European Journal of Clinical Microbiology & Infectious Diseases

, Volume 29, Issue 11, pp 1413–1416

Declining drug resistance of Mycobacterium tuberculosis isolates from elderly patients in Taiwan, 2000–2008

Authors

  • W.-L. Liu
    • Department of Intensive Care MedicineChi-Mei Medical Center
  • C.-C. Lai
    • Department of Intensive Care MedicineChi-Mei Medical Center
  • C.-K. Tan
    • Department of Intensive Care MedicineChi-Mei Medical Center
  • S.-H. Lin
    • Department of Internal MedicineTaipei County Hospital
  • Y.-T. Huang
    • Departments of Internal Medicine and Laboratory Medicine, National Taiwan University HospitalNational Taiwan University College of Medicine
  • C.-H. Liao
    • Department of Internal MedicineFar Eastern Memorial Hospital
    • Departments of Internal Medicine and Laboratory Medicine, National Taiwan University HospitalNational Taiwan University College of Medicine
Article

DOI: 10.1007/s10096-010-1019-7

Cite this article as:
Liu, W., Lai, C., Tan, C. et al. Eur J Clin Microbiol Infect Dis (2010) 29: 1413. doi:10.1007/s10096-010-1019-7

Abstract

We retrospectively investigated the prevalence of drug resistance in Mycobacterium tuberculosis (MTB) isolates recovered from elderly patients and compared the drug resistance patterns between the elderly (≥65 years old) and adult (15–64 years old) patients. Data on the prevalence of drug resistance in clinical and non-duplicate isolates of MTB recovered from 2000 to 2008 were evaluated. Among the 3,186 non-duplicate MTB isolates found during the study period, 1,497 isolates were recovered from elderly patients. Thirty-eight (2.54%) isolates were multidrug-resistant tuberculosis (MDRTB). The rates of resistance to isoniazid (INH), rifampicin (RIF), ethambutol (EMB), streptomycin (SM), ofloxacin, rifabutin, any one drug-resistant (ADR), and multidrug-resistant (MDR) were significantly lower in isolates from the elderly than from adults (p < 0.05). Significant decreasing trends in resistance rates to EMB, SM, at least any one of the four first-line agents (ADR), and MDRTB were observed (p < 0.05) . In conclusion, elderly patients had a lower rate of anti-TB drug resistance than adults and a decreasing overall trend of anti-TB drug resistance was found in the elderly in recent years, but the higher rate of MDRTB in Taiwan continues to present a challenge for the control of TB in the elderly.

Introduction

Despite the recent progress of global control efforts of tuberculosis (TB), this disease remains a serious threat to the elderly [1]. Previous studies demonstrated that the proportion of TB is increasing among the elderly [2, 3]. Data from Taiwan also showed a rising trend in the age of TB patients from 1957 to 2001 [4]. TB mortality rates of the elderly with TB as high as 20 to 26% have been reported [5, 6], which is significantly higher than in younger patients [6]. Furthermore, a particularly dangerous form of drug-resistant Mycobacterium tuberculosis (MTB) has resulted from inappropriate treatment in Taiwan and represents a growing threat. Inappropriate treatment for drug-resistant TB not only results in treatment failure, but is also responsible for further dissemination of resistant strains, rendering the control of TB a more difficult public health issue. Therefore, routine surveys of drug resistance are necessary to guide the development of treatment recommendations which are both effective and decrease the rate of anti-TB drug resistance.

However, there has been limited documentation of TB drug resistance rates among the elderly [79]. The objective of this study was to investigate the prevalence of drug resistance in MTB isolates from elderly patients during the period from 2000 to 2008 at a university hospital in Taiwan.

Materials and methods

Setting and bacterial isolates

This study was conducted at the National Taiwan University Hospital (NTUH), a 2,500-bed tertiary care center in northern Taiwan. Isolates from elderly patients (age ≥65 years) who had a positive culture for MTB from January 2000 to December 2008 were included in this retrospective analysis. In patients with multiple isolates, only a single and initial isolate was included in this study. All specimens were processed and pretreated as previously described [10]. Some of the cases were included in a previous study [11]. The study protocol was approved by the Institutional Review Board of the National Taiwan University Hospital.

