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* From the A.G. Holley State Tuberculosis Hospital (Drs. Hollender and Ashkin), Lantana, FL; Florida Department of Health, Bureau of Tuberculosis Control and Prevention (Drs. Narita and Lauzardo); Division of Pulmonary and Critical Care Medicine (Dr. Alonso), University of Miami School of Medicine; VA Medical Center (Dr. Pitchenek), Miami, FL.
Correspondence to: David Ashkin, MD, FCCP, Medical Executive Director, A.G. Holley State Tuberculosis Hospital, 1199 West Lantana Rd, Lantana, FL 33462; e-mail: David_Ashkin{at}doh state.fl.us
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Abstract |
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Methods: Retrospective chart review of all patients (n = 81) with diagnoses of MDR-TB in Florida between January 1, 1994, and July 31, 1997.
Results: The average number of resistant drugs was 4.8 (range, 2 to 11). Of 81 patients, 46 patients (57%) completed adequate therapy, 26 patients (32%) died, and 9 patients (11%) never completed a satisfactory course of treatment. Patients who received at least part of their therapy at A. G. Holley State Hospital, a specialized tuberculosis (TB) treatment center, had significantly higher treatment completion rates (79%) than those treated as outpatients alone (48% treatment completion rate, p < 0.001), even after the exclusion of patients who were acutely ill and died within 2 months of diagnosis.
Conclusion: In Florida, a specialized TB care program for MDR-TB, including at least partial inpatient therapy, yielded higher treatment completion rates compared to outpatient treatment alone.
Key Words: HIV • multidrug resistant • tuberculosis
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In 1993, the National Jewish Center for Immunology and Respiratory Medicine reported a 22% mortality attributable to MDR-TB, with resistance to a median of six TB drugs; only 56% of MDR-TB patients were disease free after a mean follow-up period of 51 months.4 Among HIV-negative patients with MDR-TB, researchers from New York reported a mortality rate of 4 to 17%.5 6 In HIV-infected patients with MDR-TB, there have been reports of mortality rates of 41 to 72%.6 7 8
The treatment of MDR-TB is frequently associated with prolonged illness and disability. Second-line TB drugs have a greater incidence of adverse reactions, which increases the morbidity as well as cost.9 Generally, these second-line agents must be administered more frequently than first-line agents, making compliance with medications more difficult. Many authorities have advocated that MDR-TB be regarded as a high-priority medical and public health issue and that these patients should be referred upon diagnosis to a specialized center for systematized, aggressive medical therapy.10
In the early and mid 1990s, Florida experienced an increase in the number of cases of MDR-TB. This has been attributed to the significant number of foreign-born residents in the state, the documented outbreaks of nosocomial MDR-TB in hospital and congregate living facilities,11 and the lack of widespread utilization of DOT prior to 1994.
In Florida, A. G. Holley State Hospital functions as a specialized TB facility treating the most medically and behaviorally difficult patients with TB in the state. A majority of these patients are court committed for nonadherence to therapy. The remainder of patients are referred from other health-care facilities due to a lack of adequate response to chemotherapy or complex concomitant medical conditions that make outpatient treatment difficult or inadvisable.
Although in Florida MDR-TB patients are often admitted to the A. G. Holley State Tuberculosis Hospital, some are treated using DOT on an outpatient basis alone. This study examines the treatment experience of patients with diagnoses of MDR-TB in Florida from January 1, 1994, to July 31, 1997, including the possible outcome effects of specialized TB consultation.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Pertinent patient data and follow-up information not contained in the state database were obtained through a medical record review of the corresponding treatment facilities, including health department clinics, community hospitals, A. G. Holley State Tuberculosis Hospital, and private health-care providers.
