5.1. Introduction

This chapter provides guidance on the strategies for the treatment of multidrug- and extensively drug-resistant TB (M/XDR-TB), with emphasis on regimen design. The treatment of mono- and poly-drug-resistant TB is addressed in Chapter 6. The strategies described in this chapter are largely based on the recommendations from the 2011 update of Guidelines for the programmatic management of drug-resistant tuberculosis, which underwent systematic review and analysis of the evidence for best treatment practice (1).

5.2. Essential assessments prior to designing a programmatic treatment strategy

Access to quality assured DST is a critical component of TB treatment. It is critical for drug-resistant TB programmes to be familiar with the prevalence of drug resistance in new patients, as well as, in different groups of retreatment cases (failure in a new patient using first-line anti-TB regimen, failure in a previously treated patient with first-line anti-TB drugs, relapse, return after loss to follow-up, and others). This data is often obtained from an analysis of a country's drug resistance surveillance (DRS) data.

In addition, it is essential to determine which and with what frequency second-line anti-TB drugs have been used within a given area served by a programmatic strategy. Some second-line anti-TB drugs may have been used only rarely and will likely be effective in drug-resistant TB treatment regimens, while others may have been used extensively, and therefore, have a high probability of ineffectiveness in a large proportion of drug-resistant TB patients.

It is recognized that some drug-resistant TB programmes may have to design strategies based on limited data, as treatment for many patients cannot wait until full assessment DRS and other information are available. In these cases the programme can still follow the basic principles put forth in this chapter on how to design an effective regimen and continue to collect the information needed to design the most optimal treatment strategy.

5.3. Definitions of terms used to describe treatment strategies

The following are definitions of terms often used to describe treatment strategies.

• Standardized treatment: DRS data from representative patient populations are used to base regimen design in the absence of individual DST. All patients in a defined group or category receive the same regimen (see Chapter 4 for risk groups for MDR-TB). Suspected MDR-TB should be confirmed by DST whenever possible.
• Individualized treatment: Each regimen is designed based on the patient's past history of TB treatment and individual DST results.

TB programmes often use a combination of standardized and individualized approaches. However, in situations where DST is unavailable or limited to only one or two first-line drugs, programmes will most commonly use a purely standardized approach. These strategies are discussed in more detail in Section 5.9, which addresses using these strategies in programme conditions.

This Handbook uses the term “empiric” to refer to the initiation of treatment prior to determination of a firm diagnosis of drug-resistant TB. Empiric regimens can be used for both standardized and individualized treatment strategies. For example, an empiric XDR regimen refers to the use of a regimen designed to treat XDR-TB before the diagnosis of XDR-TB is made.

5.4. Classes of anti-TB drugs

The classes of anti-TB drugs have traditionally been divided into first- and second-line anti-TB drugs with isoniazid, rifampicin, pyrazinamide, ethambutol and streptomycin being the primary first-line anti-TB drugs. While this classification is used in this document, it also uses a system that classifies the drugs into five different groups. The five-group system is based on efficacy, experience of use, safety and drug class. WHO will be reviewing this five-group system in the next update of the guidelines for the management of MDR-TB in view of the new drugs being introduced and the emerging evidence on its safety and efficacy. The different groups are shown in Table 5.1. Not all drugs in the same group come from the same “drug class” or have the same efficacy or safety. For more information, see individual descriptions of each group in this section. Individual detailed drug information for all anti-TB drugs is provided in the drug information sheets of Part 3.

TABLE 5.1

WHO recommended grouping of anti-TB drugs.

Group 1: First-line oral agents. Group 1 anti-TB drugs, the most potent and best tolerated, should be used if there is good laboratory evidence and clinical history that suggests that a drug from this group is effective. For patients with strains resistant to low concentrations of isoniazid but susceptible to higher concentrations, the use of high-dose isoniazid may have some benefit (when isoniazid is used in this manner it is considered a Group 5 drug, see below). The newer rifamycins, such as rifabutin, have very high cross-resistance to rifampicin.

Pyrazinamide is routinely added to MDR regimens unless there is a reasonable clinical contraindication for its use (hepatotoxicity or other serious adverse effect). DST to pyrazinamide is not reliable and for this reason it is considered an acceptable practice to use pyrazinamide in a regimen even when a laboratory result demonstrates resistance.

Ethambutol is not routinely added to MDR regimens, however, it can be added if the criteria of it being a likely effective drug are met (see Section 5.7 for criteria of a likely effective drug). Due to difficulties in testing, ethambutol is never considered a key drug in an MDR regimen, even if the strain is found susceptible.

Group 2: Injectable anti-TB drugs. All patients should receive a second-line Group 2 injectable agent in the intensive phase of MDR-TB treatment unless resistance is documented or highly suspected. Either kanamycin, amikacin or capreomycin can be used as a first choice if all meet the criteria of “likely to be effective”. Given the high rates of streptomycin resistance in patients with MDR-TB (greater than 50% is some countries) and extensive use as a first-line agent in many countries, streptomycin is not often used in MDR regimens, even if DST shows susceptibility to it. Kanamycin and amikacin have lower costs than capreomycin, have less toxicity than streptomycin and have been used extensively for the treatment of drug-resistant TB throughout the world. Amikacin and kanamycin are very similar in structure, and they have a high frequency of cross-resistance between them. Amikacin has a lower minimum inhibitory concentration and may be the most efficacious of the two (2), however, clinical comparison is lacking. Capreomycin may have cross-resistance with amikacin/kanamycin if the rrs gene mutation is present, but the clinical implications of this are not well understood. Limited evidence suggests that capreomycin has less ototoxicity than aminoglycosides (3). If an isolate is resistant to both streptomycin and kanamycin, or if DRS data show high rates of resistance to amikacin and kanamycin, then capreomycin is suggested as the injectable of choice. In cases where the strain is resistant to all the second-line injectable drugs (amikacin, kanamycin, and capreomycin), except streptomycin, streptomycin should be considered, as there is little cross-resistance between streptomycin and the other injectable agents.

