New anti-tuberculosis drugs and regimens: 2015 update

Lia D'Ambrosio; Rosella Centis; Giovanni Sotgiu; Emanuele Pontali; Antonio Spanevello; Giovanni Battista Migliori

doi:10.1183/23120541.00010-2015

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FIGURE 1
Percentage of new tuberculosis (TB) cases with multidrug-resistant TB. Figures are based on the most recent year for which data have been reported, which varies among countries. Reproduced from [1] with permission from the publisher.
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FIGURE 2
Percentage of previously treated tuberculosis (TB) cases with multidrug-resistant (MDR)-TB. Figures are based on the most recent year for which data have been resported, which varies among countries. The high percentages of previously treated TB cases with MDR-TB in Bahrain, Bonaire, Israel, Saint Eustatius and Saba, and Sao Tomé and Principe refer to only small numbers of notified cases (range 1–8 notified previously treated TB cases). Reproduced from [1] with permission from the publisher.
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FIGURE 3
Dried blood spot for therapeutic drug monitoring. a). Blood is collected on paper strips and packed in a plastic bag with a desiccant to keep the strip dry. b). Sample can be transported via regular post or any other suitable means. c). Dried blood spot is collected from the strip, drug is extracted and concentration measured using validated method. Reproduced from [31].

Tables

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TABLE 1

World Health Organization recommended treatment regimens for new patients

Intensive phase		Continuation phase
Drug	Duration months	Drug	Duration months
Ethambutol^# Isoniazid Pyrazinamide Rifampicin	2	Isoniazid^¶ Rifampicin^¶	4
Ethambutol^# Isoniazid Pyrazinamide Rifampicin	2	Ethambutol^¶ Isoniazid^¶ Rifampicin^¶	4⁺

^#: ethambutol has to be prescribed in individuals with noncavitary, sputum smear-negative pulmonary tuberculosis (TB) or with extrapulmonary TB who are known to be HIV negative; in TB meningitis, it should be replaced by streptomycin. ^¶: the World Health Organization considers the three times per week continuation phase as an acceptable alternative for any new TB patient receiving directly observed therapy. ⁺: when the level of isoniazid resistance among new cases is elevated and in vitro isoniazid drug susceptibility testing is not available, isoniazid (H)–rifampicin (R)–ethambutol regimen may be an acceptable alternative to HR regimen. Information from [17].

TABLE 2

World Health Organization recommended treatment regimens for previously treated patients, pending drug susceptibility testing (DST) results^#

Probability of MDR-TB
Medium or low^¶		High⁺
Drug	Duration months (phase)
Ethambutol Isoniazid Pyrazinamide Rifampicin Streptomycin	2 (intensive)	Empirical MDR-TB regimen
Ethambutol Isoniazid Pyrazinamide Rifampicin Ethambutol Isoniazid Rifampicin	1 (intensive)
To be changed once DST testing results are available	5 (continuation)	To be changed once DST testing results are available

MDR: multidrug-resistant; TB: tuberculosis. ^#: up to 2–3 months after the start of treatment; ^¶: relapse, lost to follow-up; ⁺: failure. Information from [17].

TABLE 3

World Health Organization groups of first- and second-line anti-TB drugs

Group	Anti-TB drugs
1) First-line oral anti-TB drugs	Isoniazid (H) Rifampicin (R) Ethambutol (E) Pyrazinamide (Z) Rifabutin (Rfb) Rifapentine (Rpt)
2) Injectable anti-TB drugs (injectable or parenteral agents)	Streptomycin (S) Kanamycin (Km) Amikacin (Am) Capreomycin (Cm)
3) Fluoroquinolones (FQs)	Levofloxacin (Lfx) Moxifloxacin (Mfx) Gatifloxacin (Gfx) Ofloxacin (Ofx)
4) Oral bacteriostatic second-line anti-TB drugs	Ethionamide (Eto) Prothionamide (Pto) Cycloserine (Cs) Terizidone (Trd) p-Aminosalicylic acid (PAS) p-Aminosalicylate sodium (PAS-Na)
5) Anti-TB drugs with limited data on efficacy and/or long-term safety in the treatment of drug-resistant TB	Bedaquiline (Bdq) Delamanid (Dlm) Linezolid (Lzd) Clofazimine (Cfz) Amoxicillin/clavulanate (Amx/Clv) Imipenem/cilastatin (Ipm/Cln) Meropenem (Mpm) High-dose isoniazid (high-dose H) Thioacetazone (T) Clarithromycin (Clr)

TB: tuberculosis. Reproduced and modified from [19] with permission from the publisher.

