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Treatment of Multidrug-Resistant Tuberculosis in San Francisco: An Outpatient-Based Approach

  1. Marcos Burgos1,
  2. Leah C. Gonzalez2,
  3. E. Antonio Paz3,
  4. Effie Gournis3,a,
  5. L. Masae Kawamura3,
  6. Gisela Schecter3,
  7. Philip C. Hopewell2, and
  8. Charles L. Daley2
  1. 1Department of Internal Medicine, Division of Infectious Diseases, University of New Mexico, and Department of Medicine, Albuquerque Veterans Affairs Medical Center, Albuquerque, New Mexico
  2. 2Division of Pulmonary and Critical Care Medicine, San Francisco General Hospital, and University of California, San Francisco
  3. 3Tuberculosis Control Section, San Francisco Department of Public Health, San Francisco, California
  1. Reprints or correspondence: Dr. Marcos Burgos, University of New Mexico, Div. of Infectious Diseases, 915 Camino de Salud, BRF 323, Albuquerque, NM 87131-5271, (mburgos{at}salud.unm.edu).

  • ↵a Present affiliation: Communicable Disease Surveillance Unit, Toronto Public Health, Toronto, Ontario.

 
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Abstract

Background. Treatment of patients with multidrug-resistant tuberculosis requires prolonged therapy, often involving long hospital stays. Despite intensive and costly therapy, cure rates are relatively low.

Methods. We reviewed the outcomes for all patients with multidrug-resistant tuberculosis treated in San Francisco, California, during 1982–2000 and identified billing charges for patients treated during 1995–2000. Mycobacterium tuberculosis isolates were genotyped by IS6110-based restriction fragment-length polymorphism analysis.

Results. Forty-eight cases were identified with resistance to a median of 3 drugs (range, 2–9 drugs). The median age of the patients was 49.5 years (range, 22–78 years); 36 (75%) of 48 patients were foreign born, 11 (23%) were human immunodeficiency virus (HIV) seropositive, and 45 (94%) had pulmonary tuberculosis. Thirty-two (97%) of the 33 HIV-seronegative patients were cured, with only 1 relapse occurring 5 years after treatment. All 11 HIV-seropositive patients died during observation. Twenty-one patients (44%) required hospitalization, with a median duration of stay of 14 days (range, 3–74 days). The estimated inpatient and outpatient aggregate cost for the 11 patients treated after 1994 was $519,928, with a median cost of $27,752 per patient. No secondary cases of multidrug-resistant tuberculosis were identified through population-based genotyping.

Conclusions. Treatment of multidrug-resistant tuberculosis in HIV-seronegative patients largely on an outpatient basis was feasible and was associated with high cure rates and lower cost than in other published studies. Patients with underlying HIV infection had very poor outcomes.

Multidrug-resistant (MDR) tuberculosis has been found in all areas of the world, with some areas having an alarming number of cases [1, 2]. Treatment of MDR tuberculosis requires the use of antituberculosis drugs that are less potent, more costly, and generally more toxic than drugs used to treat drug-susceptible tuberculosis and require prolonged administration for up to 2 or more years. Even under the best circumstances, treatment of MDR tuberculosis is associated with significant overall morbidity and mortality and substantial increase in cost [3–7].

Most studies involving MDR tuberculosis have used an inpatient approach with prolonged hospital stays [8–13]. The advantage of this approach is that patients can be assessed for drug-related adverse effects and adherence to treatment. In addition, respiratory isolation until the patient has negative results of tests of sputum smears is thought to prevent transmission of MDR organisms to others in the community. However, prolonged hospital stays account for a large proportion of the overall costs of treating patients with MDR tuberculosis [3, 5, 14, 15]. In addition, lengthy hospital stays can result in nosocomial transmission, thereby adding to the medical and financial burden of treating this disease. Most outbreaks of MDR tuberculosis have been reported in hospitals [16–18].