All Group 2 drugs are given intramuscularly – most commonly injected deeply into the upper outer quadrant of the gluteal muscle. Additionally, Group 2 drugs can be given intravenously, however, they must be given slowly (over 60 minute period) using this method. Full dosing instructions are given in Part 3. In view of the pain caused by the intramuscular injection of kanamycin, some programmes prefer to install a catheter for daily delivery of the drug (a peripherally inserted central line is often required as it is not possible to rotate a standard intravenous catheter for such a long time. However, standard peripheral IV catheters can be used to give patients short breaks from the intramuscular injections). This method of delivery is usually better accepted by the patient but comes with additional costs and requires an expertise that is not readily available in all settings.

There is limited experience in delivering injectable drugs via nebulizers for TB control and no recommendations can be made on this delivery mechanism at this stage.

Group 3: Fluoroquinolones. Fluoroquinolones are often the most effective anti-TB drugs in an MDR-TB regimen. There are two important recommendations regarding fluoroquinolone use from the 2011 update of the Guidelines for the programmatic management of drug-resistant tuberculosis (1).

• In the treatment of patients with MDR-TB, a fluoroquinolone should be used (strong recommendation, very low quality evidence).
• In the treatment of patients with MDR-TB, a later-generation fluoroquinolone rather than an earlier-generation fluoroquinolone should be used (conditional recommendation, very low quality evidence).

In a meta-analysis of MDR-TB treatment (1,2,4), fluoroquinolones were significantly associated with cure and the effect was more pronounced in later-generation fluoroquinolones. In the analysis, “later generation” quinolones were moxifloxacin and levofloxacin, which were compared against ofloxacin. However, ofloxacin is considered to be a second-generation fluoroquinolone, levofloxacin a third-generation, and moxifloxacin and gatifloxacin are considered fourth-generation fluoroquinolones (5). The analysis did not do a comparison of levofloxacin (third generation) versus moxifloxacin (a fourth generation).

Levofloxacin is the l-isomer and more active component of the racemic ofloxacin (racemic = composed of dextrorotatory and levorotatory forms of a compound in equal proportion). Levofoxacin can be considered to have approximately twice the activity against TB than ofloxacin. In one study, levofloxacin had better efficacy against ofloxacin-resistant strains than did ofloxacin, and provides some evidence that levofloxacin can overcome ofloxacin resistance (6). In theory, the weaker activity of ofloxacin could lead to fluoroquinolone resistance quicker. There is little reason for programmes to choose ofloxacin in standardized regimens, and it is likely in the future that ofloxacin will be removed as a choice for TB regimens.

Ciprofloxacin has weaker efficacy against TB than other fluoroquinolones and is not recommended as an anti-TB drug (7).

Gatifloxacin has been associated with serious side-effects, such as hypoglycaemia, hyperglycaemia and new onset diabetes (8). Until more valid data clarifies the safety profile of gatifloxacin in treatment of MDR-TB, moxifloxacin or levofloxacin are the preferred fluoroquinolones.

Fluoroquinolones are known to prolong the QT interval. QT interval prolongation predisposes to torsades de pointes, which may result in sudden death. There is variability between the fluoroquinolones in this effect; however, the prolongation is considered minimal. Additional cardiac monitoring is required when used with drugs that prolong the QT interval (see Chapter 11). Moxifloxacin and gatifloxacin have more effect of QT prolongation than do levofloxacin and ofloxacin (9)

Thus, for the fluoroquinolones, it is suggested that unless there is a strong indication for not doing so, all MDR-TB patients should be treated using “later-generation” fluoroquinolones – levofloxacin or moxifloxacin.

Group 4: Oral bacteriostatic second-line anti-TB drugs. Both ethionamide and prothionamide are prodrugs that need activation by mycobacterial enzymes. There is no clear advantage of ethionamide over prothionamide; efficacy and side-effects also appear similar. Thus, the term “ethionamide/prothionamide” is used throughout this Handbook to indicate that either one can be used. Of the Group 4 drugs, ethionamide/prothionamide performed the best in the meta-analysis of MDR-TB treatment conducted to update the 2011 guidelines (1,4). However, it should be noted that inhA gene mutation in TB bacteria has been associated with cross-resistance with low-level isoniazid resistance and high-level ethionamide resistance (10). If the inhA gene mutation is present, ethionamide/prothionamide can still be included in an MDR regimen, but it should not be counted as a “likely effective second-line anti-TB drug”. Cycloserine and/or para-aminosalicyclic acid (PAS) should be included in MDR regimens. Both PAS and cycloserine share no cross-resistance to other anti-TB drugs. Since the combination of ethionamide/prothionamide and PAS often causes a high incidence of gastrointestinal side-effects and hypothyroidism, these agents are usually used together only when three Group 4 agents are needed. Whether terizidone (containing two molecules of cycloserine) is equally efficacious as cycloserine was unknown at the time of this writing. The drugs in Group 4 may be started at a low dose and escalated over three to 10 days to reduce frequency or severity of side-effects (known as dose-ramping) (11).

Group 5. Group 5 drugs are not recommended by WHO for routine use in MDR-TB treatment. Although all of them have demonstrated some activity at least in vitro or in animal models, the quality of the evidence of their efficacy and safety in humans for the treatment of drug-resistant TB varies. Most of these drugs are, with the exception of bedaquiline and delamanid, not registered for treatment of MDR-TB making their use “off-label.”⁶ In some cases the drugs are quite costly and require intravenous administration (imepenem and meropenem). However, they remain as options in cases where adequate regimens are impossible to design with medications from Groups 1–4. If a situation requires the use of Group 5 drugs, often experts will recommend using two to three drugs from the group given the limited knowledge of efficacy. The following is information that may help choose which Group 5 drugs to use when indicated (for full drug information see Part 3 – Individual Drug Prescribing Information).

