Treatment Practices, Outcomes, and Costs of Multidrug-Resistant and Extensively Drug-Resistant Tuberculosis, United States, 2005–2007

Article (PDF Available)inEmerging Infectious Diseases 20(5):812-21 · May 2014with42 Reads
DOI: 10.3201/eid2005.131037 · Source: PubMed
Abstract
To describe factors associated with multidrug-resistant (MDR), including extensively-drug-resistant (XDR), tuberculosis (TB) in the United States, we abstracted inpatient, laboratory, and public health clinic records of a sample of MDR TB patients reported to the Centers for Disease Control and Prevention from California, New York City, and Texas during 2005-2007. At initial diagnosis, MDR TB was detected in 94% of 130 MDR TB patients and XDR TB in 80% of 5 XDR TB patients. Mutually exclusive resistance was 4% XDR, 17% pre-XDR, 24% total first-line resistance, 43% isoniazid/rifampin/rifabutin-plus-other resistance, and 13% isoniazid/rifampin/rifabutin-only resistance. Nearly three-quarters of patients were hospitalized, 78% completed treatment, and 9% died during treatment. Direct costs, mostly covered by the public sector, averaged $134,000 per MDR TB and $430,000 per XDR TB patient; in comparison, estimated cost per non-MDR TB patient is $17,000. Drug resistance was extensive, care was complex, treatment completion rates were high, and treatment was expensive.
To describe factors associated with multidrug-resistant
(MDR), including extensively-drug-resistant (XDR), tuber-
culosis (TB) in the United States, we abstracted inpatient,
laboratory, and public health clinic records of a sample of
MDR TB patients reported to the Centers for Disease Con-
trol and Prevention from California, New York City, and
Texas during 2005–2007. At initial diagnosis, MDR TB was
detected in 94% of 130 MDR TB patients and XDR TB in
80% of 5 XDR TB patients. Mutually exclusive resistance
was 4% XDR, 17% pre-XDR, 24% total rst-line resistance,
43% isoniazid/rifampin/rifabutin-plus-other resistance, and
13% isoniazid/rifampin/rifabutin-only resistance. Nearly
three-quarters of patients were hospitalized, 78% complet-
ed treatment, and 9% died during treatment. Direct costs,
mostly covered by the public sector, averaged $134,000 per
MDR TB and $430,000 per XDR TB patient; in comparison,
estimated cost per non-MDR TB patient is $17,000. Drug
resistance was extensive, care was complex, treatment
completion rates were high, and treatment was expensive.
D
rug-resistant Mycobacterium tuberculosis poses sub-
stantial obstacles to tuberculosis (TB) control. In the
United States, multidrug-resistant (MDR) TB (resistant to
at least isoniazid and rifampin) comprises only 1.0%–1.5%
of TB cases but requires lengthy regimens of toxic drugs,
imposes high costs on the health care system and society,
and causes high mortality rates.
Studies of MDR TB in the United States have been
limited by small sample sizes, limited study periods, mini-
mal information on outcomes and costs, or reliance solely
on surveillance data (16), which omit some cases of ac-
quired drug resistance and changes in regimens. Costs of
treating MDR TB are not routinely collected or reported.
Our study describes and analyzes characteristics as-
sociated with drug resistance, timely diagnosis, treatment
practices, outcomes, and costs associated with MDR TB
for cases reported to the Centers for Disease Control and
Prevention (CDC) by California, New York, and Texas
during 2005–2007. These 3 areas contribute about half of
US MDR TB cases annually.
Methods
CDC and local institutional review boards approved the
study and granted a waiver of patient informed consent and
patient authorization. We dened a 5-drug regimen (online
Technical Appendix, wwwnc.cdc.gov/EID/article/20/5/13-
1037-Techapp1.pdf) to be consistent with US and World
Health Organization recommendations (7,8). All study def-
initions are in the online Technical Appendix.
Each site identied cases of MDR TB and exten-
sively drug-resistant (XDR) TB reported to CDC during
Treatment Practices,
Outcomes, and Costs of
Multidrug-Resistant and Extensively
Drug-Resistant Tuberculosis,
United States, 2005–2007
Suzanne M. Marks, Jennifer Flood, Barbara Seaworth, Yael Hirsch-Moverman, Lori Armstrong,
Sundari Mase, Katya Salcedo, Peter Oh, Edward A. Graviss, Paul W. Colson, Lisa Armitige,
Manuel Revuelta, Kathryn Sheeran, and the TB Epidemiologic Studies Consortium
RESEARCH
812 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014
Author Afliations: Centers for Disease Control and Prevention,
Atlanta, Georgia, USA (S.M. Marks, L. Armstrong, S. Mase, TB
Epidemiologic Studies Consortium); California Department of
Public Health, Richmond, California, USA (J. Flood, K. Salcedo,
P. Oh); Texas Department of State Health Services, Tyler, Texas, USA
(B. Seaworth, L. Armitige, K. Sheeran); University of Texas Health
Science Center, Tyler (B. Seaworth, L. Armitige, K. Sheeran);
ICAP/Columbia University, New York, New York, USA (Y. Hirsch-
Moverman, P.W. Colson, M. Revuelta); and Methodist Hospital
Research Institute, Houston, Texas, USA (E.A. Graviss)
DOI: http://dx.doi.org/10.3201/eid2005.131037
MDR and XDR TB, United States
2005–2007. The study included all XDR TB cases and a
75% simple random sample of MDR TB cases from Cali-
fornia and New York (New York City), and a 50% sample
from Texas. Using standardized forms, we abstracted hos-
pital, laboratory, and public health clinic records retrospec-
tively for patient demographic, socioeconomic, and clinical
characteristics and for treatment, case management, out-
comes, and costs. Total charges for each TB-associated hos-
pitalization were abstracted from hospital UB-04 forms. To
ascertain sputum-culture conversion and drug resistance,
we examined all available culture and drug-susceptibility
testing (DST) results from diagnosis through treatment.
