The Trouble with MDR and XDR-TB – New Drugs Needed

Pulmonary tuberculosis is one of those infections that is difficult enough to treat under the best circumstances, as it requires the patient to take four drugs for an extended period of time. The development of resistance to any of the core drugs complicates matters, as it forces physicians to use other types of medications that are either less efficacious (i.e bacteriostatic) or have higher adverse events. In other words, it becomes a s***-show.  There are 2 general types of drug resistant classifications used for tuberculosis

• Multidrug Resistant Tuberculosis (MDR) – resistance to Rifampin and INH
• Extensively Drug Resistant Tuberculosis (XDR) – resistance to RIF, INH, a fluoroquinolone, or a second line injectable (usually amikacin or capreomycin) 

The WHO has a classification of drugs for tuberculosis, which follows a step-wise approach to therapy that balances side effect profiles. The basis for therapy, or the rationale I should say, is to have 2 core drugs and 2 companion drugs (1). The core drugs kill MTB in any of its metabolic phases, meaning they have good bactericidal and sterilizing activity, while companion drugs are there to avoid resistance and to protect the core drugs (this is why PZA and ethambutol fall off after the first four months). Bactericidal drugs reduce the bulk of the rapidly multiplying bacteria, decreasing infectivity and avoiding progression while the sterilizing drugs attack the dormant and semi dormant populations of bacilli (1). Prior to 2016, the classification of TB drugs went from group 1, being first line TB meds, down to group 2, being the injectables, and group 3 being FQs (1, 2). Since then, the classification deals mostly with MDR-TB, meaning the group starts with the best second line agents and goes from there (1, 3):

As you may have noted, column 3 is a proposed classification that deals away with injectables as a second line therapy and puts oral medications such as bedaquiline, delamanid, linezolid, and clofazimine as an alternative for a possible MDR and XDR TB regimen that is all PO. As such, we will discuss these drugs as it pertains to tuberculosis. 

Impact of Drug Resistance

One of the reasons why the classification matters (aside from the fact it allows you to figure out what drugs to give) is that it gives you prognostic information. For instance, a meta-analysis of over 6700 patients with MDR/XDR TB found that treatment success was highest for MDR-TB only compared to XDR-TB (4):

Notably, the use of injectables was associated with treatment success in MDR-TB and no drugs in the group 4 or group 5 category were associated with treatment success in XDR-TB:

Another meta-analysis of 13 studies totaling 560 patients with XDR-TB found that 43.7% of patients achieved a favorable outcome (5), with studies that used fluoroquinolones for their regimen having a higher proportion of favorable outcomes:

A single-center retrospective study of over 650 patients found that MDR and XDR TB patients had similar outcomes, although the time to culture conversion was shorter in the MDR group (6):

Notably, given its timing, there was no use of clofazimine, linezolid, or bedaquiline. Finally, a retrospective study (7) did not find that XDR-TB culture conversion was affected by HIV status, though use of ARV was associated with higher chances of survival:

Compare this to the treatment success rates of TB worldwide by the WHO (8):

And overall TB death rate in the US as of 2019 was 5.77% (9). As such, MDR/XDR TB tend to be more difficult to treat and this is due to the lack of reliable PO medications. 

Bedaquiline

This is an oral medication that is the first of the class of diarylquinolines. It targets both replicating and dormant bacilli, making it a good candidate for a core drug. It works by inhibiting mycobacterial ATP synthase. Early data comes from case series of compassionate uses for MDR/XDR-TB. For instance, one case series of 35 patients (10) found that in 21/29 with culture-positive pulmonary TB achieved culture conversion at 3 months while 28/29 did so at month 6. Of interest, multivariate analysis found that treatment with FQs was associated with a higher likelihood of culture conversion:

20% of patients had an increase in QTc and 9% had a QTc >500ms.  An off-label study of bedaquiline (11) in pediatric patients (of which 67% had XDR TB) found that 23 out of 27 had sputum culture negativity by week 24 with only 4 patients having QTc prolongation. 

