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

doi:10.1016/S0924-8579(02)00239-X

International Journal of Antimicrobial Agents

Volume 20, Issue 6, December 2002, Pages 464-467

https://doi.org/10.1016/S0924-8579(02)00239-X Get rights and content

Abstract

The in vitro activity of moxifloxacin, gatifloxacin, levofloxacin and linezolid was evaluated against 234 strains of Mycobacterium tuberculosis isolated in the Southeast of Spain. All drugs tested showed good activity, with an MIC₉₀ of less than 1 mg/l, and were active against isociacide and rifampicin resistant strains. Three strains were resistant to isoniazid and to the fluoroquinolones, which suggested the existence of mechanisms of resistance not yet described. These new compounds may prove to be therapeutic alternatives for treatment of multi-resistant tuberculosis and further studies should be done to demonstrate their true usefulness.

Introduction

In recent years, the epidemiology of tuberculosis has altered due to the emergence of HIV infection [1], [2], [3], and the propagation of drug-resistant strains [4], [5], [6], [7]. In order to tackle these new situations, it is necessary to develop new treatment guidelines and promising results have been obtained with fluoroquinolones [8], [9], [10], [11].

Linezolid exhibits excellent activity against Gram-positive bacteria [12], [13]. It also has activity against M. tuberculosis, both in vitro [14] and in vivo [15]. Our aim was to determine the in vitro activity of these drugs against clinical strains of M. tuberculosis isolated in the Southeast of Spain.

Section snippets

Strains studied

243 strains were studied that had been isolated in the Elche health district between 1993 and 2001. The strains were maintained frozen at −70 °C in soya tripticase–glycerol broth. The activity of isoniazid, rifampicin, ethambutol, pirazinamide and streptomycin against all the strains was known, and all were fully sensitive except seven isolates resistant to isoniazid, three to rifampicin, two to both antibiotics and one strain to isoniazid and streptomycin [16].

Antibiotics tested

Gatifloxacin (Bristol Myers

Results

The activity of the antibiotics assayed is summarized in Table 1. The MIC₅₀ of the three fluoroquinolones assayed was 0.25 mg/l and the MIC₉₀ was 0.25 mg/l for gatifloxacin and 0.5 mg/l for moxifloxacin and levofloxacin. Linezolid had an MIC₅₀ and MIC₉₀ of 0.5 mg/l. We detected the presence of five strains resistant to fluoroquinolones (MIC≥2 mg/l) and of these, three also have high minimum inhibitory concentrations for linezolid. These values are shown in Table 2 and the characteristics of the

Discussion

The need for new drugs for the treatment of tuberculosis has led to the use of fluoroquinolones ever since these drugs have been shown to have good activity against M. tuberculosis [21], [22]. However, therapeutic failures have been reported when these drugs are used [23] as well as the emergence of resistant strains [24]. The cut-off points of the fluoroquinolones against M. tuberculosis have not been clearly established, although it has been suggested that for ciprofloxacin and ofloxacin the

References (40)

B. Petrini et al.
Drug-resistant and multidrug-resistant tubercle bacilli
International Journal of Antimicrobial Agents
(1999)
J.C. Rodrı́guez et al.
Mycobacterium tuberculosis: evolución de las resistencias en nuestro medio
Archivos de Bronconeumologı́a
(1997)
J.C. Rodrı́guez et al.
In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis
International Journal of Antimicrobial Agents
(2001)
D.R. Ashtekar et al.
Oxazolidinone, a new class of synthetic antituberculosis agent: in vitro and in vivo activities of DuP-721 against Mycobacterium tuberculosis
Diagnostic Microbiology and Infectious Diseases
(1991)
P. Kloss et al.
Resistance mutations in 23 S rRNA identify the site of action of the protein synthesis inhibitor linezolid in the ribosomal peptidyl transferase center
Journal of Molecular Biology
(1999)
J.D. Porter
Mycobacteriosis and HIV infection: the new public health challenge
Journal of Antimicrobial Chemotherapy
(1996)
K.A. Sepkowitz et al.
Tuberculosis at the end of the twentieth century
European Journal of Clinical Microbiology and Infectious Diseases
(1994)
K.A. Sepkowitz et al.
Tuberculosis in the AIDS era
Clinical Microbiology Reviews
(1995)
G. Di Perri et al.
Multidrug-resistant tuberculosis
New England Journal of Medicine
(1996)
V. Ausina et al.
Prospective study of drug-resistant tuberculosis in a Spanish urban population including patients at risk for HIV infection
European Journal of Clinical Microbiology and Infectious Diseases
(1995)

