Difficult MDR-TB/XDR-TB is predominantly treated with combination anti-TB drug therapy complemented with surgery in highly selected cases. Adjunctive immunotherapy may have a role in the future.
Anti-TB drug therapy
Classification of anti-TB drugs
For MDR-TB treatment, WHO has grouped anti-TB drugs according to efficacy, experience of use and drug class.100Table 1 shows a slightly different group order that may better reflect the clearly essential roles of fluoroquinolones1–5 and SLID.5–7 Drugs from groups 1–3 should be used if there is good evidence from DST or clinical history that they are effective.100 Drug resistance is a critical determinant of treatment success, and prior TB treatment confers an increased risk.111,112 DST is fairly reliable for drugs from groups 1–3 and less so for the others.100
Table 1. Antituberculosis drugs: classification and dosages used in multidrug-resistant tuberculosis treatment
|1: First-line oral drugs||Isoniazid||16–18||800–1200|
|3: Injectable agents§||Capreomycin||12–15||750–1000|
|4: Oral bacteriostatic second-line agents¶||Ethionamide||15||500–750†|
|5: Agents with efficacy that is not totally clear (not recommended for routine use)††||Linezolid||—||600|
|Meropenem-clavulanate104||—||Initially 2000-125 t.i.d, later 2000-125 b.i.d.|
|Thioridazine105||—||Initially 25 mg daily.|
|Increase dosage weekly until 200 mg daily.|
First-line oral drugs (group 1) are the most potent and best tolerated.100 A randomized, controlled trial among relatively young MDR-TB patients suggests that in comparison with non-recipients, high-dose isoniazid (16–18 mg/kg) recipients became sputum-negative 2.38 times more rapidly and had a 2.37 times higher likelihood of being sputum-negative at 6 months113 Considering the pharmacokinetics of isoniazid,114 high-dose isoniazid (16–18 mg/kg) is likely effective when isoniazid minimal inhibitory concentration ≤1 mg/L,115 and potentially beneficial when isoniazid minimal inhibitory concentration ≤5 mg/L. Pyrazinamide may improve treatment of pyrazinamide-susceptible MDR-TB.116 Before rifampicin and fluoroquinolones were available for the treatment of drug-resistant TB, high cure and culture conversion rates were achieved by combining pyrazinamide, ethionamide and cycloserine.117–119 A small retrospective analysis suggested significantly better outcomes among MDR-TB patients given ethambutol and pyrazinamide.120 One analysis included in a WHO review suggested a slightly added adjusted benefit due to pyrazinamide.121 A retrospective cohort analysis suggests that pyrazinamide may substantially improve early sputum culture conversion and 2-year treatment success among MDR-TB patients given fluoroquinolone-based regimens.122 The potentially important role of pyrazinamide and the high prevalence of pyrazinamide resistance in MDR-TB123 underscores the need of protecting pyrazinamide in settings with substantial MDR-TB burden.
Among group 2 drugs, preference is given to newer generation fluoroquinolones, which include levofloxacin, moxifloxacin and gatifloxacin.100 Ciprofloxacin is no longer recommended. A systematic review with meta-analysis suggests that newer generation fluoroquinolones significantly improves cure or treatment completion among XDR-TB patients.124 Among predominantly second-line treatment-naïve MDR-TB patients, high relapse-free cure rates with good tolerance have been achieved by the inclusion of gatifloxacin 400–800 mg once daily for at least 9 months,103 notwithstanding initial concerns about gatifloxacin-induced dysglycaemia.125 A murine model suggested that moxifloxacin 400 mg once daily could be effective when moxifloxacin minimal inhibitory concentration ≤2 mg/L.126 An in vitro pharmacodynamic infection model suggests that moxifloxacin 800 mg once daily likely achieves excellent M. tuberculosis microbial kill with suppression of drug resistance.127 Tolerance and safety of high-dose moxifloxacin will be evaluated in a randomized, controlled trial, using standardized regimens in MDR-TB treatment.102 In view of likely cost-effectiveness,106,128 levofloxacin 1000 mg once daily may be prescribed,101 but long-term tolerance data in the literature are very limited.107
Among injectable agents (group 3), kanamycin or capreomycin is the drug of choice for second-line treatment-naïve MDR-TB because many M. tuberculosis strains resistant to either drug are still susceptible to amikacin but probably not vice versa.129 The choice between kanamycin and capreomycin is determined by cost and availability. Streptomycin is not recommended owing to relatively high rates of bacillary resistance and ototoxicity.100
Oral bacteriostatic agents (group 4) include thioamide (ethionamide or prothionamide), cycloserine, terizidone and para-aminosalicylic acid. In view of the molecular mechanism of bacillary resistance,9 a thioamide may still have activity in vitro in the presence of high-level phenotypic resistance to isoniazid. Use of a thioamide with para-aminosalicylic acid may increase the risk of gastrointestinal side-effects and hypothyroidism.100,130–132 Combined use of a thioamide with pyrazinamide or high-dose isoniazid may increase the risk of hepatotoxicity, although a retrospective study suggests that hepatotoxicity during MDR-TB treatment may not adversely affect outcome.133,134