The bactericidal activity of bedaquiline was evaluated in a 14d, double-blind, randomized study that compared bedaquiline alone, bedaquiline and pretomanid, bedaquiline-PZA, premotanid-PZA, and pretomanid-moxifloxacin-PZA in treatment naive patients and compared them to RIPE treated patients (12). A total of 85 patients were randomized and found that the combination of pretomanid-moxifloxacin-PZA had the highest bactericidal activity when compared to RIPE, while bedaquiline-pyrazinamide activity was  comparable to that of RIPE and pretomanid-PZA:

RIPE was compared with a regimen of bedaquiline, pretomanid, and pyrazinamide in susceptible TB patients over an 8 week period (13) in a multicenter, open-label trial. Patients were randomized in a 1:1:1 fashion to either a bedaquiline load (400mg daily for 14 days followed by 200mg three times per week for the last 6 weeks), standard bedaquiline dose (200mg daily for 8 weeks), or RIPE. Part of the trial also used bedaquiline in combination with moxifloxacin and other drugs in those who had RR TB. Primary endpoint was daily percentage change in time to positivity for sputum culture. 180 patients were randomized in the primary trial with an additional 60 being enrolled in the rifampin resistant arm. In both bedaquiline arms, the daily percentage change in time to positivity was greater than in the RIPE arm:

While there was no comparison, there was also a good percentage of culture negativity at day 56 in the Rifampin resistant group who got bedaquiline, at least when compared to other studies of MDR-TB outcomes:

There were no significant adverse events in either group.

Mortality and treatment success is also improved with the implementation of bedaquiline to a MDR-TB regimen. For instance, a retrospective cohort study (14) with RR TB evaluated the mortality difference that bedaquiline had upon its implementation. In this cohort of over 19,000 patients bedaquiline was associated with improved mortality in both RR/MDR TB and XDR TB:

Another study of 200 patients with either pre-XDR TB (MDR TB and resistance to either FQ or an injectable second agent) and XRD-TB who were treated with bedaquiline (400mg load for 2 weeks followed by 200mg three times per week for the remainder of therapy) for 24 weeks found that 69.5% were cured (15). After adjusting for HIV status and resistance status, Poisson regression found that completion of bedaquiline was associated with increased incidence of success:

The largest, best designed study was a randomized, double-blind, placebo-controlled trial, where patients were randomized to either bedaquiline or placebo along with a background regimen for MDR TB (16). Bedaquiline/placebo was continued for 24 weeks, with primary endpoint being time to sputum conversion. 160 patients were randomized, with a higher proportion of patients in the placebo group having HIV. In the mITT analysis, the time to sputum-culture conversion was faster in the bedaquiline group compared to the placebo group (83 days vs 125 days, HR 2.44, 95%% CI 1.57 to 3.8):

Notably, 10 patients in the bedaquiline group died, compared to 2 patients (p=0.02), of which 6 were attributed to tuberculosis. QTc in the bedaquiline group increased by 15.4msec. 

There are a few issues with bedaquiline, mainly its QTc prolongation properties and the fact one trial managed to have higher mortality despite better sputum-culture conversion. Either way, the ATS/IDSA/CDC/ERS guidelines recommend bedaquiline as part of an oral regimen that includes at least a total of 5 drugs for a total of 5-7mo (17). The recommended dose for MDR-TB is 400mg daily for 2 weeks followed by 200mg three times per week up to 24 weeks. 

Delamanid

This is a nitro-dihydro-imadazooxasole derivative that works by inhibiting the synthesis of mycolic acid. It has both sterilizing and bactericidal activity. Despite early data suggesting it may have some sort of benefit when added an optimized background regimen, the WHO released an interim analysis (18) which gave it a lukewarm recommendation: “WHO recommends that delamanid may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB (conditional recommendation; very low confidence in estimates of effect).” Indeed, the ATS/IDSA/CDC/ERS guidelines were unable to make a recommendation for or against Delamanid but seems like a reasonable option in certain patients with MDR or XDR-TB. A compassionate use case series of 78 patients found that 80% of those who used delamanid achieved culture negative status by week 24 (19), with most receiving a combination of either linezolid, clofazimine, fluoroquinolones, injectable aminoglycosides, bedaquiline, or carbapenems. A retrospective case series (20) evaluated delamanid in patients with RR TB, and found that 61% of patients with 12 month follow up had favorable outcomes (sputum culture conversion) with 67 adverse events reported, of which only 4 were QTc prolongation. A multicenter retrospective cohort from Korea found favorable outcomes in patients who were treated with either bedaquiline, delamanid, or both in combination (21), with 71% achieving culture conversion:

