Prevalence estimates for 1994 include cases that started therapy before
1994, and for 2003 are based on cases that had not finished therapy by June
Multidrug resistance is resistance to at least isoniazid and rifampin.
TB indicates tuberculosis. Denominator data for no history of TB ranged from
3189 (in 1994) to 2247 (in 2003). Denominator data for history of TB ranged
from 252 (in 1994) to 141 (in 2003).
Granich RM, Oh P, Lewis B, Porco TC, Flood J. Multidrug Resistance Among Persons With Tuberculosis in California, 1994-2003. JAMA. 2005;293(22):2732-2739. doi:10.1001/jama.293.22.2732
Author Affiliations: Division of TB Elimination,
National Center for HIV, STD and TB Prevention, Centers for Disease Control
and Prevention, Atlanta, Ga (Dr Granich); California Department of Health
Services Tuberculosis Control Branch, Sacramento (Drs Granich, Porco, and
Flood and Mssrs Oh and Lewis). Dr Granich is now with the office of the US
Global AIDS Coordinator, Washington, DC.
Context Between 1994 and 2003, tuberculosis (TB) cases in California declined
33% (4834 to 3224). However, in 2003 California reported the largest number
of cases in the nation, and over the past decade the proportion of cases with
multidrug-resistant tuberculosis (MDR-TB) has not decreased.
Objective To describe the magnitude, trends, geographic distribution, clinical
characteristics, risk factors, and outcomes of MDR-TB cases reported to the
California registry of Reports of Verified Cases of TB.
Design, Setting, and Cases Analysis of 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.
Main Outcome Measures Results of univariate and multivariable analyses of MDR-TB magnitude,
trends, geographic distribution, clinical characteristics, associated factors,
Results Of 38 291 reported TB cases, 28 712 (75%) were tested for
resistance to at least isoniazid and rifampin; of these, 407 MDR-TB cases
(1.4%) were reported from 38 of 61 California health jurisdictions (62%);
the proportion of MDR-TB cases did not significantly change over the study
period (P = .87). Cases of MDR-TB were
twice as likely to have cavitary lesions compared with non–MDR-TB cases
(P<.001) and were 7 times more likely to have
reported previous treatment for TB (P<.001). Of
MDR-TB cases with outcomes, 231 (67%) completed therapy, and those with MDR-TB
were significantly less likely to complete therapy than those without MDR-TB
(P<.001). Multivariate analysis identified previous
TB diagnosis, positive acid-fast bacilli sputum smear results, Asian/Pacific
Islander ethnicity, time in the United States less than 5 years at the time
of diagnosis, and outcomes of “died” and “moved” as
factors associated with MDR-TB.
Conclusions Multidrug-resistant TB, an airborne disease with limited, costly treatment
options, persists in 1% to 2% of all cases despite California’s control
efforts. Local and global TB control efforts are needed to prevent the further
development and spread of MDR-TB.
California has made significant advances in controlling tuberculosis
(TB), as exhibited by a 33% decrease in notified cases (4834 to 3224) during
1994 to 2003.1 Tuberculosis nevertheless continues
to have a substantial public health impact, leading in 2003 to 233 deaths
and more than 132 cases diagnosed among children younger than 5 years. Additionally,
cases of TB due to strains of Mycobacterium tuberculosis that are resistant to the mainstay first-line drugs isoniazid and
rifampin (ie, multidrug-resistant [MDR] strains) continue to appear in California
despite high rates of treatment success.
The emergence of such cases, requiring prolonged treatment for at least
18 months and exhibiting higher rates of treatment failure and poorer outcomes,
threatens the efficacy of TB control efforts.2- 10
Case fatality in multidrug resistant tuberculosis (MDR-TB) ranges from
12% among individuals without human immunodeficiency virus (HIV) infection
to as high as 90% among persons infected with HIV.11 Moreover,
managing 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 $1 278 066.12 Finally,
MDR-TB has also been associated with serious sizeable nosocomial and community
outbreaks in California and the greater United States.5,13- 18
Through cooperation with local health departments, the California Department
of Health Services Tuberculosis Control Branch has collected data since 1985
on the numbers of reported TB cases for the purpose of state and national
surveillance. Nationally, during the late 1980s and early 1990s, a resurgence
of TB disease and M tuberculosis strains resistant
to multiple anti-TB drugs seriously threatened TB control efforts. In response,
the US Centers for Disease Control and Prevention conducted drug resistance
surveys in 1991 and 1992 and in 1993 added susceptibility results to the information
collected by the national surveillance system.4,19 Since
1994, California has collected population-based drug susceptibility results
for M tuberculosis isolates. To better understand
the impact of resistance to multiple drugs on TB control in California and
to plan public health interventions, we 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.