Outpatient treatment of MDR tuberculosis may be perceived as problematic because of recommendations for daily supervision and, frequently, multiple daily doses of medications. Several reports of outpatient-based treatment of patients with MDR tuberculosis have demonstrated encouraging results [19–22]. Here, we present the outcomes and costs of treatment of patients with MDR tuberculosis in San Francisco by use of a largely outpatient approach. In addition, we assessed the spread of MDR strains of Mycobacterium tuberculosis by means of genotyping techniques.

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Methods

We retrospectively reviewed the records for all patients infected with M. tuberculosis isolates resistant to at least isoniazid and rifampin reported to the Tuberculosis Section of the San Francisco Department of Public Health during the period of 1 January 1982 through 31 December 2000. The study was stopped in the year 2000 to provide ⩾2 years of follow-up for patients who completed therapy. The Committee on Human Research at the University of California, San Francisco, approved the study.

All antituberculosis drugs taken by the patient, duration of treatment, and number of weeks of directly observed therapy (DOT) were recorded. DOT was provided in the field by unlicensed public health personnel or at the clinic by an assigned nurse. The ratio of patients receiving field-based versus clinic-based DOT was ∼1 : 3. Medications used in field-based DOT were individually prepackaged by clinic nurses before each visit. During the period of the study in which costs were calculated, the Tuberculosis Control Program used 4–5 registered nurses, 3–4 disease-control investigators, and ∼8 health care workers.

Culture conversion date was defined as the report date of the first negative culture result in a series of at least 3 consecutive negative culture results. Patients were considered to have responded to therapy if their culture results converted to negative and to have experienced treatment failure if culture results remained positive. A patient was considered cured on finishing a prescribed course of treatment with a combination of the drugs to which the isolate was susceptible (table 1) with a microbiological response and on demonstrating clinical evidence of resolution of symptoms. Relapse was defined as the reoccurrence of a positive culture result after having been considered cured. Patients were considered to have abandoned treatment if they stopped therapy before cure. Acquired MDR referred to the development of isoniazid and rifampin resistance in a strain that was initially susceptible to 1 or both of these drugs. Patients were monitored for signs of drug toxicity, and for the purposes of this study, adverse effects were characterized according to World Health Organization guidelines [23]. Follow-up assessments included clinical and microbiological evaluation at least 6, 12, and 24 months after completing therapy.

Table 1
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Table 1

Frequency of drugs received among patients with multidrug-resistant tuberculosis and adverse reactions leading to cessation of therapy.

Smears for acid-fast bacilli (AFB), cultures for mycobacteria, and drug susceptibility testing were done in licensed laboratories by use of standard methods [24, 25]. Drug resistance results were confirmed by culture on solid media. Any patient found to be infected with an MDR strain had susceptibility testing repeated for both first- and second-line antituberculosis drugs. For isolates obtained from 1991 through 2000, IS6110-based restriction fragment-length polymorphism (RFLP) and polymorphic guanine cytosine rich sequence-based genotype analysis were done and analyzed by internationally standardized methods [26, 27].

Cost data were calculated from the health services provided to 11 patients with MDR tuberculosis treated during the period of 1 January 1995 through 31 December 2000. Charge data were used as a proxy for costs. Outpatient charges were itemized by codes for allowable insurance services. The services provided were based on the American Medical Association's Current Procedural Terminology, 1999 codes, and the charges were based on the prevailing charges in San Francisco Bay Area public health and community hospitals. Charges for health services that were included were all visits to the tuberculosis clinic that required a physician or registered nurse encounter; visits in the field by the health care personnel; the local price of drugs; mode, dose, and frequency of administration; and whether the drugs were given by DOT. All laboratory, microbiological, and imaging studies were included in the cost analysis. Hospitalization charges for MDR tuberculosis were extrapolated from data published in a prospective study conducted by the Centers for Disease Control and Prevention in which the San Francisco tuberculosis program participated [28].

Statistics were computed by use of SAS software, version 8.2 (SAS Institute). Continuous variables were compared with t tests or Wilcoxon exact tests, and categorical variables were compared by either χ2 test or Fisher's exact test [29].

