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Treatment outcomes of rifampin-sparing treatment in patients with pulmonary tuberculosis with rifampin-mono-resistance or rifampin adverse events: A retrospective cohort analysis
Respiratory Medicine 131 (2017) 43e48
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Treatment outcomes of rifampin-sparing treatment in patients with pulmonary tuberculosis with rifampin-mono-resistance or rifampin adverse events: A retrospective cohort analysis Shinhee Park, Kyung-Wook Jo, Sang Do Lee, Woo Sung Kim, Tae Sun Shim* Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 November 2016 Received in revised form 2 August 2017 Accepted 2 August 2017 Available online 4 August 2017
Background: Rifampin (RIF) mono-resistant tuberculosis (RMR-TB) is a rare disease. Current guidelines recommend that RMR-TB be treated as multidrug-resistant TB (MDR-TB) but the evidence is scarce. Methods: We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and outcomes of RMR-TB. The characteristics of RMR-TB were compared with those with adverse events to rifampin (RAE-TB). Results: Forty-four RMR-TB and 29 RAE-TB patients were enrolled. RMR-TB patients showed more alcohol use, prior history of TB, and radiologically severe disease, while RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB. A fluoroquinolone (FQ) was the drug most commonly added (70.5%, RMR-TB; 82.8%, RAE-TB). Median treatment duration was 453 days in RMR-TB and 371 days in RAE-TB (p ¼ 0.001) and treatment success rates were 87.2% (34/39) and 80.0% (20/25), respectively (p ¼ 0.586). Subanalysis of the RMR-TB group by treatment regimen (standard regimen [n ¼ 11], standard regimen þ FQ [n ¼ 12], MDR-TB regimen [n ¼ 21]) revealed a higher rate of radiologically severe disease in the MDR-TB subgroup, with similar treatment success rates for the subgroups (85.7% [6/7]), 91.7% [11/12], and 85.0% [17/20], respectively) despite different durations of treatment (345, 405, and 528 days, respectively). Two recurrences (33.3% [2/6]) developed only in standard regimen subgroup, suggesting that standard regimen is not enough to treat RMR-TB patients. Conclusions: The treatment outcome of RMR-TB with 1st-line drugs þ FQ was comparable to that of MDRTB regimen. Shorter treatment duration may be considered for RMR-TB patients compared with MDR-TB patients. © 2017 Published by Elsevier Ltd.
Keywords: Rifampin-mono-resistance Treatment outcomes Tuberculosis
1. Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis, is still a leading cause of death worldwide resulting in 1.5 million TB deaths in 2014 [1]. Rifampin (RIF or R) is a bactericidal agent that constitutes the backbone of short course anti-TB chemotherapy regimen, but concern about the emergence of drug-resistant strains is
Abbreviations: AFB, acid-fast bacilli; DST, drug susceptibility test; DOT, directly observed treatment; FQ, fluoroquinolone; HIV, human immunodeficiency virus; IQR, interquartile range; MDR, multidrug-resistant; RAE, rifampin adverse events; RIF, rifampin; RMR, rifampin mono-resistant; TB, tuberculosis. * Corresponding author. Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea. E-mail address: [email protected] (T.S. Shim). http://dx.doi.org/10.1016/j.rmed.2017.08.002 0954-6111/© 2017 Published by Elsevier Ltd.
growing [2]. RIF-mono-resistant TB (RMR-TB) is a rare disease that represents 0.8% of new TB cases and 2.1% of relapsed cases in Korea. Among 8840 new TB cases diagnosed between 1994 and 2004, 266 cases (3.0%) were resistant to RIF and only one-fifth of them were RMR-TB [3]. Most (approximately 74e83%) [4,5] of M. tuberculosis strains that are resistant to RIF are also resistant to isoniazid (INH or H); infection by such strains defines multidrug-resistant TB (MDRTB). RIF resistance is often regarded as a proxy for MDR-TB due to its rarity, but the impact and the management of RMR-TB have not been as widely studied as they have for MDR-TB. The World Health Organization (WHO) [6] and the International Union Against Tuberculosis and Lung Disease (IUATLD) [7] recommend that RMR-TB should be treated as MDR-TB for at least 20 months, with INH being added to the regimen until drug susceptibility test (DST) results to INH are available. However, the
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evidence supporting such a recommendation is weak. Some experts recommend 18-month regimens comprising INH, pyrazinamide (PZA or Z), and ethambutol (EMB or E), with or without a fluoroquinolone, on the basis of clinical experience [8]. Previous studies on RMR-TB mainly focused on the epidemiology and risk factors, while few investigated treatment regimens or treatment outcomes of RMR-TB [9e12]. Stagg et al. pointed out that there has been no randomized controlled study that focused solely on the treatment of RIF-resistant TB [13]. We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and treatment outcomes of RMR-TB. In addition, in order to evaluate the appropriate treatment regimen and treatment duration using RIF-sparing regimens, patients who had discontinued RIF due to adverse events were also included in this study.
including human immunodeficiency virus (HIV) infection, prior treatment history of TB, sputum smear results, radiologic severity, presence of cavities on chest radiograph, and combined extrapulmonary TB infections. Radiographic severity was categorized into minimal, moderately advanced, or far advanced according to the criteria proposed by the U.S. National Tuberculosis and Respiratory Disease Association [15]. Treatment outcomes were reassessed in each of the patients according to the WHO definitions, and total treatment duration, treatment duration of each anti-TB drug, acquisition of drug resistance, and recurrence were examined. The RMR-TB patients were divided into three subgroups according to the treatment regimen; standard regimen (HRE or HREZ), standard regimen plus fluoroquinolone (FQ), and INH plus MDR-TB regimen. We compared the treatment outcome and treatment duration of each subgroup.
2. Materials and methods 2.4. Statistical analyses We conducted a retrospective cohort study of pulmonary RMRTB patients treated in a tertiary referral center, Asan Medical Center, Seoul, Korea, from January 1999 to December 2013. Patients with pan-susceptible TB who had discontinued RIF due to adverse events (RAE-TB) were also selected and the clinical characteristics and treatment outcomes were compared between two groups. 2.1. Definitions and inclusion criteria Patients who had pulmonary TB with available DST results were included in the study. Patients were at least 15 years of age and had treatment started with a standard regimen comprised of HREZ or HRE. A patient with both pulmonary and extrapulmonary TB was classified as a case of pulmonary TB [14]. Generally, RMR is defined as a resistance to RIF without resistance to any other first-line anti-TB drugs. However, in this study, RMR-TB was defined as TB caused by a M. tuberculosis strain with RIF resistance and INH susceptibility on DST, regardless of other drug resistance pattern. Patients with pan-susceptible TB on DST who had experienced RIF-related adverse events and discontinued RIF within 2 months were assigned to the RAE-TB group. Treatment outcomes were defined following the WHO definitions on RIF-resistant or MDR-TB. Patients who were not started on a MDR-TB regimen were assigned an outcome from those for RIFsusceptible TB [6]. Unfavorable outcomes include treatment failure, died, lost to follow-up, recurrence and acquisition of drug resistance other than to RIF. 2.2. Bacteriological study Acid-fast bacilli (AFB) smears were examined by Ziehl-Neelsen staining. AFB culture was carried out using solid Ogawa media alone until July 2007 and then using both solid and liquid media (BACTEC 960 Mycobacterial Growth Indicator Tube; Becton Dickinson, Sparks, MD, USA) thereafter. Conventional DST was per€nsteinformed using the absolute concentration method with Lowe Jensen media at the Korean Institute of Tuberculosis. The drug concentrations for susceptibility testing were 0.2 mg per milliliters (mg/mL) for INH, 40 mg/mL for RIF, and 2 mg/mL for EMB. Pyrazinamide susceptibility was determined using the pyrazinamidase test. 2.3. Patient characteristics We reviewed the patients' electronic medical records and collected baseline characteristics including age, sex, body-mass index (BMI), alcohol use, smoking history, comorbidities
