|Year : 2013 | Volume
| Issue : 4 | Page : 191-193
The role of drug susceptibility testing in M/XDR-TB. Too little and too late – Are we doing the right things?
Sven Erik Hoffner
Swedish Institute for Communicable Disease Control, Dept. of Preparedness, Nobelsväg 18, Solna SE-171 82, Sweden
|Date of Web Publication||28-Feb-2017|
Sven Erik Hoffner
Swedish Institute for Communicable Disease Control, Dept. of Preparedness, Nobelsväg 18, Solna SE-171 82
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Hoffner SE. The role of drug susceptibility testing in M/XDR-TB. Too little and too late – Are we doing the right things?. Int J Mycobacteriol 2013;2:191-3
|How to cite this URL:|
Hoffner SE. The role of drug susceptibility testing in M/XDR-TB. Too little and too late – Are we doing the right things?. Int J Mycobacteriol [serial online] 2013 [cited 2022 Jan 25];2:191-3. Available from: https://www.ijmyco.org/text.asp?2013/2/4/191/201115
Severely drug resistant Mycobacterium tuberculosis (MTB) is increasingly recognized as an important public health concern and is causing significant problems and costs for many national TB control programs. In some settings of the former Soviet Union, the prevalence of multidrug resistant (MDR)-TB is close to 50% and around one third of all newly detected TB patients are infected with MDR-TB . Without any doubt, patients with such strains transmit drug resistant TB and the spread of certain MDR-TB clones constitutes an important part of the problem at least in high MDR-TB burden countries . Fortunately, we do know what kind of actions are needed to counteract this worrying situation; these are primarily the timely modification of TB treatment to effective combinations of drugs rendering the patient non-infectious, and increased infection control measures in settings where transmission is detected or suspected. So why is this not generally done?
In my opinion, one important reason is clear: we fail to detect the MDR-TB cases, at least to detect them early enough to be able to take the necessary actions in a timely way. According to an estimate from the World Health Organization (WHO) , in 2011 less than 4% of new laboratory-confirmed cases and 6% of previously treated cases globally were tested for the susceptibility to the two MDR-defining drugs–rifampicin and isoniazid. Particularly low figures were seen in Africa and South-East Asia. In the European Region of WHO where the highest incidence of MDR-TB is found, the situation is somewhat better, but still far from good; 56% of new and 27% of previously treated cases were tested. Among non-European high MDR-TB burden countries, the testing for MDR-TB in new cases was highest in China (2.6%). It is thus obvious that a strong majority of the global MDR-TB patients is not detected and will thus get inappropriate therapy and continue to transmit resistant TB. They are also at risk for developing even more resistant forms of TB, since exposure to suboptimal drug combinations will favor both additional development/selection of drug resistance and transmission of increasingly resistant MTB strains in the community.
Not even one out of four laboratory-confirmed MDR-TB cases in 2011 had DST results for the XDR-TB defining compounds: fluoroquinolones and second-line injectable drugs . Without any doubt, we have a major quantitative problem in the detection of M/XDR-cases. How about the quality of testing?
It will of course vary, and it is not possible to have the full picture. But I do believe things are moving in the right direction. The global network of WHO Supranational Reference Laboratories for TB now offers external quality assurance by panel testing not only for first-line drugs, but also for the XDR-defining second-line agents. It is important to strengthen this activity in a sustainable way and to find a long-term financial solution to maintain it. It is, however, not enough that the national reference laboratories are quality assured. Every national TB control program should, together with its NRL, develop and implement a national quality management system for all laboratories performing DST of MTB in their country.
With today's knowledge, available diagnostic tools and epidemiological situation regarding M/XDR-TB, it cannot be considered acceptable to have to wait for 8–10 weeks to know if a clinical isolate is susceptible or not. Thus, the generally used algorithm of isolation on solid media followed by subsequent DST on solid media must be seen as obsolete. Unfortunately, globally this is still likely the most commonly used way to detect drug resistance in MTB. Today, we have automated culturing systems  that significantly shorten the turnaround time, but I believe the future is molecular PCR-based assays. Besides a number of locally developed non-commercial such assays, there are mainly two commercial alternatives; the GeneXpert from Cepheid and a number of line probe assays (LPA) from Hain Life Science. The Xpert system  is the most rapid technique, and it is developed to be easy to use. It offers the simultaneous detection of MTB and resistance to rifampicin in, for example, a smear-positive sputum sample. Often, rifampicin resistance is seen as a proxy for MDR-TB, but this praxis is not undisputed, and it has been reported that rifampicin resistance is not a valid MDR marker everywhere ,. The LPA  is more informative since it investigates resistance to both rifampicin and isoniazid. It is, however, somewhat more time-consuming and more laborious to perform. Both these assays have demonstrated excellent specificity (for both drugs) and sensitivity (rifampicin). The sensitivity to detect resistance to isoniazid is somewhat lower, since the underlying molecular resistance mechanisms in this case are more complicated than for rifampicin.
