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Linezolid to treat extensively drug-resistant TB: retrospective data areconfirmed by experimental evidence
Extensively drug-resistant tuberculosis (XDR-TB) (defined as TB caused by Mycobacterium tuberculosisstrains with in vitro resistance to isoniazid and rifampicin plus any fluoroquinolone and at least one of thesecond-line injectable drugs, amikacin, capreomycin or kanamycin) on top of being a growing public healthconcern, represents a nightmare for the clinician The crucial therapeutic issue is the difficulty ofidentifying at least four available ‘‘active’’ anti-TB drugs, to ensure treatment success as well as to preventthe emergence of additional drug resistance
After more than 40 years without new anti-TB drugs appearing on the horizon, new chemical compounds(i.e. bedaquiline, PA-824 and delamanid) seem promising for these difficult-to-treat cases of TB
While the necessary experimental studies will prove how to use them, more and more interest is currentlyfocused on existing antibacterial drugs with new indications for drug-resistant TB, particularly linezolid,meropenem, clofazimine and cotrimoxazole
Based on in vitro and pharmacological data, suggesting that linezolid (an oxazolidinone antibiotic) could beefficacious in treating mycobacterial infections, and on anedoctal evidence of its effectiveness in the smallestgroups of patients, it was used off-label, despite its high price, to treat multidrug-resistant (MDR) TB casesin several countries. The little scientific supporting data on the efficacy, safety and tolerability of linezolidcame from ad hoc randomised, controlled clinical trials, as well as from large observational studies
The European Respiratory Journal recently published a systematic review and a meta-analysis of individualpatients focused on the main published epidemiological observational studies (n512), describing cohorts ofTB patients (n5121) treated with linezolid-containing regimens in 11 countries The selected papers hadthe following inclusion criteria: description of at least five culture- and drug-susceptibility testing confirmedMDR- or XDR-TB patients treated with linezolid-containing regimens; proportion of childhood patientsless than 25% of the total sample; available evidence on efficacy, safety and tolerability.
Individual data were extracted from the manuscripts and collected in an ad hoc electronic form containingvariables related to the efficacy, safety and tolerability profiles. The information retrieved was confirmedand/or updated, when possible, by the responsible authors of the selected papers. The guidelines of thePreferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed.
A high proportion of MDR-TB cases achieved sputum smear (86 out of 93; 92.5%) and culture (100 out of107; 93.5%) conversion after treatment with individualised linezolid-containing therapeutic schemes and 99out of 121 (81.8%) achieved treatment success, with no differences in efficacy between those treated with adaily linezolid dosage f600 mg versus .600 mg.
Unfortunately, adverse events were observed in 58.9% (63 out of 107) of the cases (68.4% of them reportedmajor adverse events); moreover, the frequency was significantly higher when the daily linezolid doseexceeded 600 mg.
More recently, a study by LEE et al. provided, for the first time, the prospective experimental evidenceneeded on the efficacy, safety and tolerability of linezolid to treat XDR-TB.
Out of 39 XDR-TB, patients 87% showed a negative sputum culture after 6 months of treatment withlinezolid-containing regimens. Linezolid (600 mg) was prescribed daily to the enrolled cohort at thebeginning of the clinical trial; after 4 months of exposure to linezolid or after sputum smear conversion, asubgroup was administered a 300 mg daily dosage. Adverse events, potentially attributable to linezolid,occurred in 31 out of 38 (82%) patients, with a smaller proportion in those randomised to a 300 mg dailydosage (11 out of 16; 69%).
The aim of the present study was to analyse the safety, tolerability and efficacy of linezolid in the XDR-TBsubgroup of the meta-analytic cohort and to compare these results with those described by LEE et al.
Statistical analyses were carried out using Stata 9.0 (StataCorp, College Station, TX, USA).
TABLE 1 Retrospective evaluation of the safety and tolerability of linezolid in 39 extensively drug-resistant tuberculosis cases
Total adverse events presumably due to linezolid
Data are presented as n/n (%) or median (interquartile range), unless otherwise stated. LNZ: linezolid daily dose.
The XDR-TB patients enrolled in the meta-analysis were 39 out of 120 (32.5%) cases; most of them weremale (24 out of 39; 61.5%), with a median (interquartile range) age of 36 (28–42) years. A daily dose oflinezolid f600 mg and .600 mg were prescribed to 25 out of 39 (64.1%) and 14 out of 39 (35.9%)patients, respectively. The safety and tolerability profile is summarised in
The proportion of adverse events in 34 XDR-TB patients was .60%, with 75% determining an interruptionof treatment. After a median exposure to linezolid of 315 days, peripheral neuropathy was the mostcommon adverse effect (55.2%), followed by anaemia (31.0%) and optic neuritis (20.0%). Although theproportion of adverse events was higher in the group of individuals treated with a linezolid daily dosage off600 mg, the difference was not statistically significant.