Statistical analyses were performed by SPSS statistics version 21. Analysis of categorical variables was done using the chi square test and Fisher's exact test and continuous variables were analyzed by independent t-test and Mann-Whitney test. Treatment outcomes of the three RMR-TB subgroup according to the treatment regimen were compared using Kruskal-Wallis H-test and linear-by-linear association, and the treatment duration was compared using analysis of variance (ANOVA) models. For the ANOVA models, post hoc analysis was done using the Bonferroni correction method. A pvalue of <0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics Fifty-six patients with RMR-TB and 259 patients with RAE-TB who were treated at our hospital from January 1999 to December 2013 were identified. Of the 56 patients with RMR-TB, 12 patients not treated initially with the standard regimen were excluded, for a total enrollment of 44 RMR-TB patients. Of 259 patients with RAETB, 52 who were not treated initially with the standard regimen, 59 without available DST, and 119 patients treated with RIF for more than 2 months were excluded, for a total enrollment of 29 RAE-TB patients. The baseline characteristics of the two groups were compared (Table 1). The RMR-TB patients were younger and had more alcohol use, prior history of TB and radiologically more severe disease compared with the RAE-TB patients. The RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB than the RMR-TB patients. The remaining patient characteristics, including sex, BMI, proportion of ever-smoker and HIV infection status, and sputum positivity were not different between the RMRTB and RAE-TB groups. Three RMR-TB patients were resistant to EMB and six were resistant to PZA: one of them had both EMB and PZA resistance. No patients enrolled in this study had resistance to fluoroquinolones. 3.2. Treatment regimens and durations Daily treatment was prescribed during the whole treatment duration. Treatment was not directly observed but instead specialized private-public-mix (PPM) cooperation nurses monitored the treatment courses. Comparison of treatment duration of each anti-TB medication in the RMR-TB and RAE-TB groups is shown in Table 2. INH, PZA, injectable drugs, and some of the second-line oral drugs were prescribed longer in the RMR-TB
S. Park et al. / Respiratory Medicine 131 (2017) 43e48 Table 1 Baseline characteristics of the patients. Characteristics
RMR-TB (n ¼ 44)
RAE-TB (n ¼ 29)
p-valuea
Age, years Male sex, no. (%) Body mass index, kg/m2 Ever-smoker, no. (%) Alcohol use, no. (%) Co-morbidity Diabetes mellitus, no. (%) Liver disease, no. (%) Chronic kidney disease, no. (%) Malignancy, no. (%) Organ transplantation, no. (%) Others, no. (%) HIV infection, no. (%) Prior treatment for TB, no. (%) Combined extrapulmonary TB (%) Sputum smear-positive, no. (%) Radiologic Severity Minimal, no. (%) Moderately or far advanced, no. (%) Cavity on chest radiograph Additional drug resistance Resistance to pyrazinamide Resistance to ethambutol Extrapulmonary TB, no. (%)
43.0 ± 14.5 28 (63.6) 21.6 ± 3.3 21/38 (55.3) 11/32 (34.4) 13 (29.5) 6 (13.6) 2 (4.5) 0 (0) 4 (9.1) 0 (0) 6 (13.6) 1/25 (4.0) 24/43 (55.8) 5 (11.4) 29 (65.9)
58.2 ± 16.8 19 (65.5) 21.7 ± 2.6 15 (51.7) 1/28 (3.6) 22 (75.9) 6 (20.7) 4 (13.8) 3 (10.3) 8 (27.6) 2 (6.9) 15 (51.7) 0/24 (0) 5 (17.2) 11 (37.9) 12 (41.4)
<0.001 1.000 0.385 0.809 0.003 <0.001 0.524 0.207 0.059 0.053 0.154 0.001 1.000 0.001 0.002 0.054 0.007
20 (45.5) 24 (54.5) 21 (47.7)
23 (79.3) 6 (20.7) 5 (17.2)
0.012
3 (6.8) 6 (13.6) 5b (11.4)
0 (0) 0 (0) 11c (37.9)
0.272 0.075 0.008
Abbreviations: HIV ¼ human immunodeficiency virus, RAE ¼ rifampin adverse events, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Statistical analysis was carried out using independent t-test for age and BMI, and the chi square test and Fisher's exact test for other variables. b Pleurisy (n ¼ 2), lymphadenitis (n ¼ 2), and disseminated disease with CNS involvement (n ¼ 1). c Lymphadenitis (n ¼ 3), endobronchial TB (n ¼ 2), TB pleurisy (n ¼ 2), bone (n ¼ 2), pericarditis (n ¼ 1), and colitis (n ¼ 1).
patients than the RAE-TB patients. The treatment durations of EMB and FQs, however, were not different between the RMR-TB and the RAE-TB groups. The FQs were the most frequently added drug in both RMR-TB (70.5%) and RAE-TB (82.8%) patients. In standard þ FQ subgroup, FQ was added at a median of 112 (interquartile range, IQR 69e117) days after initiation of standard regimen; in MDR-TB subgroup, standard regimen was switched to MDR-TB regimen at a median of 90 (IQR 30e120) days after initiation of standard regimen. We analyzed treatment duration in patients who completed their treatment (Table 3). The median treatment duration in patients who completed their treatment was significantly longer in the RMR-TB group (453 days) compared with the RAE-TB group (371 days) (p ¼ 0.003). The median treatment duration after sputum conversion was also longer in RMR- TB (352 days) when compared to RAE-TB (296 days) (p ¼ 0.020).
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Generally, patients were followed-up on a monthly basis with sputum culture during treatment. However, some patients were not able to expectorate their sputum, in which case the sputum culture was not obtained. The mean interval of sputum culture was 1.47 and 1.75 months during treatment in RMR-TB and RAE-TB patients, respectively. In RMR-TB patients, the mean interval of sputum culture was 1.42, 1.61, and 1.43 months in standard regimen, FQ-added regimen, and MDR-TB regimen groups, respectively. 3.3. Treatment outcomes We also analyzed time to sputum conversion in patients who completed their treatment (Table 3). The median time to sputum culture conversion was 93 days and 60 days, respectively. The time to sputum conversion was longer in RMR-TB patients than in RAETB patients (p ¼ 0.033). Comparison of treatment outcomes including recurrence and acquisition of drug resistance for each group are shown in Table 4. The treatment success rates were 87.2% (34/39) in RMR-TB and 80.0% (20/25) in RAE-TB. The frequency of unfavorable outcomes was not different between two groups. The median follow-up duration after treatment completion was 532 days (IQR 126e1160) in RMR-TB and 448 days (IQR 338e1017) in RAE-TB. The follow-up duration was not significantly different between two groups. The numbers of patients who were followed up for more than 1-year and 2-year were 43 (67.2%) and 29 (45.3%), respectively. Recurrence occurred in two of 34 (5.9%) RMR-TB patients and one of 20 (5.0%) RAE-TB patients. One of 35 (2.9%) RMRTB patients acquired drug resistance to INH while none of the 18 (0%) RAE-TB patients did, but the difference between the groups was not significant. 3.4. Treatment outcomes according to treatment regimens in RMRTB patients We divided the RMR-TB patients into three subgroups according to treatment regimens and compared baseline characteristics, treatment outcome and treatment duration (Tables 5 and 6). Eleven patients were continuously treated with the standard regimen (HRE or HREZ), 12 patients with standard regimen plus FQ, and 21 patients with MDR-TB regimen (plus INH). The MDR-TB regimen subgroup had a higher percentage of smoking (27.3% vs. 63.6% vs. 68.8%, respectively, p ¼ 0.043) and radiologically moderately or faradvanced disease (36.4% vs. 41.7% vs. 71.4%, respectively, p ¼ 0.043), but other baseline characteristics were similar between the subgroups. All patients with PZA or EMB resistance except one EMB resistance in standard regimen subgroup were included in MDR-TB regimen subgroup. While the treatment duration between the
Table 2 Treatment duration of each anti-TB medications. p-valuea
Treatment drugs
RMR-TB (n ¼ 44)
RAE-TB (n ¼ 29)
Median (IQR)
No. (%)
Median (IQR)
No. (%)
Isoniazid Rifampin Ethambutol Pyrazinamide Injectable drugs Fluoroquinolones Prothionamide Cycloserine Para-aminosalicylic acid
372 (185e461) 93 (43e118) 203 (114e434) 141 (68e397) 88 (49e127) 296 (131e412) 254 (82e354) 276 (82e423) 154 (62e321)
44 44 44 44 20 31 22 24 14
194 (52e325) 27 (11e41) 194 (74e321) 52 (25e186) 29 (10e48) 225 (133e336) 83 (26e85) 138 (41e280) 35 (15e83)
29 (100) 29 (100) 29 (100) 29 (100) 6 (20.7) 24 (82.8) 5 (17.2) 16 (55.2) 6 (20.7)
(100) (100) (100) (100) (45.5) (70.5) (50.0) (54.5) (31.8)
Abbreviations: IQR ¼ interquartile range, RAE ¼ rifampin adverse events, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Statistical analysis was carried out using Mann-Whitney test.