We analyzed data for TB cases submitted during 1994-2003 to the California
Department of Health Services’ registry of Reports of Verified Cases
of TB (RVCT). We included M tuberculosis culture-positive
cases with initial drug susceptibility test results for at least isoniazid
and rifampin. To describe the association between MDR-TB and prior TB treatment
in general, we used the RVCT variable describing previous TB history. To describe
the association between MDR-TB and prior treatment in California, we queried
the TB registry of preceding years (1985-1993) for evidence that a case reported
in the study period had previously received TB treatment in the state.
Since the RVCT does not include HIV status, the case registry was matched
with the State of California AIDS case registry for 1994-2002. Immigrants
identified as having smear-positive pulmonary TB during overseas screening
examinations are classified in the A category and may be permitted to immigrate
if TB therapy results in sputum conversion; those with radiological abnormalities
consistent with TB who are smear-negative are given class B status. We crossmatched
MDR-TB cases with the California immigration A/B notification registry, which
was only available for 1998-2003. Analyses considering completion of therapy
were conducted only on cases reported between 1995 and 2001. Incidence rates
for foreign-born population groups were computed using California Department
of Finance population estimates.20,21 The
MDR-TB midyear point prevalence was determined using start and stop dates
of TB drug therapy.
Categorical data were compared by the χ2 test. The Wilcoxon
rank sum test was performed to determine differences in distributions of continuous
variables. The Cochran-Armitage test was used to identify trends. P values less than .05 were considered statistically significant. Univariate
analyses were performed with SAS version 8.0 (SAS Institute Inc, Cary, NC).
We conducted multivariable analyses to compute odds ratios (ORs) adjusted
for other covariates. Commonly used methods (eg, stepwise regression) do not
consider the effect of variable selection and for this reason may yield biased
estimates of effect size as well as misleadingly small P values.22,23 We used
the method of Bayesian model averaging,22 since
this method yields adjusted ORs that take into account the effect of variable
selection; the multivariable analyses themselves were conducted in S-Plus
version 3.4 (Insightful Corp, Seattle, Wash) using the program bic.glm.24 This method yields adjusted
ORs, approximate confidence intervals (CIs), and posterior probabilities that
the OR corresponding to each correlate differs from the null value of 1; values
greater than 50% support the statement that the particular correlate corresponds
to a risk factor.22 Specifically, we used the
following variables as correlates for MDR status: previous TB diagnosis, positive
acid-fast bacilli sputum smear results, abnormal radiography findings, age,
sex, race/ethnicity (self-reported as part of routine surveillance data, using
categories determined by the US Census Bureau), health care provider type,
type of TB drug therapy (self-administered therapy, directly observed therapy,
or both), homelessness, treatment outcome, and length of time in the United
States for foreign-born cases.
Of 38 291 TB cases reported in California between January 1, 1994,
and December 31, 2003, 29 393 (77%) had a culture positive for M tuberculosis, and 28 712 (75%) were tested for resistance
to at least isoniazid and rifampin. Of these, 407 (1.4%) were MDR. The sociodemographic
characteristics of the 28 712 cases are shown in Table 1. The number of incident MDR-TB cases decreased during the
9-year period, from 57 in 1994 to 33 in 2003 (Figure 1). Although there was also a 33% decrease in the number
of annually reported TB cases over the study period, the proportion of cases
with MDR-TB did not significantly change (P = .87).
Additionally, the proportion of isoniazid resistance among those with no reported
history of TB did not significantly change over the study period (P = .33) (Figure 2).
The mean annual incidence of MDR-TB was 0.13 and ranged from 0.09 to 0.18
per 100 000 population. The median MDR-TB point prevalence was 60 cases
Cases of MDR-TB were found in 38 (62%) of California’s 61 health
jurisdictions and were reported both from large urban areas and from smaller
health jurisdictions with less experience managing TB. Health jurisdictions
reporting an average of 30 or fewer TB cases per year over the study period
reported 9% of MDR-TB cases. In these jurisdictions with lower TB morbidity,
reporting of MDR-TB increased from 7% of all MDR-TB cases in 1994 to 21% in
2003 (P = .39).
