Running head: TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 1

Optimal Treatment of Multidrug-Resistant Tuberculosis:

A Literature Review

Hilari Head and Terry Kallner

State University of New York Polytechnic Institute

TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 2

Optimal Treatment of Multi-Drug Resistant Tuberculosis:

A Literature Review

One-quarter of all humans on planet Earth are infected with tuberculosis (Houben & Dodd,

2016). Most of these are latent infections, but the World Health Organization (WHO, 2017) found that

10.4 million people became ill with active tuberculosis (TB) in 2015, and 1.8 million of those died.

Without proper treatment for the active disease, the mortality rate is 45% for those without the human

immunodeficiency virus (HIV), and nearly 100% for those who are HIV-positive. In part, this explains

why it is the number one killer of HIV-positive people, accounting for 35% of all HIV-related deaths

worldwide. Given these grave statistics, the value of implementing proper treatment cannot be

overstated. However, the identification of proper treatment is complicated in the setting of increasing

drug resistance.

Resistance to TB drugs is widespread, constantly evolving, and diagnostically significant.

Resistance to both isoniazid (INH) and rifampin (RIF) defines multidrug-resistant tuberculosis

(MDRTB), and such resistance is not rare. In the year 2015, an estimated 480,000 people developed

MDRTB (WHO, 2016a). MDRTB significantly affects the efficacy of TB treatment. Instead of

obtaining the 85% success rates seen in susceptible cases, patients with MDRTB have a success rate of

only 52% when provided the standard of care.

The standard of care for MDRTB can be identified in WHO (2011). In this guideline, the

antibiotic regime started with an intensive phase of 5-drug treatment. The drugs could include

pyrazinamide (PZA), a fluoroquinolone, a parenteral agent, ethionamide, and cycloserine or para-

aminosalicylic acid. Additionally, ethambutol (EMB) could be used, but was not part of the

standardized regime. In this regime, the fluoroquinolone should not be ciprofloxacin, and the parenteral

agent could be kanamycin (KM), amikacin, or capreomycin. This intensive phase should last at least

eight months, and could be extended depending on the patient's response. Response to treatment should
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 3

be monitored monthly by sputum smear microscopy and bacterial smear cultures. After the intensive

phase, a continuation phase should bring the total treatment duration to twenty months, depending on

patient's response to therapy. During this continuation phase, PZA and the parenteral agent may be

discontinued.

Purpose

Given the fact that barely over half of MDRTB patients are treated successfully, this paper will

perform a review and analysis of the most current literature to determine the best practice for treatment

of the disease. Its purpose will be to examine the current state of scientific evidence concerning the

treatment of MDRTB. By providing a synthesis of the best available evidence, this review hopes to

provide direction for healthcare providers, administrators, and system developers concerning the

implementation of effective, quality care.

While the plan of care for any individual is customized to the patient, many modifying factors

will be neglected in this analysis. The current treatment guidelines from WHO (2016b) indicate that

there is no known reason to differ treatment for children with MDRTB. Thus, the current review of

adult patients should apply to children. Conversely, these guidelines state that pregnant women should

be given individualized treatment, as antibiotics must not be teratogenic. This individualization and

selection procedure is beyond the scope of this review, and will thus be neglected. Finally, the

guidelines recommend that some surgical interventions may be used for those with MDRTB, but that

the evidence indicates that the prognosis is similar whether surgery is pursued or not. Since surgery

does not significantly affect prognosis, it too will be neglected. Therefore, this review will limit itself to

discussion of the pharmacologic treatment of non-pregnant adults with MDRTB.

Method

For this review, relevant articles were obtained from the State University of New York,

Polytechnic Institute, Cayan Library database search. Particular attention was paid to those databases
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that were in the “Medicine/Nursing/Health” catalog, which were Alt HealthWatch, CINAHL Plus with

Full Text, Cochrane Collection Plus, Ebsco Clinical Ebook Collection, Health Source: Consumer

Edition, Health Source: Nursing/Academic Edition, MEDLINE, and Nature Complete. Additionally,

some citations were found by those databases, but their referenced articles could not be accessed

through the Cayan Library website, so they were accessed through Google Scholar. For background

information, the websites for the CDC and WHO were also utilized.

The search terms used in the aforementioned databases for this review were 'MDRTB treatment,

drug-resistant TB treatment, drug-resistant tuberculosis treatment, TB shorter regime, and tuberculosis

shorter regime'. The search was restricted to peer-reviewed journal articles published in the English

language between the years 2012 and 2017. The search results were reviewed for relevance, and the

reference lists of the relevant articles were reviewed for new articles. After database searches had been

completed, the reference list of WHO (2016b) was compared with the search results, and additional

articles were found. Inclusion criteria included a focus on regulatory-approved pharmacologic

treatments yielding quantitative data. Exclusion criteria included meta-analyses, case studies, official

guidelines, and a focus on pregnant women. From this procedure, fifteen articles were located and

obtained. The full text of each was subsequently reviewed, and a summary was completed (see

Appendix A for summary table). These summaries were then logically organized and analyzed with

reference to the purpose of this paper.

Results

Upon review of the included articles, they were divided into those that tested shorter-duration

treatment regimes based on fluoroquinolones, those that augmented standard-duration therapies with

experimental medications, and those that studied the effects of antiretroviral therapy (ART) on standard

therapy for those with HIV.

Shorter-duration Treatment Regimes

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The first reviewed trial, Aung et al. (2014), built on the success of previous efficacious drug

regimes that were of shorter duration than standard treatment. In this study, 515 patients were enrolled

in a treatment regime that consisted of gatifloxacin (GFX), clofazimine (CFZ), prothionamide (PTH),

KM, INH, EMB, and PZA to be given for the intensive phase of at least 4 months. This intensive phase

could be extended until smear conversion, which was then followed by a fixed, five-month

continuation phase that consisted of GFX, CFZ, EMB, and PZA. Follow-up testing was done every six

months after completion for two years. At the end of this period, the cure rate was 84.4 percent.

