cases whose isolates were not strain typed: sex, birth outside the United States, ethnicity, homelessness, injection drug use, alcohol abuse, HIV serostatus, sputum smear positivity for AFB, and type of MDR-TB (i.e., initial, primary, or acquired). No significant differences were found. The geographic distribution of the 102 cases of MDR-TB is shown in Figure 1. Although cases were scattered across the county, they were closely grouped together in the central health districts that have the highest population densities. Table 1 shows the demographic and clinical data for the 102 cases whose isolates were analyzed by RFLP. Most of the 102 cases of pulmonary MDR-TB were men, born outside the United States, and had acquired MDR-TB. Of the 76 patients with acquired MDR-TB, six were diagnosed with MDR-TB prior to arriving in LAC (median 1 yr, range 2 mo to 2 yr). Another six cases with acquired disease were diagnosed with MDR-TB almost immediately after arrival in LAC. The remaining 64 cases lived in LAC with a diagnosis of TB for a median of 6 mo (range 1 month to 7.2 yr) prior to being diagnosed with MDR-TB.
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TABLE 1. CHARACTERISTICS OF CULTURE-CONFIRMED PULMONARY TB CASES, LOS ANGELES COUNTY, CALIFORNIA, AUGUST 1993–1998 Trait Sex Male Female Country of origin‡ United States Outside the United States Mexico Korea Philippines Vietnam Ethnicity Hispanic Asian Black White Homelessness Alcohol abuse Use of injectable drugs Smear-positive Cavitary lesion on CXR HIV infection
MDR-TB Cases* (N 102 [%])
Non-MDR-TB Cases† (No./N [%])
70 (69%) 32 (31%)
3,403/4,987 (68%) 1,584/4,987 (32%)
0.93
21 (21%) 81 (79%) 29 (28%) 16 (16%) 9 (9%) 8 (8%)
1,541/4,986 (31%) 3,445/4,986 (69%) 1,312/4,986 (26%) 260/4,986 (5%) 486/4,986 (10%) 242/4,986 (5%)
0.03
51 (50%) 36 (35%) 12 (12%) 3 (3%) 8 (8%) 23 (23%) 6 (6%) 94 (92%) 71 (70%) 15 (15%)
2,172/4,984 (44%) 1,359/4,984 (27%) 911/4,984 (18%) 526/4,984 (11%) 577/4,634 (12%) 768/3,841 (20%) 244/3,848 (6%) 2,933/4,980 (59%) 1,048/4,946 (21%) 721/3,147 (23%)
0.02
p Value
0.16 0.52 0.89 0.01 0.01 0.18
Definition of abbreviations: CXR chest radiograph; MDR-TB multidrug-resistant tuberculosis. * Cases of culture-confirmed pulmonary MDR-TB with RFLP results. † Data may be incomplete due to deletion of low-frequency values, missing information, and/or changes in reporting criteria implemented in 1993. ‡ Top five of total of 13 countries of origin shown.
