After decades during which tuberculosis (TB) became an almost universally curable disease, the emergence of strains of Mycobacterium tuberculosis (M. tuberculosis) resistant to the most active drugs available has once again made TB a major threat and a challenge to global public health.1 It is, however, important to remember that if access to appropriate diagnosis and treatment are guaranteed, the chances of curing all patients with TB are very high, even among carriers of highly resistant strains. Protocolized clinical management is essential if the treatment of these patients is to be successful.2–9

The current global status of multidrug-resistant TB (MDR-TB) – TB resistant to at least isoniazid (H) and rifampicin (R) – is worrying, and the overall response to this situation has been unsatisfactory.1,10 An estimated 3.9% of new TB cases worldwide are thought to be MDR-TB, and this rate rises to 21% in previously treated patients.1 Of the estimated 10.6 million cases of TB occurring in 2015 (1.8 million deaths), about 580000 cases may have been rifampicin-resistant (RR-TB) or MDR-TB, leading to around 250000 deaths.1 Worldwide, however, less than 150000 cases (26% of the estimated total) were reported, with a cure rate of 52%.1 In other words, only about 10% of the estimated MDR-TB patients worldwide were cured, a rate that is totally ineffective for controlling the epidemic.

Although the prevalence of MDR-TB in Spain remains difficult to pinpoint due to underreporting of TB and failure to perform systematic resistance testing, the situation seems more favorable: 0.1% cases of TB in Spanish natives and 2.2% in immigrants were primary MDR-TB, of which 3.4% and 10.2%, respectively, showed primary resistance to H.11,12

TB diagnosis is still based on clinical suspicion, radiology, and microbiological testing.13 The clinical and radiological features of drug-resistant tuberculosis (DR-TB) are indistinguishable from those of drug-susceptible TB, so diagnosis of DR-TB must always be based on microbiological and/or molecular evidence.6

Drug Susceptibility Studies

Spanish guidelines currently recommend cultures and susceptibility studies, including at least isoniazid (H) and rifampicin (R), in all patients with TB, irrespective of whether the patient is treatment-naïve or presents a risk factor for DR-TB (Table 1)3,6,16,17 (strong recommendation, high quality of evidence [⊕⊕⊕⊕]).

Table 1.

Risk Factors for Drug-Resistant Tuberculosis.3,6,16

High risk factors

Patients previously treated for TB, particularly those who failed previous treatment regimens, but also relapsers and drop-outs resuming treatment

Cohabitant or close contact of an MDR-TB patient

Moderate risk factors

Patients with positive sputum smear at the end of the second month of initial treatment (HRZE) and in whom initial drug susceptibility is unknown

Patients from countries with high rates of initial MDR-TB

Patients who live in closed institutions, such as prisons or hostels where there have been cases of MDR-TB

Healthcare personnel, particularly those who treat MDR-TB cases

Patients with comorbidities that may lead to situations of malabsorption

HIV infection

If resistance to R is shown, the susceptibility study should be extended to include the fluoroquinolone (FQ) and the second-line injectable drug (SLID) that will be used in the rescue treatment offered to the patient6 (levofloxacin [Lfx]/moxifloxacin [Mfx] and amikacin [Am]/capreomycin [Cm] in Spain) (conditional recommendation, moderate quality of evidence [⊕⊕

]).

The results of conventional susceptibility testing to all these drugs are very reliable, so this information can be used to guide the recommended treatment regimen. In contrast, the clinical credibility of susceptibility testing to other drugs such as ethambutol (E), pyrazinamide (Z), ethionamide/prothionamide (Eth/Pth), cycloserine (Cs), para-aminosalicylic acid (PAS), or clofazimine (Cfz) is significantly lower, and these results can often confound rather than assist decisions regarding the possible treatment regimen needed by the patient. For this reason, routine testing is not recommended, and if these tests are performed, the results must be viewed with caution5,6,18 (conditional recommendation, low [⊕

] to very low [

] quality of evidence).