• Bedaquiline – See Annex 4 for description of bedaquiline including its indications and safety monitoring requirements.
• Linezolid – Linezolid has shown good activity in vitro and in animal studies. There are also a number of cases of off-label use in M/XDR-TB; it has recently been demonstrated to improve outcomes in XDR-TB (12,13) Of the Group 5 drugs it is considered one of the most effective against TB and is often a key drug in XDR treatment regimens (also see Section 5.15 and Box 5.4). It has numerous severe side-effects including: myelosupression (anaemia, leucopenia, thrombocytopenia and pancytopenia), peripheral neuropathy and lactic acidosis. When serious adverse effects arise the drug often needs to be stopped (in some cases the adverse effect can be managed by decreasing the dose (usually from 600 mg daily to 300 mg daily). While 300 mg dosing is associated with fewer side-effects, it is not known if the lower dosing is as effective or if it will lead to a higher chance of resistance amplification, though some clinical experts have found that the lowering of the dosing due to anaemia quite often coincides with culture conversion, which increases the chance to keep the drug in the treatment regimen.
• Clofazimine – A significant amount of experience with clofazimine in MDR-TB treatment exists (14–16), and it has been included in 9- to 12-month regimens and reported to have very good outcomes (17). However, the efficacy of clofazimine against TB remains unclear. Clofazimine is often added to regimens for XDR-TB. In relation to adverse effects, skin pigmentation occurs in 75% to 100% of patients within a few weeks; reversal can take months to years after the treatment.
• Amoxicillin/clavulanate – Generally, beta-lactam antibiotics are not regarded as very useful drugs against TB, but the addition of the beta-lactamase inhibitor makes them active in vitro against TB. There is limited evidence of in vivo bactericidal activity (18). While amoxicillin/clavulanate is probably a relatively weak anti-TB drug, it is often included within regimens because it is available, inexpensive and with few side-effects.
• Imipenem/cilastin and meropenem. Imipenem and meropenem belong to the drug class “beta-lactam-carbapenem,” given only intravenously. Due to cost and difficulty in dosing, it is not commonly used in resource-constrained settings. A similar drug – Meropenem – is preferred for use in children and adults with central nervous system disease, as there is less association with seizure. Given that imipenem is rapidly degraded by renal proximal tubule dipeptidases, it is marketed in combination with the dipeptidase inhibitor, cilastatin. Conversely, meropenem is stable to renal dipeptidases and requires no cilastatin (19). Since it is in the beta-lactam class of antibiotics it is likely that these imipenem/cilastin and meropenem can benefit from the addition of clavulanate 125 mg every 8–12 hours. Clavulanate was added to merpenem in one study of XDR-TB patients with reasonably good outcome results (13). (Clavulanate is not readily available alone and some give it as amoxicillin/clavulanate 500 mg/125 mg oral tablet).
• High-dose isoniazid. Many experts feel that high-dose isoniazid can be used against strains resistant to low concentrations of isoniazid but susceptible to higher doses (20) (>1% of bacilli resistant to 0.2 mcg/ml but susceptible to 1 mcg/ml of isoniazid), whereas, isoniazid is not recommended for high-dose resistance (>1% of bacilli resistant to 1 mcg/ ml of isoniazid). Some experts give 900 mg three times a week (21) in adults while others use as high as 16–20 mg/kg/day (22) Good data are not available on the safety of high-dose isoniazid and there may be possible associated higher rates of peripheral neuropathy, hepatitis and other unforeseen adverse effects. Experts also recommend not using isoniazid if the strain is documented to have a katG gene mutation. The katG mutation is detected by line probe assay tests available today.
• Thioacetazone. While thioacetazone is a drug with known efficacy against TB, it is placed in Group 5 because its role in drug-resistant TB treatment is not well established. Overall, a weak bacteriostatic drug, thioacetazone has cross-resistance with ethionamide (23) and isoniazid (24,25). Thioacetazone is contraindicated in HIV-infected individuals (26) due to a serious risk of adverse reaction that can result in Stevens-Johnson Syndrome and death. The drug is also not well-tolerated in persons of Asian origin. For all these reasons, this drug is rarely added as a Group 5 drug. Until there is more information on its role in MDR-TB therapy, most experts advise drug-resistant TB programmes not to include thioacetazone, especially if HIV status is unknown.
• Clarithromycin. Clarithromycin is included in Group 5, but its activity against M. tuberculosis is uncertain. Some studies suggest that clarithromycin may have a synergistic effect with oral first-line agents (27,28) but synergy data with second-line drugs is absent. Most experts consider clarithromycin a very weak anti-TB drug and consider it to have no role in MDR-TB treatment.

5.5. Standard code for TB treatment regimens

There is a standard code for writing TB treatment regimens. Each anti-TB drug has an abbreviation (shown in Table 5.1 and in the abbreviations list provided at the front of this book). A drug-resistant TB regimen consists of two phases: the first phase is the period in which the injectable agent is used, and the second is after it has been stopped. These two phases are generally separated by a backslash (/). The number before each phase stands for phase duration in months, and this number is the minimum amount of time that the stage should last. The number in subscript (e.g. ₃) after a letter is the number of drug doses per week. If there is no number in subscript, treatment is daily (injectables are generally given for 5–6 days per week). The drugs in the higher groups are written first followed by others in descending group order. Examples are given in Box 5.1.

BOX 5.1

EXAMPLES OF STANDARD DRUG CODE USED TO DESCRIBE DRUG REGIMENS. 8Km⁶-Lfx⁷-Eto⁷-Cs⁷-Z⁷/12Lfx⁷-Eto⁷-Cs⁷-Z⁷ The initial phase consists of five drugs and lasts for eight months in most patients (see Section 5.9). Kanamycin is given six days a week and all (more...)

