Multidrug-resistant tuberculosis: standardized or individualized treatment? The question has already been answered

Despite global control efforts, drug-resistant strains of Mycobacterium tuberculosis remain a public-health challenge, infecting millions of people worldwide [1]. Multidrug-resistant TB (MDR-TB), defined as TB resistant to at least isoniazid and rifampin, represents a serious obstacle to TB control, especially in areas where its prevalence is high [2]. The most recent estimates suggest that globally there were more than half a million cases of MDR-TB in 2007, of which fewer than 30,000 were notified to the WHO; this amounts to only 8.5% of the estimated global total of smear-positive cases of MDR-TB [3].

In an increasingly integrated world, these lethal TB strains do not stay at home for long. In the 1990s, a global surveillance project demonstrated that drug-resistant strains of M. tuberculosis were globally ubiquitous, and in several countries were sufficiently common as to potentially threaten control programs [4]. Globally, cases of MDR-TB are unevenly distributed; the prevalence of drug-resistant TB is inversely correlated with the quality of TB control programs, with the most important factor being improper use of first- and second-line anti-TB drugs [5].

Multidrug-resistant TB development is also attributable to inadequate laboratory diagnosis and unsupervised treatment. This is particularly the case in settings where limited resources restrict access to drug susceptibility testing (DST) and implementation of universal directly observed therapy (DOT), in which a trained healthcare worker monitors the patient’s taking of each and every dose of medication [1].

In most low- and middle-income countries, drug sensitivity testing is not performed for either new cases or for most patients requiring retreatment. Therefore, patients with undetected drug resistance will receive empiric standardized treatments with ineffective first-line drugs and, consequently, can be predicted to have a high probability of failure and relapse [6]. To address this problem, the WHO and the Stop TB Partnership have called for an expansion of DST of TB drugs [3]. Unfortunately, despite the increase in funding for global TB control that has occurred over the past decade, large funding gaps remain, making DST unfeasible in many countries, particularly in those with the highest rates of MDR-TB.

Ineffective empiric treatment regimens allow the progression of untreated MDR-TB disease, as well as the uninterrupted transmission of resistant strains, within the patient’s community during the time spent undergoing ineffective treatment; they also provide ideal conditions for the development of extended drug resistance, which can occur despite good adherence. Resistance to multiple drugs arises through a process of sequential resistance acquisition, in which resistance-conferring mutations increase with successive exposures to ineffective or inconsistently administered drug regimens [1].

Nearly all developing countries have now adopted the DOT short course (DOTS) strategy, as recommended by the WHO. This strategy recommends an empirical standard initial regimen for new cases and an empirical reinforced regimen for previously treated cases [7]; new cases are treated with a 6-month regimen (WHO Category I regimen), which includes isoniazid (H), rifampin (R), pyrazinamide (Z) and ethambutol (E) for 2 months, followed by H + R for 4 months. Patients who fail treatment or relapse usually receive a standard 8-month retreatment regimen (WHO Category II regimen) typically consisting of HRZE + streptomycin (S) for 2 months, followed by HRZE for 1 month and then HRE three times a week for 5 months.

These standardized regimens have proven efficacy in patients with drug-sensitive TB, but in patients with drug-resistant strains their efficacy has been shown to be much lower, both in clinical trials and under TB program conditions [8]. The short-course empiric treatment with first-line anti-TB drugs for new cases will not be sufficient in settings with a high degree of resistance to anti-TB drugs (primary resistance of 3% or higher). A retrospective cohort study of treatment of MDR-TB with this regimen in six countries showed treatment success rates of only 52% (range 11–60%) in new cases, and 29% (range 18–36%) in previously treated cases [9]. With such low cure rates, many patients with MDR-TB remain infectious for long periods of time [10]; in addition, the frequency of TB recurrence among MDR-TB patients previously considered to be cured with this regimen has been reported to be 28% [11].

Unfortunately, as previously mentioned, in most low- and middle-income countries that have adopted the DOTS strategy, DST is not performed for new cases or for most patients requiring retreatment. Therefore, patients with undetected drug resistance will again receive the same ineffective standardized treatment with first-line drugs [8]. As most resource-limited high-burden countries do not have the means to test every new case of TB for drug susceptibility at enrollment, innovation is needed to address the issue. Culture and identification of M. tuberculosis plus DST could at least be performed for all cases with positive sputum smears at the end of the second month (coinciding with the end of the intensive phase of primary treatment) and for all patients entering a retreatment regimen owing to relapse or failure [12]; in cases of drug resistance, they could then be transferred to a stronger treatment regimen.