Drug susceptibility test

Drug susceptibility testing to first-line anti-TB drugs including isoniazid (INH, 0.2 μg/mL and 1.0 μg/mL), rifampicin (RIF, 1 μg/mL), and ethambutol (EMB, 5 μg/mL) was performed in the Mycobacteriology Laboratory of the NTUH using the modified proportional disk elution method as described previously [1215]. From 1st January 2005 onwards, susceptibility testing to second-line anti-TB drugs including streptomycin (SM, 2 μg/mL and 10 μg/mL), rifabutin (0.5 μg/mL), ofloxacin (1 μg/mL), ethionamide (5 μg/mL), and para-aminosalicyclic acid (2 μg/mL) was also performed using the same method. M. tuberculosis suspension was inoculated onto Middlebrook 7H10 agar (BBL Microbiology Systems, Cockeysville, MD) that contained anti-TB drugs at respective concentrations.

Isolates for which growth on the drug-containing media presented >1% of the number of colonies that developed on the drug-free media were considered to be resistant to that agent [11]. Any one drug-resistant (ADR) was defined as resistance to any of INH (0.2 μg/mL), RIF (1 μg/mL), EMB (5 μg/mL), or SM (2 μg/mL). A multidrug-resistant (MDR) isolate was defined as resistance to at least INH (0.2 μg/mL) and RIF (1 μg/mL).

Statistical analysis

Differences in the drug susceptibility patterns of MTB between adult (age from 15 to 64 years) and elderly patients were analyzed using the χ2 test. Drug resistance trends over time were evaluated by the Cochran–Armitage trend test. A p-value of less than 0.05 was considered to be statistically significant.

Results

A total of 3,186 non-duplicate isolates were recovered from various clinical specimens during the nine-year study period. Table 1 compares the drug resistance rates of 1,689 isolates from adults (15–64 years of age) and 1,497 isolates from the elderly. The rates of resistance to INH, RIF, EMB, SM, ADR, and MDR were significantly lower in the elderly than in adults (p < 0.005). The rates of resistance to EMB and SM and the rates of ADR and MDR among MTB isolates recovered from the elderly decreased significantly during the nine-year study period (Fig. 1a, b).
Table 1

First-line drug resistance rates for Mycobacterium tuberculosis isolates from adults (15–64 years old) and elderly patients (≥65 years old) using the modified agar proportion method

Agent (concentration [μg/mL] tested)

No. of isolates (%) from each indicated patient population

p-value

Adults (n = 1,689)

Elderly (n = 1,497)

Isoniazid (0.2)

266 (15.8)

172 (11.5)

<0.001

Rifampin (1)

120 (7.1)

47 (3.1)

<0.001

Ethambutol (5)

149 (8.8)

78 (5.2)

<0.001

Streptomycin (2)

191 (11.3)

120 (8.0)

<0.005

Resistant to any drug

413 (24.5)

254 (17.0)

<0.001

Multidrug-resistant

97 (5.7)

38 (2.54)

<0.001

https://static-content.springer.com/image/art%3A10.1007%2Fs10096-010-1019-7/MediaObjects/10096_2010_1019_Fig1_HTML.gif
Fig. 1

Trend of resistance rates to isoniazid, ethambutol, rifampin, and streptomycin (a). Any drug resistance (ADR, any one of these four drugs) and multidrug resistance (b) among Mycobacterium tuberculosis isolates recovered from elderly patients (≥65 years old) treated at the National Taiwan University Hospital (NTUH) in Taiwan from 2000 to 2008, determined using the modified agar proportion method. p-values <0.05 were considered to be statistically significant

Additional tests on the susceptibilities to four second-line anti-TB agents, including rifabutin, ofloxacin, ethionamide, and para-aminosalicyclic acid, were performed for 420 isolates recovered from the elderly and 394 isolates from the adults (Table 2). The rates of resistance to ofloxacin and rifabutin were significantly lower in the elderly than in adults (p < 0.05).
Table 2