Although Aung et al. (2014) showed great effectiveness with a shorter-duration regime, its

structural disadvantages limit its strength. It tested its regime on a large sample size, with a long

follow-up period, thus lending credence that the study's cure state was permanent. Additionally, testing

was completed on a wider range of drug resistance, with the finding that resistance to those drugs in the

regime were not significant except for high-level resistance to GFX. However, like previous shorter-

course trials, this was an uncontrolled cohort analysis, which limits its strength. Furthermore, the

authors note that HIV prevalence for their tested population is almost entirely absent. Therefore, further

testing of this regime in multiple locations would be needed to demonstrate its applicability to those

areas where resistance patterns, co-morbid conditions, and cultural differences may affect its efficacy.

As an alternate location for a shorter-course trial, Piubello et al. (2014) used a related regime of

a shorter-coarse trial in Niger, with similar results. The regime structure and medication selection were

the same, except that the continuation phase was extended from the five months utilized in Aung et al.

(2014) to eight months. Smear microscopy was performed every month during the intensive phase and

every two months during the continuation phase. Cultures were obtained every 2 months during

treatment. The cure rate was 89.2%, with 84.5% of those remaining culture-negative after two years of

follow-up.

While helping to bolster the findings of the previous studies, Piubello et al. (2014) suffers from
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similar structural defects. It, too, is an uncontrolled cohort study, and therefore sub-optimally rigorous.

The GFX-resistance that was noted to be significant in Aung et al. (2014) was not tested in this study.

As within the prior studies, previous MDRTB treatment excluded participants. Less ideally, the

continuation phase was extended, so that the identical regime was not being studied. However, the

similar cure rate across two continents adds much credence to the general applicability of the regime.

In an attempt to further establish the general applicability of shorter-course treatment regimes,

Kuaban et al. (2015) studied a similar standardized, shorter treatment regime in Cameroon yielding

similar results. The regime was tested on 236 participants with MDRTB who were enrolled

sequentially, and consisted of a minimum four-month intensive phase of GFX, CFZ, EMB, PZA, PTH,

KM, and INH, followed by an eight-month, fixed-duration continuation phase of the former five drugs.

Monthly smear and culture tests guided decisions to possibly extend the intensive phase up to a total of

six months' duration. These monitoring laboratory tests were continued monthly throughout therapy,

then twice over a year-long follow-up. This regime produced an 89.3% cure rate, with no instances of

relapse.

While there are a number of positive results for this study, Kuaban et al. (2015) still has

fundamental, structural weaknesses. The inclusion of 20% of participants with HIV adds great credence

to the shorter-course's general applicability, since under multivariate analysis there was no statistical

difference in their outcome rates. However, it is unfortunate that substantial differences exist between

its regimen and that of previous studies. Its eight-month continuation phase is identical in duration to

that used by Piubello et al. (2014), but it maintained treatment with PTH during this phase, unlike any

other study. Dosages of INH and GFX were also halved compared to the other studies. Like all

previous studies, Kuaban et al. (2015) is set up as a prospective cohort study, thus lacking the rigor that

comes with a randomized controlled trial. Its year-long follow-up was also shorter than was that for the

previous studies. Also, as in previous short-course studies, it excluded those patients who had
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previously been treated for MDRTB. Such repeat patients may benefit from clinical trials that attempt

to improve on success rates by optimizing the selection of drugs while retaining a long duration of

treatment.

Standard-duration Treatment Regimes

Among the standard-duration trials, a large variety of experimental drugs were represented,

including linezolid, clofazimine, bedaquiline, and delamanid.

Linezolid. Utilizing one such standard-duration regime, Singla et al. (2012) demonstrated the

efficacy of linezolid (LZD). In this study, 29 participants with MDRTB received individualized therapy

based on WHO (2011) guidelines which all included LZD. An intensive phase lasted for six months or

until culture conversion. This was followed by a continuation phase, which only included oral agents

and lasted for eighteen months. During this trial, smear and culture conversion was achieved in 89.7%

of cases within six months of therapy, although 10% of patients had to stop linezolid due to adverse

reactions. Follow-up results were not published.

Even more than in previously discussed studies, Singla et al. (2012) suffers from structural

defects. Like the others, it too is a prospective cohort analysis, and therefore does not have the

statistical power of a randomized controlled trial. It systematically excluded patients with HIV, who

make up a considerable percentage of MDRTB patients worldwide, and excluded a follow up phase.

However, this study does fill in a major gap by not excluding those patients who have previously been

treated with second-line agents.

The need for a controlled trial was fulfilled by Tang, Yao, Hao, and Zhang et al. (2015). All 65

participants had treatment regimes in accordance with WHO (2011). However, 33 participants were

randomly assigned to have LZD included as part of their individualized regime. Both groups were

composed of those with “intractable” MDRTB, who had previously failed standard therapy. The

experimental group included treatment with LZD at double the dose that was studied by Singla et al.
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 8

(2012) for the first 4-6 weeks, followed by a similar dose for the remainder of the study. At the end of

the study, a significantly higher proportion of patients in the LZD group had successful treatment

outcomes and had converted to negative sputum cultures.

While Tang, Yao, Hao, and Zhang et al. (2015) demonstrates the efficacy of LZD therapy, there

are some aspects that should raise qualms. Specifically, 81.6% of participants in the LZD group had

significant adverse reactions, including anemia, vomiting, optic neuropathy, and peripheral neuropathy.

