Linezolid For The Treatment Of Multi-Drug And Extensovely Drug Resistant TB a systemic review.pdf

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10/14/14 Internet Scientific Publications

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Original Article

Linezolid For The Treatment Of Multi-Drug And Extensively Drug Resistant Tuberculosis:A Systematic Review On Efficacy And Toxicity

A Agyeman, R Ofori-Asenso

Keywords

drug therapy, linezolid, systematic review, tuberculosis

Citation

A Agyeman, R Ofori-Asenso. Linezolid For The Treatment Of Multi-Drug And Extensively Drug Resistant Tuberculosis: ASystematic Review On Efficacy And Toxicity . The Internet Journal of Pharmacology. 2014 Volume 13 Number 1.

Abstract

Background

Since 2006, the World Health Organisation (WHO) has been advocating for the use of Linezolid in the treatment of multi-drugresistant (MDR) and extensively drug resistant (XDR) TB. However, several concerns have been raised about Linezolid’sefficacy and safety and the optimal dose of the drug remains unclear. This systematic review was conducted with the aim of summarising the evidence on the efficacy and associated toxicity of Linezolid in the treatment of MDR-TB and XDR-TB and toact as an update to previously conducted reviews.

Methods

We conducted a systematic search to identify primary studies published between January 2006 and July 2013 on the efficacyand toxicity of Linezolid in MDR and XDR TB. The s tudies were ass ess ed for methodological quality and meta-analysis wasperformed on key variables pertaining to outcome measures of efficacy (i.e. culture conversion, treatment success) andtoxicity (i.e. myelosuppression, neuropathy, treatment discontinuation).

Results

We included 17 studies compris ing of case reports, randomis ed comparative trials and retrospective cohort studies. Norandomis ed placebo controlled trial was identified. The pooled proportion of culture conversion was 91.1% (95% CI 86.6%to 94.7%). However, the summary proportion for treatment success was 62.6% (95% CI 46.8% to 77.3%). Myelosuppress ionwas also observed at a pooled proportion of 32.9% (95% CI 21.836% to 45.022%). The occurrence of ne uropathy was a lsofound to be higher than myelosuppress ion at a pooled proportion of 40.9%% (95% CI 24.4% to 58.6%). A total proportion of 14.9% (95% CI 7.8% to 23.8%) were withdrawn from Linezolid due to adverse events. Other adverse events occurred at10.9% (95% CI 3.2% to 22.4%). Comparis on between doses ≤ 600mg and > 600mg daily showed a s tatistical s ignificancefor treatment success (p value = 0.0001) and myelosuppress ion (p value =0.0001) occurring in the higher dose than thelower dose.

Conclusions

Linezolid has a promising efficacy in multidrug and extensively drug resis tant tuberculosis based on clinical reports other than randomis ed controlled trials. Higher doses above 600mg daily result in favourable culture conversion and treatmentsuccess. However, treatment at such high doses is complicated by high incidence of myelosuppression and neuropathy.

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Lower doses at 600mg daily or below also s how good treatment outcomes with reduced incidence of adverse effects.Randomised controlled trials are urgently needed to streamline the use of Linezolid in drug resistant tuberculosis .

Introduction

Tuberculosis (TB) remains one of the major cause of global morbidi ty and mortality (1). One in three persons worldwide

