Abstract
The emergence and spread of drug-resistant strains of Mycobacterium tuberculosis (M. tuberculosis) have become tremendous challenges for clinical and programmatic tuberculosis (TB) management. Until recently, TB diagnosis was largely based on 120-year-old smear microscopy, and treatment was based on a limited number of drugs developed prior to 1970. During the past few years, we have witnessed a revolution in the ability of laboratories to detect TB and anti-TB drug resistance. Furthermore, after several years of silence, several new anti-TB drugs have recently appeared on the scene, offering hope for patients with very limited therapeutic options. There is also new evidence supporting the appropriate use of existing drugs in the treatment of MDR-TB and a better understanding of the relevance of additional resistance beyond extensive drug resistance patterns. In this article, we review the management of drug-resistant TB and highlight recent developments concerning its diagnosis and treatment.
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Introduction
Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis (TB) that is resistant to at least rifampicin and isoniazid, and extensively drug-resistant TB (XDR-TB), defined as MDR-TB that is also resistant to fluoroquinolone and any second-line injectable anti-TB drug, have become tremendous challenges for clinical and programmatic TB management as well as an enormous threat to global TB control.
The inadequate management of patients with susceptible TB, poor TB infection control measures, and the persistent high prevalence of HIV in some settings have allowed the number of M-XDR/TB cases to increase year after year.
According to World Health Organization (WHO) estimates, in 2011 MDR-TB accounted for 3.7 % of new TB cases and 20 % of re-treated cases [1]. Additionally, by the end of 2012, there were 84 countries reporting at least one case of XDR-TB [1], and isolates with increased patterns of drug resistance (resistance to 10 drugs) have become increasingly frequent in certain settings [2–5]. In 2011, 60,000 new MDR-TB cases were reported, and this represented less than one-fifth of estimated cases [1] Furthermore, only about 20 % of the estimated MDR-TB cases were enrolled in treatment, and successful outcomes were reached in just 46 % of cases [1]. Most MDR-TB cases, in fact, occur in resource-constrained countries with very limited capacity to diagnose resistance and little access to second-line drugs (SLD). DR-TB cases need longer and more toxic treatment, and usually experience poorer outcomes.
This is especially evident in patients co-infected with HIV, in patients where diagnosis and access to treatment are delayed until the disease has advanced significantly, and in patients who are not properly managed [6]. It can be very difficult to standardize the management of these patients, who usually present with various patterns of resistance and a wide range of clinical conditions and comorbidities. Additionally, the situation is complicated by the low clinical reliability of drug susceptibility testing (DST) for many SLDs, delays in obtaining DST results, and the limited efficacy and frequent toxicity of many SLDs [7••].
There still exists a large unmet need in the area of DR-TB management, and new needs continue to emerge as a consequence of the dynamic interactions among M. tuberculosis, the environment, anti-TB drugs, and humans (Table 1). Fortunately, there have been greater efforts in recent years to address these needs. After many stagnant years, TB is once again in the spotlight with the emerging global threat of MDR/XDR-TB as well as recent advances in diagnosis and, potentially, in treatment. Hopefully, this new evidence will be used to improve the clinical management of MDR/XDR-TB.
Diagnosis of drug-resistant tuberculosis
There are no differences between susceptible and resistant TB in terms of clinical presentation, smear microscopy results, and radiographic features. MDR-TB diagnosis should start with the identification of patients who are more likely to be infected with resistant strains of M. tuberculosis. Previously treated patients, especially treatment failures, and patients with MDR-TB case exposure are at highest risk of anti-TB drug resistance. Other groups at greater risk of harboring resistant strains include patients who remain smear-positive at the end of the second month of category I treatment, those who present comorbidities associated with malabsorption or HIV, and those whose treatment is irregular due to poor adherence or frequent drug stock-outs [7••, 8, 9].