0.002 <0.001 0.347 0.001 0.004 0.250 0.024 0.071 0.052
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S. Park et al. / Respiratory Medicine 131 (2017) 43e48
Table 3 Treatment duration and time to sputum culture conversion in patients who completed treatment. RMR-TB (n ¼ 34)
Total treatment duration, days Time to culture conversion, days Treatment duration after culture conversion, days
p-valuea
RAE-TB (n ¼ 20)
Median (IQR)
No. (%)
Median (IQR)
No. (%)
453 (368e549) 93 (57e143) 352 (279e442)
34 (100) 31 (91.2) 31 (91.2)
371 (246e407) 60 (35e81) 296 (181e338)
20 (100) 18 (90.0) 18 (90.0)
0.003 0.033 0.020
Abbreviations: IQR ¼ interquartile range, RAE ¼ rifampin adverse events, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Statistical analysis was carried out using Mann-Whitney test.
Table 4 Treatment outcomes of 73 pulmonary TB patients with rifampin-sparing regimens. Treatment outcomesa
RMR-TB n ¼ 44, no. (%)
RAE-TB n ¼ 29, no. (%)
p-valueb
Treatment success Cured Treatment completed Treatment failed Died Lost to follow-up Not evaluated Recurrence Acquisition of drug resistance Unfavorable outcomesc
34 (77.3) 30 (68.2) 4 (9.1) 0 (0) 1 (2.3) 4 (9.1) 5 (11.4) 2/34 (5.9) 1/35 (2.9) 7/39 (17.9)
20 (69.0) 11 (37.9) 9 (31.0) 0 (0) 2 (6.9) 3 (10.3) 4 (13.8) 1/20 (5.0) 0/18 (0) 6/25 (24.0)
0.586
1.000 1.000 0.751
Abbreviations: RAE ¼ rifampin adverse events, RIF ¼ rifampin, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Treatment outcomes were defined following the World Health Organization definitions on RIF-resistant/MDR-TB, or RIF-susceptible TB for the patients who were not started on a MDR-TB regimen. b Statistical analysis was carried out using Fisher's exact test. c Unfavorable outcomes include treatment failure, death, lost to follow-up, recurrence, and acquisition of resistance to drugs other than RIF.
regimens varied (Standard regimen, 345 days; Standard regimen þ FQ, 405 days; INH þ MDR-TB regimen, 528 days), the treatment success rates were not significantly different between the subgroups: 85.7% (6/7), 91.7% (11/12) and 85.0% (17/20), respectively.
All two recurrences in RMR-TB patients developed in the standard regimen group. First patient was 36-year old male who had positive AFB smear and moderately advanced radiologic severity with a cavity and a history of receiving HREZ treatment for a year. His treatment compliance was not optimal even though a PPM nurse monitored the treatment course. Immediately after treatment completion, the patient relapsed with a strain resistant to both rifampin and isoniazid. The second patient was 44-year old male who had positive AFB smear and far-advanced radiologic severity with several cavities. Treatment was initiated with 2 months of HREZ followed by 4 months of HRE. The patient relapsed about 6 years after treatment completion. DST result was not available at the time of relapse. Even though the recurrence rate was not significantly different among the three groups, probably due to the small number of subjects, it was higher in the standard regimen subgroup than in both standard þ FQ and MDR-TB regimen subgroups (33.3% vs. 0% vs. 0%, respectively, p ¼ 0.063). 4. Discussion We evaluated the characteristics and treatment outcomes of RMR-TB patients in a Korean hospital over a 14-year study period. We found that the treatment outcomes for RMR-TB were comparable to those for RAE-TB, and that the treatment duration in both groups was shorter than the current guidelines recommended for MDR-TB. When we further analyzed the management of RMR-TB by
Table 5 Clinical characteristics of 44 RMR-TB patients, according to treatment regimens. Characteristics
Age, years Male sex, no. (%) Body-mass index, kg/m2 Ever-smoker, no. (%) Alcohol use, no. (%) Co-morbidity Diabetes mellitus, no. (%) Liver disease, no. (%) Chronic kidney disease, no. (%) Malignancy, no. (%) Organ transplantation, no. (%) Immunosuppression, no. (%) HIV infection, no. (%) Prior treatment for TB, no. (%) Combined extra-pulmonary TB (%) Sputum smear-positive, no. (%) Radiologic Severity Minimal, no. (%) Moderately or far advanced, no. (%) Cavity on chest radiograph Additional drug resistance Resistance to pyrazinamide Resistance to ethambutol a
Treatment regimens Standard (n ¼ 11)
Standard þ FQ (n ¼ 12)
MDR-TB (n ¼ 21)
p-valuea
43.8 ± 15.8 5 (45.5) 22.0 ± 3.4 3 (27.3) 1/10 (10.0) 3 (27.3) 1 (9.1) 0 (0) 0 (0) 1 (9.1) 0 (0) 0 (0) 0 (0) 5/10 (50.0) 0 (0) 7 (63.6)
44.6 ± 15.9 9 (75.0) 22.9 ± 2.0 7 (63.6) 5/10 (50.0) 5 (41.7) 3 (25.0) 1 (8.3) 0 (0) 1 (8.3) 0 (0) 0 (0) 0 (0) 8 (66.7) 2 (16.7) 4 (33.3)
41.7 ± 13.6 14 (66.7) 20.6 ± 3.7 11 (68.8) 5/12 (41.7) 5 (23.8) 2 (9.5) 1 (4.8) 0 (0) 2 (9.5) 0 (0) 0 (0) 1/11 (9.1) 11 (52.4) 3 (14.3) 18 (85.7)
0.849 0.320 0.183 0.043 0.142 0.704
7 (63.6) 4 (36.4) 4 (36.4)
7 (58.3) 5 (41.7) 4 (33.3)
6 (28.6) 15 (71.4) 13 (61.9)
0.125
1 (9.1) 0 (0)
0 (0) 0 (0)
5 (23.8) 3 (14.3)
0.179 0.146
Statistical analysis by ANOVA, Kruskal-Wallis H test and linear by linear association.
0.317 0.958 0.287 0.092 0.043
S. Park et al. / Respiratory Medicine 131 (2017) 43e48
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Table 6 Treatment outcomes of 44 RMR-TB patients according to treatment regimens. Treatment outcomesa
Treatment regimens Standard (n ¼ 11), no (%)
Standard þ FQ (n ¼ 12), no (%)
MDR-TB (n ¼ 21), no (%)
P-value
Treatment success Cured Treatment completed Treatment failed Died Lost to follow-up Not evaluated Recurrence Acquisition of drug resistance Unfavorable outcomese
6 (85.7) 5 (71.4) 1 (14.3) 0 (0) 0 (0) 1 (9.1) 4 (36.4) 2/6 (33.3) 1/6 (16.7) 1/7 (14.3)
11 (91.6) 10 (83.3) 1 (8.3) 0 (0) 0 (0) 1 (8.3) 0 (0) 0/11 (0) 0/11 (0) 2/12 (16.7)
17 (80.9) 15 (71.4) 2 (9.5) 0 (0) 1 (4.8) 2 (9.5) 1 (4.8) 0/17 (0) 0/17 (0) 4/20 (20.0)
0.157
Durations Total treatment duration Time to culture conversion
(n ¼ 10) 345 (273e459) 61 (57e111)
(n ¼ 10) 405 (367e459) 79 (33e93)
(n ¼ 16) 528 (443e617) 140 (81e192)
Treatment duration after culture conversion
327 (240e490)
333 (374e371)
370 (327e442)
0.063 0.223 0.719 P-valueb 0.020c 0.020c 0.020d 0.493
Abbreviations: FQ ¼ fluoroquinolones, MDR ¼ multidrug-resistant, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Treatment outcomes were defined following the World Health Organization definitions on RIF-resistant/MDR-TB, or RIF-susceptible TB for the patients who were not started on a MDR-TB regimen. b Statistical analysis by ANOVA, post-hoc analysis was carried out using the Bonferroni correction method. c P-values of comparisons between standard and MDR-TB regimen subgroups. d P-values of comparisons between standard þ FQ and MDR-TB regimen subgroups. e Unfavorable outcomes include treatment failure, death, lost to follow-up, recurrence, and acquisition of resistance to drugs other than RIF.