Of the 407 MDR-TB cases, 367 (90%) were pulmonary (Table 2). Smear-positive TB cases were nearly twice as likely to
be MDR than were smear-negative cases (adjusted OR, 1.71; 95% CI, 1.30-2.26)
(Table 3). Cases of MDR-TB were twice
as likely to have cavitary lesions compared with non–MDR-TB cases (P<.001), and having a cavitary lesion was significantly
associated with being smear-positive (P<.001).
Additionally, MDR-TB cases were 7 times more likely to have reported previous
treatment for TB (P<.001). Of all MDR-TB cases,
124 (31%) had had a prior episode of TB according to the RVCT. Of these, 27
(22%) had been treated for previous TB in California, and nearly half of these
demonstrated increased resistance from the previous TB episode to the study
episode. Tuberculosis cases with HIV/AIDS were significantly less likely to
have MDR-TB compared with those without HIV/AIDS (P = .01).
Of the 407 MDR-TB cases, 280 (69%) occurred in persons who reported
no prior history of TB, and the proportion of MDR-TB cases without a history
of prior TB treatment increased from 65% (n = 37) in 1994 to 71%
(n = 22) in 2003, though this increase was not statistically significant
(P = .89). The adjusted OR for reported
previous diagnosis as a risk factor was 7.02 (95% CI, 5.37-9.18) (Table 3). Patients resistant to either isoniazid
or rifampin may develop resistance to the other drugs and thus become classified
as MDR cases. Of all culture-positive cases reported from 1994-2003, 2665
(9%) had isolates that were not MDR but were resistant to at least isoniazid
or rifampin, and this proportion did not change during the study period (P = .65). Resistance to at least isoniazid among
persons without a known history of TB ranged from 8% to 10% and did not increase
during the study period (P = .33). Resistance
to rifampin only averaged 0.4% per year for the study period, and TB cases
with AIDS were nearly 7 times more likely to have rifampin-only resistance
compared with those without AIDS (35 [1.7%] vs 67 [0.3%]; relative risk, 6.97;
95% CI, 4.62-10.51).
Cases of MDR-TB were younger than other TB cases (mean age, 43 vs 48
years; P<.001 (Table
1); adjusted OR for the age category 65 years and older, 0.36; 95%
CI, 0.25-0.53) (Table 3). Of all MDR-TB
cases, 6 (2%) were children younger than 5 years. Non–US-born cases
were twice as likely to be MDR compared with US-born cases (P<.001). Of non–US-born MDR-TB cases, 113 (35%) were among
persons who had been in the United States for less than 1 year at diagnosis
(median, 3.5 years). At the time of case report, non–US-born MDR-TB
cases had been in the United States for a shorter mean duration than other
TB cases (6.7 vs 12.1 years, P<.001); the adjusted
OR for MDR-TB (with US-born as baseline) was 2.47 (95% CI, 1.34-4.55) for
those in the United States for less than 1 year at the time of diagnosis.
Mexico, the Philippines, Laos, Vietnam, and South Korea were the most common
countries of origin of MDR-TB cases originating outside the United States
(Table 4). The incidence of MDR-TB among
foreign-born cases (3.5 per 100 000 population) was significantly higher
than the 0.2 per 100 000 among US-born cases (P<.001).
The 5-year A/B registry crossmatch found that only 19 (10%) of foreign-born
MDR-TB cases arrived in the United States with an A/B notification following
overseas screening. Of these, 4 of 13 class A classifications had MDR-TB and
the remaining 15 MDR-TB cases arrived with a class B classification.
Cases of MDR-TB were less likely to report excessive alcohol use or
homelessness compared with non–MDR-TB cases (P<.001
and P = .02, respectively) (Table 1). Similarly, MDR-TB was less associated with injection drug
use, residence in a long-term care facility, incarceration, or high-risk occupation
(eg, health care, correction, migratory agricultural worker). However, the
adjusted OR for homelessness did not differ from 1.
Of the 346 MDR-TB cases with treatment outcome data (85%), 231 (67%)
completed therapy, 49 (14%) died, 48 (14%) moved, 9 (3%) were lost to follow-up,
1 refused therapy, and 8 (2%) had an unspecified outcome (Table 2). Cases with MDR-TB isolates were significantly less likely
to complete therapy when compared with those without MDR-TB (P<.001). Cases with MDR-TB who died during TB treatment were significantly
younger (mean age, 53 vs 63 years; P = .001)
but were not significantly more likely to have AIDS (P = .56).
Significantly fewer MDR-TB cases were managed exclusively by private
physicians compared with non–MDR-TB cases (50 [14%] vs 9674 [35%], P<.001) (Table 2).