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Results

Demographic and disease characteristics. A total of 5407 cases of tuberculosis were reported in San Francisco during the period of 1 January 1982 through 31 December 2000. Of the 4046 cases for which drug susceptibility results were available, 51 (1.3%) were identified as being due to MDR strains. Three cases were excluded from the study: 1 was determined by RFLP analysis to have been misidentified as the result of laboratory contamination; the other 2 were not treated in San Francisco. The 48 remaining cases constitute the study population. The 2 most common associated medical conditions observed in the cohort were HIV infection (n = 11), all with CD4 cell counts of <121 cells/µL, (median CD4 cell count, 50 cells/µL; range, 0–120 cells/µL) and diabetes mellitus (n = 5).

Twelve patients (25%) were born in the United States, and 36 (75%) were foreign born. Thirty-one patients (65%) had a prior diagnosis of tuberculosis; 27 (87%) of these were foreign-born. The median time between any prior treatment and current diagnosis of MDR tuberculosis was 9 years (range, <1–30 years). Cavitary tuberculosis was present in 21 (47%) of 45 patients with pulmonary disease. Only 1 of the HIV-infected patients had cavitary tuberculosis. Thirty-one patients (65%) had AFB identified in the initial microscopic examination of sputum specimens. Susceptibility testing of the isolates showed resistance to a median of 3 drugs (range, 2–9 drugs).

Thirty-six (75%) of 48 patients had MDR strains identified in the first culture result reported, and 12 (25%) had MDR strains develop during the initial course of treatment; 7 (58%) of these 12 patients were HIV seropositive. Of the 12 patients whose strains developed MDR, 6 had strains that were initially resistant to either isoniazid or rifampin alone and during therapy subsequently became MDR. Only 2 patients developed MDR after 1995, and both were HIV seropositive. The demographic, clinical, and microbiological characteristics of the 48 patients with MDR tuberculosis, together and stratified by HIV status, are summarized in table 2.

Table 2
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Table 2

Demographic, clinical, and microbiological characteristics of patients with multidrug-resistant tuberculosis by HIV status

Treatment regimens. Isolates from 41 (85%) of 48 patients were initially susceptible to pyrazinamide and/or ethambutol. These patients received 1 or both agents in combination with other antituberculosis drugs during the course of therapy. The most common additional drugs given were aminoglycosides or polypeptides (96%), fluoroquinolones (69%), and cycloserine (60%). A mean of 5 second-line agents were used by both HIV-seronegative and -seropositive patients (range, 3–12 agents and 2–10 agents, respectively) (table 3). Forty-two (88%) of 48 patients received DOT throughout their treatment for MDR tuberculosis, with the remaining 6 patients receiving partial DOT; for patients who received partial DOT, only the administration of parenteral drugs was observed directly. After 1994, all patients with MDR tuberculosis were treated with DOT.

Table 3
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Table 3

Outcomes of treatment for multidrug-resistant tuberculosis, by HIV status.

Hospitalization and surgery. Twenty-one (44%) of 48 patients required hospitalization, with a median stay of 14 days (range, 3–74 days). Of the 21 hospitalized patients, 11 (52%) were HIV seropositive; all HIV-seropositive patients were hospitalized. The median durations of hospitalization were 21 days (range, 5–74 days) for HIV-seropositive patients and 10.5 days (range, 3–45 days) for HIV-seronegative patients. Three HIV-seronegative patients with persistently positive culture results underwent surgical procedures: 2 had a modified Eloesser flap performed for drainage of a tuberculous empyema, and 1 had a left upper lobectomy. Results of sputum cultures for these 3 patients subsequently became negative, and all 3 patients were cured.

Adverse effects. Twenty-three (48%) of 48 patients reported no adverse effects, 8 (17%) had minor adverse effects, and 17 (35%) had more severe adverse effects: 13% had a toxic reaction, 9% had a hypersensitivity reaction, and 13% had an idiosyncratic reaction (table 1). Severe adverse events occurred in 3 HIV-seropositive patients (27%) and 14 HIV-seronegative patients (38%). All 17 patients with severe side effects required discontinuation of at least 1 antituberculosis agent, and for 3 of these patients, hospitalization was necessary because of the reaction.