The primary method of identifying resistant strains is through bacterial culture (performed in solid or liquid culture medium) and drug susceptibility testing (DST) based on phenotypic detection of bacterial growth in the presence of different anti-TB drugs. These techniques are costly and not always easily accessible, however, and they are at high risk of contamination and have very long turnaround times (at least 2–4 months and 2–3 weeks, respectively). Additionally, with the exception of rifampicin, isoniazid, fluoroquinolones, and aminoglycosides, the DST for the other anti-TB drugs is limited in reproducibility and clinical reliability, with a poor correlation between in vitro and in vivo results. Therefore, a detailed analysis of the history of anti-TB drugs taken by the patient in the past exploring possible monotherapies and the history of drug use in the country are valuable complements to the information provided by DST results [7••, 9, 10•, 11].
New rapid molecular methods have recently become available and have been widely implemented in some settings. Line probe assays (INNO-LiPA Rif.TB® and GenoType MTBDRplus®) and the GeneXpert MTB/RIF® system are molecular PCR-based tests that simultaneously diagnose TB and detect resistance to INH and/or RIF. This is accomplished through the detection of M. tuberculosis DNA in the specimen and identification of specific gene mutations responsible for resistance to RIF in the case of GeneXpert, and resistance to RIF and INH in the case of GenoType. The main advantage of these systems is the short turnaround time (2 days with GenoType and 2 hours with GeneXpert). Line probe assays require properly configured molecular laboratories, while GeneXpert can be performed at a peripheral level without special laboratory facilities, and thus could have an enormous impact in TB and RIF resistance detection. As approximately 95--98 % of M. tuberculosis RIF-resistant strains also show resistance to INH, the identification of RIF resistance serves as a surrogate diagnosis of MDR-TB. In light of this, the World Health Organization has recently published revised case definitions [12].
As recently as 2010, very promising results were published in studies from four countries with a high prevalence of MDR-TB, in which GeneXpert MTB/RIF® was shown to have identified 98.2 % of smear-positive and 72.5 % of smear-negative TB cases, correctly detecting 97.6 % of cases with rifampin-resistant strains [13]. These results were confirmed by a larger study involving more than 6,000 patients from 6 countries, where excellent sensitivity was also indicated for patients with HIV co-infection, and where the median time to treatment for smear-negative TB was reduced from 56 to 5 days [14•]. In 2011, WHO recommended Xpert MTB/RIF as the initial diagnostic test in individuals suspected of having MDR-TB or HIV-associated TB [15]. Since then, several studies have shown that GeneXpert MTB/RIF® offers additional value in the diagnosis of extra-pulmonary TB and in detecting TB in children [16, 17]. A recent study [18] of more than 1,000 patients with extra-pulmonary TB found that GeneXpert had greater than 85 % sensitivity in tissue biopsies, urine samples, pus, and cerebrospinal fluids, although lower than 50 % sensitivity in cavitary fluids, as compared to culture.
A limiting factor in all molecular methods is that they cannot be used for monitoring treatment because, as a PCR, they do not distinguish between live and dead bacilli, and so they can be used only for diagnosis. However, GeneXpert can be used for detecting RIF resistance in patients who are not converting bacteriologically during treatment for susceptible TB, especially in the case of failure. Furthermore, in the case of GenoType MTBDRplus® information regarding possible resistance to INH can be very relevant at the end of the second month of category I treatment for patients who are still smear-positive. In fact, the early detection of mono-resistance to INH but no resistance to RIF can alert clinicians to avoid shifting to the standard continuation phase with just INH+RIF, thereby avoiding RIF monotherapy, drug resistance amplification, and MDR-TB development [7••].
In many settings during the past two years, the large-scale implementation of these rapid molecular tests – and GeneXpert in particular – has led to a two- to threefold increase in the detection of MDR-TB cases [19••]. With the facilitation of MDR-TB diagnosis that these tools enable, we must ensure that an adequate number of quality-assured SLDs are available to treat the growing patient population and that there are enough skilled health professionals to manage these cases.
