Multi-drug Resistant TB Persists in California

Despite significant advances in reducing the number of cases of tuberculosis in California, the proportion of multi-drug resistant cases has not decreased but remains steady, according to a study in the June 8 issue of JAMA, a theme issue on tuberculosis.

Lead author Reuben M. Granich, MD, MPH, of the Centers for Disease Control and Prevention (CDC) presented the findings of the study at a JAMA media briefing on tuberculosis at the National Press Club.

The number of tuberculosis (TB) notified cases has decreased by 33 percent in California, from 1994 to 2003, according to background information in the article. TB nevertheless continues to have a substantial public health impact, leading to 233 deaths in 2003. California led the nation in 2003 in the number of cases. Additionally, cases of TB due to strains of Mycobacterium tuberculosis that are at least resistant to the mainstay first-line drugs isoniazid and rifampin (i.e., multidrug-resistant [MDR] strains) continue to appear in California despite high rates of treatment success. The emergence of these life-threatening, airborne strains, which require prolonged treatment for at least 18 months and exhibit higher rates of treatment failure and poorer outcomes, threatens the efficacy of TB control efforts.

Treatment of patients with drug resistance requires considerable expertise and resources; health care cost estimates for individual MDR TB patients in the United States range from $28,217 to $1,278,066. MDR TB has also been associated with serious sizeable hospital and community outbreaks in California and the greater United States.

Granich and colleagues analyzed drug susceptibility data in the California TB surveillance system to describe the magnitude, trends, geographic distribution, clinical characteristics, risk factors, and outcomes of drug-resistant TB cases to better understand the impact of resistance to multiple drugs on TB control in California and to plan public health interventions. The analysis included 38,291 TB cases reported from all 61 local health jurisdictions in California during 1994-2003. Multidrug-resistant TB was defined as resistance to at least isoniazid and rifampin.

Of 38,291 reported TB cases, 28,712 (75 percent) were tested for resistance to at least isoniazid and rifampin. The researchers found that of these, 407 MDR TB cases (1.4 percent) were reported from 38 of 61 California health jurisdictions (62 percent); the proportion of MDR-TB cases did not significantly change over the study period.

Cases of MDR TB were 7 times more likely to have reported previous treatment for TB compared with nonMDR TB cases. Of MDR TB cases with outcomes, 231 (67 percent) completed therapy, and those with MDR TB were significantly less likely to complete therapy than those without MDR TB. Further analysis identified previous TB diagnosis, positive results when examining sputum for the TB germ under a microscope, Asian/Pacific Islander ethnicity, time in the United States less than five years at the time of diagnosis, and outcomes of died and moved as factors associated with MDR TB.

Our findings are of concern and suggest that the cases of MDR TB in California may have appeared for any of 3 reasons: importation of MDR strains from outside the state, endogenous development of MDR strains due to inadequate case management or poor treatment within California, or ongoing transmission, the authors write.

The researchers found that MDR TB was strongly associated with birth outside the United States: 83 percent of MDR TB cases were foreign born, from 30 different countries.

The findings of our study have several clear implications for TB control efforts. First, the fact that the majority of MDR TB cases were foreign born highlights both the importance of international TB control (prevention of MDR development and transmission abroad) as well as the need to expand overseas screening programs to encompass additional high-risk groups, coupled with measures to ensure timely detection and treatment of MDR TB once it develops. Second, our results suggest that adherence to recommended TB treatment guidelines must be improved to ensure that poor case management does not contribute to further cases of MDR within California.

Third, the higher proportion of individuals moving or lost to follow-up, as well as the longer time to culture conversion and clinical characteristics favoring transmission, suggest that measures to reduce transmission and improve outcomes are also necessary. Fourth, additional resources (e.g., additional staff, regional centers of excellence, and warm lines that provide clinical consultations) are needed because an increasingly large proportion of MDR cases appear to be arising in rural or smaller health jurisdictions with limited resources and expertise; the threat of MDR TB is exacerbated by a shrinking pool of clinicians experienced in managing these complex patients, who require intensive monitoring (e.g., drug levels, second-line drug susceptibilities, and renal function) over an 18- to 24-month period, the authors write.

The researchers add that to help support the efforts of local programs to manage patients with complex MDR- TB, the California Department of Health Services TB Control Branch established an MDR- TB clinical service that provides clinical support, collaborates with model centers, and will participate in the efforts of the Centers for Disease Control and Prevention to support several TB consultation medical training centers. Our study suggests that clinicians should consider MDR TB in younger persons with TB who are Asian and/or Pacific Islander, non-U.S.-born from countries with known MDR TB epidemics, recent arrivals (less than five years) in the United States, and those reporting prior TB treatment.

Multidrug-resistant TB requires complex management decisions, and additional resources will be required to successfully interrupt transmission and cure patients through timely diagnosis, treatment with adequate drug regimens and DOT, and through a patient-centered approach to ensure adherence. Although MDR TB may be curable at a great individual and societal cost, the implementation of both local and global TB control strategies is needed to prevent the further development and spread of MDR TB, the researchers conclude.

Reference: JAMA. 2005;293:2732-2739.