J.D. Van Embden et al.

Establishment of a European network for the surveillance of Mycobacterium tuberculosis, MRSA and penicillin-resistant pneumococci

Journal of Antimicrobial Chemotherapy

(1996)

Y.X. Furet et al.

Newly documented antimicrobial activity of quinolones

European Journal of Clinical Microbiology and Infectious Diseases

(1991)

M.R. Jacobs

Activity of quinolones against mycobacteria

Drugs

(1995)

S.H. Gillespie et al.

Fluoroquinolones: a new treatment for tuberculosis?

International Journal of Tubercle Lung Diseases

(1998)

G.J. Alangaden et al.

The clinical use of fluoroquinolones for the treatment of mycobacterial diseases

Clinical Infectious Diseases

(1997)

A.P. Johnson et al.

Activity of linezolid against multi-resistant gram-positive bacteria from diverse hospitals in the United Kingdom

Journal of Antimicrobial Chemotherapy

(2000)

J.W. Chien et al.

Use of linezolid, an oxazolidinone, in the treatment of multidrug-resistant gram-positive bacterial infections

Clinical and Infectious Diseases

(2000)

G.E. Zurenko et al.

In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents

Antimicrobial Agents and Chemotherapy

(1996)

M.H. Cynamon et al.

Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model

Antimicrobial Agents and Chemotherapy

(1999)

C.B. Inderlied et al.

Antymicobacterial agents and susceptibility tests

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

Abstract

Introduction

Section snippets

Strains studied

Antibiotics tested

Results

Discussion

International Journal of Antimicrobial Agents

Archivos de Bronconeumologı́a

International Journal of Antimicrobial Agents

Diagnostic Microbiology and Infectious Diseases

Journal of Molecular Biology

Mycobacteriosis and HIV infection: the new public health challenge

Journal of Antimicrobial Chemotherapy

Tuberculosis at the end of the twentieth century

European Journal of Clinical Microbiology and Infectious Diseases

Tuberculosis in the AIDS era

Clinical Microbiology Reviews

Multidrug-resistant tuberculosis

New England Journal of Medicine

Prospective study of drug-resistant tuberculosis in a Spanish urban population including patients at risk for HIV infection

European Journal of Clinical Microbiology and Infectious Diseases

Establishment of a European network for the surveillance of Mycobacterium tuberculosis, MRSA and penicillin-resistant pneumococci

Journal of Antimicrobial Chemotherapy

Newly documented antimicrobial activity of quinolones

European Journal of Clinical Microbiology and Infectious Diseases

Activity of quinolones against mycobacteria

Drugs

Fluoroquinolones: a new treatment for tuberculosis?

International Journal of Tubercle Lung Diseases

The clinical use of fluoroquinolones for the treatment of mycobacterial diseases

Clinical Infectious Diseases

Activity of linezolid against multi-resistant gram-positive bacteria from diverse hospitals in the United Kingdom

Journal of Antimicrobial Chemotherapy

Use of linezolid, an oxazolidinone, in the treatment of multidrug-resistant gram-positive bacterial infections

Clinical and Infectious Diseases

In vitro activities of U-100592 and U-100766, novel oxazolidinone antibacterial agents

Antimicrobial Agents and Chemotherapy

Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model

Antimicrobial Agents and Chemotherapy

Antymicobacterial agents and susceptibility tests