Lastly, another potential contribution of the GenoType MTBDRsl is the detection of resistance to fluoroquinolones and second-line injectables [20, 21]. However, given the suboptimal sensitivity (despite very high specificity) and lack of capacity to identify resistance to specific individual second-line injectables, currently the MTBDRsl test should be used only as a triage test to guide further therapeutic decisions and not as a replacement for phenotypic DST.
Treatment of drug-resistant tuberculosis
All forms of TB should be treated with a combination of drugs to avoid the selection of naturally resistant mutant bacilli and the development of drug resistance, and treatment should be of sufficient duration to kill all populations of bacilli, depending on the different metabolic conditions, and to avoid relapse. In the case of a drug-resistant TB regimen, the number of drugs and the total treatment duration depend on the bactericidal and sterilizing activities of the specific TB drug [22]. Drug selection should follow rational criteria, and it will depend on the availability of drugs likely to be effective in a given patient. Unfortunately, the choice of drugs narrows as the pattern of drug resistance becomes more extensive. Thus far, there have been no randomized clinical trials comparing different regimens and drugs. Therefore, most of the current evidence and recent recommendations are based on expert opinions and personal experiences, at times with limited consensus [23••].
Designing a regimen for MDR-TB – selection of drugs
From a bacteriologic point of view, 3 active second-line drugs may be sufficient to cure MDR-TB, but because some drugs may be compromised or very weak, it is important to include at least 4 drugs likely to be effective [23••]. In fact, more drugs may be needed in some cases – for instance, with many drugs that are weak or have doubtful efficacy. The current WHO guidelines recommend a standardized MDR-TB treatment regimen with at least 4 likely effective drugs, including a second-line-injectable in the intensive phase, a fluoroquinolone, a thioamide, and either cycloserine or PAS plus pyrazinamide [24, 25].
Anti-TB drugs are organized into 5 groups, primarily on the basis of efficacy, route of administration, availability, cost, and tolerability [7••, 23••, 26•, 27, 28••] (Table 2). In designing a MDR-TB treatment regimen, drugs likely to be effective (because they are new to the country, have not been taken previously by the patient, or because of DST results, taking into account the limited clinical reliability of DST for SLD, ETB, and PZA) should be included according to the hierarchy of drug groups.
Group 1: first-line anti-TB drugs
PZA should be included and ETB should be considered (Table 2). High-dose INH may be effective [29, 30•] in the case of low drug-resistance levels – as in the case of mutations in the inhA gene and not in the KatG gene (both identifiable by GenoType). Mutations in InhA, in fact, confer low levels of resistance to INH and frequently high levels of resistance to thionamides [31]. Rifapentine cannot be recommended, given its complete cross-resistance with rifampicin. On the contrary, strains resistant to rifampicin may be susceptible to rifabutin in some cases, but due to limited availability and lack of clinical evidence, this drug should not be routinely recommended [26•].
Group 2: Fluoroquinolones (FQs)
Just one drug of this group should be included. Cross-resistance among FQs is probably incomplete, and about 50 % of strains resistant to ofloxacin are susceptible to high doses of levofloxacin (Lfx) and moxifloxacin (Mfx) [32]. Unfortunately, most laboratories test resistance to ofloxacin only, which does not provide information useful in therapeutic decision-making because ofloxacin is seldom used in the treatment of MDR-TB. Thus far, there have been no studies evaluating the cross-resistance between Lfx and Mfx. High doses of Lfx show extended early bactericidal activity similar to that of Mfx and higher still than that of INH [33]. Mfx, however, carries better sterilizing capacities [34, 35] and excellent concentration in the tissues (better than Lfx). Unfortunately, Mfx is generally more costly and less available in limited-resource settings.
