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Programmatic approaches to MDR-TB treatment depend in part on the type of labo- ratory method used to confirm MDR (see Figure 7.1). Once MDR-TB is confirmed (by either type of laboratory method), patients can be treated with:

— a standard MDR regimen (standardized approach); or

— an individually tailored regimen, based on DST of additional drugs.

For NTPs using conventional DST methods, there is often a delay of months before results are available to confirm or exclude MDR. These countries need to consider MDR treatment at two stages: when MDR is suspected but laboratory confirmation is pending, and once MDR is confirmed. While awaiting results, patients who are highly likely to have MDR-TB (such as those whose prior treatment has failed) need an empirical MDR regimen. If MDR is confirmed, this regimen may be continued, or it may be tailored on the basis of susceptibility to drugs other than isoniazid and rifampicin, as discussed in section 7.7.

NTPs using rapid molecular-based DST will be able to confirm MDR-TB within 1–2 days,2 _{and then can initiate treatment with a standard MDR regimen immediately, or}

1 _{Programmatic strategies for MDR-TB treatment (standardized or individualized approaches) are} described in section 7.5.

2 _{Line probe assays detect resistance to rifampicin alone or in combination with isoniazid resistance.} Overall high accuracy for detection of MDR is retained when rifampicin resistance alone is used as a marker for MDR (3, 4).

may tailor the regimen later when DST results for second-line drugs become avail- able, as discussed in section 7.7.

Standardized and individualized approaches each have advantages. Standard MDR- TB regimens (5) make it easier to estimate drug needs, to order, manage and dis- tribute drug stocks, and to train personnel in the treatment of MDR-TB patients. Even when standard regimens are used throughout treatment, patients experiencing severe adverse effects will need to have their MDR treatment individualized. Thus all programmes need some capacity to individualize treatment.

7. TrEaTmEnT of druG-rESISTanT TubErCuloSIS

Table 7.2 generAl principleS for deSigning mdr-TB TreATmenT regimenSa

Principles Comments

1. use at least 4 drugs certain to be effective

The more of the following factors are present, the more likely it is that the drug will be effective:

• resistance to these drugs is known from surveys to be rare in similar patients.

• dST results show susceptibility to drugs for which there is good laboratory reliability: injectable agents and fluoroquinolones.

• The drug is not commonly used in the area. • (for decisions about an individual patient – no prior

history of treatment failure with the drug; no known close contacts with resistance to the drug.)

2. do not use drugs for which there is the possibility of cross-resistance

• many antituberculosis agents exhibit cross-resistance both within and across drug classes (see section 7.3). 3. eliminate drugs that are not

safe

• quality of the drug is unknown.

• (for decisions about an individual patient – known severe allergy or unmanageable intolerance; high risk of severe adverse drug effects such as renal failure, deafness, hepatitis, depression and/or psychosis.)

4. include drugs from groups 1–5 in a hierarchical order based on potency (see Table 7.1 and section 7.3)

• use any of the first-line oral agents (group 1) that are likely to be effective.

• use an effective aminoglycoside or polypeptide by injection (group 2).b

• use a fluoroquinolone (group 3).

• use the remaining group 4 drugs to complete a regimen of at least four effective drugs.

• for regimens with fewer than four effective drugs, consider adding two group 5 drugs. The total number of drugs will depend on the degree of uncertainty, and regimens often contain five to seven.

a _{Adapted from Table 7.3 of reference 1.}

b _{Avoid streptomycin even if dST suggests susceptibility because of high rates of resistance with resis-} tant TB strains and higher incidence of ototoxicity.

Changing to an individualized regimen (once DST results are available for additional drugs beyond isoniazid and rifampicin) is advantageous because it:

• Allows clinicians to design a regimen with knowledge of resistance to particular injectables and fluoroquinolones, which is especially important if patients have received second-line drugs in the past. This knowledge helps in avoiding the use of toxic and expensive drugs to which the patient’s M. tuberculosis is found to be resistant.

• Allows clinicians to tailor the regimen in settings with high rates of resistance to second-line drugs where it may be difficult to find a standard regimen that is ap- propriate for all patients.

• Provides flexibility if patients experience adverse effects related to one drug. In some settings, individualized regimens may achieve higher cure rates than stand- ard MDR regimens (6).

figure 7.1 diAgrAm of mdr TreATmenT STrATegieS depending on lABorATory meTHod To confirm mdr

Treatment timeline (time since Tb diagnosis)

Tb diagnosis ---/---/---/---/---/---/---/---/---/---/----

Countries using conventional methods to detect MDR:

While awaiting dST results for isoniazid, rifampicin;

mdr-Tb is suspected

once mdr is confirmed

Empirical treatment with mdr regimen continue standard mdr regimen

or

change to individualized mdr regimen (once susceptibility testing for second-line drugs is available)

Countries using rapid method to detect MDR:

once mdr is confirmeda

Standard mdr regimen

or

Individualized mdr regimen (once susceptibility testing for second-line drugs is available)