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Journal of Clinical Microbiology, October 1999, p. 3255-3259, Vol. 37, No. 10
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Evidence from Molecular Fingerprinting of Limited
Spread of Drug-Resistant Tuberculosis in Texas
Rebecca W.
Wilson,1
Zhenhua
Yang,2,3
Michael
Kelley,4
M. Donald
Cave,2,5
Janice M.
Pogoda,6
Richard J.
Wallace Jr.,1,7
J. Peter
Cegielski,1,8
Denise F.
Dunbar,4
David
Bergmire-Sweat,4
L. Bruce
Elliott,4 and
Peter F.
Barnes1,8,9,*
Center for Pulmonary and Infectious Disease
Control,1 Departments of
Microbiology,7 Cell
Biology,9 and
Medicine,8 University of Texas Health
Center at Tyler, Tyler, and Texas Department of Health,
Austin,4 Texas; Regional
Tuberculosis Genotyping Laboratory2 and
Departments of Pathology3 and
Anatomy,5 University of Arkansas for
Medical Sciences, Little Rock, Arkansas; and Statotology,
Truckee, California6
Received 2 December 1998/Returned for modification 20 March
1999/Accepted 26 June 1999
 |
ABSTRACT |
To determine the contribution of recent transmission to spread of
drug-resistant tuberculosis in Texas, we performed
IS6110-based and pTBN12-based restriction fragment length
polymorphism (RFLP) analyses on Mycobacterium tuberculosis
isolates. Isolates collected from 201 patients in Texas between 1992 and 1994 were studied. The distribution of cases was strikingly focal.
All cases were reported from 35 of the 254 counties in Texas, and 74%
(148 of 201) were reported from only 9 counties. One hundred sixty-one (80%) of the patients had M. tuberculosis isolates with
unique RFLP patterns, and 41 (20%) patients were in 20 clusters, each comprising 2 to 3 patients. The largest number of cases of
drug-resistant tuberculosis were reported in counties bordering Mexico,
but the percentage of clustered cases was highest in northeast Texas
and in counties that included the cities of Dallas, Fort Worth, and Houston. Compared to nonclustered patients, clustered patients were
more likely to be African American and to have been born in the United
States. Clustered patients were significantly more likely to be from
the same geographic area, and clustered patients from the same
geographic area were more likely to have isolates with identical drug
susceptibility patterns, suggesting that they were linked by recent
transmission. In 11 of 20 clusters, clustered patients were from
geographically separate regions, and most isolates did not have
identical drug susceptibility patterns, suggesting that tuberculosis
was contracted from a common source in the remote past. Based on the
low percentage of clustered cases and the small cluster size, we
conclude that there is no evidence for the extensive transmission of
drug-resistant tuberculosis in Texas.
| |
INTRODUCTION |
Texas consistently ranks third in
the United States in the number of tuberculosis cases reported to the
Centers for Disease Control and Prevention, behind New York and
California (6). In addition, Texas ranks third in the number
of reported cases of multidrug-resistant tuberculosis (resistant to
isoniazid and rifampin) (6). Because southern Texas borders
Mexico, where drug resistance is more common than in the United States
(7), the transmission of drug-resistant tuberculosis in
Texas is a major public health concern.
Researchers' understanding of the dynamics of the transmission of
tuberculosis has been greatly enhanced by restriction fragment length
polymorphism (RFLP) analysis of Mycobacterium tuberculosis isolates, allowing the identification of specific genotypes. Recent studies based on RFLP analysis have demonstrated that 19 to 54% of
tuberculosis cases in urban areas of the United States result from
recent disease transmission (1, 2, 4, 18). Most isolates in
these studies were fully drug susceptible, and no data are available on
the contribution of recent transmission to the spread of drug-resistant
tuberculosis in the United States, except during outbreaks of the
disease (9, 10). To investigate this issue, we performed
RFLP analysis on drug-resistant isolates from 201 tuberculosis patients
in Texas.
| |
MATERIALS AND METHODS |
M. tuberculosis strains.
From January 1992 through December 1994, 5,987 patients with culture-confirmed
tuberculosis were diagnosed in Texas (19-21). We studied
334 M. tuberculosis isolates from 201 patients diagnosed in
Texas from May 1992 through August 1994. Two or more isolates were
evaluated for 44 patients, and one isolate was evaluated for 157 patients. These represented all isolates with resistance to isoniazid,
rifampin, ethambutol, or streptomycin available from the
mycobacteriology laboratories of the Texas Department of Health or the
University of Texas Health Center at Tyler. During this period, 304 cases of drug-resistant tuberculosis were reported in Texas. Isolates
not included in the study were those that were no longer viable
(n = 19), those that could not be located (n = 13), and those that were processed at other laboratories
(n = 71). Of the 103 isolates that were excluded from
the study, 81 were from patients in Harris, Dallas, or Tarrant
counties, where specimens were often processed by local hospitals or
health departments.