FQs are essential components of the regimen, and their use has been associated with more favorable outcomes in both MDR and XDR-TB cases [36•, 37•]. The importance of late-generation FQs over second-line injectables (SLIs) in successful outcomes of MDR-TB treatment is well-documented in a recent publication of Falzon et al. [38••]. The authors evaluated approximately 7,000 MDR-TB patients from 26 centers and found that treatment success rate was higher in MDR-TB with no additional resistance (64 %), and then decreased progressively to 56 % for MDR-TB resistant to SLIs only, to 48 % for MDR-TB resistant to FQs only, to 40 % for XDR-TB patients. Therefore, a late-generation FQ should always be included in a DR-TB regimen, and should be considered as one of the 4 main effective drugs in MDR-TB but not as one of the 4 main effective drugs in XDR-TB.
Group 3: Second-Line Injectables (SLIs)
Just one drug of this group should be included. They are all bactericidal, with high levels of toxicity. TB strains resistant to streptomycin (Str) almost always remain susceptible to the other SLIs. Strains resistant to capreomycin (Cm) frequently remain susceptible to kanamycin (Kn) and amikacin (Ak). Strains resistant to Ak are resistant to Cm and Kn. Strains resistant to Kn show different levels of resistance to the other SLIs. Based on these cross-resistance patterns, the selection of these drugs should logically start with Str, followed by Cm, then Kn, and finally Ak. Streptomycin is no longer recommended, given the high rate of resistance (50 % of strains resistant to INH also show worldwide resistance to Str) and the lack of reliable laboratory testing [7••, 26•]. Unfortunately, Cm is more costly and less available than the remaining two SLIs. Therefore, Kn is the most frequently used SLI, followed by Ak. A DR-TB regimen should always include a SLI, and this should be considered as one of the 4 main effective drugs in MDR-TB but not as one of the 4 main effective drugs in XDR-TB due to the possibility of cross resistance.
Group 4
This group includes three classes of drugs: the thionamides (ethionamide, Eto; or prothionamide, Pto); cycloserine (Cs) or terizidone (Trd); and p-aminosalicylic acid (PAS). Thionamides should be selected first [24, 25] because they are more bactericidal, better tolerated, and less expensive than the other group 4 drugs. However, their efficacy is adversely affected by the presence of an inhA mutation [31], which can be detected by GenoType. The next selection should be cycloserines or terizidone, which are bacteriostatic with limited toxicity and no cross-resistance with other compounds. PAS should be the last choice due to its poor toxicity profile and limited effectiveness. The primary role of this drug is to protect the other components in the regimen from resistance amplification. We could speculate that PAS should probably be moved to a less relevant drug group.
Group 5
This is a very heterogeneous group and includes drugs with limited experience in TB and low efficacy or high toxicity profiles.Based on effectiveness, potential adverse reactions, and cost, it was previously thought that the sequence of introduction of this group of drugs should be: clofazimine (Cfz), amoxicillin-clavulanate (Amx/Clv), linezolid (Lzd), carbapenems (imipenem/meropenem), clarithromycin, and then thioacetazone [7••, 26•]. However, in light of emerging evidence of their ability to provide support in M-XDR/TB treatment and their increasing availability in limited-resource settings, group 5 drugs should probably be reconsidered. Based on their effectiveness, without considering cost and adverse reactions, the sequence of introduction should begin with linezolid, followed by clofazimine, then carbapenems, and eventually amoxicillin-clavulanate. Although published evidence is still limited to a small number of patients and cost is a high barrier in some settings, there have been increasingly excellent experiences with regimens including linezolid [39•, 40•, 41]. Adverse reactions (mainly hematological toxicity and polyneuritis) are sometimes a concern [42], but a reduced Lzd dose or initial dose adjustment appear to have no negative effect on outcomes and can improve tolerability [39•, 43–45]. We believe that linezolid deserves a higher ranking among anti-TB drugs and, that if price were not a limitation, it should be considered among groups 2 (FQs) and 3 (SLIs).