To assess representativeness, we compared our sample
with National TB Surveillance System data from all US
sites. We identied characteristics among MDR TB patients
associated with the following 3 dichotomous outcomes: drug
resistance acquisition, expert consultation use, and death
during TB treatment. Multivariable logistic regression was
used with backward selection at p<0.05 to identify variables
remaining in nal models (SAS version 9.2/9.3; SAS Insti-
tute, Cary, NC, USA). Adjusted odds ratios (AORs) signi-
cant at 95% CIs and Schwarz Criterion statistics are reported
for goodness-of-t. Variables included in initial models were
patient demographics (gender, age group, race/ethnicity,
foreign birth), socioeconomic factors (homelessness, unem-
ployment, illicit substance use, excess alcohol use, smoking),
medical risks (HIV infection, diabetes), TB history, disease
severity (acid-fast bacilli [AFB]–smear positivity, cavita-
tion, dissemination), drug-resistance pattern, receipt of TB
clinic outpatient care, and additional relevant characteristics
(for acquired resistance: receipt of >4 effective medications;
for expert consultation: incarceration in a correctional insti-
tution, long-term-care facility residence, pregnancy, death
during treatment, number of adverse events, private outpa-
tient insurance; for death during treatment: pregnancy, incar-
ceration in a correctional institution).
Inpatient costs were measured; outpatient costs and
productivity losses were estimated (online Technical Ap-
pendix). Hospital charges were converted to costs by us-
ing hospital-specic operating cost-to-charge ratios (9).
All costs were converted to 2010 US dollars (10) and
were adjusted for cost of living (1.13 for California, 1.08
for New York City, and 0.94 for Texas) (11) to facilitate
aggregation. For 17 patients for whom hospital charges
data were missing, we multiplied hospitalization duration
by average cost per day for patients for whom data were
available ($1,419).
Study total direct costs were compared with estimated
direct costs for cases of non-MDR TB (online Technical
Appendix). We report SEMs to display cost variability.
For productivity losses from hospitalization, we ap-
plied an updated 2010 dollar value of work-plus-home
production of $224/day for employed patients and $40/day
for home-only production of unemployed patients (12). For
TB-related deaths, we estimated the value of remaining
lifetime productivity, updated to 2010 dollars, based on the
age at death (12). For patients experiencing adverse events
during treatment, we calculated a disability adjustment per
patient (100%, 83%, 67%, 50%, 33%, 17%, 0%). We es-
timated direct and productivity-loss costs and examined
associated characteristics by using multivariable linear re-
gression with backward selection. Adjusted R
2
statistics are
reported to show goodness-of-model-t.
Results
The sample consisted of 135 patients (130 with MDR
TB and 5 with XDRTB), representing 36% (130/364) of
MDR TB and 56% (5/9) of XDR TB cases reported in the
United States during 2005–2007. Among these patients,
87% were foreign born and 36% had prior TB disease (Ta-
bles 1–3). Among patients for whom information about con-
current medical conditions was available, 24 (20%) of 121
had diabetes and 14 (12%) of 116 had HIV infection. The
study population resembled all US MDR TB patients; how-
ever, fewer study participants were White or unemployed,
and more used noninjection drugs, had prior TB, or had
AFB-positive smear specimens. Similar to all foreign-born
TB patients in the United States, most foreign-born MDR
TB study participants arrived from Mexico, the Philippines,
India, and Vietnam. Of the 135 patients, 7% were homeless
before diagnosis (6 patients) or during treatment (3 patients).
Case management to obtain housing during treatment was
needed by 23 (17%) patients; 38 (28%) patients had been
unemployed before diagnosis, and of the 97 remaining pa-
tients, 27% stopped work because of MDR TB.
Of the 135 patients, disease was pulmonary for 85%,
extrapulmonary only for 6%, and disseminated for 9%. Of
127 patients with pulmonary or disseminated disease, 69
(54%) had extensive disease. Of 8 patients with extrapul-
monary-only disease, 2 (25%) had extensive disease. Of
134 patients alive at diagnosis, 77% (103) had at least 1
AFB-smear–positive specimen, 72% from sputum.
Drug Resistance
At various times during treatment, M. tuberculosis
isolates were tested for susceptibility (median 14 medica-
tions, range 4–19) and were resistant to several (median
5 medications, range 2–16) at any time during treatment.
The following mutually exclusive resistance patterns were
identied: 4% XDR, 17% pre-XDR, 24% total rst-line re-
sistance, 43% isoniazid/rifampin/rifabutin-plus-other resis-
tance, and 13% isoniazid/rifampin/rifabutin-only resistance
(Figure 1). Initial M. tuberculosis isolates obtained within
30 days of treatment initiation revealed isoniazid/rifampin
resistance among 122 (94%) of the 130 MDR TB patients
and XDR among 4 (80%) of the 5 XDR TB patients. DST
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014 813
RESEARCH
was conducted for rst-line drugs during the rst month of
treatment, for second-line drugs during the second month
of treatment, for linezolid during the fourth month, and for
clofazimine during the seventh month.
Among 128 patients for whom DST was conducted
multiple times on separate dates, acquired resistance to an
anti-TB medication during treatment was detected for 27
(21%). According to multivariable analysis, acquisition
of drug resistance during treatment was more likely for
patients who were recently homeless (AOR 5.8, 95% CI
1.2–28.9), who had pre-XDR or XDR TB (AOR 5.1, 95%
CI 1.9–14.2), or who were Black (AOR 4.1, 95% CI 1.1–
15.4) (Table 4). Acquisition of resistance to isoniazid or ri-
fampin, resulting in MDR TB, occurred for 6% of patients,
to uoroquinolones for 3%, and to injectable drugs for 4%.
Other medications to which resistance was acquired were
ethambutol (10% of patients), pyrazinamide (6%), strepto-
mycin (5%), ethionamide (5%), rifabutin (2%), cycloserine
(1%), and clofazimine (1%). For 1 patient, uoroquinolone
resistance was acquired, resulting in XDR TB.
Time to Diagnosis
For 74 patients who had TB symptoms before diagno-
sis, a median of 1.6 months elapsed from symptom onset to
initial TB diagnosis. Of 134 patients alive at diagnosis, 123
(92%) started receiving >2 second- or third-line medica-
tions a median of 2.4 months after initial TB diagnosis. The
median duration of infectiousness was 10 months.