The proportion of MDR cases managed exclusively by county health departments
increased from 48% in 1994 to 59% in 2001 (P = .02).
Although MDR-TB cases were more likely to receive directly observed therapy
(DOT) compared with non-MDR cases (P<.001), 52
(15%) of 345 MDR-TB cases with available therapy data were reported as receiving
only self-administered therapy. Patients cared for by private physicians were
less likely to receive DOT when compared with those managed by public providers
(34% vs 60%; relative risk, 0.35; 95% CI, 0.18-0.70; P = .002).
However, patients with MDR-TB managed by private physicians were just as likely
to complete therapy (56% vs 68%; relative risk, 0.60; 95% CI, 0.31-1.17; P = .16).
Of the 407 cases with MDR, 71 (17%) were resistant to only isoniazid
and rifampin and 86 (21%) were resistant to at least all 4 first-line drugs
(Table 5). Although reporting of test
results for fluoroquinolone resistance was limited to 236 (58%) MDR-TB cases,
28 (12%) were resistant to fluoroquinolone(s) and this proportion did not
increase over the study period. Resistance to injectable TB drugs occurred
in 62% of all MDR-TB cases and this proportion did not significantly change
over the study period.
We used the following variables in the multivariable model: reported
history of previous TB, smear status, chest radiography results, age category,
sex, race/ethnicity, provider type, type of therapy (eg, directly observed
or self-administered), length of time in the United States for non–US-born
cases (categorized as indicated), homelessness, treatment outcome, and AIDS.
Previous TB diagnosis, positive acid-fast bacilli sputum smear results, Asian/Pacific
Islander ethnicity, time in the United States of less than 5 years at the
time of TB report, as well as the outcomes of “died” and “moved”
were identified by multivariable analysis as independent correlates positively
associated with MDR-TB (Table 3).
In California, MDR-TB, a life-threatening airborne disease with expensive
and limited treatment options, continues to persist despite current TB control
efforts. Although the annual number of TB cases decreased 33% over the study
period, the proportion of MDR-TB remained at approximately 1.4%. Additionally,
we found that 83% of MDR-TB cases had resistance to other drugs in addition
to isoniazid and rifampin. Cases of MDR-TB not only occurred in large urban
jurisdictions, but we found an increasing proportion of cases in rural or
smaller jurisdictions where staffing, resources, and TB expertise may be less
available. Our findings are of concern and suggest that the cases of MDR-TB
in California may have appeared for any of 3 reasons, which will be discussed
in turn: 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.
We found that MDR-TB was strongly associated with birth outside the
United States and that 83% of MDR-TB cases were foreign born, from 30 different
countries. Population-based surveys in the 3 most common countries of origin
(Mexico, the Philippines, and Vietnam) for individuals born outside the United
States with TB in California have demonstrated levels of drug resistance that
are 2 to 4 times that in the United States.25- 27 We
also found disproportionately high representation in individuals from Laos,
the former Soviet Union, Korea, and Peru. While these findings highlight the
value to California of international TB control measures such as DOT, only
19 persons (10%) with MDR-TB were identified through preimmigration screening,
despite the fact that nearly one third of non–US-born MDR-TB cases were
diagnosed within 1 year of arrival. Most people (such as students, workers,
or undocumented immigrants) entering the United States from countries with
high TB rates enter without TB screening at all, and even the mandated screening
program for legal immigrants does not include sputum culture or susceptibility
testing. As a result, MDR-TB is often not identified until diagnosed in the
While TB rates among US-born persons have decreased, rates of TB and
MDR-TB among minorities remain significantly elevated.25- 27 Additionally,
many risk factors previously observed to be associated with TB outbreaks among
US-born persons (eg, homelessness, drug use, and AIDS) were found less frequently
among MDR-TB cases in California compared with non–MDR-TB cases.13- 17 Several
MDR-TB outbreaks in the early 1990s that occurred in the eastern United States
were associated with HIV, drug use, and health care workers.28,29 However,
we found no association with drug use or health care workers, and AIDS was
twice as likely to be associated with non-MDR-TB compared with MDR-TB. These
findings suggest that considerable geographic differences may exist in TB
and MDR-TB epidemiology in the United States and that these differences may
change over time.