Also, the study structurally excluded those with HIV. Like others, this trial did not include follow-up

after the end of treatment, and therefore relapse rates are unavailable. However, it does bolster the

evidence for the efficacy of LZD in those who have failed previous MDRTB therapy. While every

participant had failed more than one year of previous treatment, 69.7% had successful treatment when

it included LZD. Optimally, additional studies should combine this inclusion of previous treatment

failures with more structurally sound trial procedures.

In one such trial, De Lorenzo et al. (2013) paired LZD treatment with meropenem-clavulanate

(MEC) in a 90-day inpatient setting. The control group was 61 participants with MDRTB who were

given WHO (2011)-guided treatment including LZD. The experimental group was 37 participants who

were given WHO-guided treatment including LZD and MEC. Despite the fact that the experimental

group was more clinically severe at the beginning of the trial, it had significantly higher smear- and

culture-conversion rates by the end of 90 days.

While De Lorenzo et al. (2013) demonstrated the efficacy of inpatient MEC therapy, it had its

own defects. This study did benefit from inclusion of participants who had failed previous MDRTB

treatment, and from the inclusion of HIV positive participants, both of which vastly increase its

applicability. However, the dosing of LZD varied across sites, with the experimental group receiving—

on average—a higher dose. This makes it difficult to dissect whether the increased efficacy of the

experimental group came from the inclusion of MEC or from the higher LZD dose. This is significant,
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as almost all adverse drug reactions in the study came from the higher dose of LZD. Also, the lack of

follow-up data plagues this study with questions about relapse rates. A more rigorous study would

follow the experimental regime all the way to cure.

Clofazimine. In one trial that does follow patients to this later end-point, Tang, Yao, Hao, and

Liu et al. (2015) studied the effects of incorporating CFZ into a standard-duration drug regime. One-

hundred and five participants with MDRTB were randomly assigned into either a control group which

received five individualized antibiotics based on WHO (2011), or to an experimental group that

received five individualized antibiotics plus CFZ. Compared to the control sample, those given CFZ

had a faster rate of culture conversion, a faster rate of lung cavitation closure, and a 73.6% higher cure

rate.

As a randomized control trial, the structure of this study was the gold standard for rigor, but it

still has its weaknesses, it did not include follow-up testing results. The study was also not blinded, so

placebo effects are possible. Additionally, the experimental group was given six antibiotics, instead of

the control group, which followed the standard five-drug therapy. It is not clear if similar gains would

occur if CFZ had replaced another medication in the standard five-drug regime, instead of being added

to it. Also, HIV-infected patients and those with psychiatric illnesses were excluded from this trial,

which impairs generalizing results. The latter were excluded because CFZ has a widespread side effect

of skin discoloration which has previously been linked to suicide, and which occurs in a startlingly high

94.3% of participants.

Bedaquiline. An additional drug developed for MDRTB is bedaquiline (BDQ), which Diacon

et al. (2014) studied for efficacy. Participants from eight countries were randomly separated into a

double-blinded, placebo-controlled group, which were given standard MDRTB treatment plus a

placebo, and an experimental group, which was given BDQ along with the standard treatment. BDQ

was only given during the six-month intensive phase, which was followed by a 24-month continuation
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 10

phase. Compared with the control group, the BDQ group achieved significantly faster culture

conversion, had a higher culture conversion rate at the end of the six-month BDQ treatment, and had a

higher cure rate at the end of the 30-month trial. With its placebo-controlled, double-blinded,

randomized controlled structure, as well as its multi-national sampling, Diacon et al. (2014) was by far

the most rigorous trial discussed thus far.

Even with structural rigor, Diacon et al. (2014) could not answer all questions about utilizing

BDQ. HIV-positive participants were allowed into the study, but only if their disease was stable and

hematologically insignificant. While this is not as limiting as the structural exclusion of HIV-positive

patients, it is unclear what proportion of MDRTB patients who are HIV positive would fit this

definition. This problem is further exacerbated by the exclusion of patients who had failed previous

MDRTB therapy. A significantly higher mortality rate occurred among the BDQ group without any

discernible pattern, except it often occurred after BDQ treatment was complete. New studies would be

needed to examine the efficacy of BDQ for those with HIV and to explain the increased mortality rate.

The follow-up study that inquired into the relationship between HIV and BDQ was Ndjeka et al.

(2015). A convenience sampling of 91 participants was given a standard, individualized medication

regime in addition to BDQ for 24 weeks. Of those 91 participants, 59% were HIV-positive. Since the

study was an interim report, only 64% of participants had completed the full 24 weeks, and even these

had limited time for follow-up. However, of those patients who had at least six months of follow-up,

76% had converted and remained culture-negative. Additionally, only one patient died, and adverse

reaction rates were comparable to previous studies in the literature. Weaknesses of this study include its

lack of a control group and lack of extensive follow-up, especially considering that the majority of

those who died in Diacon et al. (2014) did so during the follow-up phase. Additional studies would be

needed to assess the safety of BDQ.

The study that took up this burden was Pym et al. (2015). In this study, 233 patients with
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MDRTB were treated with BDQ for 24 weeks, in addition to an individualized treatment regimen, then

were followed for a full 120 weeks. At the end of this extensive follow-up period, 72.2% of participants

had maintained a culture-conversion status, even though 87.1% of patients had previously undergone

and failed MDRTB treatment. Further, the mortality rate was only 6.9%, which is lower than in

previous studies of standard treatment. Weaknesses of the study included the lack of a control group

and the exclusion of HIV-positive patients if their disease was hematologically significant.

Delamanid. A second new anti-TB medication, delamanid (DLM) was studied by Gler et al.