Outcomes of treatment. The median time for conversion of results of smears for AFB and cultures for mycobacteria to negative after initiation of therapy for all patients was 12.4 weeks (range, 2.3–166.6 weeks) and 14.6 weeks (range, 4.0–179.3 weeks), respectively. Conversion of smear and culture results, by patients' HIV status, is shown in table 3.

Overall, 40 patients (83%) had conversion of sputum culture results to negative in response to the initial treatment regimen for MDR organisms. When stratified by HIV infection status, 34 (92%) of the 37 HIV-seronegative patients had conversion of culture results to negative, compared with only 6 (55%) of the 11 HIV-seropositive patients (P = .01; table 3). Four patients (all HIV seronegative) were excluded from the end-of-treatment outcome analysis because they were transferred to another tuberculosis-control jurisdiction (n = 3) or abandoned therapy (n = 1) before completion. Two of the 3 patients who transferred had negative results of AFB smears and cultures 1 month after initiation of treatment and continued to have negative results of culture after 6 months of treatment. The patient who abandoned therapy had negative results of culture after 6 weeks of therapy.

The cure rates by HIV status for patients who completed treatment were 97% (32 of 33 patients) for HIV-seronegative patients and 9% (1 of 11) for HIV-seropositive patients. The 1 HIV-seronegative patient with treatment failure died of chronic MDR tuberculosis after 8 years of chemotherapy. This patient had a large cavity but was not a candidate for surgery because of his advanced age and overall poor medical condition. An additional HIV-seronegative patient who had been cured initially had relapse with the same strain of M. tuberculosis ∼5 years later. Of the 10 HIV-seropositive patients who died during treatment, 5 had conversion of culture results to negative, and all had other HIV-associated diseases at the time of death. The only HIV-seropositive patient who was cured relapsed 3 months after completion of 31 months of treatment and died of disseminated MDR tuberculosis (Mycobacterium bovis) and other complications related to his advanced HIV disease.

Cost analysis. Only 4 of the 11 patients treated between 1995 and 2000 required hospitalization; all 4 were HIV seropositive, and all died. The combined total inpatient and outpatient cost for the 11 patients was $519,928, with a mean cost of $47,266 per patient (median, $27,752; table 4). The median cost of treatment for HIV-seronegative patients was $21,929 (range, $15,765-$103,910), and for HIV-seropositive patients, it was $66,359 (range, $38,495–$119,630) (P = .04). The cost for 1 HIV-seronegative patient whose isolate was resistant to 5 drugs was ∼$100,000; that patient received prolonged intravenous therapy with imipenem and amikacin.

Table 4
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Table 4

Treatment costs for 11 patients with multidrug-resistant tuberculosis, 1995–2000.

Genotyping data. Thirty-three of 35 MDR tuberculosis cases between 1991 and 2000 had strain genotyping information available for analysis, of which 10 (30%) were clustered. None of these cases clustered with another MDR tuberculosis case; thus, no secondary cases of MDR tuberculosis were identified on the basis of genotyping and contact investigation (data not shown). Analysis of individual strains showed that 1 United States-born patient whose isolate had a unique genotype pattern in our database was hospitalized because of an HIV-related condition in a hospital in Argentina in January 1996. This patient's infecting isolate had the same resistance and genotype pattern as the strain that caused a nosocomial outbreak in the Nerin Hospital in Buenos Aires in 1996 [16].