representing over 2 billion individuals are known to be infected with Mycobacterium tuberculos is (2). In 2011 a lone, 8.7mil lion new TB cases were estimated with 1.4 mil lion recorded deaths. Approximately one million deaths were among HIV-negative persons and 430,000 am ong HIV-positive individuals (3). Moreover, TB has been estimated to cause close to 35mil lion deaths in the next two decades (2). Although, TB is present in every country, majority of cases occur in low incomeand middle income countries es pecially Sub-Saharan Africa and Asia (1). This high incidence of TB in these regionspresents a huge threat to development as approximately 98% of TB related deaths occur among adults in the productive agegroups (2). Nevertheless , according to the 2012 Global TB Report (3), the global target of halting and reversing TB as part of the millennium development goals (MDGs) has been achieved. This s tatement rests in the consistent decline in new casesover the years with decline rate of 2.2 between 2010 and 2011 (3). Moreover, as part of the MDGs, the global mortality ratereduction of TB aimed at 50% by 2015 is recorded to be on track as a res ult of the attainment of 41% reduction rate between1990 and 2011 (3). In the midst of these positive developments, the increasing emergence of MDR-TB and XDR-TB in mostparts of the world poses a threat to the success attained by TB care and control (4). According to the World HealthOrganisation (WHO), about 3.7% TB of all new cases of TB in the world accounts for MDR-TB with a higher incidence of 20% in previously treated patients (4). Worldwide, an es timated 440,000 MDR-TB cases emerged in 2008 contributing to anestimated 150,000 deaths (5). China and India were es timated to have contributed about 50% of these MDR-TB cases (5).China alone has recently reported 100,000 MDR-TB cases emerging annually. Also, most countries in Eastern Europe andcentral Asia have reported MDR-TB cases to account for 50% of previously treated TB patients (5). The cost of managingmulti-drug res istant TB remains enormous . According to the Stop TB Partnership’s Global Plan to Stop TB, 2011-2015 (6),an es timation of over 2 million cases of MDR-TB will emerge between 2010 and 2015 if there is no significant increase in TBfunding and poli tical commitment. In the sam e Global Plan, 2011-2015, approximately US $1.7 billion is required towardsMDR-TB with an annual increase of US $0.9 billion in 2011 to US $1.9 billion in 2015 (6). There have been many calls for

greater efforts at reducing the emergence of multi-drug resis tance TB if the battle to reduce the global burden of TB is to beachieved (6, 7). The treatment options for drug resis tant TB still remains l imited as treatment is based on cas e series andexpert opinions instead of randomis ed controlled trials (8). According to Alffenaar et al . (9), no new anti-tubercular drugshave been regis tered since the early 1980. Nonetheless, promising new drugs for MDR-TB and XDR-TB are in the pipel ineof drug development. The Working Group on New Drugs (10), supported by the Stop TB partnership has been acceleratingthe drug development process of potentially new drugs for drug resistant TB since its es tablishment in 2001. Since 2006,Linezolid has been recommended for off-label treatment of drug resis tant TB based on unclear efficacy resulting from caseseries and expert opinions (8). In vitro studies conducted by Alcala et al. (11), Guna et al. (12) and Yang et al. (13) have alsoconcluded Linezolid’s effectiveness in both sus ceptible and drug resis tant strains of Mycobacterium tuberculosis clinicaliso lates. Linezolid has been given at a dose of 600mg twice daily or lower in some case s eries reports which havehypothesis ed the effectiveness in MDR-TB and XDR-TB (14-16). In some ins tances, doses higher than 600mg daily have

been given creating conflicting reports as to the most effective dose of the drug. Moreover, serious toxic side effects such ashaematological adverse reactions and neuropathies have been reported with the use of Linezolid (17). To overcome theuncertainty surrounding Linezolid, we conducted a s ystematic review to s ummarize the available information towardsanswering three main ques tions (a) Are there subs tantial evidence on the efficacy and toxicity on Linezolid to inform i tsclinical us e in MDR-TB and XDR-TB? (b) Is Linezolid potent enough to cause posi tive sputum culture conversion? (c) Arethere severe or life-threatening toxicity associated with prolonged use of Linezolid in MDR-TB and XDR-TB patients?

Method

We conducted the review in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta- Analyses ) Statement (18) .





Search Strategy

A systematic search was conducted in PubMed, EMBASE, Web of Science and Clinicaltrials .gov. The keywords werededuced by the PICO (Patient population, Intervention, Comparison and Outcome respectively) approach (19). The researchquestion was thus fragmented to identify the correlation with the PICO categories. Since the research question does notinvolve a comparison, the C component of PICO was exempted from the keyword search. The PICO approach was adoptedfor only PubMed, EMBASE and Web of Science. The fourteen keyword terms generated for the patient population s earch forMDR-TB were multidrug res istant tuberculos is, multidrug resis tant TB, multi-drug resistant tuberculosis, multi-drug resistantTB, multi-drug-resis tant TB, multiple drug resis tant tuberculosis , multiple drug res istant TB, multiple-drug resis tanttuberculosis, multiple-drug resistant TB, drug resistant tuberculosis, drug resistant TB, MDRTB, MDR TB and MDR-TB. For XDR-TB, the following seven keywords were generated for the patient population search; extensively drug resistanttuberculosis, extensively drug resistant TB, extensively-drug resistant tuberculosis, extensively-drug resistant TB,extens ively-drug-res is tant TB, XDRTB, XDR-TB and XDR TB. For the intervention category, six keyword terms were employed;Linezolid, oxazolidinone antibacterial, oxazolidinone antibiotic, Zyvox, Zyvoxid and Zyvoxam. Zyvox is the trade name under which Linezolid is marketed in the United States of America and other countries. In Europe, it is marketed under the nameZyvoxid whiles in Canada and Mexico, Zyvoxam is used (20). Finally, the outcome category was subdivided under ‘efficacy’and ‘toxicity’ which are the two main outcome meas ures in this study. Seven keyword terms were employed for ‘efficacy’;efficacy, effective, potency, effectiveness , effect, efficacious , potent and potency. Under ‘toxicity’, eight keyword terms were