subgroups categorized by treatment regimen, we observed that the standard regimen þ FQ, instead of MDR-TB regimen, may be enough to successfully complete treatment without recurrence in some RMR-TB patients. The RMR-TB patients had more alcohol use, which is consistent with previous studies [2,12] and may lead to poor treatment compliance and emergence of resistant strains. RMR-TB patients were more often treated for TB prior to the diagnosis of RMR-TB, which is a known risk factor for RMR-TB [9]. We observed extrapulmonary TB more frequently in patients with RAE-TB than those with RMR-TB. However, among 44 RMR-TB and 29 RAE-TB patients, one patient (TB meningitis) and two patients (bone TB), respectively, had concomitant extrapulmonary TB that might have prolonged treatment duration. The numbers of those patients were not significantly different between RMR-TB and RAE-TB (p ¼ 0.333) and too small in both groups to have significantly altered the results. We observed severe disease more frequently in terms of radiologic assessment in RMR-TB than in RAE-TB, which may have influenced the longer treatment duration in the RMR-TB. The RAE-TB patients were older than the RMR-TB patients and had more comorbidities, which may have initially predisposed them to the adverse events of RIF [16]. MDR-TB regimen subgroup had more patients with additional drug resistance to PZA or EMB than the other two subgroups but the difference was not statistically significant, probably owing to the small sample size. The decision to implement MDR-TB regimen on these patients may have been affected by the drug resistance pattern. The treatment durations of first-line anti-TB drugs, i.e. INH and PZA, as well as injectable drugs, were significantly longer in the RMR-TB group. This is likely due in part to the adverse reaction to other anti-TB agents in the RAE-TB group, and in part to the MDR regimen implemented in the RMR-TB group. FQs were the drugs most frequently added in both groups: 70.5% (31/44) in RMR-TB and 82.8% (24/29) in RAE-TB. Patients in RMR-TB and RAE-TB groups both received shorter durations of treatment (453 days and 371 days, respectively) than 20 months, which is currently recommended for MDR-TB treatment. As previously mentioned, the WHO and the IUATLD
recommend RMR-TB to be treated as MDR-TB. The treatment of MDR-TB usually includes an injectable drug and this could be difficult for the patients due to its toxicity and manner of administration. The recommended treatment duration for MDR-TB is a minimum of 20 months, but recent trials have supported the possibility of shorter treatment duration in MDR-TB [17,18]. The optimal treatment duration for RMR-TB has not been studied, but our data suggest that the shorter treatment duration may be sufficient in RMR-TB patients. Meyssonnier et al. evaluated 39 RMR-TB patients in France [12]. The treatment success rate was 66.7% (20 out of 30 cases). Among the 20 patients who were cured or completed treatment, 19 patients had received treatment for at least 9 months. The authors reported heterogeneous patterns of management and a worse outcome of RMR-TB, attributed to the lack of thorough understanding for the disease and the paucity of treatment consensus during the study period. It has only been a few years since the IUATLD published guidelines on RMR-TB to be treated as MDR-TB. However, Dramowski et al. have shown that the regimen comprising INH, ethambutol, PZA, an injectable drug and a secondline oral drug such as ethionamide can successfully treat RMR-TB with a shorter treatment duration [19]. Differences in the proportion of successful treatment outcome among the three regimen subgroups were not statistically significant (85.7% vs. 91.6% vs. 80.9%, respectively, p ¼ 0.157). A possible reason for continuation of standard regimen irrespective of RIF resistance may be that initial treatment response was favorable before we received DST results or negative conversion of sputum culture was already achieved with standard regimen at the time of DST report. However, in this study, the denominator was only 7 for analyzing treatment outcomes in the standard regimen subgroup. The patients in the standard regimen subgroup had milder disease in terms of radiological assessment compared with MDR-TB regimen subgroup. In addition, albeit short of statistical significance, recurrence rate was higher in the standard regimen subgroup than in standard þ FQ subgroup and MDR-TB regimen subgroup (33.3% vs. 0% vs. 0%, respectively, p ¼ 0.063). Therefore, these findings suggest that 1st-line standard regimen is not
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recommended for the treatment of RMR-TB as did by the WHO. The appropriate treatment duration was not studied yet when FQ was added in the anti-TB regimens. In our study, FQ was the most frequently added drug in RIF-sparing regimens, and standard regimen þ FQ alone, without MDR-TB regimen and without injectable drugs, achieved favorable treatment outcomes as we evidenced 91.6% of treatment success and 0% of recurrence rate. In addition, total treatment duration was shorter than in MDR-TB regimen subgroup (405 days vs. 528 days, respectively) even though post hoc analysis did not reveal statistical significance. These findings suggest that standard regimen þ FQ, without injectable drugs, may be enough in the treatment of RMR-TB patients, especially in patients with mild and/or low bacillary-burden TB. Our study has several limitations. Because RMR-TB is a rare disease in areas with low prevalence of HIV, our study was limited by a small sample size. Study population was restricted to pulmonary TB patients and adjustments for potential confounding factors nor effect modification were not made. We included patients whose treatment was initiated with standard regimen, but this population may not represent all RMR-TB patients. A multivariate analysis of treatment outcome in RMR-TB subgroup according to the treatment regimen was not available because of the small sample size. Thus, this study lacks the power to draw any firm conclusion due to these limitations. Another shortcoming in our study is that the directly observed treatment (DOT), an international standard TB care method, was not adopted; instead, PPM nurses monitored the treatment courses. However, previous studies conducted in Korea showed that PPM-based monitoring resulted in favorable outcomes for TB patients even though the treatment outcome was not compared between DOT and PPM groups [20,21]. RIF resistance includes any resistance to RIF, in the form of mono-resistance, poly-resistance, MDR or XDR. However, in this study, the definition of RMR-TB included both mono-resistance and poly-resistance to RIF. Genotyping data were not available in the 3 recurrent cases so that we cannot differentiate between relapse and reinfection. 5. Conclusions The treatment regimens were heterogeneous for RMR-TB patients, but favorable clinical outcomes were achieved with regimens with treatment durations shorter than 20 months, which is currently recommended for MDR-TB treatment. We further analyzed the management of RMR-TB by subgroups categorized according to treatment regimen; the results showed that at least in some RMR-TB patients, the standard regimen þ FQ, instead of MDRTB regimen, may be considered for completing the treatment without recurrence. Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript and Dr. Jung Bok Lee from the Department of Clinical Epidemiology and Biostatistics for statistical counseling.
Conflict of interest The authors declare no conflicts of interest.
References [1] World Health Organization (WHO), Global tuberculosis report 2015, http:// www.who.int/tb/publications/global_report/en/(accessed 17.03.19). [2] F.K. Mukinda, D. Theron, G.D. van der Spuy, K.R. Jacobson, M. Roscher, E.M. Streicher, A. Musekiwa, G.J. Coetzee, T.C. Victor, B.J. Marais, J.B. Nachega, R.M. Warren, H.S. Schaaf, Rise in rifampicin-monoresistant tuberculosis in western cape, South Africa, Int. J. Tuberc. Lung Dis. 16 (2012) 196e202. [3] G.H. Bai, Y.K. Park, Y.W. Choi, J.I. Bai, H.J. Kim, C.L. Chang, J.K. Lee, S.J. Kim, Trend of anti-tuberculosis drug resistance in Korea, 1994-2004, Int. J. Tuberc. Lung Dis. 11 (2007) 571e576. [4] I.C. Sam, F. Drobniewski, P. More, M. Kemp, T. Brown, Mycobacterium tuberculosis and rifampin resistance, United Kingdom, Emerg. Infect. Dis. 12 (2006) 752e759. [5] L. Villegas, L. Otero, T.R. Sterling, M.A. Huaman, P. Van der Stuyft, E. Gotuzzo, C. Seas, Prevalence, risk factors, and treatment outcomes of isoniazid- and rifampicin-mono-resistant pulmonary tuberculosis in Lima, Peru, PLoS ONE 11 (2016) e0152933. [6] Companion Handbook to the WHO Guidelines for the Programmatic Management of Drug-resistant Tuberculosis, World Health Organization 2014, Geneva, 2014. [7] J.A. Caminero, Guidelines for the Clinical and Operational Management of Drug-resistant Tuberculosis, Paris, France: International Union Against Tuberculosis and Lung Disease, Paris, 2013. [8] C.R. Horsburgh Jr., C.E. Barry 3rd, C. Lange, Treatment of tuberculosis, N. Engl. J. Med. 373 (2015) 2149e2160. [9] L. Sandman, N.W. Schluger, A.L. Davidow, S. Bonk, Risk factors for rifampinmonoresistant tuberculosis: a case-control study, Am. J. Respir. Crit. Care Med. 159 (1999) 468e472. [10] M. Sanders, A. Van Deun, D. Ntakirutimana, J.P. Masabo, J. Rukundo, L. Rigouts, K. Fissette, F. Portaelst, Rifampicin mono-resistant Mycobacterium tuberculosis in Bujumbura, Burundi: results of a drug resistance survey, Int. J. Tuberc. Lung Dis. 10 (2006) 178e183. [11] Y.M. Coovadia, S. Mahomed, M. Pillay, L. Werner, K. Mlisana, Rifampicin mono-resistance in Mycobacterium tuberculosis in KwaZulu-Natal, South Africa: a significant phenomenon in a high prevalence TB-HIV region, PLoS One 8 (2013) e77712. [12] V. Meyssonnier, T.V. Bui, N. Veziris, V. Jarlier, J. Robert, Rifampicin monoresistant tuberculosis in France: a 2005-2010 retrospective cohort analysis, BMC Infect. Dis. 14 (2014) 18. [13] H. Stagg, H. Hatherell, M. Lipman, R. Harris, I. Abubakar, Treatment regimens for rifampicin-resistant tuberculosis: highlighting a research gap, Int. J. Tuberc. Lung Dis. 20 (2016) 866e869. [14] World Health Organization, Definitions and Reporting Framework for Tuberculosise2013 Revision, World Health Organization, Geneva, 2013. [15] National Tuberculosis Association, Diagnostic Standards and Classification of Tuberculosis, The Association, New York, 1961. [16] T. Schaberg, K. Rebhan, H. Lode, Risk factors for side-effects of isoniazid, rifampin and pyrazinamide in patients hospitalized for pulmonary tuberculosis, Eur. Resp. J. 9 (1996) 2026e2030. [17] K.J. Aung, A. Van Deun, E. Declercq, M.R. Sarker, P.K. Das, M.A. Hossain, H.L. Rieder, Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients, Int. J. Tuberc. Lung Dis. 18 (2014) 1180e1187. [18] C. Kuaban, J. Noeske, H.L. Rieder, N. Ait-Khaled, J.L. Abena Foe, A. Trebucq, High effectiveness of a 12-month regimen for MDR-TB patients in Cameroon, Int. J. Tuberc. Lung Dis. 19 (2015) 517e524. [19] A. Dramowski, M.M. Morsheimer, A.M. Jordaan, T.C. Victor, P.R. Donald, H.S. Schaaf, Rifampicin-monoresistant Mycobacterium tuberculosis disease among children in Cape Town, South Africa, Int. J. Tuberc. Lung Dis. 16 (2012) 76e81. [20] H.J. Kim, G.-H. Bai, M.K. Kang, S.J. Kim, J.K. Lee, S.-I. Cho, W.J. Lew, A publicprivate collaboration model for treatment intervention to improve outcomes in patients with tuberculosis in the private sector, Tuberc. Respir. Dis. 66 (2009) 349e357. [21] J.S. Park, Increasing the treatment success rate of tuberculosis in a private hospital through public-private mix (PPM) project, Tuberc. Respir. Dis. 70 (2011) 143e149.