For the present study, the following data were reviewed: age; gender; race; country of origin; site of TB disease; chest radiograph (CXR) findings (normal, cavitary, noncavitary infiltrates, adenopathy, and/or pleural effusion); HIV status; history of homelessness within 1 year prior to the diagnosis of TB; risk factors for MDR-TB (previous exposure to MDR-TB, prior inadequate treatment [defined as documented nonadherence to a TB regimen and/or a shorter duration of TB chemotherapy than recommended by CDC/American Thoracic Society guidelines],15 concomitant illness such as diabetes mellitus, malignancy, end-stage renal disease, or silicosis, which may all increase the risk of progression to TB disease); the initial treatment regimen begun after diagnosis of MDR-TB; the date the MDR-TB susceptibility testing was reported to the health care provider; the date appropriate MDR-TB treatment was initiated (the start of treatment with at least two medications to which the strain of M tuberculosis showed susceptibility); the results of in vitro TB drug susceptibility testing obtained before the initiation of a new regimen; the date of culture conversion (defined as the first in a series of two or more consecutive negative cultures at least 2 weeks apart); and the treatment facility and outcome (completed TB treatment, death, or incomplete treatment). In accordance with CDC guidelines,13 completion of TB treatment was defined as the documented treatment with at least two drugs to which the strain of M tuberculosis is known to be susceptible, for at least 12 months after culture conversion. Primary MDR-TB was defined as M tuberculosis isolated from a patient who had not received prior antituberculous treatment, and acquired MDR-TB was defined as that from a patient with a history of antecedent TB chemotherapy.
In order to be admitted to A. G. Holley State Tuberculosis Hospital, patients with MDR-TB must have met one of the following criteria: (1) any patient whose clinical course fails to demonstrate notable improvement after an appropriate treatment interval, (2) any patient with a concomitant or complex medical condition incompatible with outpatient treatment or inadvisable in that setting, or (3) any patient court committed for hospitalization due to nonadherence to TB therapy. In addition to tuberculosis, most patients admitted to the A. G. Holley State Tuberculosis Hospital also have salient medical, psychiatric, and/or behavioral problems, and therefore benefit from intensive, specific medical, nutritional, psychiatric, and behavioral treatment regimens, as well as pharmacokinetic TB drug monitoring, in order to optimize their probability of cure.
Statistical analysis was performed using the Student’s t
test for continuous variables (age); Mann-Whitney rank-sum test for
nonparametric variables (number of TB drugs to which the organism was
resistant, number of TB drugs prescribed after diagnosis of MDR-TB,
days from diagnosis of MDR-TB to initiation of appropriate therapy,
days from initiation of appropriate therapy to culture conversion); and
2 test; or Fisher’s Exact Test, if
appropriate, for categorical variables (gender, race, country of
origin, primary site of disease, CXR findings, HIV status, history of
homelessness, risk factors for MDR-TB, and outcome). Completion rate is
defined as follows: (all patients who completed adequate
therapy)/([all patients who completed adequate therapy] + [all
patients who died before completing therapy] + [all patients who
did not complete a course of adequate therapy]).
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Results |
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Thirty-nine of the 81 MDR-TB patients (48%) were admitted to A. G. Holley State Tuberculosis Hospital at some point during their treatment interval; 14 of these patients (35%) were court committed. The median duration of hospitalization was 270 days (range, 5 to 1,601 days). One patient was hospitalized < 1 month, 12 patients were hospitalized from 1 to <6 months, 12 patients were hospitalized from 6 to <12 months, 6 patients were hospitalized from 12 to <18 months, 6 patients were hospitalized from 18 to 24 months, and 2 patients were hospitalized > 24 months. Nine of the 39 patients (23%) completed their entire MDR-TB treatment in the hospital, either due to the complexity of their TB or other disease involvement or for a history of recurrent nonadherence to therapy. Twenty-two patients were discharged from the hospital while receiving treatment for MDR-TB, were followed up by local health departments, and completed their treatment receiving DOT (median length of hospitalization, 182 days; range, 5 to 615 days). Seven of the 39 patients (18%) died: 5 of the 7 patients died from medical conditions other than TB (3 patients had culture-negative findings and 2 patients had culture-positive findings at the time of death), and 2 of the 7 patients died after surgical resection of their MDR-TB (see below). One patient fled and was lost to follow-up. Five patients (all HIV negative) underwent a surgical resection of tuberculous cavitary lesions; three of these five patients went on to complete treatment successfully, and two patients died after surgery (one patient died of non-TB pneumonia while in hospital 1 month after surgery, and the other patient died of acute alcohol intoxication as an outpatient 1 year after surgery; both patients had culture-negative findings for M tuberculosis at the time of their death). All 31 patients who completed TB treatment remained sputum culture negative after their culture conversion.