A letter to the editor (22) from NEJM reported that XDR-TB patients who got delamanid for 2 months had higher rates of sputum-culture conversion than those who got placebo (44% vs 10%, p=0.10). Further, therapy with delamanid for either 2 or 6 months were not significantly different when it came to sustained sputum-culture conversion or successful therapy at 24 months, though the number of patients were too small to drawn conclusions:

These suggest the utility of delamanid in MDR/XDR especially when it comes to designing an all oral regimen for these patients. A few randomized trials have attempted to investigate its utility more thoroughly. For instance, a multicenter, double-blind, randomized placebo controlled trial (23) evaluated the efficacy of delamanid 100mg BID or 20mg BID against placebo in a 1:1:1 fashion.  Primary endpoint was the proportion of patients who achieved culture conversion by 2 months. 481 patients were randomized, of which 402 had positive cultures at baseline. A higher proportion of patients who got delamanid at either dose had higher sputum culture conversion by both liquid and solid culture compared to placebo:

The frequency of QTc prolongation was higher in the 200mg group (13.1%) compared to the 100mg group (9.9%). The increase in the dose from 100mg BID to 200mg BId yielded a 50% increase in exposure. Another phase 3 multicenter trial evaluated 100mg BID of delamanid for 2 months followed by 200mg BID of delamanid for 4 months with placebo in a 2:1 fashion, with primary outcome being sputum culture conversion over 6 months (24). 327 patients were included in the mITT population, with no statistical difference noted in the time to SCC between both groups:

There was no difference in either of the secondary endpoints, though the study was not powered for these outcomes. An observational cohort study of 2 previous trials (trial 204 and 208) evaluated the impact of delamanid at the end of an observational period of up to 24 months (25). Patients in trial 204 were randomized to either delamanid 100mg BID, delamanid 200mg BID, or placebo after which there was a period of time between the end of trial 204 and the start of tral 208, the latter which evaluated an additional 6 months of either dose (delamanid 100mg BID vs 200mg BID). These were then enrolled in a observational cohort that included all patients enrolled in the 204 trial:

Confusing, I know. 481 patients were enrolled, with patients who got delamanid achieving favorable treatment outcomes (sputum conversion), around 74%. Further, patients who got therapy for at least 6 months had better outcomes compared to those who only got 2 months, which was also seen when looking at XDR-TB outcomes only:

Given all this, it seems that delamanid may be an upcoming PO option for MDR/XDR TB. As noted by the WHO, however, there are issues with the observational study 116 (which is composed of trials 204 and 208), which included the absence of randomization, self-selection of patients, absence of blinding for treatment allocation,  variable gap between the end of trial 204 and the start of trial 208, variations nn doses, timing, and duration of exposure to the drugs and variable follow up and duration of therapy in study 116. Indeed, there is a lack of high quality randomized trials, with the best one comparing two different doses for 2 months, though interim WHO analysis recommend delamanid 100mg BID for 6 months, regardless of bodyweight. 

Linezolid

I think most people are quite familiar with linezolid, an oxazolidinone that is traditionally used for gram positive infections, usually Staph aureus. It is the first of a generation and has found use in MDR/XDR TB patients, though it is largely limited by adverse events. A phase 2a, randomized trial evaluated linezolid 600mg daily starting at enrollment or after a 2 month delay in patients with XDR-TB (this was done to ensure the effect was due to linezolid) for sputum-culture conversion at 4 months (26). A percentage of patients underwent randomization after conversion to negative smears to receive either linezolid 600mg daily or 300mg daily for an additional 18 months. 39 patients were randomized, with 79% of patients in the early-start group achieving negative sputum culture conversion at 4 months compared to 39% in the late-start group:

89% of patients who received linezolid achieved culture conversion by 6 months. 7 patients had myelosuppression and 2 had optic neuritis. In the second part of the study, 17 patients received 600mg of linezolid while 16 got 300mg. Those in the 600mg group were 2.7 times more likely to have an adverse event c compared to those in the 300mg group (p = 0.03).