Group 5 drugs, generally representing repurposed agents, is perhaps indispensable in the treatment of difficult MDR-TB/XDR-TB.100,121 Abundantly supported by in vitro135–138 and clinical data,139,140 linezolid is likely beneficial in the treatment of difficult MDR-TB/XDR-TB.139,140 Although linezolid 300 mg once daily may reduce the risk of neurotoxicity,141,142 uncertainty still prevails regarding the optimal dosage.143 The carbapenem class of beta-lactams are very poorly hydrolysed by BlaC gene products that are encoded by M. tuberculosis.144 When combined with the beta-latamase inhibitor clavulanate, meropenem showed potent anti-TB activity in vitro, including anaerobically grown cultures that mimic mycobacterial persisters.144 Thioridazine may improve the cure of XDR-TB by several mechanisms. It affects the transport of K+ and Ca2+ from the phagolysosome, thereby rendering better acidification and activation of hydrolases and enhancing the killing of intracellular M. tuberculosis.145 It also inhibits the genetic expression and the activity of existing efflux pumps that contribute to the MDR phenotype.146 Clinical evidence that may support use of meropenem-clavulanate104,147 or thioridazine105 in XDR-TB treatment is limited and confounded by the concomitant use of linezolid in many assessed patients. Although clofazimine may be beneficial among second-line treatment-naïve patients,103 its role among previously treated patients, who were more frequently treated with a fluoroquinolone and SLID, appeared less impressive.148 This may cast doubt on the role of clofazimine in the treatment of difficult MDR-TB/XDR-TB. Use of amoxicillin-clavulanate is based on anecdotal evidence and inconsistent in vitro findings.149–155
New drugs with potentials
New drugs for TB treatment have been recently reviewed.156 Three new drugs with potential for improving MDR-TB treatment in the near future may deserve some attention, namely bedaquiline, PA-824 and delamanid.
Bedaquiline (a.k.a. TMC207 and J compound) is a novel diarylquinoline that inhibits mycobacterial adenosine triphosphate synthase.157 Metabolized by cytochrome P450 3A4, plasma levels of bedaquiline may be affected through interaction with rifampicin and some antiretroviral drugs (protease inhibitors/non-nucleoside reverse transcriptase inhibitors). Its use in mice suggested synergism with pyrazinamide, and potential for shortening treatment158 and enabling once-weekly dosing.159 A double-blind, randomized placebo-controlled phase II clinical trial showed that adding bedaquiline to a standard five-drug MDR-TB regimen significantly hastened and increased the proportion with sputum culture conversion (48% vs 9%),160 and helped prevent acquired resistance to companion drugs.161
As derivatives of metronidazole, PA-824 (a nitroimidazo-oxazine) and delamanid (a.k.a. OPC-67683, a nitro-dihydro-imidazooxazole) are nitroimidazopyrans that share cross-resistance. They probably act by inhibiting cell wall biosynthesis, among other possible actions,162 with OPC-67683 having 20 times higher potency. High protein binding (94%) may render PA-824 less accessible in cavities of pulmonary TB.163 Use of PA-824 in mice suggested synergism with moxifloxacin and pyrazinamide and potential for shortening treatment.164,165 Likewise, use of OPC-67683 with rifampicin and pyrazinamide in mice demonstrated TB treatment-shortening potential and considerable intracellular post-antibiotic effects.162 A randomized trial that compared delamanid with placebo used alongside a background MDR-TB treatment regimen showed that delamanid significantly improved 2-month sputum culture conversion from 29.6% to 41.9%/45.4%,166 with a substantially increased risk of asymptomatic QT prolongation as a side-effect.166
General principles for designing a desirable treatment regimen
Without specific evidence-based guidelines on treatment of difficult MDR-TB/XDR-TB, we may perhaps adapt the latest WHO guidelines on programmatic management of MDR-TB in designing treatment regimens for these formidable diseases. On the basis of low-quality clinical evidence for non-XDR-TB, WHO has recommended the following principles.121 First, the intensive-phase treatment should include pyrazinamide in addition to at least four second-line anti-TB drugs likely to be effective. Although pyrazinamide may improve fluoroquinolone-based treatment of MDR-TB,122 its role in the treatment of difficult MDR-TB/XDR-TB may be substantially reduced by the high prevalence of pyrazinamide resistance in fluoroquinolone-resistant MDR-TB167 and XDR-TB.168 To balance treatment efficacy and toxicity, it appears prudent to identify pyrazinamide susceptibility with molecular assays whenever possible.116 Second, the four second-line drugs should include a fluoroquinolone, a SLID, a thioamide and cycloserine, which may be replaced by para-aminosalicylic acid if necessary. A rule of thumb is to include two core drugs with potent bactericidal activity plus two accompanying drugs. Third, the number of second-line drugs may be further increased in case of uncertainty about effectiveness but not for extensive disease per se. Thus, for the reasons given earlier, linezolid and high-dose isoniazid may be included after carefully weighing tolerability and safety.
