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Treatment and Outcome Analysis of 205 Patients with Multidrug-resistant Tuberculosis

Department of Medicine, Program in Cell Biology and Division of Biostatistics, National Jewish Medical and Research Center; Division of Pulmonary Sciences and Critical Care Medicine and Division of Infectious Diseases, University of Colorado Health Sciences Center; Denver Veterans Administration Medical Center, Denver, Colorado; and Wilford Hall USAF Medical Center, San Antonio, Texas

Correspondence and requests for reprints should be addressed to Michael D. Iseman, M.D., J223, Molly Blank Building, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: isemanm{at}njc.org

	ABSTRACT

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Multidrug-resistant tuberculosis, a disease caused by Mycobacterium tuberculosis strains that are resistant at least to rifampin and isoniazid, entails extended treatment, expensive and toxic regimens, and higher rates of treatment failure and death. We retrospectively analyzed the outcomes in 205 patients treated at our center for multidrug-resistant tuberculosis, with strains resistant to a median of six drugs, and compared the results with those of our previous series. Logistic regression and survival analysis were used to evaluate short- and long-term outcomes, respectively. Initial favorable response, defined as at least three consecutive negative sputum cultures over a period of at least 3 months, was 85% compared with 65% in the prior cohort. The current cohort had greater long-term success rates, 75% versus 56%, and lower tuberculosis death rates, 12% versus 22%, than the earlier one. Surgical resection and fluoroquinolone therapy were associated with improved microbiological and clinical outcomes in the 205 patients studied after adjusting for other variables. The improvement was statistically significant for surgery and among older patients for fluoroquinolone therapy.

Key Words: drug resistance • Mycobacterium tuberculosis • fluoroquinolones • surgery

In a previous study of 171 patients with pulmonary multidrug-resistant tuberculosis (MDR-TB) treated at our institution between 1973 to 1983, the overall cure rate was only 56%, and the overall mortality rate was 37% despite intensive hospital-based chemotherapy (1). Since then, two major changes have occurred in our treatment model: (1) aggressive use of resectional lung surgery and (2) the introduction of fluoroquinolone (FQN) antibiotics. The rationale for resectional lung surgery is the removal of cavitary lesions or areas of destroyed lung that harbor a high burden of organisms. The FQN agents are the first novel compounds since the rifamycins to have significant activity against Mycobacterium tuberculosis (2). In view of the rising number of MDR-TB cases identified globally (3, 4) and relatively disappointing therapeutic outcomes even in recent MDR-TB case series (1, 5–7), we believe that it is important to assess the contributions of these elements in case management. Although circumstances did not allow us to randomize these modalities, we have compared outcome data from our previously reported cohort (1) to our more recently treated patients, a group with comparable drug resistance and extent of disease. Some of the results of these studies have been previously reported in the form of an abstract (8).

	METHODS

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Study Population and Data Collection
The National Jewish Medical and Research Center (NJMRC) specializes in the treatment of MDR-TB. We reviewed the records of 205 such patients who were treated on the inpatient service and discharged between January 1, 1984, and December 31, 1998. Records were reviewed for (1) demographics; (2) previous number of drugs taken for TB (defined as the administration of an agent for 3 or more months) and other potential risk factors for development of MDR-TB; (3) susceptibilities to the anti-TB drugs; and (4) drugs used, drug toxicity, surgical intervention, results of sputum cultures, and clinical outcomes.

Medical and Surgical Treatment
In vitro susceptibility testing was used to guide therapy of MDR-TB patients (9), preferentially choosing drugs that had not been used previously. In instances of highly resistant organisms, drugs to which the organisms were at least partially susceptible or that had been given previously for only a short time were used. Injectable agents such as amikacin, kanamycin, or capreomycin were recommended for 3 to 6 months after the initial date of culture conversion; oral drugs were continued for 15 to 18 months after the last positive sputum culture. Directly observed therapy was enforced during hospitalization and was encouraged after discharge. Rigorous efforts were made to continue therapy in spite of adverse drug reactions unless they were deemed potentially life threatening or intolerable.