TABLE 4

World Health Organization recommended treatment regimen for multidrug-resistant (MDR) tuberculosis (TB)

1	Chose an injectable (group 2)	Kanamycin Amikacin Capreomycin	Choose a drug based on DST and treatment history Streptomycin is generally not used because of high rates of resistance in patients with MDR-TB
2	Choose a higher-generation fluoroquinolone (group 3)	Levofloxacin Moxifloxacin	Use a later-generation fluoroquinolone If levofloxacin (or ofloxacin) resistance is documented, use moxifloxacin Avoid moxifloxacin if possible when using bedaquiline
3	Add group 4 drugs	Cycloserine/terizidone PAS Ethionamide/prothionamide	Add two or more group 4 drugs until there are at least four second-line anti-TB drugs likely to be effective Ethionamide/prothionamide is considered the most effective group 4 drug Consider treatment history, side-effect profile and cost DST is not considered reliable for the drugs in this group
4	Add group 1 drugs	Pyrazinamide Ethambutol	Pyrazinamide is routinely added in most regimens Ethambutol can be added in the case of full sensitivity If isoniazid DST is unknown or pending it, can be added to the regimen until DST results become available
5	Add group 5 drugs	Bedaquiline Linezolid Clofazimine Amoxicillin/clavulanate Imipenem/cilastatin plus clavulanate Meropenem plus clavulanate High-dose isoniazid Clarithromycin Thioacetazone	Consider adding group 5 drugs if four second-line anti-TB drugs are not likely to be effective from groups 2–4 If drugs are needed from this group, it is recommended to add two or more DST is not standardised for the drugs in this group

DST: drug susceptibility testing; PAS: p-aminosalicylic acid. Information from [19].

TABLE 5

Summary of the main repurposed antituberculosis drugs with the most relevant studies and related findings