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Discussion

This study demonstrates that, within the context of an effective tuberculosis-control program [30], it is feasible to treat MDR tuberculosis in HIV-seronegative patients with the use of appropriate intensive treatment regimens, largely with an outpatient approach, and achieve high cure rates comparable with those obtained for patients with drug-susceptible tuberculosis. The costs incurred, although still quite high, were much lower than has been described previously [3–5, 14, 15]. Among HIV-seronegative patients, the overall cure rate was 97%, with only 1 patient experiencing relapse. In striking contrast, however, only 1 HIV-infected patient was cured, and this patient subsequently experienced relapse and died. In another cohort of patients with MDR tuberculosis treated on an outpatient basis, the probable cure rate was 83% (cure by HIV status was not reported) [21], whereas treatment responses from 50% to 80% have been described in other reports of therapy with an inpatient approach [7–13]. In our cohort, most of our patients received DOT as outpatients, and fewer than one-half required hospitalization and only for a median stay of 2 weeks. Of note, no secondary cases of MDR tuberculosis were observed in known contacts or other members of the San Francisco community, a finding that we have reported previously [31].

The differences between our experience and other reported outcomes of treatment for MDR tuberculosis are likely related to differences in patient populations with varying degrees of drug resistance, severity of lung involvement, and differences in treatment regimens [22]. For example, in the reports from Peru [21] and from the National Jewish Medical and Research Center [9], patients had tuberculosis for a median of 6–8 years, with isolates that were resistant to an average of 6 drugs. In contrast, in San Francisco, MDR tuberculosis was recognized early, and patients had isolates that were resistant to a median of 3 drugs only. Therefore, we were able to use ethambutol and/or pyrazinamide to treat 85% of patients. Patients infected with strains susceptible to ethambutol and pyrazinamide tended to have a favorable outcome in the report from Peru [21]. In addition, ∼70% of our patients received a fluoroquinolone, which has also been associated with better treatment outcomes in patients with MDR tuberculosis [12].

In a recent case series from National Jewish Medical and Research Center, the overall cure rates were better for patients who had lung resection [12]. In our study, only 3 patients underwent surgical procedures, only 1 of which was a resection, after they did not respond to appropriate drug regimens. These patients had negative results of AFB smears and cultures shortly after surgery and were eventually cured.

Prolonged hospitalization can result in nosocomial spread and greatly increases the overall cost of treating MDR tuberculosis. In this study, the only patient with documented proof of transmission of an MDR strain acquired the strain during an outbreak of MDR tuberculosis at a hospital in Argentina [17]. Previous studies have estimated that the costs of MDR tuberculosis range from $60,000 to $180,000 [3, 5, 15]. These studies have included prolonged hospital stays that greatly increased the cost of care. In a recent study published by the Centers for Disease Control and Prevention that reported both direct and indirect costs, the average inpatient and outpatient costs of treating a patient with MDR tuberculosis were $25,853 and $19,028 per person, respectively [14]. The estimated combined inpatient and outpatient median cost of therapy for patients with MDR tuberculosis in our cohort was $27,752 per patient (table 4). During the same period, the cost of treating ambulatory patients with tuberculosis caused by susceptible organisms with use of DOT was $7193, and without DOT, it was $3557. Thus, the overall short durations of hospitalization for patients with MDR tuberculosis in San Francisco resulted in the reduced cost of treatment. With this strategy, we did not observe any nosocomial or community transmission of MDR tuberculosis [31].

A limitation of our study is that charges were used to estimate the costs of treatment for MDR tuberculosis. Although our cost estimates are lower than published treatment costs [3, 5, 15], we likely overestimated the actual expense of the services provided [14, 32] because we used charges as a proxy to estimate cost. Our outpatient-based treatment experience and the experience in Peru [6] make a strong case for moving treatment of MDR tuberculosis to the outpatient setting, at least among HIV-seronegative patients infected with isolates that are resistant to only a few drugs.