Surgical resection of cavitary lobes or destroyed lungs was aggressively considered for patients who, from our prior experience (10), were deemed likely to fail medical treatment based on their resistance patterns and/or extent of disease. Preoperative evaluation included computed tomographic radiography, ventilation-perfusion lung scans, spirometry, and arterial blood gas analysis. Because of the retrospective nature of the study, there were no rigid criteria for selection or exclusion for surgery. The medical and surgical staff clinically evaluated each patient individually with the following general criteria for an acceptable surgical candidate: (1) a high likelihood of medical failure based on extensive drug resistance, (2) localized cavitary disease within a lobe or total destruction of one lung, and (3) predictably adequate postoperative lung function.

Sputum Examination, Culture, and Drug Susceptibility Testing
During hospitalization, sputa were examined every 1 to 2 weeks by fluorochrome staining of the concentrated specimen and culture on Bactec 7H-12 liquid media (Becton-Dickinson, Franklin Lakes, NJ), 7H-11 solid agar, and Lowenstein-Jensen media. Drug susceptibility testings were performed according to the protocols of the Mycobacteriology Clinical Reference Laboratory at NJMRC (11).

Definitions of Outcome Terms
Patients were classified into three microbiologic outcome groups: (1) "initial favorable response" includes patients with at least three consecutive negative sputum cultures over a period of at least 3 months while on treatment; (2) "microbiologic failure" includes patients who failed to achieve three consecutive negative sputum cultures over at least a 3-month period; and (3) "indeterminate" describes patients with insufficient respiratory samples as defined in the previous study (1) (i.e., failure to obtain at least three sputum cultures at least 3 months apart between the first and third samples) to qualify as either (1) or (2) mentioned here. "Relapse" describes those with an initial favorable response who later became culture positive. This could occur either during or subsequent to treatment. Long-term outcomes were based on the most recent information available for the subjects; this could come from patient or doctor surveys after date of discharge or medical records before discharge from NJMRC. A long-term success was a subject judged to be free of TB when the most recent information was available, and a failure was either one who died from TB or was judged to have TB when the most recent information was available. A subject with an initial favorable response could relapse or die from TB and hence be a long-term failure, whereas a subject who initially failed treatment could be deemed to be clinically free of TB at a later time. A subject initially classified as an indeterminate could also be categorized as a long-term success or failure based on their most recent information. Indeterminates for whom there was not enough information to classify as long-term successes or failures were not factored into the long-term success rate. "Extensive disease" was determined radiographically and deemed present when combined cavity diameters totaled 15 cm or more or moderately dense infiltrates involved 75% or more of lung fields or both were present (1).

For "mortality," all nonrespiratory deaths were considered to be due to conditions other than TB unless clearly stated otherwise in their records. Death was attributed to TB for any of the following criteria: (1) the patient was smear positive and/or culture positive when death occurred because of respiratory failure, (2) the patient died of overwhelming TB infection or toxicity from TB infection, (3) the patient died of respiratory failure with no other clear etiology, or (4) the death occurred as a complication of lung resection for TB. "Operative death" was defined as a fatal outcome within 30 days of lung resection; "late surgical death" was defined as demise, directly or indirectly related to surgery, occurring more than 30 days postoperatively.

Statistical Analysis
Several explanatory variables were analyzed for their association with initial favorable response using logistic regression, employing Proc Logistic in SAS. First, explanatory variables were fit in separate regression models. Next, a stepwise selection procedure was used to create a multiple predictor model, including those variables that were first tested individually, plus all two-way interaction terms involving surgery and/or FQN therapy. The stepwise selection procedure used a significance level for entry of 0.2 and a significance level to stay of 0.25. Goodness-of-fit criteria were also evaluated to assess model adequacy.