5.6. Role of drug susceptibility testing

See Chapter 3 for a full discussion on the use of DST in programmatic management of drug-resistant TB. Countries have varying access to reliable mycobacterial laboratories, and many do not have regular local access to DST. The inability to do routine DST in all patients should not be a barrier for patients that need MDR regimens. Fully standardized regimens using second-line anti-TB drugs have been shown to be feasible and cost-effective in drug-resistant TB treatment (29–31).

The reliability and clinical value of DST for some first-line and most second-line anti-TB drugs is not fully determined (see Chapter 3). DST does not predict with 100% certainty the effectiveness or ineffectiveness of a drug (32). DST for ethambutol, streptomycin, pyrazinamide, Group 4 and 5 drugs presents problems with accuracy and reproducibility in most settings. Thus, current WHO guidelines caution against basing individual regimens on DST results to these drugs. DST to isoniazid, rifampicin, the fluoroquinolones, and the second-line injectable agents are considered accurate and reproducible; when DST results are from a quality-assured laboratory, individual regimens can be based on the DST results for these drugs.

In countries where reliable DST is not available, the Xpert MTB/RIF assay can be quickly introduced and used as initial diagnostic tool for MDR-TB (see Chapter 4 for more information on the use of Xpert as a test for MDR-TB). While strategies can be designed with Xpert MTB/RIF as the only DST mechanism or even just based on TB treatment history to identify MDR-TB, every effort should be made to improve laboratory capacity of aTB programme to have access to conventional phenotypic DST and/or a secondary molecular DST method (see Chapter 3).

5.7. Designing and administrating an MDR regimen

This section describes the methods for designing and administrating an MDR regimen. It applies to standardized and individualized regimens. WHO interim policy on the use of delamanid will be released later in 2014, and should be taken into account when designing a MDR-TB treatment regimen.

5.7.2. Adjusting an empiric standardized regimen or designing an individualized regimen

Empiric standardized regimens often need to be adjusted based on patient clinical history, once additional history or when DST results becomes available. Individual regimens are designed based on DST of the infecting strain, patient's history of TB treatment and contact history. Figure 5.1 describes the steps to build a regimen for drug-resistant TB treatment.

Figure 5.1

Building an MDR-TB Regimen (34).

5.8. Designing a treatment strategy for the drug-resistant TB component of the TB programme

Treatment strategies for drug-resistant TB may vary depending on access to DST and drugs, rates of drug-resistant TB, HIV prevalence, technical capacity and financial resources. TB programmes may need to adjust the strategy to meet special circumstances and the local context.

Representative DST survey data for different types of patients – new, relapse, retreatment after loss to follow-up, failure of initial or retreatment with first-line anti-TB treatment, and failure of treatment with second-line anti-TB drugs – are critical when making choices in treatment strategies.

For a standardized regimen that will treat the vast majority of patients with four effective second-line anti-TB drugs plus pyrazinamide, it is may be necessary to use more than four second-line drugs plus pyrazinamide to cover all possible resistance patterns.

When using an empiric standardized regimen, TB programmes are strongly encouraged to also order drugs from groups and classes that are not routinely included in the standardized regimen. For example, a programme that uses an empiric standardized regimen that does not include PAS will still need PAS in the following situations: (i) patients intolerant to one of the core drugs; (ii) pregnant patients with drug-resistant TB who cannot take all the drugs in the standard regimen; (iii) as part of a regimen in whom the standardized MDR treatment regimen has failed or in regimens for XDR-TB. All programmes are encouraged to have regimens designed to treat XDR-TB for when the standardized MDR regimen fails.

In MDR treatment strategies that initially enrol patients based on their strain being resistant to rifampicin alone, isoniazid may be included in the standard regimen until DST to isoniazid can be done to determine if it should be continued. Even when mono- or poly-rifampicin resistance is relatively common, isoniazid can be added to the regimen. However, in situations where mono- or poly-rifampicin resistance is extremely rare (only 1% or 2% of all rifampicin resistance), it is reasonable to leave isoniazid out of an empiric standardized MDR treatment regimen; it can be added later if the patients strain is determined to be susceptible.

Box 5.2 provides three examples to design an MDR treatment regimen. The first example is designing a standardized regimen based on drug resistance survey data and the second example illustrates designing a regimen based on individual DST. Regimen design for XDR-TB is described in Section 5.15.

BOX 5.2

EXAMPLES OF STANDARDIZED AND INDIVIDUALIZED REGIMEN DESIGN. EXAMPLE 1: A standardized MDR regimen based on drug resistance survey data where resistance to second-line anti-TB drugs is low. Survey data from 200 consecutively enrolled relapse patients from (more...)

Some programmes or clinicians may choose to use a shorter (eg. 9–12 months) MDR-TB treatment regimen consisting of combinations of later-generation fluoroquinolones (moxifloxacin or gatifloxacin), clofazimine, ethambutol and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin, and high-dose isoniazid during an intensive phase. The evidence for these shorter regimens comes from limited observational studies. By May 2014, only one study of a patient series in Bangladesh using a short regimen had as yet been published in a peer-reviewed journal (17). An ongoing randomized clinical trial is evaluating the efficacy and safety of a shorter regimen to treat MDR-TB treatment and results should be available around 2017 (51). Those who choose to use shorter regimens should be aware that these regimens have not been evaluated in the treatment of XDR-TB, and are likely to acquire additional resistance in patients already harbouring bacilli resistant to second-line drugs. Hence such regimens should not be considered for treatment of XDR-TB, among patients with demonstrated resistance to a second-line injectable or any fluoroquinolone, or for patients who have been previously exposed for more than one month to second-line anti-TB drugs. The combined off-label use of clofazimine and other drugs that prolong the QTc interval on the ECG (i.e. fluoroquinolones) in these regimens require active pharmacovigilance (see Chapter 11) to enable proper surveillance management of safety issues. The longer treatment regimens for MDR-TB represent the standard of care which has been used more widely and for much longer (52); they also have shown to bear good outcomes in a number of countries and the adverse drug reactions associated with them have been well documented (53). It is therefore imperative that clinicians and/or NTPs pursue an informed consent process with patients before the start of treatment, under the oversight of a national or local ethics committee. Some programmes may choose to enrol cohorts of patients for treatment with shorter regimens within the context of observational studies, aimed at producing evidence on its safety and effectiveness to inform local and global policy. Adherence to the international standards of good clinical practice should be applied by the corresponding programme managers of those observational studies, including appropriate independent monitoring (54).