All isolates were identified as M. tuberculosis by using a
commercial DNA probe (ACCUPROBE; Gen-Probe, San Diego, Calif.
[16]) or high-performance liquid chromatography to
determine the mycolic acid profile (5). Isolates were
screened for susceptibility to isoniazid (1.0 µg/ml), rifampin (1.0 µg/ml), and ethambutol (5.0 µg/ml) by the Bactec radiometric method
(Becton Dickinson, Mountain View, Calif.). For isolates that were
resistant to any of these three agents, susceptibilities to isoniazid
(1.0 µg/ml), rifampin (1.0 µg/ml), ethambutol (5.0 µg/ml), and
streptomycin (2.0 µg/ml) were tested by the proportion method on 7H10
agar. Drug resistance was defined as the presence of at least 1%
growth on the drug-containing agar compared to growth on the control agar (12).
RFLP analysis.
M. tuberculosis isolates were
subcultured in 5 ml of Dubos medium supplemented with albumin (Difco,
Detroit, Mich.) and incubated at 37°C for 2 to 3 weeks prior to DNA
extraction. All isolates were subjected to IS6110-based RFLP
analysis, as previously described (22, 24). Briefly,
chromosomal DNA was prepared by chloroform-isoamyl alcohol DNA
extraction, and 1 µg of DNA from each isolate was restricted with
PvuII and then hybridized to the IS6110 probe. The molecular size standard was PvuII-restricted chromosomal
DNA of M. tuberculosis H37Rv and two additional DNA
fragments which hybridize to IS6110 (24).
IS6110-based RFLP results were considered inconclusive if
RFLP patterns with fewer than six fragments were identical or if RFLP
patterns with six or more fragments were identical except that one
isolate showed an additional fragment or a fragment that differed in
size. In these cases, pTBN12-based RFLP analysis was performed, as
described previously (8). Briefly, chromosomal DNA was
restricted with AluI and then hybridized to the pTBN12
probe. The molecular size standard was a 1-kb DNA ladder.
To analyze IS6110-based RFLP patterns, hybridized blots were
exposed to a phosphor screen, which was scanned with ImageQuant software (Molecular Dynamics, Sunnyvale, Calif.). The patterns were
analyzed with Whole Band Analyzer software (version 3.3; BioImage, Ann
Arbor, Mich.), allowing a fragment size deviation of 2.5% when
patterns were matched pTBN12-based RFLP patterns were evaluated by
visual comparison in adjacent lanes.
We considered
M. tuberculosis isolates from different
patients to be the same strain if the IS
6110-based RFLP
patterns (i)
revealed six or more fragments of identical sizes, (ii)
revealed
six or more fragments of identical sizes except that one
isolate
showed one additional fragment or one fragment of a different
size and the pTBN12-based RFLP patterns were identical, or (iii)
revealed five or fewer fragments of identical sizes and the
pTBN12-based
RFLP patterns were identical. Two or more patients
infected with
the same
M. tuberculosis strain constituted a
cluster.
Demographic data.
Demographic data on the 201 study patients
were obtained from the tuberculosis reporting forms sent to the Texas
Department of Health and from laboratory records.
Statistical analysis.
To compare the distributions of
categorical variables among clustered and nonclustered patients, the
two-sided Fisher exact test was used. To determine if patients in a
cluster were more likely to have the same ethnicity than patients
randomly selected in groups the sizes of the clusters, we assumed a
binomial distribution for the number of clusters in which all patients
were matched for ethnicity, based on the distribution of ethnicity
among nonclustered patients. We then computed the probability of
obtaining at least the observed number of clusters in which all
patients were matched for ethnicity. The same method was used to
determine if all patients in a cluster were more likely than randomly
selected patients to be from the same group of counties.
| |
RESULTS |
Demographics of drug-resistant tuberculosis patients.
Demographic features of the patients in the study population are shown
in Table 1. Hispanic and Asian patients
comprised 71% of those with drug-resistant tuberculosis, but only 46%
of reported tuberculosis patients in Texas from 1992 to 1994 (19-21). At least 48% of patients with drug-resistant
tuberculosis were foreign-born, compared to 23% of tuberculosis
patients in Texas (19-21). Twelve percent of patients with
drug-resistant tuberculosis were known to be infected with human
immunodeficiency virus (HIV), similar to the 13% HIV coinfection rate
among tuberculosis patients in Texas (19-21). Counties were
divided into five groups, based on geographic location as follows: (i)
adjacent Dallas and Tarrant counties in north-central Texas, which
include the cities of Dallas and Fort Worth, respectively; (ii) Harris
county on the Gulf coast, which includes the city of Houston; (iii)
counties along the U.S.-Mexico border; (iv) counties in northeast
Texas; and (v) all other counties. Thirty-eight percent of patients
with drug-resistant tuberculosis were reported from six counties along
the U.S.-Mexico border compared to only 14% of tuberculosis patients
in Texas (19-21).