(2012). Like Diacon et al. (2014), this was a multi-national, double-blinded, randomized, placebo-

controlled trial for treatment of MDRTB. The control group was given the standard background drug

regime plus placebo, and two experimental groups were given two different dosages of DLM. At the

end of the two-month trial, both DLM groups achieved statistically higher sputum conversion rates.

Tolerability was also positive, with adverse events spread evenly throughout the three groups.

Significantly, no deaths occurred during the entirety of the study.

Although Gler et al. (2012) shared a similar structural rigor to Diacon et al. (2014), it too was

plagued by some weaknesses. The study was almost completely devoid of HIV-positive participants

due to similar exclusion criteria as was used in Diacon et al. (2014), therefore limiting its applicability.

Compounding this problem is the fact that, like Diacon et al. (2014) and those trials of shorter-course

treatment, Gler et al. (2012) excluded those patients who had failed previous MDRTB therapy. Its

biggest problem, however, was its short duration. The study period was only two months, and without a

follow-up period, it is unknown whether relapses would occur. Optimally, follow-up analysis would be

needed to monitor the continued culture-negative status for those treated with DLM.

Such treatment was given to participants by the follow-up study, Skripconoka et al. (2013). For

this trial, participants who had received DLM were separated into step-wise groups of increasing

treatment duration of either two months, six months, or eight months of DLM-based therapy. The
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control group completed six months of intensive therapy, including 4-6 anti-TB drugs, followed by the

standard simplified continuation phase for an additional 12-18 months. At the end of the two-year trial,

those who had completed six or eight months of DLM therapy had significantly improved outcomes

compared with those who only completed two months of DLM therapy or who had never taken the

drug. The mortality rate was also significantly improved for those patients taking longer courses of

DLM. No additional benefit over six-month therapy was seen in the duration of eight months, nor was

any benefit seen in two-month therapy over the standard therapy plus placebo. Since the participants

were initially recruited by Gler et al. (2012), it suffers from the applicability problems of this previous

study. However, while it does not adequately address those who have previously failed MDRTB

treatment or those who are HIV-positive, it does demonstrate the long-term efficacy of DLM, as well as

identify an optimal 6-month length for treatment duration.

Antiretroviral Therapy

For those with HIV, the initiation of ART can be a crucial component in the overall treatment of

MDRTB. This relationship was explored in Palacios et al. (2012) where 52 participants with co-

infection of MDRTB and HIV were studied. After an individualized MDRTB treatment regime, the

mortality rate was a staggeringly high 57 percent. However, upon statistical analysis it was found that

ART intervention resulted in a statistically significant reduction in mortality. One weakness of this

study was the aggregating of data for those who were already on ART at the time of MDRTB diagnosis

and those who initiated therapy afterwards. Studies that analyze the time-to-treatment with ART may

be beneficial.

In Satti et al. (2012), 94 patients who were co-infected with HIV and MDRTB were compared

based on the timing of ART initiation. While 53.2% of those patients started TB treatment while

already on ART, 42.6% had never been on ART and delayed initiation for a median of sixteen days.

The study found that there was no association between mortality and ART initiation, but that the time-
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to-death was significantly shorter for those who delayed ART. Weaknesses of this article include its

small sample size, and its weak conclusion, as the comparison does not help determine when an ART-

naive patient should initiate treatment. Other randomized controlled studies would be needed to

determine if timing of ART initiation really was associated with MDRTB cure.

This niche was filled by Padayatchi, Karim, Naidoo, Grobler, and Friedland (2014), who

randomly assigned 23 patients to either initiate ART at the same time as MDRTB therapy, or to delay

initiation until after the MDRTB therapy was finished. At the end of the 18-month follow-up period,

the mortality rate for the concomitant-therapy group was found to be 86% lower than that of the

sequential-therapy group. Despite the small sample size, this finding retained statistical significance.

The glaring weakness of this study, however, is that small sample size. Otherwise, its structure is the

gold standard to assess differences in efficacy of treatments.

Discussion

When reviewing the best available evidence for the pharmacologic treatment of MDRTB,

numerous trials report improved outcomes compared to standard treatment based on WHO (2011).

These include standardized, short-course treatments based on GFX and CFZ. For those trials that left

duration-length unchanged, improved outcomes were noted for those regimes that included either LZD,

CFZ, BDQ, or DLM. Each of these regimes has its individual benefits and risks.

Due to the mounting evidence of more effective treatments, WHO (2011) was amended by

WHO (2016b). The impetus for many of its changes can be seen in the evidence already reviewed.

Short-course treatments based on GFX and CFZ were recommended, a greater preference was given to

LZD and CFZ, and the new guidelines also included the possibility of utilizing BDQ or DLM, but only

if the required number of medications could not be obtained from more-preferred groupings (see

Appendix B for additional details for the new selection algorithm). The conclusions of this review,

however, would be slightly different than those of WHO (2016b).

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Shorter-duration Treatment Regimes

Standardized, short-course treatments are centered around GFX and CFZ. The treatment

regimes studied by Aung et al. (2014), Piubello et al. (2014), and Kuaban et al. (2015) are all similar,

yet not the same. Even so, short-course regimes have proven safe and effective across various cultures

and continents. Since the standardized short courses are not changed based on drug susceptibility

results, the need for such testing could be reduced in resource-limited settings. The shorter duration

itself would be beneficial for such settings, reducing labor costs and the amount of medication required

per patient.

Short-course regimes, however, have a number of limitations. The only trial which included any

substantial number of participants with GFX resistance, Aung et al. (2014), found significantly worse

outcomes for these patients, which calls into question the applicability of short-course treatments for

those localities that have higher resistance patterns. Additionally, Aung et al. (2014), Piubello et al.