Rates of survival from TB were estimated using the Kaplan-Meier method, performed with SAS, Proc Lifetest. Three survival analyses were performed based on different groupings of subjects. Within each analysis, comparisons between groups were made using the log-rank test. Survival time was defined as the time from the hospital admission date to the date of the most recent information (or date of death). For subjects without follow-up information after discharge from hospital, the most recent date of information used was their discharge date. Survival times for subjects without known TB death were right censored. A second set of survival analyses was conducted for survival from all causes of death. Survival rates were also estimated using Cox's proportional hazards model (employing SAS, Proc Phreg) in order that multiple predictors could be included in the same model. It was found that the estimates for the variables of primary interest (surgery and FQN usage) did not vary much with the addition of covariates for both survival from TB death and from all causes of death, justifying the use of the simpler Kaplan-Meier method.

The "indeterminates," subjects who had insufficient data to be classified either as initial favorable responders or failures, were further analyzed to determine whether their demographic and behavioral characteristics were more like those in the initial favorable response group or the failure group. This was considered an important analysis because it could provide insight as to whether there were likely to be particular biases in the final estimates. A similar analysis was conducted to determine whether differences existed between those who had follow-up information after date of discharge and those who did not.

All statistical tests were two sided. For tests in which certain directions were expected (e.g., improved outcomes with surgery and/or FQN use), this can be considered a conservative testing approach.

	RESULTS

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Demographics
Two hundred five patients were discharged with MDR-TB between 1984 and 1998. Their median age was 39.9 years (minimum = 2, maximum = 85). The 118 males had a higher median age than the 87 females (43.7 and 35.9 years, respectively). Racial and ethnic distributions included non-Hispanic white (32%), Asian/Pacific Islander (27%), non-Hispanic black (19%), Hispanic (18%), Native-American (1.5%), and others (3%). A total of 109 (53%) were foreign-born, with 56 of these originating from East Asia or Pacific islands.

Duration of Disease, before Treatment, and Level of Resistance
The median duration of recorded disease before treatment at NJMRC was 4.2 years. The patients had previously received a median of five antituberculosis drugs for 3 or more months. The strains were resistant to a median of six drugs. Table 1 shows the drug-resistance rates for the current and previous cohort (1). Drug resistance was defined as the resistance at any level in at least one of the two samplings.

Microbiologic Responses to Treatment
Among the 162 subjects for whom there were sufficient data to evaluate outcome, 137 (85%) converted their sputum cultures to negative ("initial favorable response"), and 25 (15%) had adequate number of sputum samples but failed to convert to negative ("microbiologic failure"). The remaining 43 patients had insufficient sputum samples ("indeterminate response"). There was also a trend in improved microbiologic responses over time within the study period. Favorable microbiologic response rates were 75% (40 of 53), 85% (50 of 59), and 94% (47 of 50) for those discharged within the three successive 5-year intervals.

Follow-up Information and Change of TB status
Information was obtained about the status of 131 subjects after they were discharged from NJMRC (95 in the initial favorable response group, 15 microbiologic failures, and 21 indeterminates). This information was primarily obtained from questionnaires sent to the patients and their caregivers. In addition, eight subjects died before discharge. Among these 139 subjects, a change in TB status (from their initial grouping based on response to treatment) occurred for 35. There were 13 subjects in the initial favorable response group that were classified as long-term failures: six relapsed and died from TB, six relapsed but had no known death, and one was classified as a late operative death but otherwise had no known cause of death. Conversely, only one patient in the microbiologic failure group was deemed "clinically free from TB" with long-term follow-up, based on assessment by local clinicians. Thirteen subjects in the indeterminate response group were found to be clinically free from TB, and eight were known to have died from TB.