While this suggests that 300mg dose would be the way to go after culture conversion, trough level was lower in the 300mg dose compared to the 600mg dose and it was below the MIC in 9 patients, though there was no association with culture conversion and peak or trough level measured after 2 weeks. A smaller prospective, randomized trial evaluated a higher dose of linezolid, 1200mg daily for 4-6 weeks followed by 300-600mg per day until patients provided two negative sputum cultures during a 2 month period (27). 65 patients were randomized, with patients in the linezolid group having a higher rate of culture conversion by month 24 (79% vs 38% p <0.001) as well as having a faster time to cavity closure:

A higher percentage of patients had peripheral neuropathy and optic neuropathy:

A review of 11 studies totaling 218 patients (28), of which 148 had evaluable outcomes, found that linezolid had a pooled treatment success of 67.99% (95% CI 58-79), with no change when therapy lasted <7 months or when doses were <600mg daily:

Of course, there was a higher heterogeneity here, with doses ranging from 300mg daily to 1200mg daily. Bone marrow suppression occurred in 28% of patients while neuropathy (peripheral and optic) occurred in 31%. It seems there is evidence that regimens including linezolid are able to clear sputum in patients with XDR/MDR TB, however the dosing is inconsistent in several studies and the duration of therapy is also another thing to consider, with daily dosing of 600mg being considered. One exception seems to be the Nix-TB study (29), which was an open-label, single group study evaluating bedaquiline 400mg daily for 2 weeks followed by 200mg three times per week, pretomanid 200mg daily, and linezolid 1200mg daily for 26 weeks with an option to extend to 39 weeks. 109 patients were enrolled (the first 44 were started on linezolid 600mg BID while the remaining 65 were started on linezolid 1200mg daily). 90% of patients in the ITT population had a favorable outcome:

81% of patients had peripheral neuropathy, which was not statistically different when comparing the 600mg dose group or the 1200mg group.

Clofazimine 

This is an old drug that was originally made for treatment of TB, however inconsistent results in animal models back in the 1950s hindered its use against TB. As a result, it has been used mostly for leprosy. This riminophenazine works through effects on intracellular redox cycling and membrane destabilization, and it has anti-inflammatory and pro-oxidative properties. It is highly lipophilic, accumulating in fatty tissues. An animal study evaluated 2 different therapies, one of which included clofazimine, and found that animals who had clofazimine-containing regimens had a significant decrease in lung cfu counts at 9 months (30):

Robust human data is scarce, however there seems to be a good track record for clofazimine in the recent years. A 12-year prospective study (31) evaluated several therapy for MDR-TB in Bangladesh and found the most effective therapy was one that consisted of a 4 month intensive therapy with Kanamycin, clofazimine, gatifloxacin, ethambutol, INH, PZA, and prothionamide, followed by 5 months of gatifloxacin, ethambutol, PZA, and clofazimine. The relapse-free cure rate was 87.9% in this cohort (95% CI 82.7-92). Indeed, the two regimens which included clofazimine throughout had the highest success rate:

A prospective multicenter, randomized, open-label study (32) from China evaluated the superiority of clofazimine-based therapy for 21 months. Primary end-point was sputum culture conversion. 105 patients were evaluated, with 74% of the patients in the clofazimine group achieving treatment success by month 21, compared to 54% in the control group:

The clofazimine group also had a shorter time to cavity closure:

Most of the side effects noted in the clofazimine group was pink or bronshish-black discoloration of skin, seen in 94% of patients:

Finally, a review of 599 patients with drug resistant tuberculosis treated with clofazimine demonstrated a favorable outcome in 65% of patients, which was similar in both MDR-TB and XDR-TB (33):

Summary of Drug Doses (17):

EDIT: And of course, as I wander through the literature, I come across updates to this. The WHO had released a rapid communication in 2018 (34) that recommended an all oral regimen that includes bedaquiline for MDR/RR TB. Further, group A now includes the quinolones (levofloxacin/moxifloxacin), bedaquiline, and linezolid (35):

This allows the use of an all PO regimen for 9-12 months provided there is no resistance to any of the other components and no prior therapy has been tried.

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