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Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
Treatment outcomes of rifampin-sparing treatment in patients with pulmonary tuberculosis with rifampin-mono-resistance or rifampin adverse events: A retrospective cohort analysis Shinhee Park, Kyung-Wook Jo, Sang Do Lee, Woo Sung Kim, Tae Sun Shim* Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history: Received 9 November 2016 Received in revised form 2 August 2017 Accepted 2 August 2017 Available online 4 August 2017
Background: Rifampin (RIF) mono-resistant tuberculosis (RMR-TB) is a rare disease. Current guidelines recommend that RMR-TB be treated as multidrug-resistant TB (MDR-TB) but the evidence is scarce. Methods: We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and outcomes of RMR-TB. The characteristics of RMR-TB were compared with those with adverse events to rifampin (RAE-TB). Results: Forty-four RMR-TB and 29 RAE-TB patients were enrolled. RMR-TB patients showed more alcohol use, prior history of TB, and radiologically severe disease, while RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB. A fluoroquinolone (FQ) was the drug most commonly added (70.5%, RMR-TB; 82.8%, RAE-TB). Median treatment duration was 453 days in RMR-TB and 371 days in RAE-TB (p ¼ 0.001) and treatment success rates were 87.2% (34/39) and 80.0% (20/25), respectively (p ¼ 0.586). Subanalysis of the RMR-TB group by treatment regimen (standard regimen [n ¼ 11], standard regimen þ FQ [n ¼ 12], MDR-TB regimen [n ¼ 21]) revealed a higher rate of radiologically severe disease in the MDR-TB subgroup, with similar treatment success rates for the subgroups (85.7% [6/7]), 91.7% [11/12], and 85.0% [17/20], respectively) despite different durations of treatment (345, 405, and 528 days, respectively). Two recurrences (33.3% [2/6]) developed only in standard regimen subgroup, suggesting that standard regimen is not enough to treat RMR-TB patients. Conclusions: The treatment outcome of RMR-TB with 1st-line drugs þ FQ was comparable to that of MDRTB regimen. Shorter treatment duration may be considered for RMR-TB patients compared with MDR-TB patients. © 2017 Published by Elsevier Ltd.
Keywords: Rifampin-mono-resistance Treatment outcomes Tuberculosis
1. Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis, is still a leading cause of death worldwide resulting in 1.5 million TB deaths in 2014 [1]. Rifampin (RIF or R) is a bactericidal agent that constitutes the backbone of short course anti-TB chemotherapy regimen, but concern about the emergence of drug-resistant strains is
Abbreviations: AFB, acid-fast bacilli; DST, drug susceptibility test; DOT, directly observed treatment; FQ, fluoroquinolone; HIV, human immunodeficiency virus; IQR, interquartile range; MDR, multidrug-resistant; RAE, rifampin adverse events; RIF, rifampin; RMR, rifampin mono-resistant; TB, tuberculosis. * Corresponding author. Department of Pulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, South Korea. E-mail address: [email protected] (T.S. Shim). http://dx.doi.org/10.1016/j.rmed.2017.08.002 0954-6111/© 2017 Published by Elsevier Ltd.
growing [2]. RIF-mono-resistant TB (RMR-TB) is a rare disease that represents 0.8% of new TB cases and 2.1% of relapsed cases in Korea. Among 8840 new TB cases diagnosed between 1994 and 2004, 266 cases (3.0%) were resistant to RIF and only one-fifth of them were RMR-TB [3]. Most (approximately 74e83%) [4,5] of M. tuberculosis strains that are resistant to RIF are also resistant to isoniazid (INH or H); infection by such strains defines multidrug-resistant TB (MDRTB). RIF resistance is often regarded as a proxy for MDR-TB due to its rarity, but the impact and the management of RMR-TB have not been as widely studied as they have for MDR-TB. The World Health Organization (WHO) [6] and the International Union Against Tuberculosis and Lung Disease (IUATLD) [7] recommend that RMR-TB should be treated as MDR-TB for at least 20 months, with INH being added to the regimen until drug susceptibility test (DST) results to INH are available. However, the
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evidence supporting such a recommendation is weak. Some experts recommend 18-month regimens comprising INH, pyrazinamide (PZA or Z), and ethambutol (EMB or E), with or without a fluoroquinolone, on the basis of clinical experience [8]. Previous studies on RMR-TB mainly focused on the epidemiology and risk factors, while few investigated treatment regimens or treatment outcomes of RMR-TB [9e12]. Stagg et al. pointed out that there has been no randomized controlled study that focused solely on the treatment of RIF-resistant TB [13]. We conducted a retrospective cohort study on pulmonary TB patients to investigate the characteristics and treatment outcomes of RMR-TB. In addition, in order to evaluate the appropriate treatment regimen and treatment duration using RIF-sparing regimens, patients who had discontinued RIF due to adverse events were also included in this study.
including human immunodeficiency virus (HIV) infection, prior treatment history of TB, sputum smear results, radiologic severity, presence of cavities on chest radiograph, and combined extrapulmonary TB infections. Radiographic severity was categorized into minimal, moderately advanced, or far advanced according to the criteria proposed by the U.S. National Tuberculosis and Respiratory Disease Association [15]. Treatment outcomes were reassessed in each of the patients according to the WHO definitions, and total treatment duration, treatment duration of each anti-TB drug, acquisition of drug resistance, and recurrence were examined. The RMR-TB patients were divided into three subgroups according to the treatment regimen; standard regimen (HRE or HREZ), standard regimen plus fluoroquinolone (FQ), and INH plus MDR-TB regimen. We compared the treatment outcome and treatment duration of each subgroup.