Specific Molecular Techniques: Xpert MTB/RIF (Cepheid) and GenotypeMDRplus (Hain)

One of the most important of these molecular techniques is the Xpert MTB/RIF (Cepheid) that can detect resistance to R within 2h with a sensitivity of 95% and a specificity of 98%.14,17 This technique is much more sensitive than sputum smears (positive in up to 70%–90% of cases with negative smear test and positive culture), and represents an important advance in early detection. The GenotypeMDRplus (Hain) or line probe assay can also simultaneously detect mutations in genes that encode resistance to isoniazid (katG and inhA) and rifampicin (rpoB) within a period of 6–24h.19,20

Both molecular techniques can be carried out in direct samples, without the need to wait for the isolate to grow in culture. The clinical significance of the inh A gene mutation and/or the katG gene and the recommendation to use H despite proven resistance are described in detail in the online version of this guideline.21–28

Version 2 of the GenotypeMDRsl (Hain) line probe assay can be used to detect resistance to FQ (gyrA and gyrB mutations) and to SLID (genetic mutations in rrs and the eis promoter region). The specificity of this method for both FQs and SLID is higher than 98%,29–31 so this information should be taken into consideration in the design of the treatment schedule32,33 (conditional recommendation, moderate quality of evidence [⊕⊕

]).

Clinical History of Previously Administered Drugs

It is of utmost importance to consult the clinical records of patients previously treated for TB to determine their drug history.6 When the wrong drug has been administered for more than 1 month, the possibility of resistance and reduced efficacy must be suspected, even if the susceptibility testing suggests the opposite.6,34 There are simple drug history templates that can help with this task, as shown in Fig. 1.6 It is also necessary to determine if the patient's index case had DR-TB.

Fig. 1.

Template for collecting patient anti-TB drug history. Adapted from Caminero et al.6

(0.38MB).

All TB treatment must meet 2 basic bacteriological requirements: drugs must be combined to prevent the selection of resistance and the treatment must be administered for long enough to ensure cure and avoid relapses.6,35,36

To ensure cure of TB without relapse as far as possible, it is recommended that all treatment regimens involve a combination of at least 4 previously unused drugs or drugs to which the M. tuberculosis has shown susceptibility.6,15,36 Of these, 2 must be core drugs, capable of eliminating the majority of the bacilli and curing the patient. At least 1 of these core drugs must have good bactericidal activity (ability to eliminate rapidly multiplying bacilli located in cavitated lesions that cause symptoms and transmission), and at least 1 must have good sterilizing activity (ability to eliminate those bacilli in semilatent phases that are responsible for relapses). The other 2 drugs are what we call companion compounds, and their mission is to protect the core drugs from selection of resistance6,36 (conditional recommendation, moderate quality of evidence [⊕⊕

To assist in the selection of the drugs needed to make up a TB regimen, Fig. 2 shows the bactericidal and sterilizing capacity of the different drugs, their ability to prevent the selection of resistance, and their toxicity profile.36

Fig. 2.

Characteristics of drugs with activity against M. tuberculosis. Adapted from Caminero et al.36

Prevention of resistance, bactericidal activity and sterilizing activity are listed in descending order (high, moderate, and low activity), while toxicity (right-hand arrow) is listed in ascending order (low, moderate, high), so that the best available drugs combining all these features appear in the top row.

(0.27MB).

Tables 2a and 2b list in detail the doses of the different drugs with activity against M. tuberculosis, the route of administration, and the most common adverse effects.

To assist in the selection of the 4 drugs that must be included in any treatment of initial phase TB, these compounds should be classified into 5 different groups (Table 3), starting with Group 1, the group with the greatest activity, and continuing with the others in decreasing order of effectiveness and tolerance.3,8,37,38 Prescribing physicians should work their way down through these groups until at least 4 new drugs or drugs very likely to be susceptible have been combined, ensuring the inclusion of at least 1 bactericidal drug and 1 sterilizing drug. Guidelines for starting each of the drugs included in these groups are shown in Table 3 (conditional recommendation, moderate quality of evidence [⊕⊕

Group 1 consists of “first-line oral drugs”, so called because these are used in the first instance in practically all patients with drug-susceptible TB. This group comprises the most effective, the best tolerated, and the least expensive products.37,38 Drugs classified as core because of their bactericidal (H and R) or sterilizing (R and Z) activity must be distinguished from companion drugs (E).6,36

Group 2 consists of the FQs (high-dose Lfx or Mfx), which are also core drugs with bactericidal and sterilizing activity and low toxicity.6,37,38 Moreover, if these products can be used, they clearly affect prognosis in the treatment of MDR-TB.6,39,40 Although no specific studies have been performed, evidence suggests the presence of considerable cross-resistance between these 2 FQs.

Group 3 consists of second-line injectable drugs. These are also core drugs, due to their bactericidal activity, but with little or no sterilizing ability and they are far more toxic than the FQs.6,37,38 This cumulative toxicity and the need for administration by injection greatly limit their use.