Treatment Practices
Among 105 patients who completed treatment, treat-
ment duration varied. Median durations were 32.3 months
(interquartile range [IQR] 30.6–37.8) for those with XDR,
25.1 months (IQR 23.6–29.2) for those with pre-XDR, 25.7
months (IQR 22.4–26.9) for those with total-rst-line–re-
sistant, 24.1 months (IQR 20.1–27.0) for those with iso-
niazid/rifampin/rifabutin-plus–resistant, and 20.0 months
(IQR 19.4–24.5) for those with isoniazid/rifampin/rifabu-
tin-only–resistant TB.
Providers changed medications for 134 patients alive
at diagnosis a median of 7 times during treatment; 33% of
988 medication changes were because of adverse events
and 10% because of DST results. Of 134 patients, 34%
received a 5-drug regimen before sputum-culture conver-
sion, and 61% ultimately received a 5-drug regimen. Of
the 134 patients, 81% received an effective (i.e., medica-
tion to which their isolate was never resistant) injectable
medication and 86% received an effective uoroquinolone
medication during treatment. Of 123 patients who received
outpatient care, 90% received >80% of outpatient medica-
tion doses by directly observed therapy (DOT).
Most study patients were hospitalized for TB, often sev-
eral times; 73% (98) were hospitalized at least 1 time and
29% were hospitalized >2 times (range 2–6). Detailed data
were available for 83% of inpatients. Among multiple pos-
sible reasons, severe worsening of TB disease was the reason
for 50% of hospitalizations, followed by the need to initiate
or change treatment (40%), implement respiratory isolation
(21%), manage adverse events (7%), manage concurrent
conditions (3%), and perform surgery (1%). One patient had
undergone TB-related lung lobectomy. Four XDR TB pa-
tients were hospitalized for a median of 282 days (range 14–
850) and non-XDR patients for a median of 27 days (range
1–759). Home isolation was prescribed for 37% of patients;
a median of 102 days (range 4–337) for non-XDR TB pa-
tients and 257 days for the 1 XDR TB patient.
814 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014
Table 1. Demographic characteristics of study participants and all patients with MDR and/or XDR TB, United States, 20052007*
Characteristic
Study participants, no. (%), n = 135
All US MDR TB patients, no. (%), n = 370
Sex
M
68 (50)
205 (55)
F
67 (50)
164 (44)
Age, y
Median
38.2
014
1 (1)
13 (4)
1524
24 (18)
64 (17)
2544 62 (46) 171 (46)
4564
40 (30)
91 (25)
>65
8 (6)
31 (8)
Race/ethnicity
Hispanic
42 (31)
100 (27)
White
4 (3)
31 (8)
Black
14 (10)
63 (17)
Asian
72 (53)
173 (47)
Other/unknown
3 (2)
3 (1)
Geographic origin
Foreign born‡
118 (87)
305 (82)
US born
17 (13)
64 (17)
*Study patients were from California, New York City, and Texas. MDR, multiple-drug resistant; XDR, extensively drug resistant; TB, tuberculosis.
Statistically significant differences between percentages of study patients and all US MDR TB patients at p<0.05.
For 110 participants, median no. years after first entry into United States = 3.5.
MDR and XDR TB, United States
Of the 134 patients alive at diagnosis, 81% had docu-
mentation of physician consultation with an MDR TB ex-
pert during inpatient or outpatient care. Expert consulta-
tion was more likely for patients managed primarily by a
TB clinic (AOR 5.7, 95% CI 1.9–16.8) and less likely for
those with private insurance (AOR 0.2, 95% CI = 0.1–0.7)
(Table 5). Overall, each patient received a median of 3
expert consultations.
Of the 134 patients alive at diagnosis, ≈90% were
assigned a case manager. Case management activities in-
cluded home visits (68%), social worker assistance (37%),
transportation assistance (32%), incentives (25%), housing
assistance (17%), and other activities including legal orders
for DOT or isolation (9%–15%). Only 4% of patients re-
ceived none of these case management services. Interpreter
use was documented for 60% of 107 patients who under-
stood some or no English.
Outcomes
Of 112 eligible patients, including all XDR TB pa-
tients, sputum culture converted to negative for 109 (97%).
Patients considered ineligible for culture conversion in-
cluded 1 patient whose TB was diagnosed after death, 6
who died during treatment, 3 who were transferred to an-
other US jurisdiction or out of the United States, 7 who had
extrapulmonary-only disease, and 6 without a positive spu-
tum culture result. Of the 3 for whom no culture conversion
was documented, 1 was lost to follow-up after 166 days and
2 completed treatment. Culture conversion occurred within
a median of 2 months from starting a 5-drug-regimen but
varied by resistance pattern (online Technical Appendix).
Of the 134 patients alive at diagnosis, 78% completed
treatment, 11% transferred within or outside the United
States or were lost to follow-up, and 1% stopped treatment
because of adverse events (Table 6). For no patients did
treatment fail or TB recur within the year after treatment
completion. Of the 134 patients, 12 (9%) died during treat-
ment; 75% of these deaths were considered TB related. No
XDR TB patient died. Death during treatment was signi-
cantly associated with age >65 years (AOR 20.2, 95% CI
2.3–181.0), smoking (AOR 6.4, 95% CI 1.0–39.4), or HIV
infection (AOR 6.3, 95% CI 1.1–37.7) (online Technical
Appendix). When TB medications and interaction terms
were initially included in the model, HIV infection was
no longer associated with death and receipt of an effective
injectable medication was associated with lower odds of
dying (AOR 0.02, 95% CI 0.002–0.2) (online Technical
Appendix). No HIV-infected patient who received an ef-
fective injectable medication died. Of 9 patients who died
of TB-related causes, only 2 who had received a 5-drug
regimen died, both after 8 months; 1 had received 3 non–
rst-line medications and died after 5 months, and the re-
maining 6 never received >2 MDR TB second- or third-line
medications and died within 49 days of treatment initiation.