2. Materials and methods 2.4. Statistical analyses We conducted a retrospective cohort study of pulmonary RMRTB patients treated in a tertiary referral center, Asan Medical Center, Seoul, Korea, from January 1999 to December 2013. Patients with pan-susceptible TB who had discontinued RIF due to adverse events (RAE-TB) were also selected and the clinical characteristics and treatment outcomes were compared between two groups. 2.1. Definitions and inclusion criteria Patients who had pulmonary TB with available DST results were included in the study. Patients were at least 15 years of age and had treatment started with a standard regimen comprised of HREZ or HRE. A patient with both pulmonary and extrapulmonary TB was classified as a case of pulmonary TB [14]. Generally, RMR is defined as a resistance to RIF without resistance to any other first-line anti-TB drugs. However, in this study, RMR-TB was defined as TB caused by a M. tuberculosis strain with RIF resistance and INH susceptibility on DST, regardless of other drug resistance pattern. Patients with pan-susceptible TB on DST who had experienced RIF-related adverse events and discontinued RIF within 2 months were assigned to the RAE-TB group. Treatment outcomes were defined following the WHO definitions on RIF-resistant or MDR-TB. Patients who were not started on a MDR-TB regimen were assigned an outcome from those for RIFsusceptible TB [6]. Unfavorable outcomes include treatment failure, died, lost to follow-up, recurrence and acquisition of drug resistance other than to RIF. 2.2. Bacteriological study Acid-fast bacilli (AFB) smears were examined by Ziehl-Neelsen staining. AFB culture was carried out using solid Ogawa media alone until July 2007 and then using both solid and liquid media (BACTEC 960 Mycobacterial Growth Indicator Tube; Becton Dickinson, Sparks, MD, USA) thereafter. Conventional DST was per€nsteinformed using the absolute concentration method with Lowe Jensen media at the Korean Institute of Tuberculosis. The drug concentrations for susceptibility testing were 0.2 mg per milliliters (mg/mL) for INH, 40 mg/mL for RIF, and 2 mg/mL for EMB. Pyrazinamide susceptibility was determined using the pyrazinamidase test. 2.3. Patient characteristics We reviewed the patients' electronic medical records and collected baseline characteristics including age, sex, body-mass index (BMI), alcohol use, smoking history, comorbidities
Statistical analyses were performed by SPSS statistics version 21. Analysis of categorical variables was done using the chi square test and Fisher's exact test and continuous variables were analyzed by independent t-test and Mann-Whitney test. Treatment outcomes of the three RMR-TB subgroup according to the treatment regimen were compared using Kruskal-Wallis H-test and linear-by-linear association, and the treatment duration was compared using analysis of variance (ANOVA) models. For the ANOVA models, post hoc analysis was done using the Bonferroni correction method. A pvalue of <0.05 was considered statistically significant. 3. Results 3.1. Baseline characteristics Fifty-six patients with RMR-TB and 259 patients with RAE-TB who were treated at our hospital from January 1999 to December 2013 were identified. Of the 56 patients with RMR-TB, 12 patients not treated initially with the standard regimen were excluded, for a total enrollment of 44 RMR-TB patients. Of 259 patients with RAETB, 52 who were not treated initially with the standard regimen, 59 without available DST, and 119 patients treated with RIF for more than 2 months were excluded, for a total enrollment of 29 RAE-TB patients. The baseline characteristics of the two groups were compared (Table 1). The RMR-TB patients were younger and had more alcohol use, prior history of TB and radiologically more severe disease compared with the RAE-TB patients. The RAE-TB patients were older and had more comorbidities and combined extrapulmonary TB than the RMR-TB patients. The remaining patient characteristics, including sex, BMI, proportion of ever-smoker and HIV infection status, and sputum positivity were not different between the RMRTB and RAE-TB groups. Three RMR-TB patients were resistant to EMB and six were resistant to PZA: one of them had both EMB and PZA resistance. No patients enrolled in this study had resistance to fluoroquinolones. 3.2. Treatment regimens and durations Daily treatment was prescribed during the whole treatment duration. Treatment was not directly observed but instead specialized private-public-mix (PPM) cooperation nurses monitored the treatment courses. Comparison of treatment duration of each anti-TB medication in the RMR-TB and RAE-TB groups is shown in Table 2. INH, PZA, injectable drugs, and some of the second-line oral drugs were prescribed longer in the RMR-TB
S. Park et al. / Respiratory Medicine 131 (2017) 43e48 Table 1 Baseline characteristics of the patients. Characteristics
RMR-TB (n ¼ 44)
RAE-TB (n ¼ 29)
p-valuea
Age, years Male sex, no. (%) Body mass index, kg/m2 Ever-smoker, no. (%) Alcohol use, no. (%) Co-morbidity Diabetes mellitus, no. (%) Liver disease, no. (%) Chronic kidney disease, no. (%) Malignancy, no. (%) Organ transplantation, no. (%) Others, no. (%) HIV infection, no. (%) Prior treatment for TB, no. (%) Combined extrapulmonary TB (%) Sputum smear-positive, no. (%) Radiologic Severity Minimal, no. (%) Moderately or far advanced, no. (%) Cavity on chest radiograph Additional drug resistance Resistance to pyrazinamide Resistance to ethambutol Extrapulmonary TB, no. (%)
43.0 ± 14.5 28 (63.6) 21.6 ± 3.3 21/38 (55.3) 11/32 (34.4) 13 (29.5) 6 (13.6) 2 (4.5) 0 (0) 4 (9.1) 0 (0) 6 (13.6) 1/25 (4.0) 24/43 (55.8) 5 (11.4) 29 (65.9)
58.2 ± 16.8 19 (65.5) 21.7 ± 2.6 15 (51.7) 1/28 (3.6) 22 (75.9) 6 (20.7) 4 (13.8) 3 (10.3) 8 (27.6) 2 (6.9) 15 (51.7) 0/24 (0) 5 (17.2) 11 (37.9) 12 (41.4)
<0.001 1.000 0.385 0.809 0.003 <0.001 0.524 0.207 0.059 0.053 0.154 0.001 1.000 0.001 0.002 0.054 0.007
20 (45.5) 24 (54.5) 21 (47.7)
23 (79.3) 6 (20.7) 5 (17.2)
0.012
3 (6.8) 6 (13.6) 5b (11.4)
0 (0) 0 (0) 11c (37.9)
0.272 0.075 0.008
Abbreviations: HIV ¼ human immunodeficiency virus, RAE ¼ rifampin adverse events, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Statistical analysis was carried out using independent t-test for age and BMI, and the chi square test and Fisher's exact test for other variables. b Pleurisy (n ¼ 2), lymphadenitis (n ¼ 2), and disseminated disease with CNS involvement (n ¼ 1). c Lymphadenitis (n ¼ 3), endobronchial TB (n ¼ 2), TB pleurisy (n ¼ 2), bone (n ¼ 2), pericarditis (n ¼ 1), and colitis (n ¼ 1).
patients than the RAE-TB patients. The treatment durations of EMB and FQs, however, were not different between the RMR-TB and the RAE-TB groups. The FQs were the most frequently added drug in both RMR-TB (70.5%) and RAE-TB (82.8%) patients. In standard þ FQ subgroup, FQ was added at a median of 112 (interquartile range, IQR 69e117) days after initiation of standard regimen; in MDR-TB subgroup, standard regimen was switched to MDR-TB regimen at a median of 90 (IQR 30e120) days after initiation of standard regimen. We analyzed treatment duration in patients who completed their treatment (Table 3). The median treatment duration in patients who completed their treatment was significantly longer in the RMR-TB group (453 days) compared with the RAE-TB group (371 days) (p ¼ 0.003). The median treatment duration after sputum conversion was also longer in RMR- TB (352 days) when compared to RAE-TB (296 days) (p ¼ 0.020).
