In vitro activity of linezolid against multidrug-resistant Mycobacterium tuberculosis isolates

doi:10.1016/j.ijantimicag.2005.03.006

International Journal of Antimicrobial Agents

Volume 26, Issue 1, July 2005, Pages 78-80

https://doi.org/10.1016/j.ijantimicag.2005.03.006 Get rights and content

Abstract

Information in the literature regarding the activity of linezolid against multidrug-resistant (MDR) Mycobacterium tuberculosis strains is scarce. We therefore tested the in vitro activity of this drug against 39 MDR M. tuberculosis strains isolated from clinical specimens using the Bactec^® 460 TB system. All strains were inhibited by ≤8 mg/L (minimum inhibitory concentration (MIC); MIC₅₀ = 4 mg/L, MIC₉₀ = 8 mg/L). Although the MIC values are higher than in other studies, based on proposed breakpoints all strains were found to be susceptible to linezolid. Further investigations to prove its usefulness in the treatment of MDR tuberculosis should be carried out.

Introduction

Multidrug-resistant (MDR) tuberculosis is a serious threat to tuberculosis control and is associated with high rates of treatment failure and death [1]. MDR Mycobacterium tuberculosis strains are resistant to at least isoniazid and rifampicin, the two fundamental compounds of any regimen for the treatment of drug-susceptible tuberculosis [2]. In addition, this resistance is often associated with resistance to other antituberculous drugs [3]. There is therefore an urgent need for new potent antimycobacterial drugs for the treatment of these cases. Linezolid is the first clinically available oxazolidinone, a new class of antibacterial protein synthesis inhibitors mainly used to treat infections caused by Gram-positive bacteria [4]. This drug has shown promising anti-M. tuberculosis activity in a murine test system [5]. The literature regarding the in vitro activity of linezolid against clinical M. tuberculosis strains is very limited [6], [7], [8]. In addition, the majority of strains tested in previous studies were not MDR. The aim of this study was to determine the in vitro activity of linezolid against clinical MDR M. tuberculosis strains isolated in our laboratory.

Section snippets

Strains studied

A total of 39 MDR M. tuberculosis strains isolated from clinical specimens (32 sputum, 4 urine, 2 bronchoalveolar lavage fluid and 1 biopsy specimen) of different patients in the Department of Microbiology and Clinical Microbiology, Istanbul Medical Faculty, were included in this study. Susceptibility testing of these strains to streptomycin (S), isoniazid (I), rifampicin (R) and ethambutol (E) was performed by the Bactec^® 460 TB system (Becton Dickinson, Sparks, MD). Of all the strains tested,

Results and discussion

All strains were inhibited between 2 mg/L and 8 mg/L. The MIC₅₀ and MIC₉₀ values were found to be 4 mg/L and 8 mg/L, respectively. The activity of linezolid against MDR M. tuberculosis strains is summarised in Table 1.

To our knowledge, three studies have reported the in vitro activity of linezolid against clinical M. tuberculosis strains [6], [7], [8]. However, these investigators tested only a few MDR strains. Zurenko et al. [6] tested five multiply-resistant isolates (resistant to one or more of

References (11)

M.A. Espinal
The global situation of MDR-TB
Tuberculosis (Edinb)
(2003)
B. Bozdogan et al.
Oxazolidinones: activity, mode of action, and mechanism of resistance
Int J Antimicrob Agents
(2004)
J.C. Rodriguez et al.
In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis
Int J Antimicrob Agents
(2002)
M.A. Espinal et al.
Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries
JAMA
(2000)
N.W. Schluger
The impact of drug resistance on the global tuberculosis epidemic
Int J Tuberc Lung Dis
(2000)

There are more references available in the full text version of this article.