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014 815
Table 2. Socioeconomic characteristics of study participants and all patients with MDR and/or XDR TB, United States, 20052007*
Characteristic
Study participants, no. (%), n = 135
Unemployed
38 (28)
Homeless
9 (7)
Correctional institution resident 6 (4) 7 (2)
Long-term care facility resident
4 (3)
Injection drug use
5 (4)
Noninjection drug use
12 (9)
Excess alcohol use 15 (11) 31 (8)
Smoker
31 (23)
Pregnant at treatment initiation
6 (4)
Private health insurance, % of 112 known
24 (21)
Public health insurance, % of 112 known 49 (44)
Jail/prison health coverage, % of 112 known
2 (2)
Other health insurance, % of 112 known
5 (4)
No health insurance, % of 112 known
32 (29)
HIV+ 14 (10) 29 (8)
Receiving HAART
9 (64)
Receiving ART
1 (7)
Receiving neither HAART nor ART
3 (21)
Receipt of ART not documented
1 (7)
Not HIV infected
102 (76)
HIV status unknown
19 (14)
Diabetes, % of 121 known 24 (20)
ESRD, % of 121 known
3 (2)
Prolonged corticosteroid therapy, % of 121 known
2 (2)
Other immunosuppressive therapy, % of 121 known
2 (2)
Cancer, % of 121 known
3 (2)
Hematologic diseases, % of 121 known 2 (2)
*Study patients were from California, New York City, and Texas. MDR, multidrug resistant; XDR, extensively drug resistant; TB, tuberculosis; HIV+, HIV
infected; HAART, highly active antiretroviral therapy; ART, antiretroviral therapy; ESRD, end-stage renal disease. Blank cells indicate data not available.
Statistically significant differences between percentages of study patients and all US MDR TB patients at p<0.05.
RESEARCH
Of the 4 HIV-infected patients who died of TB-related
causes, 3 had a CD4 count of <50 cells/mm
3
at initiation of TB
treatment and the other had a CD4 count of <100 cells/mm
3
.
Of these 4 patients, 2 were taking >3 anti-HIV medications.
Among patients alive at diagnosis, a median of 1 ad-
verse event (average 2.9) resulted in medication change or
adjustment, but only 2 patients completely stopped treat-
ment. According to multivariate linear regression, use of
clofazimine was signicantly associated (p<0.05) with
more adverse events but was not associated with death
during treatment. Of 9 patients receiving clofazimine, 6
experienced postinitiation gastrointestinal effects that
resulted in their discontinuing clofazimine. Because of
MDR TB or its treatment, of the 134 patients, 13% ex-
perienced hearing impairment, 13% hepatitis, 11% renal
impairment, 8% difculty ambulating, 7% visual impair-
ment, and 1% seizures. Depression or psychosis was
documented for 19% (80% of whom were taking cyclo-
serine), and pulmonary impairment was documented for
4%. Of 103 impairments, 66% were mild, but another 7%
were graded most severe and occurred for 6 patients, 3 of
whom completed treatment; 2 of those patients died (lung
and mobility impairments), and 1 transferred outside
the country.
816 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014
Table 3. Clinical characteristics of study participants and other patients with MDR and/or XDR TB, United States, 20052007*
Characteristic
Study participants, no. (%),
n = 135
All US MDR TB patients, no. (%),
n = 370
History of LTBI, % of 130 known
21 (16)
History of completing LTBI Rx, % of 21 with history of LTBI
14 (67)
History of TB disease
48 (36)
60 (16)
Contact with infectious TB patient, % of 87 known 10 (11)
Contact with infectious MDR TB patient, % of 10 contacts
6 (60)
Dead at TB diagnosis
1 (1)
5 (1)
Smear positive at any time, % of 134 alive at diagnosis
103 (77)
223 (60)
Sites of TB disease
Pulmonary
115 (85)
332 (90)
Extrapulmonary only
8 (6)
37 (10)
Disseminated at any time
12 (9)
Extent of pulmonary disease at diagnosis
Extensive
69
Moderate
31
Minimal
21
Undocumented 6
Description of extensive pulmonary disease, at any time
Miliary
4
Cavitary
58
127
Multiple lobes 70
Collapsed lobes
6
Extent of extrapulmonary disease at diagnosis
Extensive
2
Moderate 3
Minimal
3
*MDR, multidrug resistant; XDR, extensively drug resistant; TB, tuberculosis; LTBI, latent TB infection; Rx, treatment. Blank cells indicate data not
available.
†Statistically significant differences between percentages of study patients and all US MDR TB patients at p<0.05.
Figure 1. Percentage of 135 patients
for whom Mycobacterium tuberculosis
isolates had the following mutually
exclusive resistance patterns. INH/
RIF/RBT-only, resistant to isoniazid
(INH)/rifampin (RIF)/rifabutin (RBT)
only; INH/RIF/RBT-plus, resistant to
a median of 4 medications; rst-line,
resistant to a median of 6 medications;
pre-XDR, resistant to a median of
8 medications; XDR, resistant to a
median of 11 medications.
MDR and XDR TB, United States
Cost of MDR TB and XDR TB
Direct costs averaged $134,000 (SE $9,683) per MDR
TB patient and $430,000 (SE $73,109) per XDR TB pa-
tient. In comparison, costs are estimated at $17,000 (SE
$1,210) per non-MDR TB patient (Figure 2 and online
Technical Appendix). For isoniazid/rifampin/rifabutin-
only, direct costs averaged $77,000 (SE $15,448) and
direct-plus-productivity-loss costs averaged $226,000 (SE
$73,338). Outpatient medications comprised ≈40% of di-
rect costs, averaging $53,300 for MDR TB and $164,000
for XDR TB patients. Direct-plus-productivity-loss costs
averaged $260,000 (SE $23,212) per MDR TB patient and
$554,000 (SE = $127,707) per XDR TB patient. Highest
costs were nearly $1.8 million. Applying these averages to
364 cases of MDR TB and 9 cases of XDR TB in the Unit-
ed States during 2005–2007, direct costs were ≈$53 million
and direct-plus-productivity-loss costs were ≈$100 million.