Drug	Class	Main findings	[Ref.]
Linezolid	Oxazolidinone	Systematic review and meta-analysis of efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis of 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases. Most MDR-TB cases achieved SS (86 (92.5%) out of 93) and C (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (interquartile range) times for SS and C conversions were 43.5 (21–90) and 61 (29–119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤600 versus >600 mg). AEs were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major AEs that included anaemia (38.1%), peripheral neuropathy (47.1%), gastrointestinal disorders (16.7%) optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity for caution in the prescription of linezolid.	[23]
		Retrospective, nonrandomised, unblinded observational study evaluating safety and tolerability of linezolid (600 mg once or twice daily). In MDR/XDR-TB treatment in four European countries. Out of 195 MDR/XDR-TB patients, 85 were treated with linezolid for a mean of 221 days. Of these, 35 (41.2%) out of 85 experienced major AEs attributed to linezolid (anaemia, thrombocytopenia and/or polyneuropathy), requiring discontinuation in 27 (77%) cases. Most AEs occurred after 60 days of treatment. Twice-daily administration produced more major AEs than once-daily dosing (p=0.0004), with no difference in efficacy found. Outcomes were similar in patients treated with/without linezolid (p=0.8), although linezolid-treated cases had more first-line (p=0.002) and second-line (p=0.02) drug resistance and a higher number of previous treatment regimens (4.5 versus 2.3; p=0.07). Linezolid 600 mg once daily added to an individualised multidrug regimen may improve the chance of bacteriological conversion, providing a better chance of treatment success in only the most complicated MDR/XDR-TB cases. Its safety profile does not warrant use in cases for which there are other, safer, alternatives.	[21]
		41 patients were enrolled, who had C-positive XDR-TB and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their OBR. The primary end-point was the time to SS/C conversion on solid medium, with data censored 4 months after study entry. By 4 months, 15 (79%) out of 19 patients in the immediate-start group and seven (35%) out of 20 in the delayed-start group had C conversion (p=0.001). 34 (87%) out of 39 patients had a negative C within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant AEs that were possibly or probably related to linezolid, including three patients who discontinued therapy. Patients who received 300 mg per day after the second randomisation had fewer AEs than those who continued taking 600 mg per day. 13 patients completed therapy and did not relapse. Four cases of acquired resistance to linezolid were observed. Linezolid is effective at achieving C conversion among patients with treatment-refractory pulmonary XDR-TB but patients must be monitored carefully for AEs.	[24]
		The authors evaluated treatment with linezolid (800 mg once daily for 1–4 months as guided by SS/C status and tolerance, and then at 1200 mg thrice weekly until ≥1 year after C conversion) in addition to OBD among 10 consecutive patients with XDR-TB or fluoroquinolone-resistant MDR-TB. All achieved stable cure, with anaemia corrected and neuropathy stabilised, ameliorated, or avoided after switching to intermittent dosing. Serum linezolid profiles appeared better optimised.	[28]
		Prospective pharmacokinetic study aimed at quantifying the effect of clarithromycin on the exposure of linezolid. All subjects received 300 mg linezolid twice daily during the entire study, consecutively co-administered with 250 and 500 mg clarithromycin once daily. Linezolid exposure increased by a median (interquartile range) of 44% (23–102%, p=0.043) after co-administration of 500 mg clarithromycin (n=5) compared to baseline, whereas 250 mg clarithromycin had no statistically significant effect. Co-administration was well tolerated by most patients; none experienced severe AEs. One patient reported common toxicity criteria grade 2 gastrointestinal AE. Clarithromycin significantly increased linezolid serum exposure after combining clarithromycin with linezolid in MDR-TB patients. The drug–drug interaction is possibly P-glycoprotein-mediated. Due to large interpatient variability, TDM is advisable to determine individual effect size.	[29]
Meropenem/clavulanate	Carbapenem/clavulanic acid	The study aimed to evaluate the contribution of meropenem/clavulanate when added to linezolid-containing regimens in terms of efficacy and safety/tolerability in treating MDR/XDR-TB cases after 3 months of second-line treatment. The clinical severity of cases was worse than that of controls (drug susceptibility profile, proportion of SS positive and of re-treatment cases). The group of cases yielded a higher proportion of SS converters (28 (87.5%) out of 32 versus nine (56.3%) out of 16; p=0.02) and C converters (31 (83.8%) out of 37 versus 15 (62.5%) out of 24; p=0.06). Excluding XDR-TB patients (11 (11.2%) out of 98), cases scored a significantly higher proportion of C converters than controls (p=0.03). One case had to withdraw from meropenem/clavulanate due to increased transaminase levels. The results of our study provide: 1) preliminary evidence on effectiveness and safety/tolerability of meropenem-clavulanate; 2) reference to design further trials; and 3) a guide to clinicians for its rationale use within salvage/compassionate regimens.	[30]

MDR: multidrug-resistant; TB: tuberculosis; SS: sputum smear; C: culture; AE: adverse event; XDR: extensively drug-resistant; OBR: optimised background regimen; SS/C: sputum smear and culture; TDM: therapeutic drug monitoring.

TABLE 6

Summary of the main new antituberculosis drugs with the most relevant studies and related findings

