CDC and local institutional review boards approved the study and granted a waiver of patient informed consent and patient authorization. We defined a 5-drug regimen (Technical Appendix) to be consistent with US and World Health Organization recommendations (7,8). All study definitions are in the Technical Appendix.

Each site identified cases of MDR TB and extensively drug-resistant (XDR) TB reported to CDC during 2005–2007. The study included all XDR TB cases and a 75% simple random sample of MDR TB cases from California and New York, NY (New York City), and a 50% sample from Texas. Using standardized forms, we abstracted hospital, laboratory, and public health clinic records retrospectively for patient demographic, socioeconomic, and clinical characteristics and for treatment, case management, outcomes, and costs. Total charges for each TB-associated hospitalization 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 identified 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 final models (SAS version 9.2/9.3; SAS Institute, Cary, NC, USA). Adjusted odds ratios (AORs) significant at 95% CIs and Schwarz Criterion statistics are reported for goodness-of-fit. Variables included in initial models were patient demographics (gender, age group, race/ethnicity, foreign birth), socioeconomic factors (homelessness, unemployment, illicit substance use, excess alcohol use, smoking), medical risks (HIV infection, diabetes), TB history, disease severity (acid-fast bacilli [AFB]–smear positivity, cavitation, 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 institution, long-term-care facility residence, pregnancy, death during treatment, number of adverse events, private outpatient insurance; for death during treatment: pregnancy, incarceration in a correctional institution).

Inpatient costs were measured; outpatient costs and productivity losses were estimated (Technical Appendix). Hospital charges were converted to costs by using hospital-specific 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 (Technical Appendix). We report SEMs to display cost variability.

For productivity losses from hospitalization, we applied 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 estimated direct and productivity-loss costs and examined associated characteristics by using multivariable linear regression with backward selection. Adjusted R² statistics are reported to show goodness-of-model-fit.

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 (Tables 1–3). Among patients for whom information about concurrent 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; however, 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 patients, 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 extrapulmonary-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

Figure 1

Figure 1. Percentage of 135 patients for whom Mycobacterium tuberculosis isolates had the following mutually exclusive resistance patternsINH/RIF/RBT-only, resistant to isoniazid (INH)/rifampin (RIF)/rifabutin (RBT) only; INH/RIF/RBT-plus, resistant to a median of 4...

At various times during treatment, M. tuberculosis isolates were tested for susceptibility (median 14 medications, 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 identified: 4% XDR, 17% pre-XDR, 24% total first-line resistance, 43% isoniazid/rifampin/rifabutin-plus-other resistance, 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 was conducted for first-line drugs during the first 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 rifampin, resulting in MDR TB, occurred for 6% of patients, to fluoroquinolones for 3%, and to injectable drugs for 4%. Other medications to which resistance was acquired were ethambutol (10% of patients), pyrazinamide (6%), streptomycin (5%), ethionamide (5%), rifabutin (2%), cycloserine (1%), and clofazimine (1%). For 1 patient, fluoroquinolone resistance was acquired, resulting in XDR TB.

Cost of MDR TB and XDR TB

Figure 2

Figure 2. Average, median, and distribution of direct costs per patient in 2010 US dollars by drug resistanceThis box-plot diagram shows the minimum and maximum values (vertical lines), the averages and medians (numbers),...

Direct costs averaged $134,000 (SE $9,683) per MDR TB patient and $430,000 (SE $73,109) per XDR TB patient. In comparison, costs are estimated at $17,000 (SE $1,210) per non-MDR TB patient (Figure 2 and 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 direct 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 United States during 2005–2007, direct costs were ≈$53 million and direct-plus-productivity-loss costs were ≈$100 million.

When days hospitalized were controlled for, characteristics 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 R² = 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 (R² = 0.66) (Technical Appendix)

Table 2 shows that known insurance status was indicated 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 financed 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).

In this population-based sample, which comprised 36% (130/364) of MDR TB and 56% (5/9) of XDR TB cases reported in the United States during 2005–2007, MDR/XDR TB diagnosis and treatment were very complex: M. tuberculosis isolates were resistant to a large number of medications, 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 isoniazid/rifampin-susceptible TB (8%) (L. Armstrong, pers. comm.). Among patients who died, 75% (9/12) of deaths 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 first-line and second-line medications was conducted within 2 months of treatment initiation for most patients. At some point during treatment, 61% of patients were receiving 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 monitoring and numerous medication changes. Case management services were also intensive; a case manager was assigned to ≈90% of patients.

Deficiencies in practices were identified. 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 difficult to treat (those who had pre-XDR TB or XDR TB or were homeless), suggesting a need for more vigilant treatment monitoring. 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 medications, 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 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 hospitalization 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-associated hospitalizations and deaths. Prevention opportunities for MDR TB are limited. Maintaining the capacity of public health departments and of publicly financed hospitals 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 capacity 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 hospitalization records were unavailable for 17 patients. Moreover, documentation of care for incarcerated patients was limited. Follow-up data for all patients were unavailable 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.

In this population-based sample of MDR/XDR TB patients in the United States, despite the extensive drug resistance 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 the United States to prevent MDR/XDR TB. Preventing MDR/XDR TB in the United States will require addressing factors associated with development of drug resistance in countries where foreign-born US patients originate, as well as rapid diagnosis, appropriate regimen selection, robust case management practices, and continued emphasis on DOT in the United States.