However, all data on specificity and sensitivity must be taken with some caution, since the prevalence of drug resistance related mutations varies in different geographical settings , so will the characteristics of molecular tests. An exception to the high sensitivity to detect resistance is reported in patients with so-called hetero-resistant TB. This is the case when a patient harbors both susceptible and resistant bacteria, which can happen during the phase of developing resistance and when an individual is infected with one resistant and susceptible strain of MTB. In these cases, culture-based DST has been shown to be more sensitive to detect a minority of both rifampicin  and isoniazid  resistant bacterial cells. There is also an LPA for rapid detection of XDR-TB, but before this test could be generally recommended, it needs to be improved concerning the sensitivity to identify resistance to the second-line injectable drugs.
Molecular assays offer early warning systems to MTB resistance. This is crucially important both from a public health and clinical perspective since it makes early optimization of therapy possible to tender the individual patient non-infectious and subsequently cured.
In my opinion we should, whenever possible, aim at knowing more than the possible resistance to rifampicin; if the bacteria is resistant, we need to combine the remaining drugs in an effective way; if it susceptible, we risk fueling the development of MDR if isoniazid and the other components of the standard first-line therapy is jeopardized by (undetected) resistance to some or all of them. Further development and improvements of existing tests should be given priority, as well as implementation of QMS for their use. Each country should develop national diagnostic algorithms for how, if and when rapid molecular assays should be combined with phenotypic DST. This will aim at ensuring a correct and timely diagnostic service in the fight against M/XDR-TB, but will depend on the local epidemiological situation, as well as what is financially possible, and the availability of culture/DST laboratories. PZA has a special role. It is an important first-line drug, which has also been proven to be very useful in the therapy of M/XDR-TB if the strain is susceptible. Due to its importance for treatment and outcome, it was recently suggested that MDR strains be classified as MDR-Zs and MDR-Zr for PZA susceptible and resistant strains respectively . PZA has also been shown to have an important role in combination with the new drug bedaquiline . Considering this, two problems are of great concern: first, in contrast to other first- and second-line TB drugs, there is no generally accepted, affordable and applicable DST assay for PZA. In the coming WHO-recommendations, only the commercial liquid culturing system, MGIT (B&D) is recommended, and, secondly, no generally available system for EQA of PZA DST is established. This leads to the fact that data on PZA susceptibility, at least quality assured data, are almost totally lacking from high incidence MDR-TB areas  where they would be most needed. The important role of EQA for PZA was recently illustrated in a study from Sweden . In my opinion, we urgently need both new tests and proficiency testing of them developed and implemented. Molecular tests seem most promising, but sequencing of the pncA gene, related to PZA resistance, showed an unfortunate and unexpected wide distribution of resistant-related mutations throughout the gene . This will make development of molecular tests for PZA more challenging than for most other TB-drugs.
There are many challenges to meet, but increasing the coverage of diagnostic DST to urgently ensure a correct and timely diagnosis of M/XDR-TB should be a priority. Thus, the laboratory capacity to perform quality assured DST must be increased, as well as new rapid diagnostic tests developed, evaluated and implemented in the routine diagnostic algorithms. We must shape up, and ensure the necessary financial resources, facilities and appropriate staff to meet increasing demands for timely, quality diagnostic support to identify the optimal therapy of patients with drug-resistant TB.
| References|| |
A. Skrahina, H. Hurevich, A. Zalutskaya, E. Sahalchyk, A. Astrauko, W. Van Gemert, et al, Alarming levels of drugresistant tuberculosis in Belarus: results of a survey in Minsk, Eur. Respir. J. 39 (2012) 1425–1431.
