See reference 2
Group 1 (Oral first-line agents)
Pyrazinamide is routinely added to MDR regimens if susceptibility (by DST) is documented or if DST is unknown. If well tolerated it is used for the entire treatment, although patients doing well and with minimal lung disease can have it stopped with the injectable agent and continue with at least three likely effective drugs.
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.
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 (see Group 5).
The newer rifamycins, such as rifabutin have very high cross-resistance to rifampicin and are not used in MDR regimens.
Group 2 (Injectable agents)
All patients should receive a Group 2 injectable agent if susceptibility is documented or the drug is considered likely to be effective.
Kanamycin or amikacin are the first choice injectable agent. Both are low cost, and have been used extensively for the treatment of MDR-TB. They are considered to be very similar and have a high frequency of cross-resistance.
Given the high rates of resistance to streptomycin in patients with MDR-TB, streptomycin is not used in MDR-TB treatment regimens.
If the strain is susceptible to capreomycin or if resistance is rare in the patient population and if aminoglycosides are contra-indicated or poorly tolerated or ineffective on the patient’s strain, capreomycin should be used. Capreomycin should also be used while waiting for the DST results in places where resistance to kanamycin and amikacin is common.
Group 3 (Fluoroquinolones)
The most potent available fluoroquinolones in descending order based on in vitro activity and animal studies are: moxifloxacin > levofloxacin > ofloxacin3,4.
This guide recommends not using ofloxacin (second-generation fluoroquinolone) as it has inferior performance against TB compared to the other Group 3 fluoroquinolones. In addition, resistance may develop more easily to the fluoroquinolone group when ofloxacin is used in a multidrug regimen. Ciprofloxacin (second-generation fluoroquinolone) is not included in Group 3 and should never be used to treat drug-susceptible or DR-TB because of its low efficacy against TB bacilli5.
Third-generation fluoroquinolones (moxifloxacin and levofloxacin) may have some efficacy against ofloxacin-resistant strains6.
Mostly based on cost and availability, levofloxacin is often the fluoroquinolone used in most MDR-TB regimens, whereas moxifloxacin is reserved for cases of high resistance (resistance to ofloxacin, injectable agents, or other second-line anti-TB drugs).
In case of resistance to fluoroquinolones, the use of bedaquiline should be considered (see below).
Group 4 (Oral bacteriostatic second-line anti-TB drugs)
Ethionamide and prothionamide are considered the most potent Group 4 drugs1. However it should be noted that these drugs do have some cross-resistance with isoniazid. Ethionamide and prothionamide can be included in the regimen if inhA gene is detected but should not be counted as a likely effective drug.
Cycloserine and/or para-aminosalicylic acid should be included in MDR-TB regimens. Both share no cross-resistance to other anti-TB drugs. Since the combination of ethionamide or prothionamide and para-aminosalicylic acid often causes a high incidence of gastrointestinal disturbances and hypothyroidism, these agents are usually used together only when three Group 4 agents are needed.
The drugs in Group 4 may be started at a low dose and escalated over 1 to 2 weeks to improve tolerance.
Group 5 (Drugs with limited data on efficacy and/or long-term safety)
Group 5 drugs are recommended in cases where adequate regimens are impossible to design with the drugs from Groups 1 to 4.
Compared to other drugs in this group bedaquiline is the only one with proven efficacy against TB. While there is no clear evidence for the hierarchy of use of Group 5 drugs, these guidelines propose that the three most attractive agents from this group in order of preference are: bedaquiline, linezolid, clofazimine.
7,8,9: Bedaquiline is a diarylquinoline with bactericidal anti-mycobacterial activity. This new drug was registered by the US FDA in December 20122
for MDR-TB patients with no other therapeutic options. It is recommended in case of resistance to fluoroquinolones or when it is not possible to have four effective anti-TB drugs from Group 2 to 4 in the regimen. The dosage in adult is 400 mg once daily for 2 weeks followed by 200 mg 3 times per week for 22 weeks.
