Research Article: First-line tuberculosis drug resistance patterns and associated risk factors in Germany, 2008-2017

Date Published: June 12, 2019

Publisher: Public Library of Science

Author(s): Saskia Glasauer, Doris Altmann, Barbara Hauer, Bonita Brodhun, Walter Haas, Nita Perumal, Alejandro Escobar-Gutiérrez.

http://doi.org/10.1371/journal.pone.0217597

Abstract

Drug-resistant tuberculosis (TB), especially multidrug-resistant TB (MDR-TB), poses a threat to public health. While standard surveillance focuses on Rifampicin and/or Isoniazid resistance, little is known about other resistance patterns. This study aims to identify predominant drug resistance (DR) patterns in Germany and risk factors associated with them in order to inform diagnostic and treatment strategies.

Case-based TB surveillance data notified in Germany from 2008–2017 were utilized to investigate DR and MDR-TB patterns for Isoniazid (H), Rifampicin (R), Pyrazinamide (Z), Ethambutol (E), and Streptomycin (S). Predominant patterns were further analyzed stratified by sex, age, country of birth, prior TB, and disease site. Multivariable logistic regression was conducted to determine risk factors associated with any resistance, MDR-TB, and complete HRZES resistance.

26,228 cases with complete DST results were included in the study, among which 3,324 cases had any DR (12.7%). Four patterns were predominant, representing about ¾ of all cases with any resistance (S: 814 [3.1%]; H: 768 [2.9%]; HS: 552 [2.1%]; Z: 412 [1.6%]). High proportions of S and H resistances were found among both German and foreign-born populations, especially those born in Eastern Europe, and were unexpectedly high among children (H: 4.3%; S: 4.6%). Foreign-born cases had significantly higher proportion of any resistance (16.0%) and MDR-TB (3.3%) compared to German-born cases (8.3% and 0.6%). Of 556 MDR-TB cases, 39.2% showed complete HRZES resistance. Logistic regression revealed having prior TB and being foreign-born as consistently strong risk factors for any DR, MDR-TB, and complete HRZES resistance.

DR patterns observed in Germany, particularly for MDR-TB were more complex than expected, highlighting the fact that detailed drug-testing results are crucial before incorporating HRZES drugs in MDR-TB treatment. Furthermore, the relatively high rate of H-resistance in Germany provides strong rationale against the use of only H-based preventive therapy for LTBI.

Partial Text

Tuberculosis (TB) is the ninth leading cause of death worldwide and the leading cause of death from a single infectious agent, exceeding even HIV/AIDS [1]. The World Health Organization (WHO) estimates that in 2017, approximately 10 million people were diagnosed with TB and 1.6 million people died due to the disease [1]. About one quarter of the world’s population is further estimated to be latently infected [1]. As a result, TB control is a top priority on the global health agenda. One of the WHO´s End TB strategy targets aims to reduce the global incidence to <100 TB cases per million by 2035 [2]. The WHO has also developed a Framework for low-incidence countries [3], asking them to reach pre-elimination phase (<10 cases per million) by 2035 and elimination (<1 case per million) by 2050 or earlier [3]. One of the biggest obstacles in achieving TB elimination is the emergence of drug resistance [1]. In 2017, 558,000 cases were estimated to be resistant to Rifampicin (R), the most effective first-line anti-tuberculosis drug [1], with 82% suffering from multidrug-resistant TB (MDR-TB) [1], which is defined as the resistance to at least Rifampicin and Isoniazid, another potent anti-TB drug [1]. Tackling MDR-TB is an especially important cornerstone of the increasingly urgent global fight against antimicrobial resistance (AMR) [4]. Between 2008 and 2017, 48,044 active TB cases that met the RKI reference definition were notified in Germany. 41,932 cases (87.3%) had a culture result available, of which 34,141 were culture positive (81.4%). Of these, DST results were available for all 5 drugs (HRZES) for 26,228 cases or 76.8% (Fig 1). These 26,228 cases were considered to be the final study population. Our study is one of the limited number of recent studies worldwide to analyze national surveillance data on drug resistance patterns over a long period of time. Our analysis revealed an overall any drug resistance proportion of 12.7% in Germany, among which four resistance patterns were clearly predominant and accounted for more than ¾ of all drug resistant cases in–monoresistance against S, monoresistance against H, combined resistance against HS and monoresistance against Z. Monoresistance against S was the most prevalent drug resistance pattern in cases born in Germany and outside Germany, as well as among all age groups, very likely due to the long historical usage. These findings confirm that the withdrawal of S as a first-line drug in 2012 in Germany [38] has minimal relevance for TB therapy due to high resistance levels against it in the population. As a result, it can be questioned whether systematic surveillance of S resistance is still essential. Drug resistance patterns observed in Germany, particularly for MDR-TB cases, are far more complex than expected. Although the overall proportions of drug-resistance and MDR-TB are low, most MDR-TB cases in Germany present with additional resistances against other standard anti-TB drugs and almost 40% of MDR cases showed complete resistance against all five standard TB drugs (HRZES). As drug resistance patterns vary significantly in different subgroups, our findings highlight the importance of considering demographic characteristics of cases and knowing the patients’ full drug resistance profile to tailor treatment for optimal outcome. This is especially significant as our study found higher than expected proportions of drug resistances and MDR-TB among children and German-born adults. Finally, our finding of considerably high H monoresistance rates is important towards informing LTBI treatment regimens in Germany.   Source: http://doi.org/10.1371/journal.pone.0217597

 

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