Compared with the excellent treatment outcomes among HIV-seronegative patients, HIV-seropositive patients with MDR tuberculosis had very poor outcomes, as has been described elsewhere [33–35]. In this study, all HIV-seropositive patients were severely immunocompromised, and of the 54.6% who achieved conversion of culture results, none survived. All HIV-seropositive patients died either during treatment or during follow-up, and the deaths were often caused by other HIV-associated conditions. Only 2 patients received combination antiretroviral treatment during therapy for their MDR disease. Although there are no data to substantiate benefit, the prolonged time to conversion of culture results and the high mortality rate suggest that combination antiretroviral treatment should be initiated promptly in patients with HIV infection and MDR tuberculosis. In addition, because of the high frequency of acquired drug resistance in HIV-seropositive persons, even with DOT, measurement of serum drug concentrations in advanced HIV disease [36, 37] should be strongly considered.

In summary, our results demonstrate that it is feasible to treat MDR tuberculosis among HIV-seronegative patients with the use of appropriate intensive treatment regimes and an outpatient-based approach and less costly than conventional treatment. With this approach, we did not observe any secondary cases of MDR tuberculosis. It is important to note that San Francisco is a relatively small urban area that has availability of MDR treatment expertise and resources focused on outpatient case management that may not be available in other programs. However, given the cost savings of outpatient management over hospitalization, it may be possible to redirect resources so that an effective outpatient management strategy can be developed. In settings that can ensure completion of treatment through DOT and have available resources for second-line drugs with an infrastructure for careful monitoring, an outpatient approach for treatment of MDR tuberculosis should be considered.

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Acknowledgments

We thank Houmpheng Banouvong, Fay Hui, and all of the staff of the Tuberculosis Control Section, San Francisco Department of Public Health, who maintain an excellent standard of care for patients with tuberculosis. We would also like to thank Peter Small and the members of the Stanford Center for Tuberculosis Research for assistance with genotyping.

Financial support. National Institutes of Health (TW-00905, AI-34238).

Conflicts of interest. All authors: no conflicts.

  • Received October 4, 2004.
  • Accepted November 17, 2004.
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References