Initial Response to Treatment and Long-Term Survival
Among the 205 subjects, there were 51 known deaths, with 25 (12%) attributable to TB and/or surgery. Known TB and/or surgical death occurred in 7 of the 137 (5%) with an initial favorable response, in 10 of the 25 (40%) with microbiologic failure, and 8 of the 43 (19%) in the indeterminate category. It was not possible to determine whether those who died in the indeterminate group ever responded favorably to treatment. Figure 1a shows the survival estimates from TB and/or surgical death for the three groups. The initial favorable response group had the slowest rate of attrition, with the survival rate still above 90% at 15 years of observation (p < 0.01 for difference between this group and each of the other two groups). The microbiologic failure group had the lowest survival rates beginning at 4 years of observation, but overall, this group was not statistically different from the indeterminate group (p = 0.86). A somewhat similar pattern was observed for the survival analysis based on death of any cause (Figure 2a) . Initial favorable responders had survival rates that were clearly separated and above the failures and indeterminates (p < 0.01 for comparison to each); the latter two groups were not statistically different (p = 0.12). There were 68 subjects who did not die before discharge but either had no follow-up information after discharge or had no dates associated with their follow-up information. These subjects were censored out at date of discharge for all of the survival analyses, which corresponded to less than 1 year of observation with few exceptions.

View larger version (23K): [in this window] [in a new window]   Figure 1. Kaplan-Meier estimates of survival from tuberculosis (TB) and/or surgical death by (a) treatment outcome (initial favorable response/microbiologic failure/indeterminate), (b) fluoroquinolone (FQN) use (yes/no), (c) surgery (yes/no) for nonextensive disease, and (d) surgery (yes/no) for extensive disease. Known TB and/or surgical deaths out of total number in group are given in parentheses. For c and d, 59 subjects with unknown extent of illness were not included. Observed levels of significance for the test of survival rate differences between groups were (a) p < 0.0001 for initial favorable responders versus the other two groups and p = 0.86 for microbiologic failures versus indeterminates, (b) p = 0.12, (c) p = 0.23, and (d) p = 0.84.

View larger version (23K): [in this window] [in a new window]   Figure 2. Kaplan-Meier estimates of survival from all causes of death by (a) treatment outcome (initial favorable response/microbiologic failure/indeterminate), (b) FQN use (yes/no), (c) surgery (yes/no) for nonextensive disease, and (d) surgery (yes/no) for extensive disease. Known deaths out of the total number in group are given in parentheses. For c and d, 59 subjects with unknown extent of illness were not included. Observed levels of significance for the test of survival rate differences between groups were (a) p < 0.0001 for initial favorable responders versus the other two groups and p = 0.12 for microbiologic failures versus indeterminates, (b) p = 0.015, (c) p = 0.08, and (d) p = 0.36.

Individual Predictors of Microbiologic Outcome
Several variables were found to be individually associated with initial favorable response to treatment based on the logistic regression analysis (Table 3). Of the 11 variables tried as predictors, only the number of current drugs not used previously, extent of illness, and sex did not reach the 5% level of significance. Chances of an initial favorable response increased most significantly with lesser extent of drug resistance (p < 0.0001) and higher number of drugs in current regimen to which isolate was susceptible (p = 0.0004).

Combined Predictors of Microbiologic Outcome
The stepwise selection procedure included six predictor variables (Table 3, last two columns), plus two interactions, drug-resistance rate by FQN use (p = 0.13) and FQN use by age (p = 0.05). The FQN by age interaction indicated that the older a subject was the greater the odds of success by taking a FQN. The FQN by drug-resistance rate interaction indicated that the lower the drug resistance, the greater the odds of success by taking a FQN. For ease of interpretation, main and interactive effects were combined for presentation in Table 3 (see caption). For the multiple predictor model, the most notable exclusion was the "number of current drugs isolate was susceptible to" variable; its omission was primarily due to its high inverse correlation with the first variable selected into the model—"number of drugs resistant to out of number tested." Based on this model, a 10% increase in the number of drugs to which there was resistance was associated with about a 40% drop in odds of initial favorable response. Those with resectional lung surgery had four times greater odds of initial favorable response than those without.