The potential role of clofazimine has recently been considered in short-duration MDR-TB treatment regimens [30•], and this was addressed in depth in the recent review by Gopal et al. [46•], but limited availability precludes wider use of the drug. Finally, although there is very little published experience with meropenem clavulanate [47–50], the results of in vitro studies are encouraging and have shown very good sterilizing activity. This drug could be better explored if price and availability were of less concern.
Finally, it is worth mentioning the new anti-TB drug bedaquiline, active against both susceptible and resistant M. tuberculosis strains. The drug just recently became available, and thus far has been relegated to compassionate use for selected patients in certain countries. Expectations for bedaquiline have been so high that the World Health Organization has recently published recommendations on its use in patients with MDR-TB resistance and extended resistance beyond MDR-TB [51].
Individualized versus standardized regimens
MDR-TB treatment can be standardized in order to facilitate prescription and prompt initiation, especially in settings with numerous cases and few skilled physicians. Standard regimens should be established for new MDR-TB cases where there is no known contact with an MDR-TB source and in patients who have previously received only FLDs. However, individualized regimens are better suited to patients who have received MDR-TB treatment in the past (with various FLDs and/or SLDs) [7••, 23••]. Experiences in countries with widely implemented standardized MDR-TB regimens have been very positive [30•, 52, 53]. In settings where expanded patterns of resistance are becoming more frequent, it may also be necessary to standardize regimens for patients failing MDR-TB standardized treatment and for new XDR-TB cases in order to facilitate the best management of these cases with the limited options available.
Duration of treatment
According to current WHO MDR-TB guidelines, duration of treatment should include an intensive phase (IP) of at least 8 months and a total duration of at least 20 months [24, 25]. It should be noted that this recommendation is based on very low-quality evidence and that the supporting data was not able to provide information on whether a minimum-duration intensive phase, post-conversion, could influence outcomes [24]. There is increasing evidence based on expert opinion that shorter treatment duration is adequate, especially in the intensive phase. In fact, although injectable drugs are fundamental in DR-TB treatment, the need for injection and drug-related toxicity warrants great caution regarding length of use [54]. Although there have been no studies analyzing the effectiveness and toxicity of different durations for injectables, it seems certain that toxicity increases with dose accumulation [55]. The concentration of these drugs is much higher in the urine and the ear than in the blood, and generally permanent auditory and vestibular damage, as well as reversible nephrotoxicity, are frequent occurrences [54].
From a bacteriologic point of view, 4 drugs should be given during the intensive phase(IP) to ensure that, during a period of high bacillary load, not only all susceptible bacilli are killed, but also naturally resistant mutants are eradicated. When the bacterial load has been reduced to a minimum, however, it is possible to continue with only 2–3 drugs (depending on their bactericidal and sterilizing activity). In fact, in the presence of low bacillary load, there is little to no likelihood of naturally resistant mutants. Therefore, if smear conversion occurs very early (first 2–4 months), it is likely because the organisms are susceptible to FQs and the other drugs, and it would be reasonable to shift to the continuation phase (CP) when smears become negative. Conversely, if conversion occurs later (after 5–6 months), it is likely due to the fact that FQ is ineffective, and the early suspension of the injectable would cause the regimen to become too weak. In these cases, it would be better to extend the injectable duration to 6–12 months after the conversion of the cultures [7••]. When standardizing recommendations, there is a tendency to recommend a fixed injectable duration (6–8 months) [7••]. Although this strategy is justified from a programmatic perspective, it results in many patients receiving excessive doses of a toxic and uncomfortable drug, while others may be receiving insufficient doses. Recent publications from high-HIV-prevalence settings showed 89 % culture conversion within the first 6 months, with no difference regarding HIV status (median time to conversion of 62 days) [56]. Data from 5 DOTS-Plus pilot projects showed that among 1,385 positive sputum-culture cases of MDR-TB, 83 % experienced at least one conversion during treatment, and the median time to conversion was 3 months [57]. Standardized duration of the intensive phase is likely necessary in the initial implementation of an MDR-TB program while countries are building experience and capacity in the management of M/XDR-TB cases. Recommendations may be slightly modified as experience is consolidated. The length of injectable should be linked to conversion of the smear (or possibly culture), and probably not fixed at 8 months.