  1. ↵
    1. Espinal MA,
    2. Laszlo A,
    3. Simonsen L,
    4. et al
    . Global trends in resistance to antituberculosis drugs. World Health Organization/International Union Against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 2001;344:1294-303.
    CrossRefMedlineWeb of Science
  2. ↵
    1. Pablos-Mendez A,
    2. Raviglione MC,
    3. Laszlo A,
    4. et al
    . Global surveillance for antituberculosis-drug resistance, 1994–1997. World Health Organization/International Union Against Tuberculosis and Lung Disease Working Group on Anti-Tuberculosis Drug Resistance Surveillance. N Engl J Med 1998;338:1641-9.
    CrossRefMedlineWeb of Science
  3. ↵
    1. Geerligs WA,
    2. Van Altena R,
    3. De Lange WCM,
    4. Van Soolingen D,
    5. Van Der Werf TS
    . Multidrug-resistant tuberculosis: long-term treatment outcome in The Netherlands. Int J Tuberc Lung Dis 2000;4:758-64.
    MedlineWeb of Science
    1. Iseman MD
    . Treatment and implications of multidrug-resistant tuberculosis for the 21st century. Chemotherapy 1999;45(Suppl 2):34-40.
  5. ↵
    1. Mahmoudi A,
    2. Iseman MD
    . Pitfalls in the care of patients with tuberculosis. Common errors and their association with the acquisition of drug resistance. JAMA 1993;270:65-8.
    Abstract/FREE Full Text
  6. ↵
    1. Gupta R,
    2. Kim JY,
    3. Espinal MA,
    4. et al
    . Responding to market failures in tuberculosis control. Science 2001;293:1049-51.
    Abstract/FREE Full Text
  7. ↵
    1. Park SK,
    2. Kim CT,
    3. Song SD
    . Outcome of chemotherapy in 107 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. Int J Tuberc Lung Dis 1998;2:877-84.
    MedlineWeb of Science
  8. ↵
    1. Yew WW,
    2. Chan CK,
    3. Chau CH,
    4. et al
    . Outcomes of patients with multidrug-resistant pulmonary tuberculosis treated with ofloxacin/levofloxacin-containing regimens. Chest 2000;117:744-51.
    Abstract/FREE Full Text
  9. ↵
    1. Goble M,
    2. Iseman MD,
    3. Madsen LA,
    4. Waite D,
    5. Ackerson L,
    6. Horsburgh CR Jr
    . Treatment of 171 patients with pulmonary tuberculosis resistant to isoniazid and rifampin. N Engl J Med 1993;328:527-32.
    CrossRefMedlineWeb of Science
    1. Telzak EE,
    2. Sepkowitz K,
    3. Alpert P,
    4. et al
    . Multidrug-resistant tuberculosis in patients without HIV infection. N Engl J Med 1995;333:907-11.
    CrossRefMedlineWeb of Science
    1. Tahaoglu K,
    2. Torun T,
    3. Sevim T,
    4. et al
    . The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med 2001;345:170-4.
    CrossRefMedlineWeb of Science
  12. ↵
    1. Chan ED,
    2. Laurel V,
    3. Strand MJ,
    4. et al
    . Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis. Am J Respir Crit Care Med 2004;169:1103-9.
    Abstract/FREE Full Text
  13. ↵
    1. Narita M,
    2. Alonso P,
    3. Lauzardo M,
    4. Hollender ES,
    5. Pitchenik AE,
    6. Ashkin D
    . Treatment experience of multidrug-resistant tuberculosis in Florida, 1994–1997. Chest 2001;120:343-8.
    Abstract/FREE Full Text
  14. ↵
    1. Rajbandary SS,
    2. Marks SM,
    3. Bock NN
    . Costs of patients hospitalized for multi-drug resistant tuberculosis. Int J Tuberc Lung Dis 2004;8:1012-6.
    MedlineWeb of Science
  15. ↵
    1. Burman WJ,
    2. Dalton CB,
    3. Cohn DL,
    4. Butler JRG,
    5. Reves RR
    . A cost-effectiveness analysis of directly observed therapy vs. self-administered therapy for treatment of tuberculosis. Chest 1997;112:63-70.
    Abstract/FREE Full Text
  16. ↵
    1. Frieden TR,
    2. Sherman LF,
    3. Maw KL,
    4. et al
    . A multi-institutional outbreak of highly drug-resistant tuberculosis: epidemiology and clinical outcomes. JAMA 1996;276:1229-35.
    Abstract/FREE Full Text
  17. ↵
    1. Ritacco V,
    2. Di Lonardo M,
    3. Reniero A,
    4. et al
    . Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 1997;176:637-42.
    Abstract/FREE Full Text
  18. ↵
    1. Moss AR,
    2. Alland D,
    3. Telzak E,
    4. et al
    . A city-wide outbreak of a multiple-drug-resistant strain of Mycobacterium tuberculosis in New York. Int J Tuberc Lung Dis 1997;1:115-21.
    MedlineWeb of Science
  19. ↵
    1. Suarez PG,
    2. Floyd K,
    3. Portocarrero J,
    4. et al
    . Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet 2002;359:1980-9.
    CrossRefMedlineWeb of Science
    1. Kim HJ,
    2. Hong YP,
    3. Kim SJ,
    4. Lew WJ,
    5. Lee EG
    . Ambulatory treatment of multidrug-resistant pulmonary tuberculosis patients at a chest clinic. Int J Tuberc Lung Dis 2001;5:1129-36.
    MedlineWeb of Science
  21. ↵
    1. Mitnick C,
    2. Bayona J,
    3. Palacios E,
    4. et al
    . Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru. N Engl J Med 2003;348:119-28.
    CrossRefMedlineWeb of Science
  22. ↵
    1. Mukherjee JS,
    2. Rich ML,
    3. Socci AR,
    4. et al
    . Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 2004;363:474-81.
    CrossRefMedlineWeb of Science
  23. ↵
    1. Scientific Panel of the Working Group on DOTS-Plus for MDR-TB
    . Guidelines for establishing DOTS-PLUS projects for the management of multidrug-resistant tuberculosis (MDR-TB). Geneva: World Health Organization; 2000.
  24. ↵
    1. Kent PT,
    2. Kubica GP
    . Public health mycobacteriology: a guide for the level III laboratory. Atlanta: Centers for Disease Control; 1985.
  25. ↵
    1. Isenberg HD
    1. Siddiqi S
    . Radiometric (BACTEC) tests for slowly growing mycobacteria. In: Isenberg HD, editor. Clinical microbiology procedures handbook. Washington, DC: American Society for Microbiology; 1992. p. 11-25.
  26. ↵
    1. van Embden JD,
    2. Cave MD,
    3. Crawford JY,
    4. et al
    . Strain identification of Mycobacterium tuberculosis by DNA fingerprinting: recommendations for a standardized methodology. J Clin Microbiol 1993;31:406-9.
    Abstract/FREE Full Text
  27. ↵
    1. Yang Z,
    2. Chaves F,
    3. Barnes PF,
    4. et al
    . Evaluation of a method for secondary DNA typing of Mycobacterium tuberculosis with pTBN12 in the epidemiologic study of tuberculosis. J Clin Microbiol 1996;34:3044-8.
    Abstract/FREE Full Text
  28. ↵
    1. Taylor Z,
    2. Marks SM,
    3. Rios Burrows NM,
    4. et al
    . Causes and costs of hospitalization of tuberculosis patients in the United States. Int J Tuberc Lung Dis 2000;4:931-9.
    MedlineWeb of Science
  29. ↵
    1. Rosner B
    . Fundamentals of biostatistics. 5th ed. Pacific Grove, CA: Duxbury Thomson Learning; 2000.
  30. ↵
    1. Jasmer RM,
    2. Hahn JA,
    3. Small PM,
    4. et al
    . A molecular epidemiologic analysis of tuberculosis trends in San Francisco, 1991–1997. Ann Intern Med 1999;130:971-8.
    Abstract/FREE Full Text
  31. ↵
    1. Burgos M,
    2. DeRiemer K,
    3. Small PM,
    4. Hopewell PC,
    5. Daley CL
    . Effect of drug resistance on the generation of secondary cases of tuberculosis. J Infect Dis 2003;188:1878-84.
    Abstract/FREE Full Text
  32. ↵
    1. Brown RE,
    2. Miller B,
    3. Taylor WR,
    4. et al
    . Health-care expenditures for tuberculosis in the United States. Arch Intern Med 1995;155:1595-600.
    Abstract/FREE Full Text
  33. ↵
    1. Flament-Saillour M,
    2. Robert J,
    3. Jarlier V,
    4. Grosset J
    . Outcome of multi-drug-resistant tuberculosis in France: a nationwide case-control study. Am J Respir Crit Care Med 1999;160:587-93.
    Abstract/FREE Full Text
    1. Mannheimer SB,
    2. Sepkowitz KA,
    3. Stoeckle M,
    4. Friedman CR,
    5. Hafner A,
    6. Riley LW
    . Risk factors and outcome of human immunodeficiency virus-infected patients with sporadic multidrug-resistant tuberculosis in New York City. Int J Tuberc Lung Dis 1997;1:319-25.
    MedlineWeb of Science
  35. ↵
    1. Park MM,
    2. Davis AL,
    3. Schluger NW,
    4. Cohen H,
    5. Rom WN
    . Outcome of MDR-TB patients, 1983–1993: prolonged survival with appropriate therapy. Am J Respir Crit Care Med 1996;153:317-24.
    Abstract/FREE Full Text
  36. ↵
    1. Gurumurthy P,
    2. Ramachandran G,
    3. Hemanth Kumar AK,
    4. et al
    . Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 2004;48:4473-5.
    Abstract/FREE Full Text
  37. ↵
    1. Sahai J,
    2. Gallicano K,
    3. Swick L,
    4. et al
    . Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. Ann Intern Med 1997;127:289-93.
    Abstract/FREE Full Text
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  1. Clin Infect Dis. (2005) 40 (7): 968-975. doi: 10.1086/428582
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