5.9. Duration of the intensive phase (length of use of injectable drugs)

The time the MDR-TB patient is on injectable anti-TB drugs is referred to as the intensive phase of treatment.

In the treatment of patients with MDR-TB, an intensive phase of eight months is suggested for most patients, and the duration may be modified according to the patient's response to therapy (conditional recommendation, very low quality evidence) (1).

The main indication of response to therapy is smear- and culture-conversion (defined in Chapter 2), however, the overall clinical picture (weight gain, resolution or improvement of respiratory symptoms and/or lesions in pulmonary images) can also be taken into consideration in deciding whether to continue an injectable agent for longer than eight months. In a meta-analysis conducted in the preparation of the WHO Guidelines for the programmatic management of drug-resistant tuberculosis (1), there was no demonstrated benefit of injectable phases beyond eight months and, in general, failure of treatment should be started to be considered for those that have not culture converted by month eight.

In respect to smear- and culture-conversion, expert opinion is that the intensive phase should also continue for at least four months past conversion; but little evidence exists and the optimal time past conversion has not been determined. The optimal duration of the injectable phase in patients with minimal disease has also not been determined; programmes may decide on a case-by-case basis that such patients could receive less than an 8-month intensive phase, provided that they have converted for at least four months.

Intermittent therapy with the injectable agent (thrice a week) can also be considered in patients who have been on the injectable for a prolonged period of time and when toxicity becomes a greater risk to the patient (11). This is based on expert opinion, as no direct comparisons of thrice a week versus daily doses exist.

If the patient was on an empiric regimen of more than four second-line anti-TB drugs, some of the oral second-line anti-TB drugs, in addition to the injectable agent, can be considered for suspension at the end of the intensive phase. This is usually done when DST results show susceptibility to at least four second-line agents, the drugs are still considered effective, and the patient has had a good response to therapy.

Usually, pyrazinamide is continued for the entire treatment, especially if there is extensive parenchymal lung damage. However, there is no data on the optimal length of time to use pyrazinamide in MDR-TB treatment. If the patient has minimal disease, some clinicians stop pyrazinamide with the injectable agent at the end of the intensive phase. In all situations, the patient should at the very least continue with three of the most potent second-line anti-TB drug that are determined to be effective against the patient's infecting strain of M. tuberculosis.

5.10. Total duration of treatment

In the treatment of patients newly diagnosed with MDR-TB (i.e. not previously treated for MDR-TB), a total treatment duration of 20 months is suggested for most patients, and the duration may be modified according to the patient's response to therapy (conditional recommendation, very low quality evidence) (1).

The main method used to assess response to therapy is through smear- and culture-conversion (defined in Chapter 2); however, clinical symptoms and radiographs can also be taken into consideration when deciding if treatment should be longer than 20 months. Whether the total treatment duration should be based on time past conversion has not been determined. Some clinicians and programmes may prefer to treat at least twelve months past conversion (but not less than 20 months total).

The meta-analysis conducted in preparation of the WHO Guidelines for the programmatic management of drug-resistant tuberculosis (1) indicated that in patients previously-treated with MDR regimen a total duration of treatment of more than 24 months was more successful, although the number of patients observed was relatively small. Therefore, patients previously treated for MDR-TB (and often XDR-TB patients) generally receive at least 24 months of therapy in most programmes.

5.11. Extrapulmonary and central nervous system drug-resistant TB

Extrapulmonary drug-resistant TB is treated with the same strategy and duration as pulmonary drug-resistant TB; the one exception is central nervous system involvement. If the patient has symptoms suggestive of central nervous system involvement and is infected with drug-resistant TB, then the regimen should use drugs, which have adequate penetration into the central nervous system. Isoniazid, pyrazinamide, prothionamide/ethionamide and cycloserine, all have good penetration into the cerebrospinal fluid, whereas kanamycin, amikacin and streptomycin do so only in the presence of meningeal inflammation. Additionally, the penetration of capreomycin is less studied and not well determined. PAS and ethambutol have poor or no penetration. The fluoroquinolones have variable cerebrospinal fluid penetration, with better penetration of moxifloxacin based on animal studies. There is no data on central nervous system penetration of clofazimine or clarithromycin. Linezolid is believed to penetrate the central nervous system, and has been used in meningitis treatment (35). Imipenem has good central nervous system penetration, but children with meningitis treated with imipenem, had high rates of seizures (meropenem is preferred for meningitis cases and children) (11,36,37).

5.12. Surgery in treatment of drug-resistant TB

The most common surgical procedure in patients with pulmonary drug-resistant TB is resection surgery (taking out part or all of a lung). Large case series analysis has proven resection surgery to be effective and safe under appropriate surgical conditions (38). It is considered an adjunct to chemotherapy and appears to be beneficial for patients when skilled thoracic surgeons and excellent postoperative care are available (39). It is not indicated in patients with extensive bilateral disease. The case series which showed surgery to be effective may have a selection bias, as very sick patients with co-morbidities, older patients, and those with extensive disease are often excluded from surgery.

Resection surgery should be timed such that the patient has the best possible chance of cure with the least morbidity. Thus, the timing of surgery may be earlier in the course of the disease when the patient's risk of morbidity and mortality are lower, for example, when the disease is still localized to one lung or one lung lobe. In other words, surgery should not be considered a last resort. Generally, at least two months of therapy should be given prior to resection surgery to decrease the bacterial infection in the surrounding lung tissue. Even with successful resection, the intensive phase and total treatment duration should be guided by the recommendations in Sections 5.9 and 5.10.