Ak and Str have a very good post-antibiotic effect (the effect of Kn and Cpm is unclear) [58], and therefore they can be administered 3 times weekly instead of daily. To date, there is no published evidence that this approach can reduce the adverse reactions related to injectables. Peloquin et al. found no differences in drug-related toxicity when injectables were administered daily versus 3 times weekly [55]. There is increasing evidence, however, that intermittent injectables cause fewer adverse reactions, while at the same time producing comparable outcomes (M. Rodriguez, Dominican Republic NTP, personal communication).
Finally, we’d like to highlight the interesting findings in a very recent publication by Falzon et al. [38••], where treatment success in XDR–TB patients was shown to be highest when duration of the intensive phase was 6.6–9.0 months and total treatment duration was 20.1–25.0 months, suggesting that treatment duration for XDR-TB and MDR-TB may be similar.
Surgery as support in DR-TB treatment
Surgery has a limited role in the management of drug-resistant TB. It is indicated only in the presence of three conditions: four likely effective drugs are not available, the lesion is localised and there is sufficient respiratory reserve. Although these three criteria are rarely present, they do occur in some XDR-TB cases. Even in this situation, however, it is important to consider that surgery implies high morbidity/mortality and that the lesions are not completely sterilized [7••, 23••].
Surgery is likely to have a greater impact in the case of XDR-TB where pharmacological options are extremely limited, and surgery may help to achieve a cure [59•, 60]. It is also important to remember that a successful outcome in a surgical approach will strongly depend on the skills of the surgical and anesthesia teams [61], and that quality surgery can seldom be performed in countries with limited resources.
The optimal time to perform surgery in DR-TB patients has not yet been determined, but in most circumstances, surgery is recommended at the time of lowest bacillary load, ideally after sputum conversion. Early surgical intervention in DR-TB is more likely to produce a cure, as it is possible to physically reduce the bacillary load and increase the chance that even a weak regimen may be effective. On the other hand, earlier surgical intervention may lead to more complications.
Management of drug-resistant tuberculosis in special situations/special care in DR-TB management
Some situations may be considered “special” because of slightly different clinical management needs. Situations such as TB/HIV co-infection, pregnancy, extra-pulmonary TB, TB in children, and MDR-TB contact may require different management strategies. These are summarized in Table 3.
Conclusions
Recent advances in the diagnosis and treatment of DR-TB have been important steps forward in the management of MDR-TB. However, it is essential that governments, stakeholders, donors, and the pharmaceutical industry are united in a firm commitment to closing the gap between the number of estimated cases and the number enrolled in treatment, and to provide all MDR and XDR-TB patients with timely access to effective treatment and potential cure. The positive experiences from Bangladesh [30], Cameroon, and other countries should provide the impetus for massive investment in the research of shorter and better-tolerated regimens. In fact, it is only with shorter and less toxic regimens that patient adherence and favorable outcomes will be achieved and that the TB transmission chain will be broken. Finally, controlling DR-TB will be possible only when the ongoing transmission of the disease is limited through the implementation of effective infection control measures and through the concrete expansion of antiretroviral treatment for HIV patients before their immune status declines. Once again, a strong commitment is needed at all levels, as many battlefronts remain in the fight against M. tuberculosis.
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Anna Scardigli and José A. Caminero declare that they have no conflicts of interest.
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Scardigli, A., Caminero, J.A. Management of drug-resistant tuberculosis. Curr Respir Care Rep 2, 208–217 (2013). https://doi.org/10.1007/s13665-013-0063-z
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DOI: https://doi.org/10.1007/s13665-013-0063-z