Fifteen (15%) of the 102 cases were known to be HIV infected; all of these were men. The risk factor for HIV infection for 9 (60%) of the 15 cases with MDR-TB and AIDS was sexual activity with other men. Four (27%) of the cases had used injection drugs, one (7%) had reported having multiple sex partners, and one (7%) had received a blood transfusion before 1985. CD4 counts of the HIV-infected cases near the time MDR-TB was diagnosed ranged from 3/mm3 to 231/mm3 with a median of 13/mm3. Table 1 compares traits of the 102 MDR-TB cases versus those of pulmonary TB cases whose organisms were not multidrug resistant. The MDR-TB cases were significantly more likely to be foreign born and of Hispanic or Asian ancestry, and more likely to have smear-positive sputa and cavitary lung lesions on chest radiograph. Although not significant, MDR-TB cases were less likely to be HIV infected. A total of 946 contacts to the 102 cases of MDR-TB were identified. The number of contacts per case ranged from 0 to 99 with an average of nine contacts per case and a median of six. CI failed to find contacts for five cases (5%). Eight contacts (0.8%) were HIV infected. CI standards did not require routine testing for HIV or documentation of HIV serostatus. TST conversions were noted in 58 (6%) of the contacts. Twentythree (40%) of the converters were younger than 4 yr old, and three converters (5%) developed MDR-TB disease. Of the four extrapulmonary cases excluded from our series, one had no available isolate; RFLP patterns of the remaining three were unique. Of the 102 pulmonary MDR-TB cases included in our series, RFLP using IS6110 identified four molecular clusters containing two cases each (Figure 2). The drug resistance patterns of the index and secondary cases are shown in Table 2. Conventional CI established that persons in three of the four molecular clusters shared a household. Both cases in only one of the molecular clusters with known epidemiologic links were HIV infected. The solitary molecular clus-
Figure 2. MDR-TB index and secondary cases occurring between August 1993 and 1998 identified by contact investigation or RFLP analysis. Alphanumeric designations correlate with Table 2. Unless otherwise specified, even-numbered lanes are index cases and odd-numbered lanes are secondary cases. (A) IS6110 fingerprints: lanes 1 and 12, M. tuberculosis reference strain Mt14323; lanes 2 and 3, cluster 1; lanes 4 and 5, cluster 2; lanes 6 and 7, cluster 3; lanes 8 and 9, siblings who shared a home; lanes 10 and 11, siblings with drug-resistant M. bovis. Note: RFLP analysis of two patients in cluster 4 was performed by California State Microbial Diseases Laboratory (image not available); both patients had identical IS6110 fingerprints with 8 bands. (B) pTBN12 fingerprints: lanes 1 and 10, M. tuberculosis reference strain H37RV; lanes 2 and 3, cluster 2; lanes 4 and 5, cluster 3; lanes 6 and 7, siblings who shared a home; lanes 8 and 9, siblings with drug-resistant M. bovis.
ter of MDR-TB cases with no known epidemiologic links was comprised of one HIV-seronegative person who was foreignborn, had lived outside California for most of his life, and had worked as a manual laborer; and one HIV-seropositive person who was born in the United States, had lived in LAC all his life, and was a health care worker. There was no known contact between these two cases. Two siblings sharing a home sequentially developed MDR-TB with identical drug resistance patterns (Table 2). Although the IS6110 RFLP patterns of their isolates differed by three bands, pTBN12 fingerprints were identical. Cross-matching of contact information to the Tuberculosis Registry of LAC identified no additional TB cases among 163 contacts to the 33 pulmonary MDR-TB cases who were excluded due to isolate unavailability. However, six additional TB cases were identified among contacts to the 102 cases included in our series. Three of the additional cases were TST converters who had culture-negative TB, one had drug-sensitive TB but no viable culture for RFLP, and one had INHresistant TB with an RFLP pattern different from that of the index case. One of the six additional cases identified by both CI and registry cross-matching had a single band IS6110 RFLP pattern identical to that of the index case, however, the pTBN12 pattern differed by one band and did not meet our definition of a molecular cluster (Figure 2); both cases were siblings who had TB due to drug-resistant M. bovis (Table 2).
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Nitta, Knowles, Kim, et al.: MDR-TB in Los Angeles TABLE 2. DRUG RESISTANCE PATTERNS OF INDEX AND SECONDARY CASES IDENTIFIED BY RFLP ANALYSIS OR CONTACT INVESTIGATION Clusters or Related Pairs 1 2 3
Susceptibility Pattern† Patient*
INH
RIF
EMB
PZA
SM
AK
CIP
CM
CS
ETA
KM
OFL
PAS
A2 A3 A4, B2 A5, B3 A6, B4 A7, B5
R R R R R R R R R R R S
R R R R R R R R R R R R
R R S S S S S S S S S S
R R S S S S S S S S R R
R R S S S S S S S S S S
S R
R R
R R S S S S S S S S S S
R S
R S S S S S S R S S S S
R R R S S S S S S S S S
R R S S S S R R S S S S
R S S S S S S S S S
4‡ 5 6
A8, B6 A9, B7 A10, B8 A11, B9
S S
S S
S S S S S S
Definition of abbreviations: R resistant; S sensitive; first-line drugs: EMB ethambutol; INH isoniazid; PZA pyrazinamide; RIF rifampin; SM streptomycin. Second-line drugs: AK amikacin; CIP ciprofloxacin; CM capreomycin; CS cycloserine; ETA ethionamide; KM kanamycin; OFL ofloxacin; PAS para-aminosalicylic acid; RFLP restriction fragment length polymorphism. * Alphanumeric patient label corresponds to lane designations in Figures 2A and 2B; index cases are listed above secondary cases in each related pair. † Drugs listed are those to which susceptibility testing was done for both index and secondary cases. ‡ RFLP images for cases in this cluster were unavailable.