also generated as follows; toxicity, toxic effects, tolerability, safety, side effects, adverse effects, adverse events and adversereactions. The Boolean operators ‘OR’ and ‘AND’ were used within and between each category respectively to combine thekeywords. The results from the three databases; PubMed, EMBASE and Web of Science were not refined by any parameter with the exception of publication year between January, 2006 to December, 2013. Search through Clinicaltrials.gov wasperformed us ing one keyword each for drug intervention and dis ease . The keywords ‘Linezolid’ and ‘Tuberculosis’ weresearched under intervention and disease respectively. PubMed, EMBASE and Web of Science were last searched on 11thMay, 2013. Clinicaltrials.gov was las t accessed on the 3rd of June, 2013 and 30th June, 2013 for the intervention (i.e.Linezolid) and disease (i.e. tuberculosis ) respectively.

Study Selection

For a study to be included, it must involve an adult population ≥ 5 patients, sputum culture confirmed MDR TB/ XDR TBpatients, DST report, data on outcome measures for efficacy or toxicity, original study, both pulmonary and extra pulmonaryTB and exclusively English publications. The publication years was limited from 2006 to 2013 because this study aims tocapture studies that have been conducted from the time WHO approved the use of Linezolid in MDR-TB and XDR-TB whichwas in 2006 (8). Studies were excluded for absence of sputum culture confirmed TB status and DST, animal and in vitrostudies , case reports or series less than five subjects, unpublished literature, review articles and any language other thanEnglish. Case reports and case series were lim ited to five subjects to eliminate the influence of selection bias which isinherently ass ociated with small sample s ize mos tly employed by such study designs (21). Also the two recent systematicreviews performed with high quality which this s tudy seeks to update employed inclusion sample size of ≥ 3 subjects (17)and ≥ 5 subjects (22). Hence the higher sample size i.e. ≥ 5 subjects was applied to this study.

Outcome Measures

The efficacy outcomes were defined according to the definitions for TB treatment outcomes adapted by WHO (23). Theprimary outcome meas ure for efficacy was themed as treatment s uccess from the definitions. Secondary efficacy outcomemeas ures were defined according to the sputum culture conversion and completion of treatment themes . For the outcomesof toxicity, primary outcome meas ures included s evere adverse events reported to be ass ociated with Linezolid which aremyelosuppression, optic and peripheral neuropathy (24). The secondary outcomes of toxicity were discontinuation of treatment and other reported adverse events.

Data Extraction





The data extraction was performed by the author (AAA). Variables to aid in descriptive characterisation of the selectedstudies included nam e of first author, year of publication, country of study, study design, presence or abs ence of controlgroup, number of patients enrolled and study duration (Table 4). The following variables were extracted for efficacy andtoxicity measures; number of subjects exposed to Linezolid, number of MDR-TB and XDR-TB patients in each study, HIV co-infection s tatus, type of anti-TB regimen adm inis tered, dose of Linezolid received, treatment outcomes and reported adverseeffects.

Ass essm ent of study quality

The methodological quality was as ses sed by the author (AAA) based on protocol involved in the conduct of selected s tudies(i.e. Institutional Review Board (IRB) approval and informed consent), Linezolid dose indicated, type of treatment regimenindicated based on DST, Linezolid initiated under hospital environment, DOT applied to treatment monitoring and treatmentoutcome measures in conformity to WHO adapted definitions . In addition, the individual studies were critically appraisedusing the McMaster critical review for quantitative s tudies (25) which was modified and us ed by Deenadayalan et al. (26)[Appendix I]. The critical appraisal focused on individual s tudy aims , study design, sampling method, outcomemeas urement, description of intervention, the quality of results analysis and reporting, the main findings , strengths andweaknesses.

