Tuberculosis Multidrug-resistant Tuberculosis – From Epidemiology to Treatment Design

European Respiratory and Pulmonary Diseases, 2015;1(1):20–24 DOI: http://doi.org/10.17925/ERPD.2015.01.01.20

Abstract:

Multidrug-resistant tuberculosis (MDR-TB) and extensively resistant tuberculosis (XDR-TB) are present in most regions of the world and represent a serious threat to the control of tuberculosis. They usually result from errors somewhere along the chain of management of the disease that favoured the selection of resistant mutants, progressively replacing drug-sensitive strains and transmitted to further patients. The currently recommended strategies for the control of this serious situation is the rapid identification of drug-resistant strains, careful drug management of patients with second-line drugs and prevention of the transmission of mycobacteria to contacts. Optimal selection and number of drugs and duration of treatment are not clearly defined. Prevention of the creation of additional cases of MDR-TB is crucial.
Keywords: Tuberculosis, multidrug-resistant tuberculosis (MDR-TB), extensively resistant tuberculosis (XDR-TB), treatment
Disclosure: Jean-Pierre Zellweger has no conflicts of interest to declare. No funding was received for the publication of this article.
Received: May 27, 2015 Accepted June 29, 2015
Correspondence: Jean-Pierre Zellweger, Swiss Lung Association, Chutzenstrasse 10, 3000 Berne, Switzerland. E: zellwegerjp@swissonline.ch
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Epidemiology

Strains of Mycobacterium tuberculosis (M. tbc) are able, like other bacteria, to develop resistance against antibiotics. The first observations were published shortly after the introduction of streptomycin and were the basis of the current recommendation of combining several antibiotics for the treatment of tuberculosis (TB).1 Rigorous application of this principle could have possibly prevented the development of drug resistance. In spite of this, drug resistance against the most active antibiotics increased progressively and is currently a widespread phenomenon. Apart from resistance against single drugs, resistance against the two most active anti-TB drugs, isoniazid and rifampicin, known as multidrug resistance (MDR-TB), has increased and new forms of resistance have emerged, like the resistance against isoniazid, rifampicin, injectable drugs and quinolones, known as extensively drug-resistant strains (XDR-TB).

The latest reports from the World Health Organization (WHO) estimate the number of MDR-TB to half a million cases, of which 10 % are XDRTB, a large part being left untreated, with a high death burden.2 In some regions of the world or in some at-risk populations, like gold miners in South Africa, the rate of MDR-TB is increasing rapidly, particularly in previously treated cases, in spite of the fact that the global incidence rate in the same population had decreased during the same time period.3 Recent reports reveal alarming levels of drug-resistant TB in many Eastern European regions,4 such as Belarus, where the rates reach 35.3 % in new patients and 76.5 % among previously treated cases5 or in Ukraine, where the association with HIV seems to increase the problem.6 In Russia, if the current trends continue, the incidence of drug-resistant TB could be higher than the incidence of drug-sensitive TB within the next few years.7 Prisons seem to be places where the incidence of TB (including drug-resistant forms) is particularly high.7,8 In China, a recent survey concluded that the proportion of MDR-TB cases among new and previously treated patients is 5.7 % and 25.6 %, respectively, and the total number of MDR-TB cases is about 110,000.9 The increase in drugresistant TB is also observed in children in some regions of the world.10

Risk Factors for MDR-TB

Most surveys report an association between previous treatment for TB and high rates of drug resistance.11,12 The prevalence of MDR-TB is higher among patients who were already treated for TB and failed or recurred, but this group represents only a minority among all cases of TB. In absolute numbers, the majority of cases is observed in new patients, who never received a treatment before and who were contaminated by a patients harbouring a resistant strain.13 As a consequence, in some regions of the world, new patients are at high risk of having MDR-TB even in the absence of previous treatment.

Apart from close contact with a patient with drug-resistant TB, other factors associated with the presence of MDR-TB are migration, young age and HIV.14

One particular cause seems to be the induction of resistance by insufficient bioavailability of some anti-TB drugs such as rifampicin.15 Low serum levels of anti-TB drugs, which are observed in some patients,16 may induce the development of resistance against one or several drugs. Some studies have confirmed that patients with a low serum level of the first-line anti-TB drugs have a worse outcome than patients with a level within the expected range.17 This may also explain why some patients develop a drug-resistant form of TB in spite of full adherence to a correct treatment.18,19 One may suspect that drugs of low quality or insufficient bioavailability may contribute to the creation of drug resistance. How important this phenomenon may be in the progressive extension of MDR-TB in some regions is unclear. Studies are ongoing to decide if the recommended dose of rifampicin will have to be changed in the future.20

Why is MDR-TB Increasing in Some Regions of the World?

There are many reasons for the increase of MDR-TB and XDR-TB worldwide, but they all have one point in common: there was some error along the chain of management, inducing a mutation in a strain of sensitive mycobacteria and the selection of mycobacteria that have become resistant to one or several antituberculous drugs, which will progressively replace the sensitive bacteria.21 Among the usual causes are inappropriate treatment of mycobacteria with an undetected resistance against a single drug, use of drugs of bad quality, insufficient drug dosage, changes in drug schedule or dosage and addition of a single drug to a failing regimen. Retreatment of patients with a recurrent episode of tuberculosis with the same drugs as for the first episode, without appropriate drug susceptibility testing (DST), is a possible cause of amplification of the drug-resistance pattern and transformation of a strain with single drug resistance to MDR-TB. This can happen even under normal programmatic conditions, if the drug sensitivity testing is not performed in suspect cases.22,23 Patients with an unsuspected drug resistance who are not cured at the first treatment attempt have a high risk of developing further resistance and harbour an MDR-TB strain.24–26 This is the reason why the ancient recommendation of WHO to use a retreatment regimen containing the same first-line drugs in addition to streptomycine, which has proven successful in settings with a low frequency of drug resistance,27 has been put into question28 and is now no more valid.29 Furthermore, some strains, like the Beijing genotype, seem to mutate more rapidly and be more virulent so that in some regions they progressively replace the other strains.30

The practical issue is that in many settings, if the DST of the strain are not performed rapidly (which is the norm in many regions lacking proper laboratory equipment), patients with MDR-TB will receive inadequate treatment for several weeks or months before the correct diagnosis is made and an appropriate treatment is started. The consequence is that many MDR-TB patients will have a prolonged period of infectiousness and be a danger to other patients and to the staff. Furthermore, as the cure rate of patients with MDR-TB strains is lower than the cure rate in patients with sensitive strains, some patients with MDR-TB can become chronic excretors (the author has observed a case surviving 27 years with a smear-positive pulmonary TB resistant to all anti-TB drugs known in the 1970s).

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Keywords: Tuberculosis, multidrug-resistant tuberculosis (MDR-TB), extensively resistant tuberculosis (XDR-TB), treatment