The odds ratio estimates for predictors did not change dramatically after accounting for other variables (i.e., estimates based on individual predictor models versus those based on multiple predictor models). The odds ratio for FQN therapy was 3.01 in the multiple predictor model for an average-aged subject (40 years) with average drug resistance (50%), whereas the odds ratio for FQN in the model by itself was 3.11. Among the six predictors in the final stepwise model, the greatest difference occurred for surgery, where the odds ratios were 4.63 and 4.23 in the individual and multiple predictor models, respectively.

The combination of FQN therapy and surgery versus neither treatment had an odds ratio of 12.74 (p = 0.02). The modest significance for the apparently strong effect was due to a relatively large standard error.

Extent of Disease
In comparing the survival rates of patients with nonextensive versus extensive disease, those with nonextensive disease had marginally better survival rate than those with extensive disease (p = 0.04, data not shown). However, when comparing the microbiologic response, there was no significant difference between the two groups in the rate of initial favorable response (Table 3). Furthermore, in those with initial favorable outcomes, there was no significant difference in relapse between those with extensive and those with nonextensive disease (data not shown). Although increased drug resistance was the most significant unfavorable prognostic indicator, the extent of disease unexpectedly appeared to have little effect on outcomes.

Characteristics of the "Indeterminate" Group
The calculated initial favorable response rate was based only on those patients with sufficient data and thus excluded the indeterminates. Obviously, this favorable rate could be biased if the incidence of favorable response among the indeterminates differed substantially from that among those for whom data were available. The survival estimates for the indeterminates were more like that of the failures within the first 4 years of observation (Figures 1a and 2a), raising concern that the reported rate of initial favorable response might be biased upward. Known characteristics for all three groups were compared to further investigate whether indeterminates were more like one group or the other. Specifically, the six variables that were included in the stepwise model were analyzed: age, percentage of drugs resistant to, time from first visit to TB diagnosis, surgery, FQN therapy, and drug resistance rate. The rates of surgery and FQN use for the indeterminates were intermediate between that of failures and initial favorable responders but were leaning more toward the failures. However, for the other four variables, the indeterminates were significantly different from the failures but not from the initial favorable responders. Overall, this information does not suggest that our initial favorable response rate may be biased either upward or downward because of exclusion of the indeterminates.

Characteristics of Those without Follow-up Information
A similar analysis to the preceding one was done for those with follow-up information after discharge from the hospital versus those without, after exclusion of eight subjects that died before being discharge. The variables examined included the 11 used in the logistic regression analysis (Table 3), plus initial treatment outcome. There were no differences between those with and those without follow-up that were statistically significant (p > 0.2 for all variables). Hence, there was no indication of a strong nonresponse bias problem with the acquisition of follow-up data.

	DISCUSSION

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Rifampin and isoniazid are the two most important drugs in contemporary therapy of TB. When both of these drugs have been lost to resistance, treatment is complicated, prolonged, and expensive and results in predictably poorer outcomes (1). Comparing outcome of patients treated at our institution during 1973–1983 with those treated during 1984–1998, the initial favorable response rate for patients treated in the latter period was significantly better than the previous cohort (85% vs. 65%). When relapses and other follow-up information were used in the analysis, the long-term favorable outcome rate in the current cohort was 75%. Because the extent of drug resistance and number of drugs previously used were similar between the two periods, we reason that the favorable trends in outcome are due to treatment modifications, namely resectional lung surgery and introduction of the FQNs.

During the 1973–1983 period, only 7 of 171 (4%) patients at NJMRC underwent resectional surgery; all 7 became consistently culture negative. In contrast, 130 of 205 (63%) of the patients in the 1984–1998 period underwent resectional surgery. Logistic regression analysis indicated that surgery was one of the more useful predictors of initial favorable outcome to treatment. Both initial favorable microbiologic outcome and frequency of surgery increased over time within the study period. Additionally, there was a trend toward improved survival in patients who underwent resection (Figures 1c, 1d, 2c, and 2d). Although surgery as a predictor for survival was not statistically significant, this may have been due to the relatively small sample size involved.