(2014) and Kuaban et al. (2015) all structurally excluded those potential participants who had

previously been treated for MDRTB. Therefore, there is no available evidence to support short-course

treatments in this population. The short-course treatment can therefore be recommended, but with

restrictions. It can only be used with those who have never previously been treated for MDRTB. In

HIV-prevalent areas, the short-course regime of Kuaban et al. (2015) should be used until the others

can prove their efficacy in the HIV-positive population. Conversely, this regime, with its half-dose of

GFX, should not be used in areas with a high incidence of fluoroquinolone resistance.

Standard-duration Treatment Regimes

Those trials that included LZD in their standard-duration regimes all report its increased

efficacy, but they also raise concerns about its tolerability. Singla et al. (2012), Tang, Yao, Hao, and

Zhang et al. (2015), and De Lorenzo et al. (2013) all reported significantly improved outcomes for

those patients whose regime included LZD. According to Singla et al. (2012), who examined multiple
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dosages, there were no dose-dependent differences in efficacy. Therefore, should the prescriber opt for

LZD therapy, the best course may be to choose a lower dosage, as the higher dose included in Tang,

Yao, Hao, and Zhang et al. (2015) had a 81.6% rate of adverse reactions. Should the adverse effects of

LZD necessitate its discontinuation, encouraging success rates were also obtained from standard-

duration regimes which included CFZ.

While CFZ may increase efficacy of MDRTB treatment, it presents its own challenges.

Evidence for increased efficacy of CFZ-containing regimes over standard care guided by WHO (2011)

comes from a single unblinded study, Tang, Yao, Hao, and Liu et al. (2015), which included barely

over one-hundred participants. Due to its exclusion criteria, there is no evidence to support CFZ

therapy in patients with concomitant HIV or psychiatric illness. This latter exclusion is due to a nearly

universal adverse effect of CFZ—skin discoloration—which has been reported to lead to suicides.

Importantly, before initiating CFZ therapy the prescriber would need to discuss its adverse effect

profile with the patient, clearly delineating the risks and benefits of such treatment.

Newer anti-TB drugs have shown increased efficacy over standard care without adverse effect

rates nearly as high as in those regimes containing LZD or CFZ. Both BDQ and DLM had their

efficacy over standard care confirmed in multi-national, double-blind, randomized, placebo-controlled

trials. The studies of BDQ by Diacon et al. (2014) and of DLM by Gler et al. (2012) and Skripconoka

et al. (2013) all suffer from their exclusion criteria. Consequently, there is very poor evidence from

these studies for the efficacy of either new drug in those with HIV, and no evidence for those

previously treated for MDRTB. Additionally, for BDQ, Diacon et al. (2014) showed a concerning

increase in mortality rate for BDQ-treated patients. However, subsequent studies by Ndjecka et al.

(2015) and Pym et al. (2015) showed no such mortality increase, and even demonstrated efficacy in

HIV-infected patients. Therefore, while both new drugs may be efficacious, prescribers may want to

lean toward BDQ for those co-infected with HIV.

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For standard-duration therapies, the evidence supports a MDRTB regime that contains at least

five different medications. The greater preference given to fluoroquinolones, injectables, LZD, and

CFZ is supported by the reviewed evidence. However, this review would add a preference for BDQ and

DLM as well. The other medications in the algorithm of WHO (2016b) were also present in WHO

(2011), and thus have some evidence for their efficacy in that the entirety of the “standard therapies”

and the majority of medications in the experimental therapies were made up from among them.

Therefore, the recommendation of this review for standard-duration MDRTB therapy is that it should

include one fluoroquinolone, one injectable, and one experimental drug—LZD, CFZ, BDQ, or DLM—

with two remaining drugs approved by WHO (2016b), for a total of five drugs.

Antiretroviral Therapy

Since such co-infection is so common, the relationship between MDRTB treatment and ART is

important. Even with their small sample sizes, Satti et al. (2012), Palacios et al. (2012) and Padayatchi

et al. (2014) all demonstrate an increased efficacy of MDRTB therapy when it is combined with ART.

Even in the former study, which did not demonstrate a decreased mortality rate with an earlier initiation

of ART, it still identified an increased length of life with prompt intervention. The latter two studies

each associated co-treatment with ART with a decreased mortality rate. Therefore, ART treatment

should not be delayed until the completion of MDRTB treatment, but should be co-administered.

Limitations of Available Evidence and Recommendations for Future Research

There are two glaring weakness in the available evidence for this review. One is the lack of a

standardized control for comparison. The guidelines in WHO (2011) did not include a selection process

that is specific enough to be repeatable. Two different individualized drug regimes could not both be

equally valid and in compliance with the treatment guidelines. This is a structural problem when

attempting to compare the efficacy of drug regimes with “standard treatment,” as the “standard” will be

different for different participants, thus clouding the experimental variable. It also inhibits comparison
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 17

between studies, as their guideline-based treatments may be different from each other even though they

are following the same guidelines. The other major weakness of the available evidence is the total lack

of testing for the relative efficacy between experimental treatment regimes. Thus, while we have

evidence that they are all more effective than standard therapy, we have no evidence of how they

compare to each other. Therefore, the only thing the prescriber can be assured of is that any of these

experimental therapies would be more efficacious than standard care.

These problems highlight some areas that are in need of future research. Most importantly,

much more study needs to be done concerning the optimal combination of medications. The optimal

“standard therapy” must be determined, as should the relative efficacy of LZD, CFZ, BDQ, DLM, or

the various short-course treatments. The effect of fluoroquinolone resistance, HIV status, and previous

MDRTB treatment on short-course treatment has to be further established. Given its efficacy, but also

its terrible adverse reaction profile, it would be useful to find a dose of LZD that is effective but

minimally toxic. Similarly, any interventions that could combat the dermatologic impacts of CFZ may

allow those with low self-esteem or other psychiatric problems to benefit from this efficacious therapy.