Drug	Class	Study ID number	Clinical trial phase	Registration number	Main findings	[Ref.]
Bedaquiline	Diarylquinoline	TMC207-TIDP13-C208	II	NCT00449644	The addition of delamanid (TMC207) to OBR reduced the time to C conversion, as compared with OBR (HR 11.8, 95% CI 2.3–61.3; p=0.003) and increased the proportion of C converters (48% versus 9%). The mean log₁₀ CFU count in SS declined more rapidly in the TMC207 group than in OBR group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without C conversion. Most AEs were mild to moderate.	[41]
Delamanid (OPC 67683)	Nitroimidazole	242-07-204	II	NCT00685360	Among patients who received OBR plus 100 mg of delamanid twice daily, 45.4% had C conversion at 2 months, as compared with 29.6% of patients receiving OBR (p=0.008). As compared with OBR, the group receiving OBR plus delamanid 200 mg twice daily had a higher proportion of SS and C conversion (41.9%, p=0.04). Most AEs were mild to moderate and evenly distributed across groups. Although no clinical events due to QT prolongation on ECG were observed, QT prolongation was reported significantly more frequently in the delamanid groups.	[42]
		242-09-213	III	NCT01424670	Patients who participated in the above trial of delamanid and the subsequent open-label extension trial were eligible to participate in a 24-month observational study designed to capture treatment outcomes. Favourable outcomes were observed in 143 (74.5%) out of 192 patients receiving delamanid for ≥6 months, compared to 126 (55%) out of 229 patients who received delamanid for ≤2 months. Mortality was reduced to 1.0% among those receiving long-term delamanid versus short-term/no delamanid (8.3%; p<0.001). Treatment benefit was also seen among XDR-TB patients.	[43]
Pretomanid (PA-824)	Nitroimidazole	NC-001-(J-M-Pa-Z)	II	NCT01215851	The 14-day EBA of PaMZ (n=13; mean±sd 0.233±0.128) was significantly higher than that of bedaquiline (n=14; 0.061±0.068), bedaquiline–pyrazinamide (n=15; 0.131±0.102), bedaquiline–Pa (n=14; 0.114±0.050) but not PaZ (n=14; 0.154±0.040) and comparable with that of standard treatment (n=10; 0.140±0.094). Treatments were well tolerated and appeared safe. One patient on PaMZ was withdrawn because of corrected QT interval changes exceeding pre-specified criteria.	[44]
		NC-002-(M-Pa-Z)	II	NCT01498419	The study evaluated a novel regimen for efficacy and safety in DS-TB and MDR-TB during the first 8 weeks of treatment. Smear positive DS, treatment-naïve PTB patients randomised were enrolled to receive 8 weeks of M, Pa (100 mg) and Z (MPa100Z, regimen 1) or M, Pa (200 mg) and Z (MPa200Z, regimen 2) or the current standard regimen for DS-PTB (HRZE) as positive control. A group of MDR-TB participants received M 400 mg, Pa 200 mg and Z 1500 mg (DRMPa200Z). The regimen 1 BA days 0–56 (n=54; 0.155, 95% BCI 0.133–0.178) in DS-TB patients was significantly greater than for standard regimen (n=54; 0.112, 95% BCI 0.093–0.131). Regimen 2 had similar BA to the standard regimen. The day 7–14 BA correlated well with days 7–56. AEs were equally distributed among group and control subjects. The most common AE was hyperuricaemia in 59 (28.5%) patients spread similarly across treatment groups. Other common AEs were nausea in 37 (17.9%) and vomiting in 25 (12.1%) patients. No patient had corrected QT interval exceeding 500 ms. No phenotypic resistance developed. The MPaZ combination, previously found to have promising activity over 14 days in DS-TB, was safe, well tolerated and demonstrated superior BA in DS-TB during 8 weeks treatment. Results were consistent between DS-TB and MDR-TB.	[45]
		NC-003-(C-J-Pa-Z)	II	NCT01691534	Experimental and clinical evidence suggests that the new drugs Bdq and Pa, combined with an existing drug, Z, and a repurposed drug, Cfz, may assist treatment shortening of both DS-TB and DR-TB. The study evaluated the 14-day EBA of Cfz and Z in monotherapy and in combinations with Pa and Bdq. Groups of 15 treatment-naïve, SS-positive PTB patients were randomised to receive combinations of Bdq with ZCfz, PaZ, PaZCfz and PaCfz, or Cfz or Z alone, or standard combination treatment for 14 days. The primary end-point was the mean daily fall in log₁₀ CFU·mL⁻¹ SS estimated by joint nonlinear mixed effects Bayesian regression modelling. Results: estimated activities were 0.167 (95% CI 0.075–0.257) for BdqPaZ, 0.151 (95% CI 0.071–0.232) for standard treatment, 0.124 (95% CI 0.035–0.214) for BdqZCfz, 0.115 (95% CI 0.039–0.189) for BdqPaZCfz and 0.076 (95% CI 0.005–0.145) for BdqPaCfz. Z alone had modest activity (0.036, 95% CI −0.026–0.099). Cfz had no activity alone (−0.017, 95% CI −0.085–0.053) or in combinations. Treatments were well tolerated and safe. BdqPaZ, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new TB treatment regimen. Cfz had no measurable activity in the first 14 days of treatment.	[46]