DISCUSSION Most cases in our series had cavitary lung lesions and smearpositive sputa indicating infectiousness; these traits were significantly more common among the MDR-TB cases compared with cases of nonmultidrug-resistant TB confirmed in the same period. Similar findings in MDR-TB cases have been reported by others (26) and may reflect the difficulty of eliminating the millions of organisms contained in cavitary lung lesions using medical therapy alone (27). Failure of medications to fully suppress bacillary replication may select for resistant strains (28). The high proportion of cases with acquired MDR-TB is also troubling as it indicates inadequate prior treatment attempts. Most of these cases lived in LAC with a diagnosis of TB for a median of 6 mo prior to being diagnosed with MDR-TB. Additionally, seven (7%) of our cases had primary MDR-TB with clearly identified contact to infectious index cases. We believe aggressive CI contributed to limiting the spread of MDR-TB in LAC. DOT is also vital as it prevents the selection of additional resistance by precluding the erratic administration of antituberculosis medications (29). M. bovis caused drug-resistant TB in two of our cases. Human TB due to M. bovis was previously reported in California (30). Although the early literature questioned aerosolized person-to-person transmission (31), a nosocomial outbreak (32) and other descriptions of human disease due to this organism (33) confirm respiratory transmission between humans. Eighty percent of our MDR-TB cases were foreign born, originating from 13 countries, mostly from Mexico. This is not surprising as Los Angeles is one of eight ports of entry to the United States (34). Overall, the proportion of TB patients who were foreign born in LAC increased from 62% of 1,495 cases in 1985 to 72% of 1,299 cases in 1998. Compared with TB cases whose organisms were not multidrug resistant, the 102 MDR-TB cases were significantly more likely to be foreign born, nonwhite, and of Hispanic or Asian ethnicity; this may be indicative of poor public health infrastructures in our cases’ home countries. Contacts were identified for most (95%) of the 102 MDR-TB cases whose strains were typed. The proportion of cases without identified contacts (5%) was slightly lower than results reported by the Centers for Disease Control (CDC) in a recent
evaluation of CI outcomes in populous metropolitan areas (35). However, it cannot be assumed that cases who initially name no contacts or lack stable housing truly have no identifiable contacts as at least one study documented the ability of homeless persons to acknowledge and recognize contacts (36). Because most cases in our series were infectious, there is clearly room for improvement in CI activities. Of the 946 contacts identified, TST conversions were documented in 58 (6%). This is considerably lower than the proportion of converters previously reported among contacts to inner city pulmonary TB cases (37), but 40% of converters in our series were less than 4 yr old. This is troubling because it indicates recent TB transmission, and there remains no treatment with proven efficacy for treating latent MDR-TB. Because active disease is more likely to develop within a few years after infection (16), it is not surprising that three (5%) of the converters in our series developed MDR-TB disease in the period analyzed. However, other converters may not develop active MDR-TB disease until years hence. This reemphasizes the need for improvement in CI with more rapid identification of new cases so that appropriate treatment to render them noninfectious can begin promptly. In our series of MDR-TB cases, only four clusters of two cases each were identified by RFLP analysis. Cross-matching of contact data with our program’s case registry identified an additional six cases; none had RFLP patterns that clustered with an index case using currently accepted criteria. These findings are unique in several ways. First, clusters in our series consisted of only two cases each whereas other transmission studies using RFLP have documented much larger cluster sizes (13, 38). Second, only 15% of our MDR-TB cases were HIV seropositive, and HIV infection was less common than in TB cases that were not multidrug resistant. In contrast, HIV has been associated with both clustering and drug resistance in other patient populations (5, 8, 13, 39). Third, in contrast with prior reports of TB transmission documented by RFLP versus epidemiologic investigations (13, 15, 40), conventional CI in our series failed to identify only one cryptic cluster of two MDR-TB cases but did identify two incidents of transmission that were missed using current molecular criteria. By the time our analysis began, the outbreaks of MDR-TB in NYC were well publicized, even in the lay press. Thus, CI for the MDR-TB cases in LAC may have