Statistical Analysis

The results were analysed by meta-analysis proportions which were performed with MedCalC meta-analysis softwareversion 12.7.0 (27). The analysis of efficacy meas ures was based on the number of patients who completed treatment.Hence culture conversion and cure outcomes were evaluated for only patients who completed treatment to evaluate efficacyon the common ground of treatment completion so that results wi ll not be biased by patients who had culture conversion butlater relapsed on follow up. For the analysis of toxicity, the proportions were determined bas ed on the number of patientsexposed to Linezolid but not lim ited to those who completed treatment. A further analysis was performed to compareproportions on efficacy and toxicity between doses ≤ 600mg and > 600mg. Statistical significance was set at p<0.05.

Results

A total of 1,007 search results were retrieved. Upon screening for duplicates and irrelevant papers based on titles andabstracts, 37 articles were found relevant for full-text analysis and reference list screening. Out of 37 articles, 20 articleswere excluded with reasons. Hence, a total of 17 studies were included in this review (Figure 4). The seventeen includedstudies were all primary studies including 10 retrospective case series, 3 prospective case series, 1 phase 1 clinical trial, 2phase 2a clinical trial and 1 retrospective cohort study. Majority (9 out of 17) of the s tudies was conducted in Asia , followed bythe Americas (5 out of 17) and finally 3 out of 17 in Europe. No s tudy was included which was performed in Africa. Only onemultinational s tudy was identified which was conducted across four countries in Europe (28). A total of 868 MDR-TB patientswere enrolled in all the 17 studies including 201 reported XDR-TB cases . Of the 868 patients enrolled, 413 were exposed toLinezolid at once or twice daily dosing of at doses ≤ 600mg or ≥ 600mg. The treatment duration for all the studies was in arange of 1month to 29months. 362 HIV-negative and 10 HIV-positive cases were reported from all the s tudies. Detailedepidemiological description of included studies is given in Table 1. Critical appraisal and methodological qualityass ess ment scores are provided in Appendices 3 and 4 respectively.

Figure 1PRISMA Flow diagram of review process





and toxicity were analysed. With respect to efficacy, sputum culture conversion and treatment success were the mainindicator measures. Toxicity was also evaluated based on four parameters namely; the occurrence of myelosuppress ion,neuropathy, discontinuation of Linezolid treatment and other adverse reactions . Furthermore, comparison of proportionsbetween doses ≤ 600mg and > 600mg dos es were tested for statistical difference in terms of the aforementioned efficacyand toxicity parameters.

(a) Proportion of XDR-TB

Fourteen s tudies reported XDR-TB cases. The s tudies which did not report XDR-TB cases were conducted in USA (n=2) andNorway (n=1). Of the studies which reported XDR-TB cases , Lee et al. (35) reported the highes t number of 41 XDR-TBpatients in South Korea. Another cohort in South Korea reported the least XDR-TB patients with a total of 4 patients (14). Fivestudies were exclus ively XDR-TB cases conducted in Asia (n=3) and the Americas (n=2). Seven s tudies s howed more than50% proportion while three s tudies s howed les s than 50% proportion of XDR-TB patients. Wide confidence intervals wereobserved in all s tudies except Lee et al. (35) with a confidence interval of 91.4 to 100. High variability was observed whichcorresponds to I2 of 94.05% (95% CI of 91.58% to 95.80%). A proportion of 72.5% was obtained for the pooled effect (95%CI 51.6%-89.2).

Figure 2

Meta-analysis proportion for XDR-TB

(b) Proportion of treatment Completion

All the studies reported some cas es having completed treatment. 100% treatment completion was achieved in five studieswhiles more than 50% but less than 100% and less than 50% were observed in twelve and two studies respectively. In allfive s tudies (14, 16, 31, 33, 39) with 100% treatment completion, a maximum dose 600mg Linezolid was given daily with theexception of Tang et al. (39) where 600mg twice daily was adminis tered for the first two months followed by 600mg daily for the remaining treatment duration. For the two studies (35, 36) achieving les s than 50% completion of treatment, a maximumdose of 600mg daily was investigated. On the contrary, varying dos es between 300mg daily to 600mg twice daily wereadministered in s tudies attaining more than 50% but les s than 100% (15, 28-30, 32, 34, 37, 38, 40, 41) treatmentcompletion. Wide confidence intervals were comm on to all the studies except four; Carroll et al. (31), Koh et al. (33), Koh etal. (34) and Udwadia et al. (43). For the pooled random effect, 79.421% treatment success was observed at a 95%confidence interval of 66.837% to 89.621%. The resul t of heterogeneity was also 88.2% for the degree of inconsistency.