Group 4 is composed of 6 different drugs that might be administered in combination because they attack M. tuberculosis via different targets.3,4,6,37,38 This is a mixed group consisting of drugs that could be considered core due to their activity, although the accumulated evidence is still scant (linezolid, bedaquiline and delamanid), and others that have stronger supporting evidence but moderate or low activity (ethionamide/prothionamide and cycloserine/terizidone) and would behave as companion drugs, and a third, clofazimine, which seems to have good sterilizing activity. The selection of one or the other will depend on their availability and possible adverse effects.

Linezolid can be considered a core drug, with bactericidal and sterilizing activity.38 Several publications38,41–43 have confirmed its role in the treatment of MDR-TB and extensively drug resistant TB (XDR-TB). Linezolid has 2 drawbacks, namely its cost and its toxicity profile when administered for more than 6–8 weeks, with frequent hematological alterations and polyneuropathies. Toxicity problems are highly dose-dependent38 and relatively easy to manage, given the low dose recommended for MDR-TB,38,41 while the price has fallen since the generic molecule became available in 2016.

Bedaquiline can also be considered core due to its bactericidal and sterilizing activity.38,44 Two clinical trials have demonstrated its efficacy in the treatment of MDR-TB,45,46 particularly in XDR-TB (MDR-TB resistant to at least 1 FQ and 1 SLID [kanamycin, amikacin, capreomycin]), and it is used in many countries.

Finally, delamanid and pretomanid are metronidazole derivatives with bactericidal and sterilizing activity.38,47–51 Two randomized clinical trials have demonstrated the usefulness of delamanid in the treatment of MDR-TB,48,49 particularly in XDR-TB.

Linezolid, bedaquiline, and delamanid are all likely to play a significant role in the treatment of MDR-TB in the very near future,38 and may also be of use in the treatment of susceptible TB.

Aside from the foregoing drugs, the most effective compounds are the thioamides (ethionamide/prothionamide). These may be mildly bactericidal,6 but show potential cross-resistance with H (inhA gene mutation, detectable by GenotypeMDRplus) and a poor gastric tolerance profile.6 The next most active is clofazimine, an important component of short treatments of MDR-TB due to its possible sterilizing activity.8,26,52 The last is cycloserine (similar to terizidone in terms of action), which has good oral tolerance, but limited activity and potentially serious psychiatric adverse effects.6,53

A hypothetical Group 5 would include the carbapenems (imipenem or meropenem) combined with clavulanic acid (as this does not exist separately, it must be administered with amoxicillin), which are probably quite active despite the scant supporting evidence6,54; PAS, which is very ineffective, with poor gastric tolerance6,37; and thioacetazone, which is very weak, potentially toxic in patients with human immunodeficiency virus (HIV), and very difficult to obtain.37

TB, according to possible resistance patterns, difficulty of treatment and the different prognoses involved, can be classified into 5 large groups in ascending order of complexity55 (Table 4).

Treatment of Tuberculosis Resistant to Isoniazid (Single or Multiple Resistances) but Susceptible to Rifampicin

This is a relatively common situation. In these cases, the recommendation is to use 9 HRZE (in this case, high doses of H may be considered),23 and to perform a susceptibility study with the remaining first-line drugs (conditional recommendation, low [⊕

] to very low (

) quality of evidence). A regimen containing 2FQ-REZ/7CF-RE could also be considered (with an FQ susceptibility study), but FQ (Lfx/Mfx) should only be included if it is administered from the beginning of treatment along with the other drugs. It should not be added if results of resistance testing to H are received after 3–4 weeks of treatment, due to possible risk of de facto monotherapy. See options in Table 4.4,6,15 A third possibility, in line with current SEPAR recommendations is 2RZE/10RE, with has been used successfully in standard treatments when H had to be discontinued due to intolerance.

Treatment of Tuberculosis Resistant to Rifampicin (Single or Multiple Resistances), but Susceptible to Isoniazid

As cases of isolated resistance to R are very rare in clinical practice, and since R is the compound that determines prognosis in patients with MDR-TB, these patients should be approached as MDR-TB cases, and treated as such, with the addition of H to the schedule, of course, because if susceptibility is confirmed, this will contribute significantly to the treatment5,6 (conditional recommendation, low [⊕

] to very low [

] quality of evidence).

Treatment of Multi-Drug Resistant Tuberculosis Susceptible to Fluoroquinolones and Second-Line Injectable Drugs

Following the rationale of this guideline, the ideal regimen for these patients would include an FQ (Mfx, or high-dose Lfx), a second-line injectable drug (at least until cultures become negative), and 2 drugs selected from Group 4 of this guideline. Z should also be included in this regimen if susceptible, due to its possible activity, taking into account that the susceptibility test is not reliable (conditional recommendation, very low [

] quality of evidence). The options listed in Table 5 should be considered.