The distribution of cases of drug-resistant tuberculosis was strikingly
focal, with all 201 cases reported from only 35 of
the 254 counties in
Texas. In contrast, during 1992 to 1994, tuberculosis
cases were
reported from 176 counties (
19-21). One case of
drug-resistant
tuberculosis was reported from each of 17 counties, and
two to
nine cases were reported from each of 11 counties (total, 36 cases).
Seventy-four percent (148 of 201) of the cases of
drug-resistant
tuberculosis were reported from only seven counties,
which contributed
62% of the reported tuberculosis cases in 1992 to
1994 (
19-21).
Comparison of clustered and nonclustered patients.
Results of
RFLP analysis with IS6110 and pTBN12 are shown in Table
2. IS6110-based RFLP analysis
alone revealed 25 clusters comprising 68 patients. pTBN12-based RFLP
analysis was performed for all isolates with one to five
IS6110 fragments and those isolates with more than five
IS6110 fragments that were similar but not identical, as
outlined in Materials and Methods. Secondary typing with pTBN12
differentiated many isolates with identical IS6110-based RFLP patterns of one to five fragments, reducing the number of clustered patients from 41 to 11 and the number of clusters from eight
to five.
The IS
6110-based RFLP patterns of one isolate from each
cluster are shown in Fig.
1. Forty-one
(20%) patients were clustered,
and 160 (80%) were not. Clustered
patients were more likely than
nonclustered patients to be African
American and less likely to
be Hispanic (Table
1). In addition,
clustered patients were more
likely to have been born in the United
States than nonclustered
patients. In clustered and nonclustered
patients, the percentages
of patients coinfected with HIV and the
patterns of drug resistance
were similar. Sixty-one percent of
clustered patients were reported
from northeast counties and from
Dallas, Tarrant, and Harris counties
compared to only 36% of
nonclustered patients. Only 2% of clustered
patients were reported
from other counties, representing many
geographically separate
locations, compared to 26% of nonclustered
patients.
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|
FIG. 1.
IS6110-based RFLP patterns of 20 drug-resistant isolates of M. tuberculosis from clustered
patients. One isolate from each cluster of patients is shown. Lane 1, DNA of M. tuberculosis H37Rv to which was added two
additional IS6110-containing markers of known molecular
weights; lanes 2 to 21, DNA of isolates from patients.
|
|
Characteristics of clustered patients.
Forty-one patients with
drug-resistant isolates were in 20 clusters. Nineteen clusters
consisted of two patients, and one cluster consisted of three patients.
Table 3 shows the demographic characteristics of the clustered patients and the drug resistance patterns of their M. tuberculosis isolates. All
patients in 9 of the 20 clusters were reported from counties in the
same geographic area (P = 0.008, binomial test),
suggesting that clustering represented recent transmission of
tuberculosis.
All patients in 12 of 20 clusters were of the same ethnicity (Hispanic
in 7, African American in 4, and Asian in 1;
P = 0.025,
binomial test). Of the 11 clusters in which patients were not
from the
same geographic region, both patients in 6 clusters were
of the same
ethnicity (Hispanic in 4, African American in 2;
P = 0.09, binomial test). Because people generally associate more
with
members of their own ethnic groups, these findings suggest
that some
transmission resulted from travel between geographically
separate parts
of the state or that clustering reflected the reactivation
of
remote infection with
M. tuberculosis strains that were
prevalent
in specific ethnic
groups.
Drug susceptibility patterns of isolates from six clusters (1 through
6) were identical. Drug susceptibility patterns of isolates
from seven
clusters (clusters 7 through 13) differed for one drug,
and those of
isolates from seven clusters (clusters 14 through
20) differed for two
or three drugs. Of the 29 patients in 14
clusters in which the drug
susceptibility patterns differed, drug
susceptibility testing was
performed for two or more isolates
from 15 patients. Susceptibility
results were the same for all
isolates from each of these 15 patients,
indicating that susceptibility
testing results were reproducible. Of
the nine clusters in which
all patients were from the same geographic
area, four (44%) had
identical drug susceptibility patterns. In
contrast, of the 11
clusters in which patients were from different
geographic regions,
only 2 (18%) had identical drug susceptibility
patterns.
| |
DISCUSSION |
This report demonstrates that the distribution of drug-resistant
tuberculosis in Texas is more focal than the distribution of
tuberculosis in general and that there is no evidence for extensive transmission of drug-resistant tuberculosis. Assuming that all clustered patients developed tuberculosis from recent infection, a
maximum of 20% of drug-resistant cases with available isolates were
due to recent infection. Making the more conservative assumption that
one patient in each cluster had reactivation tuberculosis and that the
others were recently infected (2, 4, 18), only 11% (22 of
201) of these cases were due to recent infection. Most clustered
patients were born in the United States and were from three urban areas
(Dallas, Fort Worth, and Houston) and northeast Texas.