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been especially meticulous, leaving few cases with unknown epidemiologic links. Also, our findings of limited transmission of MDR-TB in LAC using molecular analysis are consistent with trends in the state of California where the proportion of culture-confirmed cases of MDR-TB remained low at less than 1.7% between 1994 and 1998 (9). Factors that fueled outbreaks of MDR-TB in NYC certainly exist in LAC, but major differences between the two health jurisdictions may account for the limited spread of MDR-TB in Los Angeles. Southern California’s climate is more temperate than that of NYC, making it possible to spend less time indoors in the winter and to leave windows open. Because droplet nuclei can remain suspended for hours in enclosed spaces with poor intake of fresh air (41), climate may partly account for the limited transmission of MDR-TB in LAC. Also, the population density in LAC is estimated to be only 2,298 persons per square mile compared with 28,431 and 54,642 persons per square mile in Bronx County and New York County, New York, respectively (42). There are also differences in HIV transmission between the two coasts of the United States. In NYC, injection drug use is the most common mode of HIV transmission (43), but in LAC, HIV is more commonly transmitted by men having sex with men (44). These factors may partly account for differences in MDR-TB transmission by mechanisms not yet fully understood. We believe the centralized consultation and tracking unit within the TB Control Program in LAC may have also played a role in preventing outbreaks of MDR-TB. In August 1993, a physician and public health nurse were hired to monitor all MDR-TB cases in the county. Susceptibility reports showing resistance to both INH and rifampin trigger a thorough review of all available medical records; formulation of a tabular, chronologic summary of all known mycobacteriologic results and treatment changes; and issuance of written consultation to guide case management. The MDR-TB Unit assists with directing CI activities, identifying specialized services (e.g., thoracic surgery) as indicated, and monitoring the progress of each case through completion of therapy and for 2 yr thereafter. In our experience, physicians caring for the MDR-TB cases in both the private and public sectors generally welcomed programmatic intervention and guidance because of their lack of familiarity with MDR-TB. We believe our results demonstrate the benefits of the World Health Organization’s recommendation to create and maintain a specialized unit to manage MDR-TB cases (19). Repositories of expert knowledge in MDR-TB management will become more essential as TB recedes further in the United States while drug resistance increases globally. Our study was limited by several factors. First, isolates for strain typing were unavailable for 24% of the pulmonary culture-confirmed cases identified during the study period because laboratories in California were not required to send subcultures to the public health laboratory before 1996 (45). Second, amplification-based strain typing was not used to characterize nonviable MDR-TB strains. Third, RFLP analysis of all strains in LAC was not done due to lack of feasibility in a large jurisdiction (46). However, occult transmission of TB in LAC does not appear to be a major problem as the total number of new cases has fallen annually since 1992, and the TB rate in young children has not increased. Fourth, the study period covered only 5 yr. Fifth, cross-matching contact data to our case registry could have identified only contacts who were later reported as cases in LAC. Sixth, cluster criteria based primarily on RFLP results may have underestimated MDR-TB transmission. Two siblings in a home developed MDR-TB with identical resistance and pTBN12 patterns, but they did not meet molecular cluster criteria due to the three-band differ-