When days hospitalized were controlled for, charac-
teristics associated with greater direct costs, in descending
order, were having XDR TB, residency in a long-term-
care institution, non–injection-drug use, HIV infection, or
having public insurance (adjusted R
2
= 0.55). When days
hospitalized were controlled for, characteristics associated
with greater direct-plus-productivity-loss costs were death,
XDR TB, non–injection-drug use, HIV-infection, diabetes,
or being male (R
2
= 0.66) (online Technical Appendix)
Table 2 shows that known insurance status was indi-
cated on clinic records of 112 patients. Of 76 patients for
whom insurance coverage while hospitalized was known,
38% had public insurance (including 32% Medicaid), 36%
had no insurance, 24% had private insurance, 4% were in
jail/prison, and 1% had other insurance. The public sector
covered (i.e., by public insurance, for outpatients who had
no/unknown insurance, for uninsured inpatients cared for
in publicly nanced hospitals, for jail/prison inmates) 75%
of MDR TB and 100% of XDR TB patients and incurred
80% of MDR TB direct costs ($13,883,000/$17,415,000)
and 100% of XDR TB direct costs ($2,149,000).
Discussion
In this population-based sample, which comprised 36%
(130/364) of MDR TB and 56% (5/9) of XDR TB cases re-
ported in the United States during 2005–2007, MDR/XDR
TB diagnosis and treatment were very complex: M. tuber-
culosis isolates were resistant to a large number of medica-
tions, care was complicated by extensive disease and by
concurrent conditions, and patients were highly infectious.
Despite this complexity, for nearly all eligible patients,
sputum cultures converted to negative and 78% of patients
completed treatment, including all those with XDR TB.
Only 1% stopped treatment because of adverse events.
The mortality rate (10%) was lower than that for other
countries (13–17), and the mortality rate for patients during
treatment (9%) was similar to that for US patients with iso-
niazid/rifampin-susceptible TB (8%) (L. Armstrong, pers.
comm.). Among patients who died, 75% (9/12) of deaths
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014 817
Table 4. Characteristics associated with any acquired antimicrobial drug resistance during MDR TB treatment, 128 patients, California,
Texas, and New York, NY, USA, 20052007*†
Variable
Initial OR
estimate Initial 95% CI Initial Pr>
2
Final OR
estimate Final 95% CI Final Pr>
2
Age >65 y <0.001 <0.001>999.999 0.973
Black race
33.19
0.80>999.999
0.065
4.07
1.0815.37
0.039
Recent homelessness
18.76
0.93377.71
0.056
5.81
1.1728.86
0.031
Pre-XDR or XDR TB
8.78
2.3133.42
0.001
5.15
1.8614.21
0.002
AFB-smear positive
5.34
0.8633.22
0.072
Age 25-44 y
4.83
0.6536.03
0.124
Hispanic ethnicity 4.83 0.11216.20 0.417
≥4 Effective medications
3.46
0.4129.47
0.256
Age 4564 y
3.41
0.3930.21
0.271
Asian race
3.35
0.07151.32
0.534
Disseminated TB disease
2.28
0.2124.20
0.495
Foreign born 2.10 0.1528.64 0.577
Recent cigarette smoker
1.96
0.419.31
0.397
Recent excess alcohol use
0.99
0.137.65
0.988
TB clinic outpatient management
0.98
0.185.35
0.980
Recent unemployment 0.97 0.243.93 0.964
Cavitary disease
0.77
0.212.84
0.694
Diabetes
0.76
0.163.70
0.732
History of TB disease
0.44
0.121.59
0.208
HIV infection
0.39
0.034.92
0.463
Recent injection drug or noninjection
drug use
0.15 0.005.08 0.291
*MDR TB, multidrug-resistant tuberculosis; XDR TB, extensively drug-resistant TB; OR, odds ratio; AFB, acid-fast bacilli; Pr, probability. Boldface
indicates significance in the final model. Blank cells indicate variables not retained in the final model.
†Model fit intercept and covariates: Akaike information criterion, initial 136.392, final 116.619; Schwarz criterion, initial 198.964, final 127.996; 2logL,
initial 92.392, final 108.619.
RESEARCH
were TB-related, and 67% (6/9) occurred within 49 days
of TB diagnosis. Among HIV-infected patients, failure or
inability to use an effective injectable TB medication was
associated with TB-related death.
Some diagnostic and treatment practices contributed to
successful outcomes. Among symptomatic patients, initial
TB diagnosis was made relatively quickly, within 7 weeks
of symptom onset. Nearly three-fourths (73%) of patients
were hospitalized; duration was 1 month for non-XDR TB
patients and 9 months for XDR TB patients. Extensive
DST of rst-line and second-line medications was conduct-
ed within 2 months of treatment initiation for most patients.
At some point during treatment, 61% of patients were re-
ceiving a 5-drug regimen. For outpatient care, DOT was
used nearly universally, including during home isolation as
recommended by national guidelines (7). The physicians of
most patients with MDR/XDR TB consulted with experts.
However, patient management required intensive monitor-
ing and numerous medication changes. Case management
services were also intensive; a case manager was assigned
to ≈90% of patients.
Deciencies in practices were identied. Despite CDC
recommendations, 20% of patients had no documentation
of expert consultation. Outcome was unknown for 3% who
transferred within and 6% outside the United States and for
2% who were lost to follow-up. Acquisition of any drug
resistance during treatment occurred for 21% of patients
and was more likely to occur in populations difcult to treat
(those who had pre-XDR TB or XDR TB or were home-
less), suggesting a need for more vigilant treatment moni-
toring. There were delays of 3 months before patients
started a 5-drug regimen. Today, the use of more rapid
molecular diagnostic techniques could shorten the time to
initiation of an appropriate treatment regimen (18). Since
September 2009, CDC has offered US sites a molecular-
based testing service (www.cdc.gov/tb/topic/laboratory/
guide.html).
