Injectable Drugs Handbook

[Eri Pfaff]

Thischapter 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).

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.

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.

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 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).

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.

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)

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).

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.

The following are the basic principles involved in the treatment of MDR-TB (recommendations from the 2011 update of Guidelines for the programmatic management of drug-resistant tuberculosis have been incorporated and indicated where applicable) (1).

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.

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.

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.

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.

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