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ence between the IS6110 fingerprints. Also, the index and secondary cases of drug-resistant M. bovis shared a home but were not considered a cluster because their pTBN12 fingerprints differed by one band. Thus, we believe widely accepted criteria may undervalue the importance of CI in determining transmission. Finally, information on cases and contacts was extracted from and limited to contents of medical records. In conclusion, a very high proportion of pulmonary MDR-TB cases in LAC were smear and culture positive, and most had cavitary lung disease. However, RFLP results indicate limited spread of MDR-TB, even among HIV-infected persons. Moreover, conventional CI successfully identified all but one molecular cluster of cases. We believe aggressive surveillance and case management were critical in limiting the spread of MDR-TB in LAC. References 1. Centers for Disease Control. Outbreak of multidrug-resistant tuberculosis—Texas, California, and Pennsylvania. MMWR Morb Mortal Wkly Rep 1990;39:369–372. 2. Kent JH. The epidemiology of multidrug-resistant tuberculosis in the United States. Med Clin North Am 1993;77:1391–1409. 3. Dooley SW, Jarvis WR, Martone WJ, Snider DE Jr. Multidrug-resistant tuberculosis. Ann Intern Med 1992;117:257–259. 4. Binkin NJ, Vernon AA, Simone PM, McCray E, Miller BI, Schieffelbein CW, Castro KG. Tuberculosis prevention and control activities in the United States: an overview of the organization of tuberculosis control services. Int J Tuberc Lung Dis 1999;3:663–674. 5. Frieden TR, Sterling T, Pablos-Mendez A, Kilburn JO, Cauthen GM, Dooley SW. The emergence of drug-resistant tuberculosis in New York City. N Engl J Med 1993;328:521–526. 6. Reichman LB. The U-shaped curve of concern. Am Rev Respir Dis 1991; 144:741–742. 7. Moore M, Onorato IM, McCray E, Castro KG. Trends in drug-resistant tuberculosis in the United States, 1993–1996. JAMA 1997;278:833–837. 8. Alland D, Kalkut GE, Moss AR, McAdam RA, Hahn JA, Bosworth W, Drucker E, Bloom BR. Transmission of tuberculosis in New York City: an analysis by DNA fingerprinting and conventional epidemiologic methods. N Engl J Med 1994;330:1710–1716. 9. U.S. Department of Health and Human Services. Reported tuberculosis in the United States 1993–1997. Atlanta: Centers for Disease Control and Prevention; 1994–1998. 10. California Department of Health Services. Report on tuberculosis in California, 1998. Berkeley: California Department of Health Services; 1999. 11. Barnes PF, El-Hajj H, Preston-Martin S, Cave MD, Jones BE, Otaya M, Pogoda J, Eisenbach KD. Transmission of tuberculosis among the urban homeless. JAMA 1996;275:305–307. 12. Ridzon R, Kent JH, Valway S, Weismuller P, Maxwell R, Elcock M, Meador J, Royce S, Shefer A, Smith P. Outbreak of drug-resistant tuberculosis with second-generation transmission in a high school in California. J Pediatr 1997;131:863–868. 13. Small PM, Hopewell PC, Singh SP, Paz A, Parsonnet J, Ruston DC, Schecter GP, Daley CL, Schoolnik GK. The epidemiology of tuberculosis in San Francisco: a population-based study using conventional and molecular methods. N Engl J Med 1994; 330:1703–1709. 14. Kiers A, Drost AP, van Soolingen D, Veen J. Use of DNA fingerprinting in international source case finding during a large outbreak of tuberculosis in The Netherlands. Int J Tuberc Lung Dis 1997;1:239–245. 15. Behr MA, Hopewell PC, Paz EA, Kawamura LM, Schecter GF, Small PM. Predictive value of contact investigation for identifying recent transmission of Mycobacterium tuberculosis. Am J Respir Crit Care Med 1998;158:465–469. 16. Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001;345:189–200. 17. Goble M. Drug resistance. In: Friedman LN, editor. Tuberculosis: current concepts and treatment. Boca Raton, FL: CRC Press; 1994. p. 259–284. 18. Mahmoudi A, Iseman MD. Pitfalls in the care of patients with tuberculosis: common errors and their association with the acquisition of drug resistance. JAMA 1993;270:65–68. 19. Crofton J, Chaulet P, Maher D, Grosset J, Harris W, Horne N, Iseman M, Watt B. Guidelines for the management of drug-resistant tuberculosis. Geneva: World Health Organization; 1997. 20. California Health and Safety Code, §121365 (West 1996).
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