We found that MDR-TB was strongly associated with a reported history
of previous TB treatment. A reported history of previous TB treatment, although
unconfirmed, suggests that MDR-TB was acquired during a previous treatment
episode; such acquired drug resistance may indicate failure of TB control
efforts due to inadequate case management, interruptions in drug supply, or
inadequate drug regimens. Although MDR-TB may have been acquired in the United
States, the majority of non–US-born MDR-TB cases in our study reported
a history of prior TB treatment prior to arrival in the United States. In
addition to the possibility of importing MDR strains from abroad, our crossmatch
with the historical California TB registry suggests that, while comparatively
uncommon, some MDR cases arise as the result of inadequate case management
or treatment in California. This risk is highlighted by our finding that nearly
10% of TB cases were reported as being resistant to either isoniazid or rifampin,
thus placing them at higher risk of developing MDR-TB.
Finally, MDR cases may appear because individuals with MDR disease transmit
the infection to others. Recent molecular epidemiology data suggest that transmission
of MDR-TB is occurring in multiple sites in the United States, including California,
and may be responsible for as many as one third of MDR-TB cases (unpublished
data). Findings from our study revealed that MDR-TB cases are much more likely
to have smear-positive cavitary pulmonary disease, which may contribute to
the spread of drug-resistant strains. Additionally, the mean time to culture
conversion for MDR-TB cases was 46 days longer than for non–MDR-TB cases
(P<.001; data not shown). Patients with MDR-TB
often do not start effective treatment until susceptibility results are known,
which may also prolong the infectious period. The median point prevalence
in California during the study was 60 cases. The prolonged 18 to 24 months
of therapy translates into high management burdens for patients, physicians,
and health jurisdictions and may also provide further opportunities for transmission
in cases that do not respond to treatment. Finally, a higher proportion of
MDR-TB cases moved or were lost to follow-up, which may also contribute to
ongoing MDR-TB transmission.
Turning from the origin of MDR cases to their outcomes, our study has
also shown that MDR-TB cases were significantly less likely to complete treatment
and were more likely to die than those with non–MDR-TB.10 This
association between resistance and poor outcome held true regardless of history
of prior TB; a diagnosis of AIDS was associated with even poorer outcomes,
including a higher likelihood of death. An increasing proportion of the MDR-TB
cases were managed by the health department, and although private physicians
yielded similar outcomes, they were significantly less likely to use DOT.
Several limitations apply to our findings. Only 75% of reported TB cases
were culture confirmed and had drug susceptibility test results for isoniazid
and rifampin. However, the absence of significant differences between persons
with culture-positive TB with isolates available for testing and those without
isolates suggests that our sample is representative of TB cases reported during
the study period. Also, incidence rates by country of birth should be interpreted
with caution because population estimates may not accurately capture data
for migratory populations. The registry of immigrants with A/B status has
only 5 years of data and the majority of non–US-born persons are not
screened with this system when entering the United States. Treatment history
is very difficult to determine and, although our results associating history
of treatment with MDR-TB are plausible, they should be treated with caution.
Finally, it is possible that much of the MDR-TB reported among non–US-born
persons was acquired in their country of origin; however, in the absence of
more detailed information we cannot determine the contribution of ongoing
community transmission within the United States.
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.30 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 (eg, 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 (eg, drug levels, second-line drug susceptibilities, and renal
function) over an 18- to 24-month period. 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–US-born from countries with known
MDR-TB epidemics,30 recent arrivals (<5
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.
Corresponding Author: Reuben M. Granich,
MD, MPH, Office of the US Global AIDS Coordinator, 2100 Pennsylvania Ave NW,
Washington, DC 20522-2920 (firstname.lastname@example.org).
Author Contributions: Dr Granich had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Granich, Oh, Lewis,
Acquisition of data: Granich, Oh, Lewis, Flood.
Analysis and interpretation of data: Granich,
Oh, Lewis, Porco, Flood.
Drafting of the manuscript: Granich, Oh, Porco,
Critical revision of the manuscript for important
intellectual content: Granich, Oh, Lewis, Flood.
Statistical analysis: Granich, Oh, Lewis, Porco.
Obtained funding: Flood.
Administrative, technical, or material support:
Granich, Oh, Lewis, Flood.
Study supervision: Granich, Flood.
Financial Disclosures: None reported.
Acknowledgment: We thank the tuberculosis controllers
and program staff in California’s health departments who reported the
data used in this analysis. We also thank Bill Elms, Janice Westenhouse, MPH,
Ed Desmond, PhD, Scott Bradley, MPH, Amanda Simanek, Tom Bates, PhD, and Linda
Johnson, MPH, for their contributions. Finally, we thank Jose Becerra, MD,
MPH, Charles Wells, MD, Zachary Taylor, MD, MS, Michael Iademarco, MD, MPH,
and Kenneth Castro, MD, MPH, for their helpful review of the manuscript.