Figure 3Meta-analysis proportion for treatment completion






Figure 5Proportion of treatment success

(e) Proportion of Myelosuppress ion

Myelosuppress ion occurred in all the studies ; however, only fourteen s tudies indicated the number of patients who s ufferedfrom it. Abbate et al. (29), Carroll et al. (31) and Villar et al. (40) are the three studies which reported the incidence of myelosuppression but did not indicate the number of patients. Myelosuppress ion occurred at the highest rate of 81.250%(95% CI 54.4-95.9) in the American cohort with a sample size of 16 patients (30). Anger et al. (30) investigated variabledoses of linezolid i.e. 600mg twice daily, 400mg daily and 600mg daily for a mean duration of fifteen months. The leastmyelosuppression was observed in the South Korean cohort of 24 patients having a proportion of 4.167% (95% CI0.1%-21.1%). In this study, linezolid was administered at a dose of 300mg dai ly (n=17) and 600mg dai ly (n=7) for aninterquartile range of 268 days to 443 days. Heterogeneity testing was high with I2 of 81.48% (95% CI 69.9% -88.6%). Apooled proportion of 32.9% (95% CI 21.8%-45.0%) was observed.

Figure 6Proportion of Myelosuppress ion

(f) Proportion of Neuropathy

All studies reported the incidence of neuropathy with the exception of Villar et al. (40) who reported occurrence but did notindicate the number of patients. All the 11 patients enrolled in the s tudy conducted by Nam et al. (14) experienced







neuropathy (100%, 95% CI 71.5%-100%) with administered dos e of 300mg twice daily. The recorded range of treatmentduration was 3.5 months to 24 months. Migliori et al. (28) with a large sample s ize of 85 patients recorded the leastoccurrence of neuropathy with a proportion of 3.529% (95% CI 0.7%-9.9%) for a mean treatment duration of 222 days. Adose of 600mg daily was administered to 28 patients whiles 600m g twice daily was adm inis tered to 57 patients. For thesum mary proportion, 40.938% point estimate with 95% CI of 24.4%-58.5% was obtained with a correspondinginconsistency of 92.10%.

Figure 7Proportion of Neuropathy

(g) Proportion of linezolid treatment discontinuation

A total of twelve studies reported incidence of treatment discontinuation relating to linezolid. Carroll et al. (31) reportedlinezolid discontinuation but did not indicate number of patients corresponding to the occurrence. Five s tudies (16, 29, 32,39, 40) had no patient being discontinued from linezolid treatment. Nam et al. (14) had the highes t incident of linezoliddiscontinuation with a proportion of 72.7% (95% CI 39.0%-93.9%). Heterogeneity was present at an inconsis tency value of 79.7% (95% CI 67% -87.3%). The pooled proportion als o obs erved a proportion of 14.9% (95% CI: 7.796% -23.8%).

Figure 8Proportion of linezolid treatment discontinuation

(h) Proportion of other adverse events







The absence or presence of other adverse events was reported in all the s tudies. However two studies (29, 31) did notindicate the number of patients as sociated with these other adverse events which were predominantly gastrointestinaldis turbances, nausea and headache. Seven s tudies (14-16, 32-34, 36, 38) had no incidence of other adverse events apartfrom myelosuppress ion and neuropathy. Xu et al.(41) recorded the highes t occurrence of gastrointestinal dis turbances witha proportion of 83.3% (95% CI 58.58% to 96.42%). Variability was present at an inconsis tency value of 89.06% (95% CI83.66%-92.68%). The sum mary proportion yielded a proportion of 10.865% (95% CI 3.1%-22.3%).