45
Generally, patients were followed-up on a monthly basis with sputum culture during treatment. However, some patients were not able to expectorate their sputum, in which case the sputum culture was not obtained. The mean interval of sputum culture was 1.47 and 1.75 months during treatment in RMR-TB and RAE-TB patients, respectively. In RMR-TB patients, the mean interval of sputum culture was 1.42, 1.61, and 1.43 months in standard regimen, FQ-added regimen, and MDR-TB regimen groups, respectively. 3.3. Treatment outcomes We also analyzed time to sputum conversion in patients who completed their treatment (Table 3). The median time to sputum culture conversion was 93 days and 60 days, respectively. The time to sputum conversion was longer in RMR-TB patients than in RAETB patients (p ¼ 0.033). Comparison of treatment outcomes including recurrence and acquisition of drug resistance for each group are shown in Table 4. The treatment success rates were 87.2% (34/39) in RMR-TB and 80.0% (20/25) in RAE-TB. The frequency of unfavorable outcomes was not different between two groups. The median follow-up duration after treatment completion was 532 days (IQR 126e1160) in RMR-TB and 448 days (IQR 338e1017) in RAE-TB. The follow-up duration was not significantly different between two groups. The numbers of patients who were followed up for more than 1-year and 2-year were 43 (67.2%) and 29 (45.3%), respectively. Recurrence occurred in two of 34 (5.9%) RMR-TB patients and one of 20 (5.0%) RAE-TB patients. One of 35 (2.9%) RMRTB patients acquired drug resistance to INH while none of the 18 (0%) RAE-TB patients did, but the difference between the groups was not significant. 3.4. Treatment outcomes according to treatment regimens in RMRTB patients We divided the RMR-TB patients into three subgroups according to treatment regimens and compared baseline characteristics, treatment outcome and treatment duration (Tables 5 and 6). Eleven patients were continuously treated with the standard regimen (HRE or HREZ), 12 patients with standard regimen plus FQ, and 21 patients with MDR-TB regimen (plus INH). The MDR-TB regimen subgroup had a higher percentage of smoking (27.3% vs. 63.6% vs. 68.8%, respectively, p ¼ 0.043) and radiologically moderately or faradvanced disease (36.4% vs. 41.7% vs. 71.4%, respectively, p ¼ 0.043), but other baseline characteristics were similar between the subgroups. All patients with PZA or EMB resistance except one EMB resistance in standard regimen subgroup were included in MDR-TB regimen subgroup. While the treatment duration between the
Table 2 Treatment duration of each anti-TB medications. p-valuea
Treatment drugs
RMR-TB (n ¼ 44)
RAE-TB (n ¼ 29)
Median (IQR)
No. (%)
Median (IQR)
No. (%)
Isoniazid Rifampin Ethambutol Pyrazinamide Injectable drugs Fluoroquinolones Prothionamide Cycloserine Para-aminosalicylic acid
372 (185e461) 93 (43e118) 203 (114e434) 141 (68e397) 88 (49e127) 296 (131e412) 254 (82e354) 276 (82e423) 154 (62e321)
44 44 44 44 20 31 22 24 14
194 (52e325) 27 (11e41) 194 (74e321) 52 (25e186) 29 (10e48) 225 (133e336) 83 (26e85) 138 (41e280) 35 (15e83)
29 (100) 29 (100) 29 (100) 29 (100) 6 (20.7) 24 (82.8) 5 (17.2) 16 (55.2) 6 (20.7)
(100) (100) (100) (100) (45.5) (70.5) (50.0) (54.5) (31.8)
Abbreviations: IQR ¼ interquartile range, RAE ¼ rifampin adverse events, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Statistical analysis was carried out using Mann-Whitney test.
0.002 <0.001 0.347 0.001 0.004 0.250 0.024 0.071 0.052
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Table 3 Treatment duration and time to sputum culture conversion in patients who completed treatment. RMR-TB (n ¼ 34)
Total treatment duration, days Time to culture conversion, days Treatment duration after culture conversion, days
p-valuea
RAE-TB (n ¼ 20)
Median (IQR)
No. (%)
Median (IQR)
No. (%)
453 (368e549) 93 (57e143) 352 (279e442)
34 (100) 31 (91.2) 31 (91.2)
371 (246e407) 60 (35e81) 296 (181e338)
20 (100) 18 (90.0) 18 (90.0)
0.003 0.033 0.020
Abbreviations: IQR ¼ interquartile range, RAE ¼ rifampin adverse events, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Statistical analysis was carried out using Mann-Whitney test.
Table 4 Treatment outcomes of 73 pulmonary TB patients with rifampin-sparing regimens. Treatment outcomesa
RMR-TB n ¼ 44, no. (%)
RAE-TB n ¼ 29, no. (%)
p-valueb
Treatment success Cured Treatment completed Treatment failed Died Lost to follow-up Not evaluated Recurrence Acquisition of drug resistance Unfavorable outcomesc
34 (77.3) 30 (68.2) 4 (9.1) 0 (0) 1 (2.3) 4 (9.1) 5 (11.4) 2/34 (5.9) 1/35 (2.9) 7/39 (17.9)
20 (69.0) 11 (37.9) 9 (31.0) 0 (0) 2 (6.9) 3 (10.3) 4 (13.8) 1/20 (5.0) 0/18 (0) 6/25 (24.0)
0.586
1.000 1.000 0.751
Abbreviations: RAE ¼ rifampin adverse events, RIF ¼ rifampin, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Treatment outcomes were defined following the World Health Organization definitions on RIF-resistant/MDR-TB, or RIF-susceptible TB for the patients who were not started on a MDR-TB regimen. b Statistical analysis was carried out using Fisher's exact test. c Unfavorable outcomes include treatment failure, death, lost to follow-up, recurrence, and acquisition of resistance to drugs other than RIF.
regimens varied (Standard regimen, 345 days; Standard regimen þ FQ, 405 days; INH þ MDR-TB regimen, 528 days), the treatment success rates were not significantly different between the subgroups: 85.7% (6/7), 91.7% (11/12) and 85.0% (17/20), respectively.
All two recurrences in RMR-TB patients developed in the standard regimen group. First patient was 36-year old male who had positive AFB smear and moderately advanced radiologic severity with a cavity and a history of receiving HREZ treatment for a year. His treatment compliance was not optimal even though a PPM nurse monitored the treatment course. Immediately after treatment completion, the patient relapsed with a strain resistant to both rifampin and isoniazid. The second patient was 44-year old male who had positive AFB smear and far-advanced radiologic severity with several cavities. Treatment was initiated with 2 months of HREZ followed by 4 months of HRE. The patient relapsed about 6 years after treatment completion. DST result was not available at the time of relapse. Even though the recurrence rate was not significantly different among the three groups, probably due to the small number of subjects, it was higher in the standard regimen subgroup than in both standard þ FQ and MDR-TB regimen subgroups (33.3% vs. 0% vs. 0%, respectively, p ¼ 0.063). 4. Discussion We evaluated the characteristics and treatment outcomes of RMR-TB patients in a Korean hospital over a 14-year study period. We found that the treatment outcomes for RMR-TB were comparable to those for RAE-TB, and that the treatment duration in both groups was shorter than the current guidelines recommended for MDR-TB. When we further analyzed the management of RMR-TB by
Table 5 Clinical characteristics of 44 RMR-TB patients, according to treatment regimens. Characteristics
Age, years Male sex, no. (%) Body-mass index, kg/m2 Ever-smoker, no. (%) Alcohol use, no. (%) Co-morbidity Diabetes mellitus, no. (%) Liver disease, no. (%) Chronic kidney disease, no. (%) Malignancy, no. (%) Organ transplantation, no. (%) Immunosuppression, no. (%) HIV infection, no. (%) Prior treatment for TB, no. (%) Combined extra-pulmonary TB (%) Sputum smear-positive, no. (%) Radiologic Severity Minimal, no. (%) Moderately or far advanced, no. (%) Cavity on chest radiograph Additional drug resistance Resistance to pyrazinamide Resistance to ethambutol a
Treatment regimens Standard (n ¼ 11)
Standard þ FQ (n ¼ 12)
MDR-TB (n ¼ 21)
p-valuea
43.8 ± 15.8 5 (45.5) 22.0 ± 3.4 3 (27.3) 1/10 (10.0) 3 (27.3) 1 (9.1) 0 (0) 0 (0) 1 (9.1) 0 (0) 0 (0) 0 (0) 5/10 (50.0) 0 (0) 7 (63.6)
44.6 ± 15.9 9 (75.0) 22.9 ± 2.0 7 (63.6) 5/10 (50.0) 5 (41.7) 3 (25.0) 1 (8.3) 0 (0) 1 (8.3) 0 (0) 0 (0) 0 (0) 8 (66.7) 2 (16.7) 4 (33.3)
41.7 ± 13.6 14 (66.7) 20.6 ± 3.7 11 (68.8) 5/12 (41.7) 5 (23.8) 2 (9.5) 1 (4.8) 0 (0) 2 (9.5) 0 (0) 0 (0) 1/11 (9.1) 11 (52.4) 3 (14.3) 18 (85.7)
0.849 0.320 0.183 0.043 0.142 0.704
7 (63.6) 4 (36.4) 4 (36.4)
7 (58.3) 5 (41.7) 4 (33.3)
6 (28.6) 15 (71.4) 13 (61.9)
0.125
1 (9.1) 0 (0)
0 (0) 0 (0)
5 (23.8) 3 (14.3)
0.179 0.146
Statistical analysis by ANOVA, Kruskal-Wallis H test and linear by linear association.