Daily rather than intermittent scheduling is generally recommended in MDR-TB treatment.101 For patients at risk of otovestibular or renal toxicity, especially those aged ≥60 years or with mild renal insufficiency (creatinine clearance 30–60 mL/min), dosing frequency of SLID may be reduced to five times per week, which is generally considered to be effective,101 in the initial 2–3 months and then thrice weekly.101 When renal dysfunction is significant (creatinine clearance <30 mL/min), the dosing frequency of SLID, ethambutol, pyrazinamide, cycloserine and levofloxacin is preferably reduced to thrice weekly with little change in the dose size.100,101,110,169 Although use of daily high-dose isoniazid among relatively young MDR-TB patients was not associated with hepatotoxicity,113 thrice-weekly high-dose isoniazid may warrant evaluation in view of its track record of safety. Intermittent dosing of linezolid in the continuation phase has been used with promising results, albeit preliminary, to strike a balance between efficacy and toxicity of the oxazolindinone.170
Based on low-quality evidence, WHO has conditionally recommended a minimum of 8 months for the intensive phase, and a minimum of 20 months for the entire course in the treatment of newly diagnosed MDR-TB.121 Tolerability and safety must be carefully weighed. Evidence for the effectiveness of a 9-month treatment regimen is limited and confined to the treatment of predominantly treatment-naïve MDR-TB.103 Further studies/trials are warranted to ascertain the optimal duration of the entire course as well as use of SLID in the treatment of difficult MDR-TB/XDR-TB, especially when the regimen contains high-dose gatifloxacin/moxifloxacin in the presence or absence of pyrazinamide with in vitro activity.
ART significantly reduces the impact of HIV on TB by lowering HIV viral load and restoring the immune system.171 In HIV-infected patients with documented MDR-TB/XDR-TB, ART should be initiated within 2–4 weeks of confirmation of TB drug resistance and initiation of second-line TB therapy.171–176 Immune reconstitution inflammatory syndrome may occur after initiation of ART. In general, both ART and TB treatment should be continued while managing immune reconstitution inflammatory syndrome.172
Model of care
Based on low-quality evidence, WHO has conditionally recommended that MDR-TB be treated using mainly ambulatory (or community-based) rather than hospitalization care models.121 This can possibly improve the overall cost-effectiveness and reduce secondary transmission provided that proper infection control measures are also in place at home and in the clinic. These measures include proper use of surgical face masks by MDR-TB patients,87 prioritizing community-care approaches and avoiding overcrowding and unnecessary hospitalization/outpatient visits.90
The concept of community-based patient care in MDR-TB was conceived in Peru in the 1990s.177 Similar success stories have been witnessed in South Africa.178,179 A recent report from rural South Africa about integrated home-based treatment for MDR-TB and HIV has further strengthened the rationale of community-based management of these diseases.180
Adjunctive lung resection may be considered for patients with drug-resistant TB after satisfying three basic criteria: a high probability of failure or relapse with medical therapy alone, sufficiently localized disease for resection with adequate postoperative cardiopulmonary capacity, and sufficient drug activity for facilitating postoperative healing of bronchial stump.181 Poor postoperative outcomes are more likely in the presence of low body mass index <18.5 kg/m2, bacillary resistance to fluoroquinolones and unresectable cavities.182
Large cohort studies have demonstrated that the best outcomes in MDR-TB are achieved by the use of fluoroquinolones and adjunctive surgery.3,183 Lung resection can help achieve sustainable sputum culture conversion in selected XDR-TB patients.184 Large case series have also reported better outcomes among XDR-TB patients treated with adjunctive lung resection.3,185,186 A retrospective study suggests that early aggressive treatment comprising at least four effective drugs and lung resection may improve the outcome of MDR-TB/XDR-TB.187Table 2 summarizes outcomes of adjunctive surgery of MDR-TB. The median proportion (interquartile range) was 89% (78–95%) for treatment success, 1% (0–3%) for operative mortality and 16% (12–23%) for postoperative complications.
Table 2. Outcomes of adjunctive surgery of multidrug-resistant tuberculosis
|Jeon186||2009||16||56||Not available||Not available|
|Gegia205||2012||37||78||Not available||Not available|
When cardiopulmonary reserve is insufficient, collapse therapy using thoracoplasty,206 plombage207 or artificial pneumothorax208 may be considered.
Although preliminary data on supplemental cytokines209–213 and M. vaccae214 are encouraging, the limited number of enrolled patients and the frequent lack of comparable controls leaves considerable uncertainty regarding their definitive role in the treatment of difficult MDR-TB/XDR-TB.215,216 Notwithstanding a theoretical basis,217 clinical evidence has not substantiated vitamin D supplementation.218 We hope the next decade may witness rewarding results in the continual quest for effective immunomodulating agents.
Difficult MDR-TB/XDR-TB can be incurable. When the risk of treatment outweighs its benefits for both the patient and the community, palliative care is indicated to provide symptomatic treatment and ensure a dignified end of life.219–221