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New class of methyl tetrazole based hybrid of (Z)-5-benzylidene-2- (piperazin-1-yl)thiazol-4(%H)-one as potent antitubercular agents
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In search of potential therapeutics for tuberculosis, we describe here the synthesis and in vitro antitubercular activity of a novel series of thiazolone piperazine tetrazole derivatives. Among all the synthesized derivatives, four compounds (10, 14, 20 and 33) exhibited more potent activity (MIC = 3.08, 3.01, 2.62 and 2.51 μM) than ethambutol (MIC = 9.78 μM) and pyrazinamide (MIC = 101.53 μM) against Mycobacterium tuberculosis. Furthermore, they displayed no toxicity against Vero cells (C1008) and mouse bone marrow derived macrophages (MBMDMϕ). These investigated analogues have emerged as possible lead molecule to enlarge the scope of the study.
Linezolid for the treatment of drug-resistant tuberculosis in children: A review and recommendations
2014, Tuberculosis
Citation Excerpt :
Linezolid is available as 600 mg tablets and as 100 mg/5 ml powder for suspension. The in vitro activity of linezolid against Mtb has been consistently demonstrated, and minimum inhibitory concentrations (MIC) from published studies are listed in Table 1 [19–26]. The critical concentration of a drug is defined as the ‘lowest concentration of drug that will inhibit 95% of wild strains of M. tuberculosis that have never been exposed to drugs, while at the same time not inhibiting clinical strains of M. tuberculosis that are considered to be resistant’ [6,27], and the epidemiological cut-off (ECOFF) is defined as the highest MIC among the wild-type MIC distribution [27].
Options for the treatment of children with drug-resistant tuberculosis (DR-TB) are limited. Emerging evidence in adults from systematic reviews and a randomized trial has shown good efficacy of linezolid in difficult cases of DR-TB but with frequent serious adverse effects. Published data in children are limited and we are unaware of formal guidelines for linezolid in treatment of paediatric DR-TB, though it will likely be an important component of DR-TB treatment for a growing number of children. We performed a structured review of existing literature on the efficacy, adverse effects, pharmacokinetics and pharmacodynamics of linezolid in DR-TB, highlighting the key evidence from the adult literature and systematically evaluating published paediatric data. Our search identified 8 reports of 18 children receiving linezolid for difficult to treat DR-TB. All 18 had culture conversion and 15 of 18 had successful long-term treatment outcomes. Adverse events were reported in 9 of 18; a linezolid dose reduction was required in 5 of 18, and 2 of 18 permanently discontinued linezolid because of adverse events. We make specific recommendations for the use of linezolid in children with DR-TB, and identify priority questions for future research. For children with multidrug-resistant (MDR)-TB with additional resistance or with extensively drug-resistant (XDR)-TB, linezolid may make the difference between a successful or poor outcome, and until newer antituberculosis agents with better efficacy and safety become available in children, linezolid will be an important component of treatment for children with the worst forms of DR-TB.
Design, synthesis and docking studies of quinoline-oxazolidinone hybrid molecules and their antitubercular properties
2011, European Journal of Medicinal Chemistry
Citation Excerpt :
However, these oxazolidinones were inactive against Gram-negative bacteria and hence require multi-dosing regimen, as a result they produce serious side effects [24]. Linezolid, a new oxazolidinone has been extensively studied for the treatment of multidrug-resistant tuberculosis [25]. Besides, it is well reported in the literature that quinolone-oxazolidinone hybrid molecules bearing different cyclic amines as spacer groups displayed very good antimicrobial properties when two pharmacophoric groups are incorporated together [26,27].