Specialized surgical facilities should include stringent infection control measures, given that infectious substances and aerosols are generated in large quantities during surgery, mechanical ventilation and post-operative pulmonary hygiene manoeuvres.

Many programmes will have limited access to surgical interventions. General indications for resection surgery for programmes with limited access to surgery include patients that remain smear-positive, with resistance to a large number of drugs; and localized pulmonary disease. Computerized tomography, pulmonary function testing and quantitative lung perfusion/ ventilation is recommended as part of the preoperative work-up. In programmes with sub-optimal surgical facilities with no trained thoracic surgeons, resection surgery should not be performed as the result may increase morbidity or mortality.

5.13. Adjuvant therapies in drug-resistant TB treatment

The role of adjuvant therapies has not been well established. Nonetheless, some adjunctive modalities have proven beneficial in specific indications (i.e. the use of corticosteroids in certain forms of TB such as central nervous system and pericardial involvement) while others show potential to improve outcomes (i.e. immunomodulators) (40).

5.14. Nutritional support

Drug-resistant TB treatment (as with all TB treatment) and care should contain integrated nutritional assessment counselling and support for the duration of the illness.

In addition to causing malnutrition, as in other forms of TB, drug-resistant TB can be exacerbated by poor nutritional status. Without nutritional support, patients, especially those already suffering from borderline hunger, can become enmeshed in a vicious cycle of malnutrition and disease. The second-line anti-TB medications can also further decrease appetite, making adequate nutrition a greater challenge. Providing free food probably does improve weight gain during treatment, and is thought to improve quality of life but further research is necessary (41). Food support may improve treatment adherence in settings were food insecurity is an important access barriers.

Vitamin B6 (pyridoxine) should be given to all MDR-TB patients receiving cycloserine or terizidone, and a high dosage of isoniazid or linezolid to prevent neurological side effects (see Chapter 11 for dosing and more information). Vitamin (especially vitamin A) and mineral supplements can be given in areas where a high proportion of the patients have these deficiencies. If multivitamins and minerals (zinc, iron, calcium, etc.) are given they should be dosed three to four hours apart from the fluoroquinolones, as these can interfere with the absorption of these drugs. Of note, no studies have assessed whether vitamins improve TB cure. Vitamins probably don't improve weight gain, and no studies have assessed their effect on quality of life (41).

5.15. Treatment of XDR-TB

XDR-TB was first defined in 2006 and is estimated to occur in about 9.6% of MDR-TB patients (42). While it occurs all over the world, it has been reported as a significant problem in a number of countries (39,42). Likelihood of cure has proven to be much lower than in other MDR-TB cases and deaths are higher, especially in HIV-infected patients (39,44–48). There is very limited data on the different clinical approaches to XDR-TB and a recent review of treatment outcomes of XDR-TB patients could not find any associations between any specific drug or regimen and success; however, the analysis did indicate that success in XDR-TB patients was highest if at least six drugs were used in the intensive phase and four in the continuation phase (48). A different meta-analysis provides empiric evidence that the use of later-generation fluoroquinolones significantly improved treatment outcomes in patients with XDR-TB, even though DST demonstrated resistance to a representative fluoroquinolone (47).

While data on efficacy and safety is limited, the incorporation of bedaquiline into regimens designed to treat XDR-TB may be considered (49) (See Annex 4).

New anti-TB drugs are currently being developed and programme managers should keep abreast of WHO recommendations as they are released and updated though the website of the Task Force for New Drug Policy Development (50). For more information on compassionate use and early access programmes see Chapter 22.

Box 5.3 summarizes the latest expert consensus on managing XDR-TB and Box 5.4 provides an example of designing a regimen for the treatment of XDR-TB.

BOX 5.3

TREATMENT MANAGEMENT FOR PATIENTS WITH DOCUMENTED, OR ALMOST CERTAIN, XDR-TB. Use pyrazinamide and any other Group 1 agent that may be effective. Use an injectable agent to which the strain is susceptible and consider an extended duration of use (12 months (more...)

BOX 5.4

EXAMPLE OF AN XDR-TB REGIMEN DESIGN. EXAMPLE 1. A patient failed the standardized regimen of Z-Km-Lfx-Eto-Cs and remained sputum smear-positive after eight months of treatment. The DST from a specimen taken four months ago revealed resistance to HRZE-S-Km-Cm-Lfx (more...)

References

1.

Guidelines for the programmatic management of drug-resistant tuberculosis. Geneva: World Health Organization; 2011. [15 March 2014]. pp. 1–44. http://www​.who.int/tb​/challenges/mdr/programmatic​_guidelines_for_mdrtb/en/index​.html.

2.

Dooley KE, Mitnick CD, Degroote MA, Obuku E, Belitsky V, Hamilton CD, et al. Old drugs, new purpose: retooling existing drugs for optimized treatment of resistant tuberculosis. Clinical Infectious Diseases. 2012;55(4):572–581. [PMC free article: PMC3520382] [PubMed: 22615332]

3.

Sturdy A, Goodman A, Jose RJ, Loyse A, O'Donoghue M, Kon OM, et al. Multidrug-resistant tuberculosis (MDR-TB) treatment in the UK: a study of injectable use and toxicity in practice. Journal of Antimicrobial Chemotherapy. 2011;66(8):1815–1820. [PubMed: 21642291]

4.

Menzies R. Multidrug-resistant tuberculosis treatment regimens and patient outcomes: an Individual Patient Data (IPD) meta-analysis of 9153 patients. PLoS Medicine. 2012 August 28 [PMC free article: PMC3429397] [PubMed: 22952439] [CrossRef]

5.