Because MDR TB treatment lasts >2 years (vs. 6
months for drug-susceptible TB), uses expensive medica-
tions, and requires hospitalization for ≈75% of patients
(vs. 50% with drug-susceptible TB), it was very costly to
treat and manage; average direct cost was $134,000 per
MDR TB patient and $430,000 per XDR TB patient. The
estimated $17,000 per non-MDR TB patient is 8 and 25
times lower than the costs for MDR TB and XDR TB,
respectively. In contrast, lifetime care per HIV-infected
818 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014
Table 5. Characteristics associated with expert consultation for 134 patients during MDR TB treatment, California, Texas, and New
York, NY, USA, 20052007*
Variable
Initial OR
estimate
Initial 95% CI
Initial Pr>
2
Final OR
estimate
Final 95% CI
Final Pr>
2
XDR TB
>999.999
<0.001>999.999
0.939
Recent homelessness
>999.999
<0.001>999.999
0.887
Correctional institution residence >999.999 <0.001>999.999 0.939
Recent injection drug or noninjection
drug use
61.63
0.00>999.999
0.401
Recent cigarette smoker
27.88
0.56>999.999
0.096
Diabetes
26.44
1.28545.80
0.034
Disseminated TB disease
9.49
0.18501.11
0.266
TB clinic outpatient management
7.96 1.5042.32 0.015
5.67
1.9316.64
0.002
Age 4564 y
4.30
0.3848.55
0.239
Recent unemployment
3.81
0.5228.18
0.190
Age 2544 years
2.92
0.5814.63
0.192
Long-term care facility resident 1.87 <0.001>999.999 0.878
5-drug regimen
1.13
0.225.82
0.882
Total no. adverse events
1.12
0.881.42
0.371
Total first-line resistance
0.63
0.113.77
0.614
Acquired resistance
0.57
0.074.37
0.588
Foreign born 0.55 0.0312.28 0.705
History of TB disease
0.53
0.132.10
0.363
Age >65 y
0.50
0.0214.97
0.687
HIV infection
0.34
0.027.21
0.492
Pregnant
0.28
0.025.15
0.393
Private insurance
0.14 0.020.87 0.035
0.23
0.080.68
0.008
Pre-XDR
0.12
0.011.35
0.087
Male
0.12
0.020.82
0.031
Died
0.05
<0.0013.46
0.165
White race
0.05
<0.001>999.999
0.988
Recent excess alcohol use
<0.001
<0.0010.06
0.002
0.19
0.050.72
0.014
Black race <0.001 <0.001>999.999 0.937
Hispanic ethnicity
<0.001
<0.001>999.999
0.938
Asian race
<0.001
<0.001>999.999
0.943
*MDR TB, multidrug-resistant tuberculosis; XDR TB, extensively drug-resistant TB; OR, odds ratio. Boldface indicates significance in the final model.
Blank cells indicate variables not retained in the final model.
†Model fit intercept and covariates: AIC (initial 133.402, final 121.683), SC (initial 223.235, final 133.274
);
2logL (initial 71.402, final 113.683).
MDR and XDR TB, United States
patient costs $380,000 (updated to 2010 dollars) (19) and
lifetime care per breast cancer patient costs $20,000–
$100,000 (20).
During 2005–2007, the 373 MDR/XDR TB cases cost
the US health care system an estimated $53 million; during
this time there were ≈41,000 total TB cases. Direct costs
for an average XDR TB patient were 3.2 times those for an
average MDR TB patient, mostly because of hospitaliza-
tion costs. Only 20% of XDR TB and 28% of MDR TB
patients were managed solely as outpatients. The public
sector incurred 80% of the MDR TB costs and 100% of the
XDR TB costs.
With health care reform, a substantial proportion of
uninsured TB patients are expected to become eligible
for Medicaid coverage, which should increase access to
health care and early TB diagnosis and decrease TB-asso-
ciated hospitalizations and deaths. Prevention opportuni-
ties for MDR TB are limited. Maintaining the capacity of
public health departments and of publicly nanced hospi-
tals to act as safety nets (regardless of patient insurance
status) to quickly diagnose MDR/XDR TB and isolate and
effectively treat the patients will be critical for preventing
deaths and transmission of drug-resistant TB organisms.
Investment in infection control infrastructure and the ca-
pacity to prevent TB among MDR TB patient contacts is
also critical; our cost-of-illness estimates did not include
these programmatic costs of preventing cases. During the
1979–1994 TB resurgence and MDR TB outbreaks in the
United States, New York City renovated hospitals and the
Rikers Island prison and treated 20,000 excess TB patients
at a cost of ≈$1.7 billion (updated to 2010 dollars) (21).
This study had some limitations. Detailed hospital-
ization records were unavailable for 17 patients. More-
over, documentation of care for incarcerated patients
was limited. Follow-up data for all patients were un-
available after 1 year of treatment. Because outpatient
care was provided by a mixture of public and private
providers, we used average wholesale medication prices
to estimate medication costs, which overestimated actual
costs to TB clinics that have access to reduced (often
one half to one third) medication prices negotiated with
pharmaceutical companies. Estimates of out-of-pocket
costs were not included.
Conclusions
In this population-based sample of MDR/XDR TB pa-
tients in the United States, despite the extensive drug resis-
tance found at the time of diagnosis, culture conversion and
treatment completion rates were high and mortality rates
were low. Records of treatment practices documented near-
universal use of DOT. However, these outcomes came at
a high cost to the public sector, providing incentives for
Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014 819
Table 6. Treatment outcomes of MDR/XDR TB study patients alive at diagnosis, by resistance pattern, California, Texas, and New
York, NY, USA, 20052007*
Resistance pattern
Completed
treatment, %
Transferred within
United States, %
Transferred out of
United States, %
Lost to
follow-up, %
Stopped because
of side effects, %
Died during
treatment, %
All, N = 134
78
3
6
2
1
9
INH/RIF/RBT-only, n = 17
59
0
18
6
0
18
INH/RIF/RBT-plus, n = 58
83
3
7
0
0
7
First-line, n = 32
78
0
3
6
3
9
Pre-XDR, n = 22
77
9
0
0
5
9
XDR, n = 5
100
0
0
0
0
0
*MDR TB, multidrug-resistant tuberculosis; XDR TB, extensively drug-resistant TB; INH, isoniazid; RIF, rifampin; RBT, rifabutin.
Figure 2. Average, median, and
distribution of direct costs per
patient in 2010 US dollars by drug
resistance. This box-plot diagram
shows the minimum and maximum
values (vertical lines), the averages
and medians (numbers), and the
interquartile ranges (box). MDR,
multidrug-resistant tuberculosis;
XDR, extensively drug-resistant
tuberculosis.