The introduction of the FQNs in the 1980s, a new class of drugs with no cross-resistance with other anti-TB agents, has been of great interest to the TB community (13). Wild strains of M. tuberculosis are predictably susceptible in vitro to FQNs (14, 15), and several FQNs have been shown to be active in vivo against TB in murine models (16, 17). In this study, FQNs were used in 80% of the patients, with greater use in the last 10 years compared with the first 5 years of the study period. As demonstrated in Table 3, logistic regression analysis shows that FQN use was moderately related to an initial favorable response, although not to the extent seen with surgery. It is likely that a larger patient sample would show a statistically significant benefit of FQNs and that the associated health effects may be relatively small but important in the setting of multidrug regimens.

The most potent of the currently available FQNs in descending order of in vitro activity against M. tuberculosis are moxifloxacin, gatifloxacin, levofloxacin, ofloxacin, and ciprofloxacin (16, 18–20). Indeed, considerable experience in human disease documents the utility of ciprofloxacin, ofloxacin, and levofloxacin against TB, including MDR-TB cases (13, 21–24). Reports from Hong Kong (21) and Turkey (6) indicated that the outcome of treatment of MDR-TB was substantially better with in vitro susceptibility to FQNs. Recently, in a retrospective analysis of 106 MDR-TB patients, levofloxacin was shown to be more efficacious than ofloxacin (25). In light of the fact that 124 subjects in our cohort received ofloxacin and only 9 levofloxacin, we speculate that the beneficial effects of the FQN seen in this study would have been more substantial had the patients received more potent agents such as levofloxacin or moxifloxacin (26, 27).

In addition to resectional surgery and FQNs, the other novel element of our recent management program was the introduction of routine therapeutic drug monitoring. Although it is not possible to quantify the impact of therapeutic drug monitoring, it was our impression that it lessened or delayed toxicity and thus favorably influenced treatment outcomes.

In summary, we retrospectively analyzed the results of treatment of a relatively large number of patients with MDR-TB and compared their outcome with that reported previously of a cohort from the prior decade. Our analysis demonstrated that the use of resectional lung surgery was associated with overall improved outcome in patients with highly resistant MDR-TB, with a trend toward improvement for those taking FQN antibiotics.

	Acknowledgments

 
The authors gratefully acknowledge Dr. Leonid Heifets and his dedicated personnel at the Mycobacteriology Laboratory at NJMRC for the drug-susceptibility testing; Dr. Marvin Pomerantz for his consummate surgical care of the patients; and Lorie Powell, R.N., the nursing staff, and Drs. Gwen Huitt, Kevin Fennelly, and G. Scott Worthen for the excellent care of the patients and helpful discussions. The authors also thank Karen Sheff and Dr. Zung Tran for help with the initial design of the study. Finally, the authors express gratitude to the patients and their referring physicians for entrusting them to help in the management of this complex disease.

	FOOTNOTES

 
Supported by NIH-HL-66-112, the American Lung Association Career Investigator Award, and the Bettina Garthwaite Lowerre Foundation for Mycobacteriology Research Fellowship.

E.D.C. and V.L. contributed equally to the preparation of this article.

Conflict of Interest Statement: E.D.C. has no declared conflict of interest; V.L. has no declared conflict of interest; M.J.S. has no declared conflict of interest; J.F.C. has no declared conflict of interest; M-L.N.H. has no declared conflict of interest; M.G. has no declared conflict of interest; M.D.I. is a paid consultant for Ortho-McNeill, producer of levofloxacin.

Received in original form August 20, 2003; accepted in final form January 18, 2004

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