Only with further research into such areas can the world effectively fight the toughest cases of a disease

that plagues one-quarter of its inhabitants.

TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 18

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TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 21

Appendix A

Literature Review Table

Article Sample Interventio Comparator Method Setting Outcome

n
Aung et al. 515 MDRTB GFX, EMB, None Prospective Inpatient for 84.5%
(2014) patients in PZA, CFZ, cohort analysis intensive successfully
Bangladesh. PTH, KM, of 515 phase. treated (either
Exclusion and INH for participants Outpatient cured or
criteria for 4-month using for completed
overt liver intensive convenience continuation treatment),
disease or phase, sampling phase. with 6.9%
previous followed by technique. Monthly relapse rate at
MDRTB GFX, EMB, sputum 12 months
treatment. PZA, and smears and and 17.7%
Enrollment was CFZ for 5 cultures relapse rate at
irrespective of month during 24 months.
age or clinical continuation intensive Significantly
severity. While phase. phase. worse, 51.0%
not excluded, During During success rate
HIV is nearly intensive continuation for high-level
absent in the phase, phase, GFX
population. At inpatient smears and resistance.
enrollment, dosages cultures 5.6%
patients tested given by taken at 2,4, mortality rate
for drug health and 5 during
resistances. professional months. treatment.
s. During Follow-up Adverse drug
outpatient testing every events were
continuation 6 months for not
phase, 2 years. systematicall
patient self- y recorded.
administered
medications.
De 98 adult 37 61 Controlled Inpatient MEC group
Lorenzo et MDRTB participants. participants. prospective setting. had 87.5%
al. (2013) patients in Italy Individualiz Individualize cohort analysis, Duration of smear
and the ed d medication not randomized therapy was conversion
Netherlands. medication regime between two determined by 90 days,
Included HIV regime including different individually compared to
patients, those including LZD, based locations. based on 56.3% for
exposed to LZD and on drug- Convenience clinical control.
previous MEC, based susceptibility sampling. improvemen Median time
MDRTB on drug- testing in t, culture to conversion
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 22

Article Sample Interventio Comparator Method Setting Outcome

n
therapy, and susceptibilit accordance and smear was similar
extrapulmonary y testing in with WHO results, and across
TB. At accordance (2011). occurrence groups.
enrollment, with WHO Inpatient, 2- of adverse Differences
patients tested (2011). month trial reactions.. in culture
for drug Post- in the conversion
resistances. analysis Netherlands. were
Intervention showed borderline
group was individualiz significant,
significantly ed therapy 83.8% for
clinically had led to MEC versus
worse, with significantly 62.5% for
more resistance higher control.
and re- dosages of Significantly
treatment LZD higher
cases. compared adverse
with control. reaction rate
Inpatient, 2- for MEC
month trial group, but
in Italy. additional
events were
related to
higher LZD
dose.
Diacon et 160 patients 79 patients. 81 patients. Randomized, Preferred BDQ group
al. (2014) with newly- BDQ, Individualize placebo- outpatient had reduced
diagnosed, 400mg once d therapy in controlled, setting in median time
smear-positive daily x 2 accordance double-blind accordance to culture
MDRTB across weeks, with WHO trial. with conversion of
9 countries. followed by (2011) plus a national 83 days vs
Exclusion 200mg three placebo. treatment 125 days.
criteria times a programs. Also had
included week x 22 Patients increased rate
previous weeks added were of conversion
treatment for to instructed to by 24 weeks
MDRTB, HIV individualiz take BDQ or (79% vs
with CD4+ ed therapy placebo with 58%) and at
count of less in water after 120 weeks
than 300 cells accordance breakfast. (62% vs
per millimeter, with WHO Sputum 44%). No
pregnancy, (2011). culture was statistical
alcohol or drug After 24- taken differences in
abuse. week BDQ weekly adverse drug
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 23

Article Sample Interventio Comparator Method Setting Outcome

n
trial period, throughout events
96 the trial, and between
additional at 6-month groups. BDQ
weeks of follow-up. group had
individualiz significantly
ed therapy elevated
was mortality
continued rate.
without
BDQ.

Gler et al. 481 patients 8 week 125 patients Randomized, 8 week Significantly
(2012) across 9 inpatient who received placebo- inpatient higher rate of
countries who trial. standard controlled, trial, with sputum
had positive Experimenta treatment in double-blind medications conversion at
sputum culture l groups accordance trial. administered 2 months for
for MDRTB. separated with WHO via directly the 100mg
Exclusion into 141 (2011) plus observed DLM and
criteria patients who placebo. therapy.. 200mg DLM
included HIV received Morning groups vs
with CD4+ DLM sputum placebo
count less than 100mg twice specimens (45.5%,
350 per cubic daily, and were 41.9% vs
millimeter, 136 patients cultured on 29.6%). Only
antiretroviral who days -1, 1, 8, significantly
treatment, received 15, 22, 29, increased
pregnancy, and DLM 36, 43, 50, adverse event
substance 200mg twice 57, 63, 70, for DLM
abuse. Due to daily. Both 77, and 84 groups was
active groups also of the trial. QT-
randomization, received prolongation,
no statistical concurrent but no deaths,
differences standard V-tach, or
between therapy in torsades were
control and accordance noted.
experimental with WHO
groups. (2011).
Kuaban et 150 patients 4-month none Prospective Inpatient 89% of
al. (2015) with MDRTB intensive observational setting for patients
in Cameroon. phase of study. No intensive successfully
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 24