Ziganshina LE, Titarenko AF, Davies GR. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive). Cochrane Database Syst Rev. 2013 Jun 6;6 CD004795. Review. [PubMed – indexed for MEDLINE] [PMC free article: PMC6532730] [PubMed: 23744519] [CrossRef]

6.

Yew WW, Chan CK, Leung CC, Chau CH, Tam CM, Wong PC, et al. Comparative roles of levofloxacin and ofloxacin in the treatment of multidrug-resistant tuberculosis: preliminary results of a retrospective study from Hong Kong. Chest. 2003;124(4):1476–1481. [PubMed: 14555582]

7.

Moadebi S, Harder CK, Fitzgerald MJ, Elwood KR, Marra F. Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs. 2007;67(14):2077–2099. [PubMed: 17883288]

8.

Park-Wyllie LY, Juurlink DN, Kopp A, Shah BR, Stukel TA, Stumpo C, et al. Outpatient gatifloxacin therapy and dysglycemia in older adults. New England Journal of Medicine. 2006;354(13):1352–1361. [PubMed: 16510739]

9.

Stahlmann R, Lode H. Safety considerations of fluoroquinolones in the elderly. Drugs & Aging. 2010;27(3):193–209. [PubMed: 20210367]

10.

Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263(5144):227–30. [PubMed: 8284673]

11.

Drug-resistant tuberculosis: a survival guide for clinicians. Curry International Tuberculosis Center, California Department of Health Sciences; 2008. [15 March 2014]. http://www​.currytbcenter​.ucsf.edu/products/product_details​.cfm?productID=WPT-11.

12.

Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. New England Journal of Medicine. 2012;367(16):1508–1518. [PMC free article: PMC3814175] [PubMed: 23075177]

13.

De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D'Ambrosio L, Tiberi S, et al. Efficacy and safety of meropenem-clavulanate added to linezolid-containing regimens in the treatment of MDR-/XDR-TB. European Respiratory Journal. 2013;41(6):1386–1392. [PubMed: 22997218]

14.

Cholo MC, Steel HC, Fourie PB, Germishuizen WA, Anderson R. Clofazimine: current status and future prospects. Journal of Antimicrobial Chemotherapy. 2012;67(2):290–298. [PubMed: 22020137]

15.

Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N. Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. Journal of Antimicrobial Chemotherapy. 2013;68(2):284–293. [PubMed: 23054996]

16.

Gopal M, Padayatchi N, Metcalfe JZ, O'Donnell MR. Systematic review of clofazimine for the treatment of drug-resistant tuberculosis. International Journal of Tuberculosis and Lung Disease. 2013;17(8):1001–1007. [Review article] [PMC free article: PMC4003893] [PubMed: 23541151]

17.

Van Deun A, Maug AKJ, Salim MA, Das PK, Sarker MR, Daru P, et al. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. American Journal of Respiratory and Critical Care Medicine. 2010;182(5):684–692. [PubMed: 20442432]

18.

Donald PR, Diacon AH. The early bactericidal activity of anti-tuberculosis drugs: a literature review. Tuberculosis (Edinburgh, Scotland). 2008;88 Suppl 1:S75–S83. [PubMed: 18762155]

19.

Garges HP, Alexander KA. Pharmacology review newer antibiotics: imipenem/cilastatin and meropenem. NeoReviews. 2003;4(12):e364–e368.

20.

Katiyar SK, Bihari S, Prakash S, Mamtani M, Kulkarni H. A randomised controlled trial of high-dose isoniazid adjuvant therapy for multidrug-resistant tuberculosis. International Journal of Tuberculosis and Lung Disease. 2008;12(2):139–145. [PubMed: 18230245]

21.

PIH guide to medical management of multidrug-resistant tuberculosis. Boston: Partners in Health; 2003. [15 March 2014]. http://www​.pih.org/publications​/entry/pih-guide-to-the-medical-management-of-multidrug-resistant-tuberculosis/

22.

Rom WN, Garay SM, editors. Tuberculosis. Philadelphia: Lippincott Williams & Wilkins; 2004.

23.

DeBarber AE, Mdluli K, Bosman M, Bekker LG, Barry CE. Ethionamide activation and sensitivity in multidrug-resistant Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America. 2000;97(17):9677. [15 March 2014]; http://www​.pnas.org/content/97/17/9677​.short. [PMC free article: PMC16924] [PubMed: 10944230]

24.

Tsukamura M. Cross-resistance of tubercle bacilli. A review. Kekkaku. 1977;52(2):47–49. [PubMed: 404456]

25.

Lefford MJ. The ethionamide sensitivity of East African strains of Mycobacterium tuberculosis resistant to thiacetazone. Tubercle. 1969;50(1):7–13. [PubMed: 4181091]

26.

Nunn P, Brindle R, Wasunna K, Gilks C, Omwega M. Cutaneous hypersensitivity reactions due to thiacetazone in HIV-1 seropositive patients treated for tuberculosis. Lancet. 1991;337:627–630. [PubMed: 1705647]

27.

Cavalieri SJ, Biehle JR, Sanders WE. Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy. 1995;39(7):1542–1545. [PMC free article: PMC162778] [PubMed: 7492101]

28.

Mor N, Esfandiari A. Synergistic activities of clarithromycin and pyrazinamide against Mycobacterium tuberculosis in human macrophages. Antimicrobial Agents and Chemotherapy. 1997;41(9):2035–2036. [PMC free article: PMC164062] [PubMed: 9303411]

29.

Suárez PG, Floyd K, Portocarrero J, Alarcón E, Rapiti E, Ramos G, et al. Feasibility and cost-effectiveness of standardised second-line drug treatment for chronic tuberculosis patients: a national cohort study in Peru. Lancet. 2002;359(9322):1980–1989. [PubMed: 12076553]

30.

Malla P, Kanitz EE, Akhtar M, Falzon D, Feldmann K, Gunneberg C, et al. Ambulatory-based standardized therapy for multi-drug-resistant tuberculosis: experience from Nepal, 2005–2006. PLoS One. 2009;4(12):e8313. [PMC free article: PMC2794372] [PubMed: 20041140]

31.