A. Zalutskaya, M. Wijkander, P. Jureen, A. Skrahina, S. Hoffner. Multidrug-resistant Mycobacterium tuberculosis
caused by the Beijing genotype and a specific T1 genotype clone (SIT No. 266) is widely transmitted in Minsk. IJMyco 2 (2013) 194–198.
World Health Organization (WHO), Global Tuberculosis Report, 2012, ISBN 978 (2013) 4.
P. Bemer, F. Palicova, S. Rü sch-Gerdes, H.B. Drugeon, G.E. Pfyffer, Multicenter evaluation of fully automated BACTEC Mycobacteria Growth Indicator Tube 960 system for susceptibility testing of Mycobacterium tuberculosis
, J. Clin. Microbiol. 40 (2002) 150–154.
C.C. Boehme, P. Nabeta, D. Hillemann, M.P. Nicol, S. Shenai, F. Krapp, et al, Rapid molecular detection of tuberculosis and rifampin resistance, N. Engl. J. Med. 363 (2010) 1005–1015.
A.A. Velayati, P. Farnia, M.R. Masjedi, S. Hoffner, Detection of and treatment protocol for rifampicin-monoresistant tuberculosis: what is the role of isoniazid?, Int J. Tuberc. Lung Dis. 17 (2013) 849–850.
A.A. Velayati, P. Farnia, M.R. Masjedi, M. Mozafari, M.F. Sheikholeeslami, M.A. Karahrudi, et al., High prevalence of rifampin monoresistant tuberculosis, a retrospective analysis, AJTMPH (in press).
H. Albert, F. Bwanga, S. Mukkada, B. Nyesiga, J. Ademun, G. Lukyamuzi, et al, Rapid screening of MDR-TB using molecular Line Probe Assay is feasible in Uganda, BMC Infect. Dis. 10 (2010) 41.
S. Rosales-Klintz, P. Jureen, A. Zalutskaya, A. Skrahina, B. Xu, Y. Hu, et al, Drug resistance-related mutations in multidrugresistant Mycobacterium tuberculosis
isolates from diverse geographical regions, IJMyco 1 (2012) 124–130.
D.B. Folkvardsen, V.O. Thomsen, L. Rigouts, E.M. Rasmussen, D. Bang, G. Bernaerts, et al., Rifampicin heteroresistance in Mycobacterium tuberculosis
cultures detected by phenotypic and genotypic drug susceptibility test methods, J. Clin. Microbiol. (2013). [Epub ahead of print].
D.B. Folkvardsen, E. Svensson, V.O. Thomsen, E.M. Rasmussen, D. Bang, J. Werngren, et al, Can molecular methods detect 1% isoniazid resistance in Mycobacterium tuberculosis
?, J Clin. Microbiol. 51 (2013) 1596–1599.
Y. Zhang, K.C. Chang, C.C. Leung, W.W. Yew, B. Gicquel, D. Fallows, et al, ‘Zs-MDR-TB’ versus ‘Zr-MDR-TB’: improving treatment of MDR-TB by identifying pyrazinamide susceptibility, Emerg. Microbes Infect. 1 (2012) e5.
M. Ibrahim, K. Andries, N. Lounis, A. Chauffour, C. Truffot- Pernot, V. Jarlier, et al, Synergistic activity of R207910 combined with pyrazinamide against murine tuberculosis, Antimicrob. Agents. Chemother. 51 (2007) 1011–1015.
S. Hoffner, Unexpected high levels of multidrug-resistant tuberculosis present new challenges for tuberculosis control, Lancet 380 (2012) 1367–1369.
S. Hoffner, K. Ä ngeby, E. Sturega° rd, B. Jonsson, A. Johansson, M. Sellin, J. Werngren, Proficiency of drug susceptibility testing of Mycobacterium tuberculosis
against pyrazinamide: the Swedish experience, Int. J. Tuberc. Lung. Dis. 17 (2013) 1486–1490.
J. Werngren, E. Sturega° rd, P. Jureen, K. Ä ngeby, S. Hoffner, T. Schon, Reevaluation of the critical concentration for drug susceptibility testing of Mycobacterium tuberculosis
against pyrazinamide using wild-type MIC distributions and pncA gene sequencing, Antimicrob. Agents. Chemother. 56 (2012) 1253–1257.