Article Sample Interventio Comparator Method Setting Outcome

n
Exclusion KM, GFX, control group. phase. completed
criteria PTH, CFZ, Study Outpatient treatment. No
included INH, EMB, population was setting for difference in
previous and PZA, gained through continuation treatment
MDRTB followed by convenience phase, but outcome for
treatment, 8-month sampling. had to HIV positive
pregnant continuation Sputum culture receive patients. At
women, and phase of was obtained directly the end of 1
those in very GFX, PTH, monthly to observed year follow-
poor clinical CFZ, EMB, assess progress, treatment up, there
condition. and PZA. and every 6 from a were no
Twenty percent All drugs months for 1 health measured
of included were given year of worker relapses.
participants daily under followup. throughout Only serious
were HIV directly the entire adverse drug
positive. Only observed study. event was
one patient had conditions. hearing loss,
GFX likely caused
resistance. by KM.
Ndjeka et 91 patients 24 weeks of None Prospective Outpatient At 6 months
al. (2015) with MDRTB standard, observational based out of follow-up,
in South individualiz study with five 76% of
Africa. 59% ed treatment convenience approved patients had
were co- combined sampling. sites across retained
infected with with BDQ. Sputum cultures South culture-
HIV, and 45% were taken Africa. No conversion
had their monthly. mention of status.
resistance directly Adverse
further observed reaction rates
categorized as therapy. were similar
extremely-drug to standard
resistant. therapy. Only
1 patient
died.
Padayatchi 23 patients co- ART ART Randomized Outpatient At the end of
, Karim, infected with initiated initiated after controlled trial. based at 18 month
Naidoo, HIV and within the completion Monthly sputum eThekwini follow-up,
Grobler, MDRTB in first 12 of MDRTB collection plus Clinic in mortality rate
and South Africa. weeks, plus therapy 18-month Durban, was
Friedland concomitant consisting of follow-up South decreased by
(2014) standard KM, OFX, period. Africa. No 86% in
MDRTB PZA, EMB, mention of combined
therapy and ETH. directly integrated
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 25

Article Sample Interventio Comparator Method Setting Outcome

n
consisting of Due to observed treatment vs
KM, OFX, randomizatio therapy. sequential
PZA, EMB, n, treatment
and ETH. demographic group.
s for the
control and
intervention
group are
statistically
insignificant.
Palacios et 52 patients co- Standard Numerous Retrospective All medical 57% of
al. (2012) infected with regimen comparisons case series. facilities in patients died
HIV and which was made within Chart review Lima, Peru, while on
MDRTB in individualiz cohort study. was conducted which treatment.
Lima, Peru. ed after drug Baseline on the 52 reported However,
77% had CD4+ susceptibilit weight, ART identified MDRTB initiation of
level < 200. y studies. treatment, patients in and HIV ART was
Length of depression, Lima, Peru, who cases to the significantly
treatment central had co-infection ministry of associated
was 18-24 nervous TB of HIV and health. with reduced
months. status, and MDRTB. mortality.
number of
medications.
Piubello et 65 patients 4-month none Prospective Inpatient 89.2% cure
al. (2014) with proven intensive observational during the rate.
MDRTB in phase of study, with intensive Mortality rate
Niger. KM, PTH, convenience phase for of 9.2%. At
Exclusion INH, GFX, sampling. those in 24-months,
criteria CFZ, EMB, Sputum smear poor clinical no relapses
included and PZA, microscopy and condition or were
previous followed by culture were with measured.
MDRTB 8-month performed every comorbiditie Main adverse
treatment, continuation 2 months during s. effects were
pregnant phase of treatment and Continuatio vomiting in
women, and GFX, CFZ, every 6 months n phase was 26.2% of
those with liver EMB, and for the 2-year entirely patients and
disease. Poor PZA. follow-up. outpatient. hearing
initial condition Entire impairment
was noted in regime was in 20%, but
39.7% of administered none were
patients. by significant
healthcare enough to
workers stop
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 26

Article Sample Interventio Comparator Method Setting Outcome

n
under treatment.
directly
observed
conditions.
Pym et al. 233 patients 24-week none Prospective Inpatient or 72.2% cure
(2015) with proven treatment observational outpatient rate at the
MDRTB in with study with based on end of 120
China, South individualiz convenience country's weeks.
Korea, ed standard sampling. No standard Mortality rate
Philippines, regime and control group. . procedures. was 6.9%,
Thailand, BDQ, Sputum culture However, and adverse
Estonia, Latvia, followed by and smears at directly reactions
Russia, Turkey, 96 weeks of weeks observed were in-line
and Ukraine. standard 2,4,8,12,16,20,2 therapy was with other
Exclusion therapy. 4, conducted in studies of
criteria 36,48,60,72,84, either case. standardized
included HIV 96, 108,120. therapy.
positive with
CD4+ counts <
250, cardiac
arrhythmias,
prolonged QT.
No HIV
positive
patients had
initiated ART.
Satti et al. Retrospective Time to Delay-in- Retrospective All medical Timing of
(2012) chart analysis ART initiation analysis of all facilities ART was not
of 134 patients initiation. compared HIV co-infected providing associated
with confirmed Patients who with already- patients in MDRTB with overall
MDRTB who were already on-ART. Lesotho from treatment to mortality
initiated on ART at January 2008 to patients in rate.
treatment in the time of September Lesotho However,
Lesotho. MDRTB- 2009. from those patients
treatment January who delayed
initiation 2008 to ART and
were September then died had
compared 2009. a
with those significantly
who delayed shorter time-
ART after to-death than
MDRTB those who
treatment for started
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 27