The XDR-TB meta-analytic observational cohort and the experimental group of LEE et al. seem tobe not statistically different in terms of proportions of adverse events attributable to linezolid prescribed atthe daily dose of f600 mg (14 out of 20, 70% versus 31 out of 38, 82%; p50.30), as well as of cultureconverters after 4 and 6 months of linezolid exposure (14 out of 25, 56% versus 15 out of 19, 79%; p50.11;18 out of 25, 72% versus 34 out of 38, 89%; p5 0.08, respectively).
On top of sharing the same conclusions (linezolid is effective but, due to adverse events, patients needcareful monitoring), the rough statistical comparison between the two studies confirms that the dosagef600 mg?day-1 has the best risk–benefit profile It has demonstrated an equal observational andexperimental clinical efficacy in a difficult-to-treat group of TB patients, even if the limited sample sizecould represent a methodological shortcoming. More experimental evidence is urgently needed, preferablybased on strong indicators, predictive of high efficacy, after a short period of drug exposure, following theexample of randomised clinical trials on new anti-HIV and anti-hepatitis C drugs.
A growing amount of data from linezolid-exposed cohorts more and more clearly supports the rationale ofprescribing the drug daily at a low dose, tailored to the pharmacokinetic profile obtained throughtherapeutic drug monitoring
The identification of the adequate daily exposure to linezolid will prevent occurrence of adverse events, bothlife-threatening (e.g. determining the physician’s decision to stop the drug) and non-serious (e.g. loweringthe patient’s motivation to continue the prescribed treatment).
The obvious consequence will be improved patient adherence and an increased chance of achievingtreatment success.
@ERSpublicationsResults of the recent ERJ meta-analysis on linezolid to treat XDR-TB have been confirmed by a trialpublished in NEJM
Giovanni Sotgiu1, Rosella Centis2, Lia D’Ambrosio2, Antonio Spanevello3 and Giovanni Battista Migliori2 on behalf ofthe International Group for the study of Linezolid41Epidemiology and Medical Statistics Unit, Dept of Biomedical Sciences, University of Sassari, Sassari, 2World HealthOrganization Collaborating Centre for Tuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and ResearchInstitute, Tradate, and 3Universita` degli Studi dell’Insubria, Varese, and Fondazione S. Maugeri, Care and ResearchInstitute, Tradate, Italy. 4A full list of the International Group for the study of Linezolid members and their affiliationscan be found in the acknowledgements section.
Correspondence: G. B. Migliori, S. Maugeri Foundation, Via Roncaccio 16, Tradate, Varese, Italy. Email:firstname.lastname@example.org
Received: Nov 26 2012 | Accepted after revision: Dec 24 2012
Conflict of interest: None declared.
Acknowledgements: The members of ‘‘The International Group for the study of Linezolid’’ are (in alphabetical order):J.W.C. Alffenaar (University of Groningen, University Medical Center Groningen, Dept of Hospital and ClinicalPharmacy, Groningen, the Netherlands), H.A. Anger (New York City Department of Health and Mental Hygiene, Bureauof Tuberculosis Control, New York, NY, USA), J.A. Caminero (MDR-TB Unit, Dept of Pneumology, University GeneralHospital of Gran Canaria ‘‘Dr. Negrin’’, Las Palmas de Gran Canaria, Spain and International Union against Tuberculosisand Lung Disease (The Union)), P. Castiglia (Epidemiology and Medical Statistics Unit, Dept of Biomedical Sciences,University of Sassari, Sassari, Italy), S. De Lorenzo (OVV E. Morelli Hospital, Reference Hospital for MDR and HIV-TB,Sondalo, Italy), G. Ferrara (Lung Allergi Kliniken, Karolinska University Hospital, Stockholm, Sweden, and Section ofRespiratory Diseases, Dept of Internal Medicine, University of Perugia, Terni, Italy), W.J. Koh (Division of Pulmonaryand Critical Care Medicine, Dept of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine,Seoul, Republic of Korea), G.F. Schecter (Tuberculosis Control Branch, Division of Communicable Disease Control,Center for Infectious Disease, California Department of Public Health, Richmond, CA, USA), T.S. Shim (Division ofPulmonary and Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea),R. Singla (Dept of Tuberculosis and Chest Diseases, Lala Ram Sarup Institute of Tuberculosis and Respiratory Diseases,New Delhi, India), A. Skrahina (Clinical Dept, National Research and Practical Centre for Pulmonology andTuberculosis, Minsk, Belarus), Z.F. Udwadia (Dept of Pulmonary Medicine, PD Hinduja National Hospital and MedicalResearch Centre, Veer Savarkar Marg, Mahim, Mumbai, India), M. Villar (General Directorate of Health, Lisbon, LungDiseases Centre of Venda Nova, Amadora, Portugal), E. Zampogna (World Health Organization Collaborating Centre forTuberculosis and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute, Tradate, Italy), J.P. Zellweger (TBClinic, Dept of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland) andA. Zumla (Dept of Infection, Division of Infection and Immunity, Centre for Clinical Microbiology, University CollegeLondon, London, UK).
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Eur Respir J 2013; 42: 288–290 | DOI: 10.1183/09031936.00191712 | Copyright ßERS 2013
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