Sutezolid (PNU-100480)	Oxazolidinone	B1171003	II	NCT01225640	All patients completed assigned treatments and began subsequent standard TB treatment according to protocol. The 90% CI for bactericidal activity in sputum over the 14-day interval excluded zero for all treatments and both monitoring methods, as did those for cumulative WBA. There were no treatment-related serious AEs, premature discontinuations or dose reductions due to laboratory abnormalities. There was no effect on the QT interval. Seven (14%) sutezolid-treated patients had transient, asymptomatic ALT elevations to 173±34 U·L⁻¹ on day 14 that subsequently normalised promptly; none met Hy's criteria for serious liver injury. The mycobactericidal activity of sutezolid 600 mg twice daily or 1200 mg once daily was readily detected in sputum and blood. Both schedules were generally safe and well tolerated.	[47]
SQ109	Ethylenediamine	LMU-IMPH-SQ109-01	II	NCT01218217	Study to determine safety, tolerability, pharmacokinetics and bacteriological effect of different doses of SQ109 alone and in combination with rifampicin when administered over 14 days. SQ109 was safe and generally well tolerated. Mild-to-moderate dose-dependent gastrointestinal complaints were the most frequent AE. No relevant QT prolongation was noted. Maximum SQ109 plasma concentrations were lower than MICs. Exposure to SQ109 (AUC_0–24) increased by drug accumulation upon repeated administration in the SQ109 monotherapy groups. Co-administration of SQ109 150 mg with R resulted in decreasing SQ109 exposures from day 1 to day 14. A higher (300 mg) dose of SQ109 largely outweighed the evolving inductive effect of R. The daily fall in log₁₀ CFU·mL⁻¹ of sputum (95% CI) was 0.093 (0.126-0.059) with R, 0.133 (0.166–0.100) with R plus 150 mg of SQ109 and 0.089 (0.121–0.057) with R plus 300 mg of SQ109. Treatments with SQ109 alone showed no significant activity. SQ109 alone or with rifampicin was safe over 14 days. Upon co-administration with R, 300 mg of SQ109 yielded a higher exposure than the 150-mg dose. SQ109 did not appear to be active alone or to enhance the activity of rifampicin during the 14 days of treatment.	[48]
Benzothiazinones (BTZ043)	2-[(2S)-2-methyl-1,4-dioxa-8-azaspiro[4.5]dec-8-yl]-8-nitro-6-trifluoromethyl-4H-1,3-benzothiazin-4-one/Rv3790	Pre-clinical development phases			Studied the interaction profiles of BTZ043 with several anti-TB drugs or drug candidates against M. tuberculosis strain H37Rv, namely, R, H, E, delamanid, Pa, M, meropenem with or without clavulanate and SQ-109. No antagonism was found between BTZ043 and the tested compounds, and most of the interactions were purely additive. BTZ043 acts synergistically with delamanid, with a fractional inhibitory concentration index of 0.5. TMC207 at a quarter of the MIC (20 ng·mL⁻¹) used in combination with BTZ043 (quarter MIC 0.375 ng·mL⁻¹) had a stronger bactericidal effect on M. tuberculosis than delamanid alone at a concentration of 80 ng·mL⁻¹. This synergy was not observed when the combination was tested on a BTZ-resistant M. tuberculosis mutant, suggesting that DprE1 inhibition is the basis for the interaction. This finding excludes the possibility of synergy occurring through an off-target mechanism. Hypothesis that sub-MICs of BTZ043 weaken the bacterial cell wall and allow improved penetration of delamanid to its target. Synergy between two new antimycobacterial compounds (delamanid and BTZ043) with novel targets offers an attractive foundation for a new anti-TB regimen	[49]

OBR: optimised background regimen; C: culture; HR: hazard ratio; CFU: colony-forming unit; SS: sputum smear; AE: adverse event; XDR: extensively drug-resistant; TB: tuberculosis; EBA: early bactericidal activity; Pa: pretomanid; M: moxifloxacin; Z: pyrazinamide; DS: drug-susceptible; MDR: multidrug-resistant; PTB: pulmonary tuberculosis; H: isoniazid; R: rifampicin; E: ethambutol; BA: bactericidal activity; BCI: Bayesian credibility interval; Bdq: bedaquiline; Cfz: clofazimine; DR-TB: drug-resistant; WBA: whole-blood bactericidal activity; ALT: alanine transaminase; MIC: minimum inhibitory concentrations; AUC_0–24: area under the curve in the first 24 h.