Figure 9Proportion of other adverse events

Discussion

Efficacy

In all seventeen studies, DST was performed to guide individualised treatment regimen. Linezolid was also not given asmonotherapy but in combination with other anti-tubercular drugs. The indicators for efficacy as mentioned earlier weretreatment success and sputum culture conversion with treatment success as the main indicator. The pooled proportion of patients who successfully completed respective treatment regimen was 79% (95% CI 67%-90%) in a total sample of 413patients. Although, the range (1month to 29months) of treatment duration was m ostly above the recommended duration of 28 days, this high proportion of treatment completion makes linezolid promising in TB management where by the treatmentlas t for a recommended extended duration of 24 months (23). A high culture conversion of 91% (CI 87% -95%) wasobtained in the pooled result as against a pooled treatment success of 62% (CI 45% to 77%). The result of the cultureconversion is comparable to the review conducted by Sotgui et al.(44); 93% (CI 87% to 97%). On the contrary, a highertreatment s uccess was obtain by Sotgui et al. (44) (82%, 95%CI 74%-88%) and Cox and Ford (17) (68%, 95%CI 58% to78%). Nevertheless , similar observation of culture conversion proportion being higher than treatment success was made.This infers that, not all patients who attain sputum culture conversion at the completion of regimen attained the cured s tatus

upon follow up. This leads to another point of reasoning which m ay suggest that the duration of treatment correlates with thechances of attaining treatment success . For example, at the same dose of 600mg daily, Lee et al. (35) attained 23%treatment success for a duration of 18 months whiles Tang et al. (39) attained 79% treatment success for 24 monthstreatment duration. Thus there is the need to optimise treatment duration because in as much as short treatment durationcould lead to treatment failure and resistance; too long treatment durations could possibly initiate resis tance (45). In thislight, Horsburg et al. (45) has proposed a new method for antibiotic therapy which employs logistic regress ion model inrandomis ed clinical trials which links varying treatment duration to the corresponding cure proportions to determine theshortest effective treatment duration (45). According to the researchers, this model is mos t suited for anti-tubercular regimentargeted at decreas ing res istance, minimis ing toxicity, reducing cost and decreasing antibiotic pill burden. Furthermore, thefour cases of treatment failure which were obs erved by Lee et al. (35) and also found to be associated with linezolid drawsthe spotlight on further investigation into likely emergence of linezolid resis tance. Comparison of dose effect on culture






Sotgui et al. (44) (59%, 95% CI 49%-68%). This may be as a result of close to half (n=8) of the included studies in this reviewdid not report the occurrence other adverse events and two studies did not indicate the number of occurrence which led totheir exclusion from the meta-analysis . In addition, Sotgui et al. (44) reported a statistical s ignificance of 0.004 of other reported adverse events occurring with higher doses of linezolid. It is therefore necess ary to watch out for minor adverseevents when initiating linezolid treatment. A case of a 64 year old diabetic man reported by Bodnar et al. (48) in whomlinezolid was us ed to treat Methicillin resis tant Staphylococcus Aureus infected cellulitis s evered linezolid associatedhypoglycaemia. This incident was attributed linezolid mimicking monoamine oxidase inhibitory properties which causeshypoglycaemia. Linezolid has als o been reported to be associated with lactic acidosis (49) with the authors concluding on

the mechanism as being unknown while rais ing an ass umption of being associated with mitochondrial toxicity sim ilar tothose exhibited by nucleoside reverse-transcriptase inhibi tors. This ass umption is in line wi th the finding from Carroll et al.(31) who investigated the m echanism of linezolid toxicity and concluded on the toxicity being ass ociated with linezolidinduced decrease in mitochondrion function. One case of rhabdomylosis was reported in this review by Lee et al. (35) whichneed to be wel l documented to inform future class ification as a rare adverse event or not.

Strengths and Limitations of study

The major s trength of this review compared to previously conducted review is the large sample size of 413 patients exposedto linezolid compared with 121 (44) and 218 (17). This sample size was fairly dis tributed in Europe and Asia covering WHOregions where strategic plans have been put in place to stop TB as well as combat drug resis tant strains (50, 51). This s tudy

was also limited between 2006 and 2013 which gives a concise picture of how prescribing pattern have been influencedsince WHO’s (8) recommendation on l inezolid use as part of group five medications in 2006. It also s erves as an update topreviously conducted review in this subject area. Subgroup analysis comparing dos es ≤ 600mg and > 600mg of linezolidminimis es the dos e s ize as a confounder to the efficacy and toxicity outcome measures . Another limitation is theinconsistency in reporting outcome measures of included studies . Although studies included reported outcomes in amanner similar to WHO (52) adapted recommendations , there still variations which may introduce bias in the overalloutcome measures. For instance, the treatment duration varied among s tudies (1month to 29 months) coupled with varyingfollow-up times. Hence a longer follow up may be good enough to ascertained cured patients, whiles a shorter follow-uptime, may classify a patient who may relapse at a much longer period as cured due to the short time follow-up asses sm ent.