The significance of clustering in population-based studies is
controversial. In most urban areas, epidemiologic data strongly suggest
that clustering indicates recent transmission of tuberculosis (1,
2, 18). In contrast, in geographically stable, rural populations,
clustering may result from the reactivation of infection acquired from
the same source in the distant past, as has been observed in Arkansas
(3). Both phenomena probably accounted for some clustering
among drug-resistant tuberculosis patients in Texas. Clustered patients
were significantly more likely to be from the same geographic area, and
clustered patients from the same geographic area were more likely to
have isolates with identical drug susceptibility patterns, suggesting
that they were linked by recent transmission. However, in 11 of the 20 clusters, clustered patients were from geographically separate parts of the state, and most isolates did not have identical drug susceptibility patterns. Although there are many potential reasons for this finding, the most likely explanation is that tuberculosis was transmitted from a
common source in the distant past, providing time for infected persons
to travel to different locations and for M. tuberculosis organisms to develop different patterns of drug resistance.
In New York City, Los Angeles, and San Francisco, 38 to 59% of
tuberculosis cases were clustered, and there were many large clusters
comprising up to 43 patients (1, 2, 18). In contrast, in the
present study, only 20% of cases were clustered and all clusters
included only two or three patients. This striking difference indicates
that extensive transmission of drug-resistant tuberculosis did not
occur in Texas. Isolates from 81 patients from Dallas, Tarrant, and
Harris counties were not available for our study. Because 28% of the
cases in these counties were clustered (Table 1), it is possible that
the percentage of clustered drug-resistant cases may be slightly higher
than we observed. Most cases of drug-resistant tuberculosis in Texas
were diagnosed along the U.S.-Mexico border, in northeast Texas, and in
other parts of the state where widespread transmission of tuberculosis
is unlikely to occur because most persons live in stable family
settings in small cities and rural areas. A minority of drug-resistant
tuberculosis cases were diagnosed in the cities of Dallas, Fort Worth,
and Houston, where significant numbers of persons are homeless or live
in unstable social settings. These settings favor the extensive
transmission of tuberculosis (2, 13), and large clusters of
drug-susceptible tuberculosis cases have been observed in Tarrant
county (5a). The lack of extensive transmission of
drug-resistant tuberculosis in these locations during the study period
may simply be fortuitous. Alternatively, because most drug-resistant
isolates are resistant to isoniazid, a more speculative possibility is
that the transmission potential of isoniazid-resistant organisms is
less than that of drug-susceptible organisms (11).
Isoniazid-resistant organisms have an increased frequency of katG gene
mutations (17), which reduce catalase-peroxidase activity
and may inhibit the ability of M. tuberculosis to resist the
antimycobacterial activity of macrophages. In addition, studies in the
1950s showed that isoniazid-resistant M. tuberculosis was less virulent for guinea pigs than were drug-susceptible organisms (15), and more recent work revealed that katG mutations
attenuated the virulence of Mycobacterium bovis and H37Rv
for guinea pigs and mice, respectively (14, 23). Further
studies are needed to evaluate the epidemiologic and microbial factors
that influence the transmission dynamics of drug-susceptible and
drug-resistant tuberculosis.
| |
ACKNOWLEDGMENTS |
This study was supported by the National Institutes of Health
(R01A135265 and AI35222), the Centers for Disease Control and Prevention-Veterans' Administration interagency agreement for the
Tuberculosis Genotyping and Surveillance Network, and the Center for
Pulmonary and Infectious Disease Control, University of Texas Health
Center at Tyler. Peter F. Barnes holds the Margaret E. Byers Cain Chair
for Tuberculosis Research.
We thank Joyce Cowles, Marilyn Metcalf, Jeffrey Taylor, and Valerie
Robinson for assistance in obtaining patient information. We thank Sara
Shepard for database development and data entry, David Murphy, Robert
Ulrich, and the staff of the Mycobacteriology Laboratory of the Texas
Department of Health for assistance in obtaining the M. tuberculosis isolates, and JoAnne Woodring for assistance with
data entry.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Peter F. Barnes,
Center for Pulmonary and Infectious Disease Control, University of Texas Health Center at Tyler, 11937 U.S. Highway 271, Tyler, TX 75708-3154. Phone: (903) 877-5956. Fax: (903) 877-5516. E-mail: pbarnes{at}uthct.edu.
| |
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Journal of Clinical Microbiology, October 1999, p. 3255-3259, Vol. 37, No. 10
0095-1137/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