The drug is not yet recommended for children or pregnant women. The main adverse effects are nausea, arthralgia, headache and QT prolongation. QT prolongation can result in cardiac arrhythmia and sudden death. Baseline and regular electrocardiogram (ECG) monitoring should be performed. QT prolongation is more pronounced when combined with clofazimine. Combination with other QT prolonging drugs (moxifloxacin, ondansetron, etc.) should be avoided or closely monitored. Bedaquiline must not be combined with rifamycins and some antiretrovirals (see Chapter 12). Bedaquiline is not registered in most high burden countries and only available through compassionate use (see also Appendix 11).
For situations that require the use of Group 5 drugs other than bedaquiline (or when bedaquiline is not available), use at least two other drugs from Group 5 given the limited knowledge of their efficacy.
Linezolid: Linezolid has good activity in vitro and in animal studies. There are also a number of reports and case series in MDR-TB and XDR-TB10,11,12,13,14,15,16,17 and a recent study showing efficacy in XDR-TB18. It has numerous severe adverse effects including myelo-supression and irreversible peripheral neuropathy. It is presently very expensive.
Clofazimine: There is a moderate amount of experience with clofazimine in MDR-TB treatment but no clear in vivo data on efficacy against TB. It is usually added to regimens for XDR-TB.
Amoxicillin/clavulanic acid: Generally the B-lactam antibiotics are not regarded as very useful drugs in TB. However, the addition of the B-lactamase inhibitor makes them active in vitro against TB. There is one in vivo study that showed good early bactericidal activity. While amoxicillin/clavulanic acid is probably a relatively weak anti-TB drug, it is often included because it is available, inexpensive and causes only minor adverse effects.
High-dose isoniazid: High-dose isoniazid (16-20 mg/kg/day) can be used as a Group 5 drug in the presence of resistance to low concentrations of isoniazid19 (> 1% of bacilli resistant to 0.2 mcg/ml but susceptible to 1 mcg/ml of isoniazid). Isoniazid is not recommended for high-dose resistance (> 1% of bacilli resistant to 1 mcg/ml of isoniazid)20 or in presence of katG gene mutation (see LPA, Chapter 3, Section 3.4.2).
– Gatifloxacin (Group 3): Although gatifloxacin is similar to moxifloxacin in efficacy against TB, it is associated with serious hypo/hyperglycaemia, and new onset diabetes. Thus, its use is not recommended.
– Terizidone (Group 4): It is unknown whether this drug is equally efficacious as cycloserine, therefore these guidelines recommends the use of cycloserine over terizidone.
– Imipenem/cilastatin and meropenem (Group 5): These beta-lactam/carbapenems are only given intravenously. Given the cost and difficulty of the twice-daily intravenous administration, it is not commonly used in resource-constrained settings. Meropenem is preferred in children as there is more experience with its use. Meropenem can be combined with oral doses of clavulanate. These drugs are commonly used for a duration of two months past conversion.
– Clarithromycin (Group 5): This drug is included in various TB manuals21 yet evidence to support its efficacy in MDR-TB is minimal. It may have a synergistic effect on first-line anti- TB drugs with enhanced intracellular effectiveness against the TB bacilli. However, until more information on effectiveness in TB and MDR-TB, its use is not recommended.
– Thioacetazone (Group 5): While thioacetazone is known to be active against TB bacilli, it is placed in Group 5 because its role in DR-TB treatment is not well established. Thioacetazone has cross-resistance with some of the other anti-TB agents (Chapter 8, Section 8.5) and overall is a weakly bacteriostatic drug. It is contraindicated in HIVinfected individuals22 due to a risk of serious adverse reactions (Stevens-Johnson syndrome and death). Persons of Asian descent also have a higher incidence of Stevens- Johnson syndrome. For these reasons, thioacetazone is rarely added as a Group 5 drug. Until there is more information in its role in MDR-TB therapy, its use is not recommended.
Bedaquiline is relatively well tolerated. Data and experience on its use is very limited. In a blinded randomized placebo-control study there were an increase number of deaths in the study arm that received bedaquiline. While none of the deaths were considered directly related to the drug, the possibility that the use of the drug carries an increase risk of death cannot be ruled out. The risks and benefits of receiving this drug should be fully explained to the patient.