0.317 0.958 0.287 0.092 0.043
S. Park et al. / Respiratory Medicine 131 (2017) 43e48
47
Table 6 Treatment outcomes of 44 RMR-TB patients according to treatment regimens. Treatment outcomesa
Treatment regimens Standard (n ¼ 11), no (%)
Standard þ FQ (n ¼ 12), no (%)
MDR-TB (n ¼ 21), no (%)
P-value
Treatment success Cured Treatment completed Treatment failed Died Lost to follow-up Not evaluated Recurrence Acquisition of drug resistance Unfavorable outcomese
6 (85.7) 5 (71.4) 1 (14.3) 0 (0) 0 (0) 1 (9.1) 4 (36.4) 2/6 (33.3) 1/6 (16.7) 1/7 (14.3)
11 (91.6) 10 (83.3) 1 (8.3) 0 (0) 0 (0) 1 (8.3) 0 (0) 0/11 (0) 0/11 (0) 2/12 (16.7)
17 (80.9) 15 (71.4) 2 (9.5) 0 (0) 1 (4.8) 2 (9.5) 1 (4.8) 0/17 (0) 0/17 (0) 4/20 (20.0)
0.157
Durations Total treatment duration Time to culture conversion
(n ¼ 10) 345 (273e459) 61 (57e111)
(n ¼ 10) 405 (367e459) 79 (33e93)
(n ¼ 16) 528 (443e617) 140 (81e192)
Treatment duration after culture conversion
327 (240e490)
333 (374e371)
370 (327e442)
0.063 0.223 0.719 P-valueb 0.020c 0.020c 0.020d 0.493
Abbreviations: FQ ¼ fluoroquinolones, MDR ¼ multidrug-resistant, RMR ¼ rifampin mono-resistant, TB ¼ tuberculosis. a Treatment outcomes were defined following the World Health Organization definitions on RIF-resistant/MDR-TB, or RIF-susceptible TB for the patients who were not started on a MDR-TB regimen. b Statistical analysis by ANOVA, post-hoc analysis was carried out using the Bonferroni correction method. c P-values of comparisons between standard and MDR-TB regimen subgroups. d P-values of comparisons between standard þ FQ and MDR-TB regimen subgroups. e Unfavorable outcomes include treatment failure, death, lost to follow-up, recurrence, and acquisition of resistance to drugs other than RIF.
subgroups categorized by treatment regimen, we observed that the standard regimen þ FQ, instead of MDR-TB regimen, may be enough to successfully complete treatment without recurrence in some RMR-TB patients. The RMR-TB patients had more alcohol use, which is consistent with previous studies [2,12] and may lead to poor treatment compliance and emergence of resistant strains. RMR-TB patients were more often treated for TB prior to the diagnosis of RMR-TB, which is a known risk factor for RMR-TB [9]. We observed extrapulmonary TB more frequently in patients with RAE-TB than those with RMR-TB. However, among 44 RMR-TB and 29 RAE-TB patients, one patient (TB meningitis) and two patients (bone TB), respectively, had concomitant extrapulmonary TB that might have prolonged treatment duration. The numbers of those patients were not significantly different between RMR-TB and RAE-TB (p ¼ 0.333) and too small in both groups to have significantly altered the results. We observed severe disease more frequently in terms of radiologic assessment in RMR-TB than in RAE-TB, which may have influenced the longer treatment duration in the RMR-TB. The RAE-TB patients were older than the RMR-TB patients and had more comorbidities, which may have initially predisposed them to the adverse events of RIF [16]. MDR-TB regimen subgroup had more patients with additional drug resistance to PZA or EMB than the other two subgroups but the difference was not statistically significant, probably owing to the small sample size. The decision to implement MDR-TB regimen on these patients may have been affected by the drug resistance pattern. The treatment durations of first-line anti-TB drugs, i.e. INH and PZA, as well as injectable drugs, were significantly longer in the RMR-TB group. This is likely due in part to the adverse reaction to other anti-TB agents in the RAE-TB group, and in part to the MDR regimen implemented in the RMR-TB group. FQs were the drugs most frequently added in both groups: 70.5% (31/44) in RMR-TB and 82.8% (24/29) in RAE-TB. Patients in RMR-TB and RAE-TB groups both received shorter durations of treatment (453 days and 371 days, respectively) than 20 months, which is currently recommended for MDR-TB treatment. As previously mentioned, the WHO and the IUATLD
recommend RMR-TB to be treated as MDR-TB. The treatment of MDR-TB usually includes an injectable drug and this could be difficult for the patients due to its toxicity and manner of administration. The recommended treatment duration for MDR-TB is a minimum of 20 months, but recent trials have supported the possibility of shorter treatment duration in MDR-TB [17,18]. The optimal treatment duration for RMR-TB has not been studied, but our data suggest that the shorter treatment duration may be sufficient in RMR-TB patients. Meyssonnier et al. evaluated 39 RMR-TB patients in France [12]. The treatment success rate was 66.7% (20 out of 30 cases). Among the 20 patients who were cured or completed treatment, 19 patients had received treatment for at least 9 months. The authors reported heterogeneous patterns of management and a worse outcome of RMR-TB, attributed to the lack of thorough understanding for the disease and the paucity of treatment consensus during the study period. It has only been a few years since the IUATLD published guidelines on RMR-TB to be treated as MDR-TB. However, Dramowski et al. have shown that the regimen comprising INH, ethambutol, PZA, an injectable drug and a secondline oral drug such as ethionamide can successfully treat RMR-TB with a shorter treatment duration [19]. Differences in the proportion of successful treatment outcome among the three regimen subgroups were not statistically significant (85.7% vs. 91.6% vs. 80.9%, respectively, p ¼ 0.157). A possible reason for continuation of standard regimen irrespective of RIF resistance may be that initial treatment response was favorable before we received DST results or negative conversion of sputum culture was already achieved with standard regimen at the time of DST report. However, in this study, the denominator was only 7 for analyzing treatment outcomes in the standard regimen subgroup. The patients in the standard regimen subgroup had milder disease in terms of radiological assessment compared with MDR-TB regimen subgroup. In addition, albeit short of statistical significance, recurrence rate was higher in the standard regimen subgroup than in standard þ FQ subgroup and MDR-TB regimen subgroup (33.3% vs. 0% vs. 0%, respectively, p ¼ 0.063). Therefore, these findings suggest that 1st-line standard regimen is not
48
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recommended for the treatment of RMR-TB as did by the WHO. The appropriate treatment duration was not studied yet when FQ was added in the anti-TB regimens. In our study, FQ was the most frequently added drug in RIF-sparing regimens, and standard regimen þ FQ alone, without MDR-TB regimen and without injectable drugs, achieved favorable treatment outcomes as we evidenced 91.6% of treatment success and 0% of recurrence rate. In addition, total treatment duration was shorter than in MDR-TB regimen subgroup (405 days vs. 528 days, respectively) even though post hoc analysis did not reveal statistical significance. These findings suggest that standard regimen þ FQ, without injectable drugs, may be enough in the treatment of RMR-TB patients, especially in patients with mild and/or low bacillary-burden TB. Our study has several limitations. Because RMR-TB is a rare disease in areas with low prevalence of HIV, our study was limited by a small sample size. Study population was restricted to pulmonary TB patients and adjustments for potential confounding factors nor effect modification were not made. We included patients whose treatment was initiated with standard regimen, but this population may not represent all RMR-TB patients. A multivariate analysis of treatment outcome in RMR-TB subgroup according to the treatment regimen was not available because of the small sample size. Thus, this study lacks the power to draw any firm conclusion due to these limitations. Another shortcoming in our study is that the directly observed treatment (DOT), an international standard TB care method, was not adopted; instead, PPM nurses monitored the treatment courses. However, previous studies conducted in Korea showed that PPM-based monitoring resulted in favorable outcomes for TB patients even though the treatment outcome was not compared between DOT and PPM groups [20,21]. RIF resistance includes any resistance to RIF, in the form of mono-resistance, poly-resistance, MDR or XDR. However, in this study, the definition of RMR-TB included both mono-resistance and poly-resistance to RIF. Genotyping data were not available in the 3 recurrent cases so that we cannot differentiate between relapse and reinfection. 5. Conclusions The treatment regimens were heterogeneous for RMR-TB patients, but favorable clinical outcomes were achieved with regimens with treatment durations shorter than 20 months, which is currently recommended for MDR-TB treatment. We further analyzed the management of RMR-TB by subgroups categorized according to treatment regimen; the results showed that at least in some RMR-TB patients, the standard regimen þ FQ, instead of MDRTB regimen, may be considered for completing the treatment without recurrence. Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We thank Dr. Joon Seo Lim from the Scientific Publications Team at Asan Medical Center for his editorial assistance in preparing this manuscript and Dr. Jung Bok Lee from the Department of Clinical Epidemiology and Biostatistics for statistical counseling.
Conflict of interest The authors declare no conflicts of interest.
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