Conclusions

(a) Identification of evidence-based primary research

It is documented that linezolid use in drug resis tant TB is bas ed on series of case reports and expert opinions (8). Thistrend was obs erved in this review as more than half of the studies (n=13) retrieved were case s eries and case reports.Three early phase clinical trials were als o identified. One cohort study, which happens to the largest retrospective cohortstudy (28) so far identified in the investigation of linezolid use in drug res istant TB. The only randomis ed placebo controlledtrial (53) identified was reported unsuccess ful with results not publis hed to date. Hence, as it concludes in this review, theonly high evidence-based s tudy conducted on linezolid use in MDR-TB and XDR-TB is the multi-national TBNET studyconducted by Migliori et al. (28).

(b) Efficacy

It can generally be concluded that linezolid has a promising efficacy in MDR-TB and XRD-TB. Good in vitro studies (11-13)have been identified which have also been s upported by positive pharmacokinetic studies (9, 46, 47) depicting the MIC of linezolid being above that reported in in-vitro studies (9). The only identified retrospective cohort study (28) concluded nostatistical difference in treatment success between patients receiving linezolid and those not receiving linezolid. For dosecomparisons, the significant test showed no s tatis tical significance between culture conversion (p=0.3247) whiles statisticalsignificance was observed for treatment success (0.0001) considering doses ≤ 600mg and >600mg in favour of the higher dose . The res istant strains of Mycobacterium tuberculosis to linezolid obs erved in four patients in the South Korean (35)cohort raises concern about the promis ing efficacy of linezolid and as such the need for further investigation into thisobserved resis tance.





(c) Toxicity

Ass ociated adverse events can be both life threatening and manageable as well . The reported major adverse events weremyelosuppression and neuropathy. Other side effects included gas trointestinal dis orders, nausea and headache. Adverseevents resul ting in myelosuppress ion can be salvage by treatment sus pension or adminis tration of blood transfusion insevere cases (15, 32). Myelosuppress ion may be as sociated with higher dose as reported by significant p-value of 0.0001 infavour of dose > 600mg when compared with ≤ 600m g. On the other hand neuropathy may not be directly related to higher doses as statistical significance (p= 0.1186) was not achieved in the dose comparison s tudy. Neuropathy may also be alsonot be reversed and may persist for longer years (16, 35). All these reported adverse events may also complicate treatmentsuccess by compelling discontinuation.

Recommendations

The results of this s tudy add to the long s tanding need to carry out randomis ed placebo controlled trial to inform evidencebased clinical us e of linezolid in drug res istant TB. Despi te efforts being m ade by the WHO’s Working Group on New TBdrugs partnership (10) with the pharmaceutical indus tries, only one randomised placebo controlled trial have beencompleted with uns uccessful results. Though the main objectives of this pilot trial were not achieved, Padayatchi et al. (53)shares an important lesson learnt in the conduct of MDR-TB trial that, the availability of adequate number of trained staff and

the strict compliance to adm inis trative controls is paramount and may contribute to successfully accomplis hing MDT-TB trial.In the same trial, success was also hampered by non-adherence to treatment by patients pos sibly due to adverse events.There is therefore the need for dose optimisation to ensure that favourable response is achieved at lower doses . The modelfor anti-tubercular dose optimis ation proposed by Horsburg et al. (45) may be recommended for dose optimisation in futurerandomis ed controlled trials. Also further s tudies into dos e optimis ation may be investigated for combination therapy withClarithromycin 500mg dai ly (46). Finally, drug s ensi tivity testing will strongly be recommended for in itiation of linezolidtreatment in MDR-TB and XDR-TB so that poss ible res istant strains to linezolid may be identified early and necess arypreventive measures taken to protect this promis ing ray of hope from emerging into another strain of drug resis tant TB.

Appendix 1

Modified McMaster critical appraisal tool for quantitative studies (25, 26)





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