Second-line drug resistance rates for M. tuberculosis isolates from adults (15–64 years old) and elderly patients (≥65 years old) using the modified agar proportion method

Agent (concentration [μg/mL] tested)

No. of isolates (%) from each indicated patient population

p-value

Adults (n = 394)

Elderly (n = 420)

Ofloxacin (1)

21 (5.3)

10 (2.4)

0.028

Para-aminosalicyclic acid (2)

9 (2.3)

3 (0.7)

0.063

Ethionamide (5)

6 (1.5)

2 (0.5)

0.130

Rifabutin (0.5)

12 (3.0)

0 (0.0)

0.0003

Discussion

With the decreasing birth rate and increasing life expectancy, populations are aging in many parts of the world, including Taiwan. While the incidence of TB has been falling in many developed countries, there is a trend of an increasing proportion of TB among the elderly [2, 3]. Early diagnosis and appropriate treatment of TB in elderly patients is important both to avoid unfavorable outcome and to control the emergence of strains that cannot be cured by standard anti-TB drug regimens, which represent a new and potentially devastating threat to TB control [16]. Gathering data on drug resistance rates is regarded as one of the most important aspects of surveillance in the global TB control program. Clinicians must have knowledge of local epidemiology and the mycobacteriology laboratory should maintain up-to-date information on drug susceptibility test profiles of local MTB isolates. Nevertheless, studies of the drug resistance patterns of MTB isolates in the elderly have been relatively scarce. In fact, the present work represents the largest related study for this increasing segment of the population to date.

In this study, we found that the elderly had a lower overall resistance rate (17.0%) to any one of INH, RIF, EMB, and SM compared to that in adults. These findings were in agreement with previous studies in Taiwan and the United Kingdom [79, 17]. In addition, the present work showed that the rate of multidrug-resistant tuberculosis (MDRTB) was significantly higher in isolates from the adults than those from the elderly. A study from the UK also demonstrated that the MDRTB rate was significantly higher in those aged 15–44 years than in those aged ≥65 years [9]. This phenomenon might be partly attributable to the reactivation of the previous dormant infection. Because INH and RIF were introduced for the treatment of TB in 1952 and 1978, respectively, the elderly in Taiwan were not likely to have previous exposure to INH and RIF if they developed TB in their youth. Therefore, MTB isolates from the elderly in the present work might have been reactivated from the previous drug-susceptible dormant isolates and, thus, had a lower resistant rate than those found in the younger adult population. While these differences may be partly due to geographical distribution and different study timing, our results support that TB resistance profiles also differ between younger adults and the elderly. Further study is needed to clarify the extent of each of these contributions.

The present study revealed a decline in the drug resistance rates to EMB, streptomycin, ADR, and MDR during the 2000–2008 period. Similar decreasing resistance rates have been reported by other recent studies from Taiwan [18, 19], Hong Kong [20], and Saudi Arabia [21]. In Taiwan, stricter regulation mandated that each treated TB case be reported to the Center for Disease Control of Taiwan since 1997. Thereafter, the percentage of patients with TB who receive a complete course of treatment has increased, and the percentage of those lost to follow-up has decreased. Second, directly observed short-course therapy was also started in Taiwan during this period. Therefore, the implementation of two effective interventions in Taiwan might explain the decreasing rates of resistance to anti-TB drugs.

This retrospective and laboratory-based surveillance had two noteworthy limitations. First, we were unable to precisely distinguish between newly diagnosed and previously treated cases and were, thus, only able to report the combined resistance rate. Second, this study was conducted in a tertiary-care center and, as such, its findings might not reflect the overall situation in Taiwan.

In conclusion, although there has been a decreasing overall trend of anti-TB drug resistance among the elderly in recent years, the higher rate of MDRTB in Taiwan illustrate the continued challenge for TB control. Elderly patients were found to have a lower rate of drug resistance in this large study, but more studies are needed to delineate the relationship between age and resistance in TB.

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© Springer-Verlag 2010