Article Sample Interventio Comparator Method Setting Outcome

n
a median of treatment on
16 days. ART.
Singla et 29 patients who 6 month none Prospective, Inpatient for 89.7% smear-
al. (2012) previously intensive observational first part of conversion
failed treatment phase of study, with intensive by the end of
for MDRTB in injectable convenience phase, until 6 months.
India. Of those, and oral sampling. serious 72.4% show
all are resistant drugs Sputum smear adverse interim
to including and culture reactions favorable
fluoroquinolon LZD x 6 monthly for could be restuls, but a
es, and 16 are months, then intensive phase ruled out. full analysis
also resistant to continuation and bi-monthly Treatment of cure is not
injectables. phase for 18 for continuation then possible yet
months with phase. continued as since over 40
only oral outpatient, percent of
drugs. with participants
Medication compliance are still
choice is in measured by receiving
line with checking treatment.
WHO blister Serious
(2011). packs. adverse
events
requiring
discontinuati
on of therapy
occurred in
17.2% of
patients.
Skripcono 421 patients 6 or 8 2 months of Randomized, After Favorable
ka et al. with culture- months of DLM placebo- completing outcomes of
(2013) positive DLM treatment or controlled, the previous 74.5% of
MDRTB who treatment placebo double-blind trial, all patients
were along with treatment trial. patients treated with
previously concurrent concurrent were treated at least 6
randomized standard with WHO in the months of
and studied in intensive (2011)- outpatient DLM,
Gler et al. therapy in guided setting, with compared
(2012). accordance treatment. follow-up with 55% for
with WHO Remainder testing the
(2011), of intensive based on comparator.
followed by and their Additionally,
a continuation country's TB mortality rate
continuation phases treatment was
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 28

Article Sample Interventio Comparator Method Setting Outcome

n
phase of 12- according to program. significantly
18 months WHO (2011) lower in the
according to guidelines. long-term
WHO DLM group
(2011) (1% vs
guidelines. 8.3%).
Tang, Yao, 105 patients 53 patients 52 patients Randomized, Treatment Sputum
Hao, and with culture- who were who were controlled trial. was culture-
Liu et al. positive given 21 given 21 No placebo, and inpatient at conversion
(2015) MDRTB in months of months of no blinding. 6 specialty and lung
China. individualiz individualize TB cavitation
Exclusion ed therapy d therapy in- hospitals, closure was
criteria in-line with line with with significantly
included liver, WHO WHO medications shorter in the
kidney, (2011) with (2011). administered CFZ group.
psychiatric, CFZ added by health The success
hematologic throughout professional rate was also
illness, HIV, the regime. s. Sputum significantly
and pregnant or smear and higher at the
lactating culture, end of
women. Due to chest Xray treatment
randomization, and chest (73.6% vs
no statistical CT monthly 53.8%).
difference in for 3 Dermatologic
two study months, then al adverse
groups. once every 3 effects were
months for widespread in
the the CFZ
remainder of group;
the trial. discoloration
occurred in
94.3%, and
ichthyosis in
47.2%.
Tang, Yao, 65 patients in 33 patients 32 patients Randomized, Inpatient By the end of
Hao, and China with who were who were controlled trial. treatment at the trial,
Zhang et culture-positive given 24 given 24 No placebo, and 5 large-scale significantly
al. (2015) MDRTB, who months of months of no blinding. specialty TB more patients
were also individualiz individualize hospitals. in the LZD
resistant to ed therapy d therapy in- All group had
fluoroquinolon in-line with line with medications reached
es and WHO WHO were given sputum
injectables. (2011). (2011), via directly conversion
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 29

Article Sample Interventio Comparator Method Setting Outcome

n
Exclusion Additionally excluding observed (78.8% vs
criteria , they were LZD. therapy by a 37.6%). The
included HIV, given LZD healthcare overall
severe at 1200mg professional. success rate
cardiovascular, per day for Morning was also
liver, kidney, 4-6 weeks, sputum significantly
or blood then it was samples higher in the
system disease, lowered to were sent LZD group
mentally ill, 300-600mg for smear (67.9% vs
pregnant or per day until and culture 34.4%).
lactating. Due culture monthly However,
to conversion, before 81.8% of the
randomization, at which sputum LZD group
there were no time LZD conversion, had
significant was finally then every 3 significant
differences discontinued months until adverse
between . the end of reactions, all
groups. the trial. of which
were possibly
or probably
linked to
LZD.
TREATMENT OF MULTIDRUG-RESISTANT TUBERCULOSIS 30

Appendix B

Standard-Length Drug Selection Algorithm from WHO (2016b)

A) In patients with rifampicin-resistant or multidrug-resistant TB, a regimen with at least five effective
TB medicines during the intensive phase is recommended, including pyrazinamide and four core
second-line TB medicines - one chosen from group A, one from group B, and at least two from group
C. If the minimum of effective TB medicines cannot be composed as above, an agent from group D2
and other agents from D3 may be added to bring the total to five.
B) In patients with rifampicin-resistant or multidrug-resistant TB, it is recommended that the regimen
be further strengthened with high-dose isoniazid and/or ethambutol.

Table B1.
Medicines recommended for the treatment of rifampicin-resistant and multidrug-resistant TB
Group Drug Abbreviation

A. Fluoroquinolones Lefofloxacin LFX

(In descending preferential Moxifloxacin MFX
order) Gatifloxacin GFX
B. Second-line injectable agents Amikacin AM
Capreomycin CM
Kanamycin KM
Streptomycin SM
C. Other core second-line agents Ethionamide/ Prothoinamide ETO/PTO
(In descending preferential Cycloserine/ Terizidone CS/TRD
order) Linezolid LZD
Clofazimine CFZ
D. Add-on agents D1 Pyrazinamide PZA
Ethambutol EMB
High-dose Isoniazid INH

D2 Bedaquiline BDQ
Delamanid DLM

D3 P-aminosalicilic acid PAS

Imipenem-cilastatin IPM
Meropenem MPM
Amoxicillin-clavulanate AMX-CLV
(Thioacetazone)- if HIV negative (T)