Brust JCM, Shah NS, Scott M, Chaiyachati K, Lygizos M, van der Merwe TL, et al. Integrated, home-based treatment for MDR-TB and HIV in rural South Africa: an alternate model of care [Perspectives] International Journal of Tuberculosis and Lung Disease. 2012;16(8):998–1004. [PMC free article: PMC3390442] [PubMed: 22668560]

32.

Kim SJ. Drug susceptibility testing in tuberculosis: methods and reliability of results. European Respiratory Journal. 2005;25(3):564–569. [PubMed: 15738303]

33.

Bassili A, Fitzpatrick C, Qadeer E, Fatima R, Floyd K, Jaramillo E. A systematic review of the effectiveness of hospital- and ambulatory-based management of multidrug-resistant tuberculosis. American Journal of Tropical Medicine and Hygiene. 2013;89(2):271–280. [PMC free article: PMC3741248] [PubMed: 23926140]

34.

Varaine F, Rich M, editors. Tuberculosis: Practical Guide for Clinicians, Nurses, Laboratory Technicians and Medical Auxiliaries. Médecins San Frontières and Partners In Health. 2013:1–299.

35.

Tuberculosis drug information guide. 2nd edition. California: Curry International Tuberculosis Center and California Department of Public Health; 2012.

36.

Holdiness MR. Cerebrospinal fluid pharmacokinetics of the antituberculosis drugs. Clinical Pharmacokinetics. 1985;10:532–534. [PubMed: 4064452]

37.

Daley CL. Mycobacterium tuberculosis complex. In: Yu VL, Merigan TC Jr, Barriere SL, editors. Antimicrobial Therapy and Vaccines. Williams & Wilkins; 1999. pp. 531–6.

38.

Francis RS, Curwen MP. Major surgery for pulmonary tuberculosis: Final Report. Tubercle. 1964;45 Suppl:5–79. [PubMed: 14182968]

39.

Emergence of Mycobacterium tuberculosis with extensive resistance to second-line drugs – worldwide, 2000–2004. Morbidity and mortality weekly report. 2006;55(11):301–305. [PubMed: 16557213]

40.

Report of the expert consultation on immunotherapeutic interventions for tuberculosis. Geneva: World Health Organization; 2007. pp. 1–56.

41.

Sinclair D, Abba K, Grobler L, Sudarsanam TD. Nutritional supplements for people being treated for active tuberculosis. Cochrane Database Systematic Review. 2011:1–139. [PubMed: 22071828]

42.

Global tuberculosis report 2013. Geneva: World Health Organization; 2013. pp. 1–289.

43.

Gandhi NR, Moll A, Sturm AW, Pawinski R, Govender T, Lalloo U, et al. Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa. Lancet. 2006;368(9547):1575–1580. [PubMed: 17084757]

44.

Pietersen E, Ignatius E, Elizabeth, Streicher E, Mastrapa B, Padanilam X, Pooran A, Badri M, Lesosky M, van Helden P, Sirgel FA, Warren R, Dheda K. Long-term outcomes of patients with extensively drug-resistant tuberculosis in South Africa: a cohort study. Lancet. 2014;383:1230–1239. [PubMed: 24439237]

45.

Migliori GB, Ortmann J, Girardi E, Besozzi G, Lange C, Cirillo DM, et al. Extensively drug-resistant tuberculosis, Italy and Germany. Emerging Infectious Diseases. 2007;13(5):780–782. [PMC free article: PMC2738462] [PubMed: 18044040]

46.

Jeon CY, Hwang SH, Min JH, Prevot DR, Goldfeder LC, Lee H, et al. Extensively drug–resistant tuberculosis in South Korea: risk factors and treatment outcomes among patients at a tertiary referral hospital. Clinical Infectious Diseases. 2008;46(1):42–49. [PubMed: 18171212]

47.

Jacobson KR, Tierney DB, Jeon CY, Mitnick CD, Murray MB. Treatment outcomes among patients with extensively drug-resistant tuberculosis: systematic review and meta-analysis. Clinical Infectious Diseases. 2010;51(1):6–14. [PMC free article: PMC4013786] [PubMed: 20504231]

48.

Falzon D, Gandhi N, Migliori GB, Sotgiu G, Cox HS, Holtz TH, et al. Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes. European Respiratory Journal. 2013;42(1):156–168. [PMC free article: PMC4487776] [PubMed: 23100499]

49.

The use of bedaquiline in the treatment of multidrug-resistant tuberculosis. Geneva: World Health Organization; 2013. pp. 1–64.

50.

Tuberculosis (TB) Task Force for New Drug Policy Development. [15 March 2014]. [Webpage] http://www​.who.int/tb​/advisory_bodies/newdrugs_taskforce/en/

51.

STREAM to test a 9-month MDR-TB treatment regimen (underway). Available from: http://www​.theunion.org/index​.php/en/what-we-do​/research/clinical-trials​/item/254-stream-to-test-a-9-month-mdr-TB-treatment-regimen.

52.

Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, et al. Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Medicine. 2012;9(8):e1001300. [PMC free article: PMC3429397] [PubMed: 22952439]

53.

Bloss E, Kuksa L, Holtz TH, Riekstina V, Skripconoka V, Kammerer S, et al. Adverse events related to multidrug-resistant tuberculosis treatment, Latvia, 2000–2004. International Journal of Tuberculosis and Lung Disease. 2010 Mar;14(3):275–81. [PubMed: 20132617]

54.

Verma K. Base of a Research: Good Clinical Practice in Clinical Trials. Journal of Clinical Trials. 2013;3:128.

Footnotes

6

Off-label use is the practice of prescribing a drug to treat a medical condition for which a stringent drug regulatory body has not approved the indication. It may also include using the drug in an age group not yet approved for or in a dosage or form of administration different from the original approval.