RESEARCH
the United States to prevent MDR/XDR TB. Preventing
MDR/XDR TB in the United States will require address-
ing factors associated with development of drug resistance
in countries where foreign-born US patients originate, as
well as rapid diagnosis, appropriate regimen selection, ro-
bust case management practices, and continued emphasis
on DOT in the United States.
Acknowledgments
We acknowledge the efforts of many persons involved with
study data collection and management and data analysis consul-
tation, including Holly Anger, Pennan Barry, Peter Cegielski,
Jeffrey Chrismon, Carla Cueva, Wafaa El-Sadr, Denise Gar-
rett, Jerrie Givens, Anita Musafar, Thomas Navin, Hugo Ortega,
Stephanie Ott, Nicolette Palermo, Vicki Randle, Alicia Rodri-
guez, Marthe Sende, Brian Sizemore, John Stamper, Andrew
Vernon, Charles Wallace, Ying Wang, and James Watt.
This work was supported by the Tuberculosis Epidemiologic
Studies Consortium of CDC. The CDC National Center for HIV,
Viral Hepatitis, STD and TB Prevention and the Division of Tu-
berculosis Elimination supported CDC and contract staff and the
analytical resources used during the project.
Ms Marks is an epidemiologist/economist in the Division
of Tuberculosis Elimination at CDC. Her research interests in-
clude combining epidemiologic research and economic analysis
of TB diagnostics, MDR TB treatment, outcomes, and preven-
tion, and often focus on populations experiencing health dis-
parities, such as persons living with HIV or homelessness, and
sexual/gender minorities.
References
1. Munsiff SS, Ahuja SD, Li J, Driver CR. Public–private collaboration
for multidrug-resistant tuberculosis control in New York City.
Int J Tuberc Lung Dis. 2006;10:639–48.
2. Burgos M, Gonzalez LC, Paz EA, Gournis E, Kawamura LM,
Schecter G, et al. Treatment of multidrug-resistant tuberculosis
in San Francisco: an outpatient-based approach. Clin Infect Dis.
2005;40:968–75. http://dx.doi.org/10.1086/428582
3. Shah NS, Pratt R, Armstrong L, Robison V, Castro KG, Cegielski JP.
Extensively drug-resistant tuberculosis in the United States,
1993–2007. JAMA. 2008;300:2153–60. http://dx.doi.org/10.1001/
jama.300.18.2153
4. Banerjee R, Allen J, Westenhouse J, Oh P, Elms W, Desmond E,
et al. Extensively drug-resistant tuberculosis in California, 1993–2006.
Clin Infect Dis. 2008;47:450–7. http://dx.doi.org/10.1086/590009
5. Rajbhandary SS, Marks SM, Bock NN. Costs of patients hospital-
ized for multidrug-resistant tuberculosis. Int J Tuberc Lung Dis.
2004;8:1012–6.
6. Althomsons SP, Cegielski JP. Impact of second-line drug resistance
on tuberculosis treatment outcomes in the United States: MDR TB
is bad enough. Int J Tuberc Lung Dis. 2012;16:1331–4. http://dx.doi.
org/10.5588/ijtld.11.0812
7. Centers for Disease Control and Prevention. Treatment of tuberculosis.
American Thoracic Society, CDC, and Infectious Diseases Society
of America. MMWR Recomm Rep. 2003;52(RR-11):1–80.
8. Falzon D, Jaramillo E, Schünemann HJ, Arentz M, Bauer M,
Bayona J, et al. WHO guidelines for the programmatic manage-
ment of drug-resistant tuberculosis: 2011 update. Eur Respir J.
2011;38:516–28. http://dx.doi.org/10.1183/09031936.00073611
9. Centers for Medicare & Medicaid Services. Operating cost to
charge ratios (OPCCR). FY2005 Impact le (inpatient prospective
payment system) 2005 [cited 2010 May 12]. http://www.cms.gov/
Medicare/Medicare-Fee-for-Service-Payment/PCPricer/index.
html?redirect=/pcpricer
10. Bureau of Labor Statistics. Consumer Price Index—all urban
consumers, medical care. Series ID CUUR0000SAM [cited 2012
Feb 21]. http://data.bls.gov/cgi-bin/srgate
11. Centers for Medicare & Medicaid Services. Medicare geographic
adjustment factors [cited 2010 May 12]. http://www.cms.gov/
Research-Statistics-Data-and-Systems/Statistics-Trends-and-
Reports/Medicare-Geographic-Variation/GV_PUF.html
12. Grosse SD. Appendix I: productivity loss tables. In: Haddix AC,
Teutsch SM, Corso PS, editors. Prevention effectiveness: a guide
to decision analysis and economic evaluation. 2nd ed. New York:
Oxford University Press; 2003. p. 245–57.
13. Johnston JC, Shahidi NC, Sadatsafavi M, Fitzgerald JM. Treatment
outcomes of multidrug-resistant tuberculosis: a systematic review
and meta-analysis. PLoS ONE. 2009;4:e6914. http://dx.doi.
org/10.1371/journal.pone.0006914
14. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH,
Moll AP, et al. Treatment outcomes among patients with multi-
drug-resistant tuberculosis: systematic review and meta-analysis.
Lancet Infect Dis. 2009;9:153–61. http://dx.doi.org/10.1016/S1473-
3099(09)70041-6
15. Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB.
Treatment outcomes among patients with extensively drug-resistant
tuberculosis: systematic review and meta-analysis. Clin Infect Dis.
2010;51:6–14. http://dx.doi.org/10.1086/653115
16. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M,
Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment
regimens and patient outcomes: an individual patient data meta-
analysis of 9,153 patients. PLoS Med. 2012;9: e1001300. http://
dx.doi.org/10.1371/annotation/230240bc-bcf3-46b2-9b21-
2e6e584f7333
17. Dalton T, Cegielski P, Akksilp S, Asencios L, Campos Caoili J, Cho
SN, et al. Prevalence of and risk factors for resistance to second-line
drugs in people with multidrug-resistant tuberculosis in eight
countries: a prospective cohort study. Lancet. 2012;380:1406–17.
http://dx.doi.org 10.1016/S0140-6736(12)60734-X
18. Banerjee R, Allen J, Lin SYG, Westenhouse J, Desmond E,
Schecter GF, et al. Rapid drug susceptibility testing with a molecular
beacon assay is associated with earlier diagnosis and treatment of
multidrug-resistant tuberculosis in California. J Clin Microbiol.