New series of quinoline-oxazolidinone hybrid molecules were synthesized based on the preliminary docking studies. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their antimycobacterial properties based on the promising preliminary antibacterial screening results. Amongst tested compounds, compounds 8a, 8j and 13a were active at 0.65 μg/mL against Mycobacterium tuberculosis H₃₇Rv strain. The mode of action of these active compounds was carried out by docking of receptor enoyl-ACP reductase with newly synthesized candidate ligands 8a, 8j and 13a. These compounds exhibited well established bonds with one or more amino acids in the receptor active pocket. From the docking studies, compound 8j was considered to be the best inhibitor.
Anti-tubercular agents. Part 6: Synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones
2011, European Journal of Medicinal Chemistry
Citation Excerpt :
Recently, this drug has also been suggested as an alternative treatment for patients infected with M. tuberculosis isolates [10]. However, the in vitro activity of linezolid against M. tuberculosis remains limited [11]. On the other hand, the benzothiadiazine 1,1-dioxides (BTDs) belong to a class of cyclic sulfonamides that have been extensively studied as potassium channel openers [12] and has also shown broad spectrum of activity against several bacterial pathogens including M. tuberculosis [13,14].
As a part of investigation of new anti-tubercular agents in this laboratory, herein we describe the synthesis of a new class of arylsulfonamido conjugated oxazolidinones. The in vitro activity of these conjugated (6a–f, 7a–d, 9a–c and 11a–c) molecules against Mycobacterium tuberculosis H₃₇Rv by using rifampicin and linezolide as positive controls is discussed, compounds 7c and 9a–c are found to be the most active members in this series. Further, cytotoxicity of the potent conjugates of the series (7c, and 9a–c) was evaluated on human foreskin fibroblast (HFF) cells by using MTT assay. Finally, these studies suggest that compounds 7c and 9a may serve as promising lead scaffolds for further generation of new as anti-TB agents.
Linezolid
2008, Tuberculosis
Generic and additional names: Linezolid
CAS name: N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide
CAS registry #: 165800-03-3
Molecular formula: C₁₆H₂₀FN₃O₄
Molecular weight: 337.35
Intellectual property rights: Pfizer
Brand names: Zyvox, Zyvoxid (Pfizer)
Derivatives: Dong-A Pharmaceutical has reported several new oxazolidinones (DA-7157, DA-7218 and DA-7867) having somewhat improved in-vitro potency, compared to linezolid, against Mycobacterium tuberculosis, M. kansasii and M. marinum^1,2
Solubility: In water up to 3 mg/ml [DrugBank]
Polarity: Log P 0.232 [DrugBank]
Melting point: 181.5 182.5ºC [Merck Index]
Formulation and optimal human dosage: Zyvox tablets for oral administration contain 400 mg or 600 mg linezolid.
Zyvox i.v. injection is supplied as a 2 mg/ml isotonic solution for intravenous infusion.
Doses: oral or i.v. 600 mg every 12 hours for serious infections and 400 mg every 12 hours for uncomplicated infection [FDA label].
Long-term linezolid treatment in a young child with extensively drug-resistant tuberculosis
2009, Pediatric Infectious Disease Journal

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International Journal of Antimicrobial Agents

Abstract

Introduction

Section snippets

Strains studied

Results and discussion

References (11)

The global situation of MDR-TB

Tuberculosis (Edinb)

Oxazolidinones: activity, mode of action, and mechanism of resistance

Int J Antimicrob Agents

In vitro activity of moxifloxacin, levofloxacin, gatifloxacin and linezolid against Mycobacterium tuberculosis

Int J Antimicrob Agents

Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries

JAMA

The impact of drug resistance on the global tuberculosis epidemic

Int J Tuberc Lung Dis

Cited by (37)

New class of methyl tetrazole based hybrid of (Z)-5-benzylidene-2- (piperazin-1-yl)thiazol-4(%H)-one as potent antitubercular agents

Linezolid for the treatment of drug-resistant tuberculosis in children: A review and recommendations

Design, synthesis and docking studies of quinoline-oxazolidinone hybrid molecules and their antitubercular properties

Anti-tubercular agents. Part 6: Synthesis and antimycobacterial activity of novel arylsulfonamido conjugated oxazolidinones

Linezolid

Long-term linezolid treatment in a young child with extensively drug-resistant tuberculosis