Excluding relapse cases, most retreatment cases arise owing to errors during the implementation or administration of the initial treatment regimen. Up to 80% of failure of cases on Category I treatment are due to MDR-TB and, consequently, they require retreatment regimens other than therapy with exclusively first-line drugs. The principle ‘do not add a single drug to a failing regimen’ should be followed rigorously if one wants to ensure proper cure of patients who fail treatment with first-line drugs [13]. In the case of failure of an initial 6-month regimen (2HRZE/4HR), there is a high risk of resistance to H and R (~80%) and so, if a standardized 8-month regimen (WHO Category II regimen: 2HRZES/1HRZE/5H3R3E3) is prescribed, it would amount to masked monotherapy with E during the last 5 months of treatment. In worse cases, where the patient has been initially infected with a MDR strain of M. tuberculosis (primary MDR) and fails to respond to the initial 6-month regimen, selection of resistance to E + Z during the initial 2 months of treatment is highly likely, because the combination of these two drugs is weak in the context of resistance to H and R. In this case, administration of the 8-month treatment regimen would be equivalent to masked monotherapy with S for 2 months [14]. The proportion of patients with MDR-TB cured with the WHO Category II regimen (2HRZES/1HRZE/5H3R3E3) is similar to historic outcomes when no chemotherapy for TB was available. In the short term, the higher failure and relapse rates mean greater morbidity and mortality for patients, with greater economic and social harm for their families and communities. In the long term, these standardized regimens will contribute to amplification of multidrug resistance in these countries [6]. Insistence on a retreatment regimen with first-line drugs when one knows that most cases of failure in good TB control programs are due to MDR-TB will only do greater damage. This means longer infectiousness, additional drug resistance, repeated failure and higher mortality. Therefore, it is time to close the chapter on cases who fail the treatment regimen with first-line drugs and receive poor retreatment regimens based on the same drugs that (a fact worth mentioning) are not used in developed countries. In this era of evidence-based medicine, it is neither scientifically correct nor programmatically, ethically or financially appropriate to perpetuate a policy when ample evidence speaks clearly against it [13].

To tackle this need, the WHO has worked with many international partners to develop the DOTS-Plus strategy for MDR-TB control, which is designed to operate within an existing and well-functioning DOTS program (an exception more than the rule among TB programs in developing countries). Effective MDR-TB control builds on the five tenets of the DOTS strategy [7] and expands each of these areas to address the complexities associated with treating MDR-TB [15].

The major perceived barrier to an effective MDR-TB treatment is the high cost of quality-assured second-line drugs (SLDs). For this reason, and as part of the DOTS-Plus strategy, the Green Light Committee (GLC) was established by the WHO in 2000 to foster access to quality-assured SLDs at competitive prices and ensure that treatment is provided according to WHO guidelines [16].

In everyday clinical practice, once patients showing resistance have been identified, the next issue is how to treat them: either through the implementation of an individualized retreatment scheme according to the DST pattern of resistance [17] or with a standardized empiric retreatment regimen with SLDs [7] without the benefit of DST results.

The DOTS-Plus strategy offers two general approaches to treatment on the basis of existing program capabilities:

• • Standardized treatment in which all patients with MDR-TB receive the same treatment regimen derived from predominant patterns of resistance in the community in the absence of individual DST. An alternative to this approach is an individually designed empirical treatment based on the patient’s previous history of anti-TB treatment with consideration of DST data from a representative patient population;

• • Individualized treatment in which patients with MDR-TB receive culture-based DST, and treatment regimens are then tailored accordingly [10,15].