2010;48:3779–81. http://dx.doi.org/10.1128/JCM.01236-10
19. Hutchinson AB, Farnham PG, Duffy N, Wolitski RJ, Sansom SL,
Dooley SW, et al. Return on public health investment: CDC’s
expanded HIV testing initiative. J Acquir Immune Dec
Syndr. 2012;59:281-6. PMID: 22067662 doi: 10.1097/QAI.0b013
e31823e5bee
20. Campbell JD, Ramsey SD. The costs of treating breast cancer in
the U.S.: a synthesis of published evidence. Pharmacoeconomics.
2009;27:199–209. http://dx.doi.org/10.2165/00019053-200927030-
00003
21. Frieden TR, Fujiwara PI, Washko RM, Hamburg MA. Tuberculosis in
New York City—turning the tide. N Engl J Med. 1995;333:229–33.
Address for correspondence: Suzanne M. Marks, Centers for Disease
Control and Prevention, Mailstop E10, 1600 Clifton Rd NE, Atlanta, GA
30333, USA; email: smarks@cdc.gov
820 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 20, No. 5, May 2014
    • "For the US, Rajbhandary et al. analyzed the inpatient costs of 13 MDR-TB patients enrolled in a CDC study in 1995/1996 and estimated the remaining costs from a societal perspective [28]. Marks et al. [29], in their impressive population-based sample of 134 patients that comprised 36% (130/364) of all MDR-TB and 56% (5/9) of all XDR-TB cases reported in the United States during 2005e2007, calculated direct-plus-productivity-loss costs of USD 260,000 per MDR-TB patients and USD 554,000 per Table 5 GKV costs of diagnosing MDR-TB and monitoring MDR-TB treatment (in V). "
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: 4220 new cases of tuberculosis (TB) were reported in Germany in 2012; of those, 65 cases were multidrug-resistant TB (MDR-TB) or extensively multidrug-resistant TB (XDR-TB) cases. However, there is only limited information on the economic consequences of drug resistance patterns on the treatment costs of MDR-and XDR-TB patients. Methods: On the basis of drug susceptibility of the single MDR-TB/XDR-TB strains the direct medical costs of suitable therapies were calculated according to the current guidelines of the World Health Organization (WHO) and those of the German Central Committee against Tuberculosis. These costs were combined with hospital and outpatients monitoring costs and followed the most recent German invoicing system and health statistics. Total drug and monitoring costs and were determined by Monte-Carlo simulation comprising all different options. Results: According to this, the mean drug costs were €51,113.22 (range €19,586.14 to €94,767.90). The weighted costs for hospitalization were €26,000.76 per patient compared to only €2,192.13 for primary outpatients; the total treatment costs of MDR-TB amounted to €64,429.23. These are joined by the costs due to loss of productivity, varying between €17,721.60 and €44,304. From a societal perspective, the total cost per MDR-TB/XDR-TB case reach an amount between €82,150 and €108,733 per case, respectively. Conclusion: Cost analyses based on strain resistance patterns allow more reliable estimates of the real costs of treating MDR-TB/XDR-TB than do methods that ignore this factor. Advantageously, they demonstrate the economic impact of drug-resistant TB in low-incidence countries. Costs of productivity loss is of new importance because of the length of MDR-XDR therapy, but its true share of total costs has still to be determined.
    Full-text · Article · Nov 2014
    • "A limited amount of data are available measuring the healthcare costs of NTM at the national level. Previously published studies have attempted to measure various aspects of cost, but have done so using small sample sizes or with a limited study period101112. The purpose of this study is to offer a comprehensive evaluation of the inhospital costs of care for pulmonary TB and NTM using national data during a long study period beginning in 2001 up through 2012. "
    [Show abstract] [Hide abstract] ABSTRACT: Pulmonary mycobacterial diseases describe both tuberculosis (TB) and nontuberculous mycobacteria (NTM). TB is an established public health issue and a reportable disease. Efforts in treatment and surveillance have resulted in the incidence of TB to decrease in recent years. However, the incidence of NTM is increasing, classifying NTM as an emerging public health problem in the US. Despite the increasing importance of pulmonary mycobacterial diseases, few data are available measuring the cost burden of mycobacterial diseases at the national level. The purpose of this study was to evaluate the cost burden and measure emerging trends in hospitalization of pulmonary TB and NTM in the US from 2001 through 2012.
    Full-text · Article · Oct 2014
    • "Extensive resistance: it defines the ability of organisms to withstand the inhibitory effects of at least one or two most effective antimicrobial drugs. Also termed as XDR, this seemed to arise in patients after they have undergone a treatment with first line drugs, for example, XDR-TB resistance against fluoroquinolone [35, 36]. "
    [Show abstract] [Hide abstract] ABSTRACT: The resistance among various microbial species (infectious agents) to different antimicrobial drugs has emerged as a cause of public health threat all over the world at a terrifying rate. Due to the pacing advent of new resistance mechanisms and decrease in efficiency of treating common infectious diseases, it results in failure of microbial response to standard treatment, leading to prolonged illness, higher expenditures for health care, and an immense risk of death. Almost all the capable infecting agents (e.g., bacteria, fungi, virus, and parasite) have employed high levels of multidrug resistance (MDR) with enhanced morbidity and mortality; thus, they are referred to as "super bugs." Although the development of MDR is a natural phenomenon, the inappropriate use of antimicrobial drugs, inadequate sanitary conditions, inappropriate food-handling, and poor infection prevention and control practices contribute to emergence of and encourage the further spread of MDR. Considering the significance of MDR, this paper, emphasizes the problems associated with MDR and the need to understand its significance and mechanisms to combat microbial infections.
    Full-text · Article · Jul 2014
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