Forty-two of the 81 patients (52%) were treated in the community on an outpatient basis only. Of these 42 patients, 15 patients (36%) completed TB treatment, 19 patients (45%) died, and 8 patients (19%) did not complete treatment (5 patients were lost to follow-up; 1 patient received only 8 months of treatment and 2 patients received only 12 months of treatment without documented culture conversion). Of the 19 patients who died, 11 patients (58%) died within 2 months of the diagnosis of MDR-TB (median age, 50 years; range, 28 to 80 years). Nine of these 11 patients were HIV infected, and 2 patients had an unknown HIV status. These 11 patients include 3 patients who died before the diagnosis of MDR-TB was established, and none of the 3 patients received any TB treatment. Eight patients died > 2 months after the diagnosis of MDR-TB was established; at the time of death, three of these eight patients were culture negative and five patients were culture positive.
The characteristics and outcomes of patients treated at least partially as inpatients at A. G. Holley State Tuberculosis Hospital were compared to those treated in the community as outpatients alone. For purposes of this study, the 11 outpatients who died within 2 months of the diagnosis of MDR-TB were excluded from analysis in order to compare outcomes on similar groups of "stable" patients (based on the assumption that these patients would have been too ‘critically ill’ to be transferred to A. G. Holley State Tuberculosis Hospital).
The 31 patients who were treated on an outpatient basis only and did not die within 2 months of diagnosis were categorized as the Community Care Group. Patients admitted at any time to A. G. Holley State Tuberculosis Hospital were categorized as the Specialized TB Care Group. The characteristics of each group are summarized in Table 1 .
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In the Community Care Group, 9 patients were treated by physicians at local health departments, 9 patients were treated by private physicians only, and 13 patients received treatment from both. Eight patients received TB medications on their own recognizance (2 patients completed treatment, 2 patients were lost to follow-up, and 4 patients died), 7 patients were treated entirely by DOT (mean, 26.9 ± 22.6 weeks; 2 patients completed treatment, 2 patients were lost to follow-up, and 3 patients died), and 16 patients received both DOT and self-administered therapy (average, 50 ± 27.2 weeks receiving DOT; total, 77 ± 30.3 weeks receiving TB treatment; 14 patients completed treatment, 1 patient was lost to follow-up, and 1 patient died).
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine if patients who received specialized treatment differed in characteristics or outcome, those cases of MDR-TB treated solely on an outpatient basis were compared to those utilizing A. G. Holley State Tuberculosis Hospital during part or all of their treatment regimen. The Specialized TB Care Group had a higher TB treatment completion rate than the Community Care Group despite data suggesting that they were a more difficult group to treat.
It is of note that in the Community Care Group, 9 patients were treated by the health department alone, 9 patients were treated by private medical specialists alone, and 13 patients were treated by both the health department and private physicians together. These are both sectors of the medical community accustomed to treating TB routinely, yet the outcomes in this group appear to be significantly less successful when compared to the outcomes of patients treated at least partially at the specialized TB center. This may reflect the fact that few clinicians have had specialized training in the treatment of MDR-TB or extensive experience in its complex management. In addition, many facilities and physicians may lack the necessary fiscal and medical resources with which to complete successful therapy.
A possible explanation to account for this difference may be the expert TB consultation, concentrated behavioral and nutritional therapy, and intensive medical treatment of concomitant illnesses as well as the close pharmacokinetic monitoring of TB medications that the Specialized TB Care Group received. These factors have been believed by some experts to be critical to the successful treatment of patients with MDR-TB.10 Although these therapeutic services may be available individually on an outpatient basis, few facilities are able to provide them in an integrated program, or "therapeutic milieu." This is the first recent study to look at the outcomes of patients with MDR-TB treated at least partially by a specialized TB treatment center as compared to those treated solely with outpatient therapy.