The results for standardized empirical regimens in regions with high rates of MDR-TB have so far been disappointing. In a report from Peru [18], where patients were treated with a standardized SLD regimen (consisting of kanamycin, ciprofloxacin, ethionamide + ZE), only 48% were discharged as cured despite being treated under strict DOT. By contrast, also in Peru, patients treated with an individualized regimen for MDR-TB based on DST results (median resistance to six drugs) reported a cure rate of over 80% [19]. Even when the standardized regimen with SLD is designed based on the patient’s previous history of anti-TB treatment, results are extremely poor. In Korea, patients with proven MDR-TB were started on one of two standardized empiric regimens based on previous treatment history (S or kanamycin, ofloxacin, prothionamide, cycloserine and Z or para-aminosalicylic acid); DST of the infecting strain was not used to modify the treatment regimen regardless of the results and only 44% of the cases were discharged as cured [20].

A main issue regarding the control of drug-resistant TB appears to be the persistence of erroneous practices in countries where MDR-TB is already epidemic, which has generated the extension of resistance to SLDs, thus worsening the situation with the appearance of extensively drug-resistant TB (XDR-TB; defined as TB caused by mycobacteria resistant to at least isoniazid and rifampin among the first-line drugs plus resistance to any fluoroquinolone and at least one of the three injectable SLDs, kanamycin, amikacin or capreomycin) [14]. An erroneous assumption is that drug resistance to SLDs will be negligible in those countries where SLDs are not available in the national TB control program. However, especially in cases receiving retreatment in the private healthcare sector, SLDs (fluoroquinolones, injectables or both) will be frequently utilized when patients can afford it, as an add-on to a failing first-line drug regimen since these drugs have been readily available for many years in most countries [21].

Multidrug-resistant TB should be treated exclusively by highly experienced and knowledgeable health personnel; this is extremely important when it is considered that, in many cases, retreatment represents the patient’s last chance of a cure. Many professionals with restricted knowledge of MDR-TB often dare to treat these patients, worsening the problem day by day. MDR-TB patients often receive arbitrary care from health providers who systematically adapt treatment to the resources and drugs available in the country. Evidence-based medicine then becomes availability-based medicine. With the inappropriate use of fluoroquinolones and injectables, XDR-TB is inadvertently being generated all too frequently around the world [14].

Acceptable cure rates for drug-resistant TB are achievable in both developed and developing countries with individualized antibiotic regimens tailored to the patient’s mycobacterial antibiotic susceptibility results [10,17]. However, this approach requires specialized laboratory, clinical and pharmaceutical resources, which are currently unavailable in most developing countries. Nevertheless, ignoring MDR-TB is an unacceptable strategy, regardless of the stage of economic development of a given country; arguments against treating MDR-TB in developing countries are epidemiologically flawed. In settings in which susceptible disease is effectively treated while MDR-TB is ignored, the relative contribution of resistant strains to the overall case load can only increase each year. It is true that overall rates of drug resistance fall when well-functioning programs are introduced, but in no setting in the world with an already established MDR-TB problem have resistant case rates fallen when DOTS was introduced. MDR-TB incidence will only fall in settings where patients with active MDR-TB are treated effectively – with longer courses of effective SLDs selected based on patients’ drug-susceptibility patterns [21].

The feasibility and cost–effectiveness of treating patients with MDR-TB in resource-constrained countries is well established. Optimization of MDR-TB treatment is essential to fulfil the promise of universal access to effective treatment for all patients with TB [21]. The devastating outbreak of XDR-TB in KwaZulu-Natal (South Africa) is an ominous reminder of the threat MDR-TB represents to individuals and to global public health. A continued failure to make appropriate therapy for MDR/XDR-TB widely available is unacceptable, as it will have a profoundly negative impact on global TB control [22]. The often-heard argument that treatment of MDR-TB is too expensive for poor countries to implement is a failure of ethical and social analysis. It is too expensive not to treat MDR-TB now, when only a relatively small fraction of all TB cases are resistant to our best drugs. It is because MDR-TB victims tend to be poor, and thus supposedly ‘less valuable’, that such policies are seen to be acceptable. It is important for the developed nations to realize that they are not invulnerable to this misadventure; drug-resistant TB is appearing in these countries in increasing numbers [21].

A total of 25 years ago, Michael Iseman signaled the ‘inadvertent genetic engineering’ of ineffective TB control programs, and warned of a time-bomb waiting to explode. In failing to prevent or contain resistance to anti-TB drugs he wrote, “we are unwittingly transforming an eminently treatable infection into a life-threatening disease that is exorbitantly expensive to treat” [23]. Once MDR-TB is unleashed, we may never be able to stop it [21]. The time for action is now [22].

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.