Table 5.

Recommended Basic Regimens for Patients With MDR-TB.

MDR-TB cases, but without resistance to second-line drugs

Short regimen: 4a (Cm/Am+Mfxb+Pth/Eth+Cfz+E+Z+Hc)/5 (Mfxb+Cfz+E+Z)

Standard regimen:

Intensive phase (Cmd+Mfx/Lfx+Z+2 Group 4 drugse)/continuation phase (Mfx/Lfx+Z+2 Group 4 drugse)

MDR-TB cases with additional resistance to the FQ, SLID, both, or even broader XDR-TB resistance patterns

Consult experts and design a regimen that follows all the recommendations made in this guideline, looking for a minimum of 4 new drugs, following the rational classification provided (Groups 1 to 5), with the aim of including the maximum number of bactericidal and sterilizing drugs

CP: continuation phase. Until completion of 21 months of treatment; IP: intensive phase. Until cultures become negative, or up to 6 months in case of extensive lesions. Continue for at least 4 months if the patient is not expectorating and no follow-up sputum tests can be performed.

Sources: Caminero et al.6; World Health Organization8; Caminero.55

a

At least 4 months or until sputum smear testing becomes negative.

b

High doses of Mfx (800mg).

c

High doses of H (15–20mg/kg body weight).

d

The injectable drug may be given 3 times per week (with an interval of 48h between doses) when sputum smears become negative.

e

Two Group 4 drugs will be chosen on the basis of availability and potential adverse effects.

The total duration of this combination of 4 new drugs plus Z is much more controversial. The conventionally recommended regimens of more than 21 months3,4,8,9 have not achieved success rates greater than 55%–70%, particularly due to high drop-out rates,40,57,58 which are clearly associated with the extensive length of treatment, and also with poor tolerance and toxicity. For this reason, this guideline recommends that priority be given to the 9- to 12-month schedule recently recommended by the WHO8 for all patients with R-resistant TB, or with MDR-TB who have not previously received FQ or SLID, or who show susceptibility in vitro to these 2 classes of antibiotics (conditional recommendation, very low [

] quality of evidence). This regimen consists of an initial phase of 4 months (or until sputum smears become negative) with kanamycin (Am or Cm in Spain), high-dose moxifloxacin, clofazimine, ethionamide/prothionamide, pyrazinamide, ethambutol, and high-dose H. The continuation phase will be of 5 months of high-dose moxifloxacin, clofazimine, ethambutol, and pyrazinamide. Patients must be closely monitored for possible adverse effects, primarily possible prolongation of the QTc interval on electrocardiogram, due in particular to the high moxifloxacin doses recommended in this regimen.

Surgery can also contribute to the success of the treatment of MDR-TB,6,8,59 although it can only be considered in the few patients that meet the following 3 conditions6: (1) reasonably localized resectable lesion; (2) sufficient respiratory reserve for the patient to tolerate surgery and the postoperative period; and (3) lack of medications available to design a curative regimen for the patient.6 If the last premise is met, surgery may be considered in patients with FQ-resistant MDR-TB or an even broader resistance pattern (conditional recommendation, very low [

Patients should be monitored at least once a month during the intensive treatment phase, and then every 1 or 2 months during the continuation phase. Aspects that should be evaluated in each of these controls are listed in Table 6, and criteria for evaluating treatment outcomes are described in detail in Table 7.60

Available evidence suggests that if a contact of a case with MDR-TB develops TB, they should receive the same treatment as the index case while pending susceptibility test results, with possible subsequent adjustment after the test results are received. If the secondary case is not confirmed microbiologically, as can happen in children, in paucibacillary TB, or in extrapulmonary TB, the regimen of the index case must continue. Systematic treatment of the tubercular infection in contacts of MDR-TB patients is not recommended, unless they have another risk factor for MDR-TB.3,4,6,61

Although TB resistances complicate treatment and the chances of success, following basic rules of management will ensure acceptable cure rates in the vast majority of patients. The basic principles and a summary of most of these guidelines can be found in Table 8.In all cases, an expert should be consulted when designing a treatment scheme for these patients. For this purpose, the foundation of national expert groups sponsored by the health authorities and/or the scientific societies is recommended.The first priority is still to offer patients with susceptible TB the appropriate treatment, in order to avoid the appearance of resistance.

The authors state that they have no conflict of interest.