After the exclusion of those MDR-TB patients who died during outpatient therapy within 2 months of diagnosis, the characteristics of the two TB care groups appear to be comparable in the majority of the categories. There was no statistical difference in patient’s age, gender, race, and country of origin, primary site of tuberculosis, CXR findings, or homelessness. HIV status, however, may prove to be a significant factor in the outcome of MDR-TB. In this study, there were more MDR-TB patients categorized as having an "unknown HIV status" in the Community Care Group (32% vs 5%). The actual HIV status of these patients, had it been determined, might have influenced the results and is therefore a potential bias of the study. The lower rate of "unknown HIV status" in the Specialized TB Care Group may reflect the more systematic or persistent efforts to ascertain this status that an inpatient setting affords.
It is noteworthy that despite higher rates of HIV infection, a factor previously associated6 7 8 with increased mortality in patients with MDR-TB, the mortality among the HIV-positive patients treated in the Specialized TB Care Group was lower. The reason for this remains uncertain, but may be due to earlier and/or more intensive treatment of their HIV disease than they were able (or wished) to access as outpatients.
Another difference in patient characteristics was the risk factors related to the acquisition of MDR-TB. A significant number of patients are committed to A. G. Holley State Tuberculosis Hospital for nonadherence to therapy, and this, therefore, may have led to the finding that a predominance (87%) of MDR-TB patients admitted to the hospital had a history of inadequate or incomplete treatment. Traditionally, MDR-TB patients with a history of a previous treatment failure have had poorer outcomes on retreatment of their tuberculosis.4 Despite the high rate of prior treatment, patients in the Specialized TB Care Group did significantly better than those in the Community Care Group.
Following the diagnosis of MDR-TB, patients in the community care group were administered 2.87 ± 1.26 drugs, less than that recommended by the CDC (ie, at least three drugs to which the strain of M tuberculosis is known to be susceptible, until culture conversion13 ). This supports the findings of less aggressive approach by community health-care providers.14 Patients in the specialized TB care group were administered 5.51 ± 1.68 drugs (p < 0.001), including an aminoglycoside or its equivalent (eg, capreomycin) for at least 6 months past culture conversion to negative, and for a total length of treatment of at least 12 months past culture conversion. Unfortunately, 3 of 31 patients (10%) in the Community Care Group had their TB treatment prematurely terminated based on the decision of a health-care provider and therefore did not finish the recommended length of treatment for MDR-TB. Two additional patients in that group received treatment for > 12 months after culture conversion (a total of 14 months) but less than current recommendations (total duration of 18 to 24 months based on expert opinion15 ).
These findings suggest that the differences between the two groups in this study may partly reflect the availability and utilization of MDR-TB expertise. In addition to MDR-TB consultation, differences between the two groups may also originate both from an unfamiliarity with the medications used to treat MDR-TB as well as a reluctance to give multiple second-line agents, with their potential adverse effects, in an outpatient setting where close monitoring by a clinician is often unrealistic or unavailable.
A further point is that the treatment for MDR-TB is generally administered daily instead of twice or three times a week, with the exception of intermittent aminoglycoside/polypeptide agents; however, DOT was only provided for the Community Care Group on weekdays (Monday through Friday) by local county health departments; on weekends, patients were to self-administer their medications. The possible significance to the treatment outcomes in this group of omitting DOT on 2 d/wk is unknown.
In summary, Florida experienced an increase in the number of cases of MDR-TB in the early and mid-1990s. From 1994 to 1997, there were 81 MDR-TB cases, chiefly due to acquired resistance secondary to prior nonadherence to therapy or to primary transmission from an infectious case of MDR-TB. The Community Care Group had a significant portion of MDR-TB patients who received therapy that was inadequate either in regimen or length of treatment. This is believed to reflect, in part, a lack of expertise in the treatment of MDR-TB in the community. The findings of this study support the current recommendations that all patients with MDR-TB receive expert consultation from specialized centers. Further studies are necessary to examine and define the potential role of inpatient care and/or expert consultation in this complex but crucial group of patients who pose a potentially significant obstacle to the control of TB in the United States.
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Acknowledgements |
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Footnotes |
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Preliminary reports of this work were presented at the International American Thoracic Society Conference, April 26, 1998, and April 27, 1999, and published in part in abstract form.
Received for publication July 31, 2000. Accepted for publication March 13, 2001.
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392 (Tuberculosis Control)
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