Activity of 16 Antimicrobial Agents Against Drug-Resistant Strains of<i>Mycobacterium tuberculosis</i>

Fattorini, Lanfranco; Iona, Elisabetta; Ricci, Maria Luisa; Thoresen, Ove Fredrik; Orrù, Germano; Oggioni, Marco; Tortoli, Enrico; Piersimoni, Claudio; Chiaradonna, P.; Tronci, Mirella; Pozzi, Gianni; Orefici, Graziella

doi:10.1089/mdr.1999.5.265

Cited by 34 publications

(25 citation statements)

References 11 publications

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“…Sequencing analysis showed that all the 10 MT isolates carried the same katG GGG3AGG G234R allele, suggesting that the same strain persisted over time. The DNA fingerprinting results on IS6110 confirmed that all sequential isolates belonged to a unique strain (data not shown) (7).…”

Section: Resultsmentioning

confidence: 70%

“…The clinical isolates were genotyped by IS6110-based restriction fragment length polymorphism analysis to exclude the presence of different strains (7,9).…”

Section: Methodsmentioning

confidence: 99%

“…Overall, our data support the idea that in the lung of a chronically infected patient a single founder strain undergoes multiple a Abbreviations are as described in Materials and Methods, except as noted below. Drug concentrations are expressed as microliters per milliliter, and tentative critical concentrations were according to international standards and have been previously described in detail (7,12,22). OFL, ofloxacin; SPA, sparfloxacin; AK, amikacin; KM, kanamycin; CM, capreomycin; CS, cycloserine; PAS, para-amino salicylic acid; TC, thiacetazone; VM, viomycin; ETH, ethionamide.…”

Section: Vol 43 2005 Mycobacterium Tuberculosis In Chronic Infectiomentioning

confidence: 99%

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Drug Resistance Evolution of a Mycobacterium tuberculosis Strain from a Noncompliant Patient

et al. 2005

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The emergence and spread of multidrug-resistant (MDR) Mycobacterium tuberculosis (MT) represents a worldwide health care problem because of the difficulty in treating these infections. Development of drug resistance in MT arises mainly by mutation of chromosomal genes. To investigate the evolution of a MT population during a long-lasting infection, the phenotypic and genotypic changes in the drug resistance of 10 sequential MT isolates from a noncompliant chronically infected patient were investigated. During more than 12 years of active disease, a MDR population developed; molecular typing showed one single parental strain that infected the patient and persisted throughout the disease. Molecular analysis of the drug resistancerelated genes revealed that discrete subpopulations evolved over time from the parental strain by acquiring and accumulating resistance-conferring mutations to isoniazid, rifampin, and streptomycin. Overall, these observations indicate that during a chronic infection, several subpopulations may coexist in the same patient with different drug susceptibility profiles.The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (MT) strains, i.e., strains resistant at least to isoniazid (INH) and rifampin (RMP), is alarming and represents a worldwide health care problem (40). In MT, drug resistance arises mainly by mutation of chromosomal genes, while the horizontal transfer of resistance-carrying genetic elements does not occur. Drug resistance acquisition by mutation is generally recognized as a one-step process in which bacteria become resistant by single point mutations. Because of this spontaneous phenomenon, a combined therapy is recommended to avoid the selection of resistant strains. A dramatic increase in the resistance and spread of MDR strains has been observed in recent years (40). These MDR strains carry multiple mutations in different resistance-related genes, and each mutation results from an independent mutational event. An MDR strain is thus the product of a multistep process, in which a progressive accumulation of genetic alterations occurs and results in the selection of a viable and fit bacterium. Drugresistant bacteria are believed to grow more slowly than susceptible bacteria, since mutations conferring resistance reduce their overall fitness, a phenomenon known as cost of resistance (16). Several authors, however, have demonstrated that fit variants are quickly selected in a drug-resistant bacterial population, in which compensatory mutations eliminate the biological cost of resistance (1,3,17,33).All data reported on strain fitness generally refer to homogeneous bacterial populations, but due to continuously ongoing selective pressure in the host during infection, this might not be the case for a bacterial population infecting humans.The detailed characteristics of mycobacterial populations in the host during infection are still poorly understood. Kaplan et al. described the parallel evolution of different MT subpopulations from a unique strain in different si...

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Section: Resultsmentioning

confidence: 70%

“…The clinical isolates were genotyped by IS6110-based restriction fragment length polymorphism analysis to exclude the presence of different strains (7,9).…”

Section: Methodsmentioning

confidence: 99%

Section: Vol 43 2005 Mycobacterium Tuberculosis In Chronic Infectiomentioning

confidence: 99%

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Drug Resistance Evolution of a Mycobacterium tuberculosis Strain from a Noncompliant Patient

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“…The mutation conferring resistance to RMP is TCG531TTG (Ser3Leu) in the rpoB gene (4,15); the mutation conferring resistance to INH is AGC315ACC (Ser3Thr) in the katG gene (unpublished data). Comparative MICs of these and other drugs for isolate RM22 and for a susceptible M. tuberculosis strain, H37Rv (ATCC 27294), as determined by the twofold agar dilution technique on Middlebrook 7H11 agar (Difco Laboratories, Detroit, Mich.) (4)(5)(6)13), are shown in Table 1. INH, CM, CS, PAS, EMB, SM, KM (Sigma Chemical Co., St. Louis, Mo.…”

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confidence: 99%

Activities of Moxifloxacin Alone and in Combination with Other Antimicrobial Agents against Multidrug-Resistant Mycobacterium tuberculosis Infection in BALB/c Mice

Fattorini

Tan

Iona

et al. 2003

Antimicrob Agents Chemother

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The activity of moxifloxacin was enhanced by the addition of ethionamide but not by that of cycloserine, thiacetazone, capreomycin, para-aminosalicylic acid, or linezolid in BALB/c mice infected with a strain of Mycobacterium tuberculosis resistant to isoniazid, rifampin, and six other drugs. These observations are important for the therapy of multidrug-resistant tuberculosis.The emergence of multidrug-resistant strains of Mycobacterium tuberculosis, i.e., strains resistant at least to isoniazid (INH) and rifampin (RMP), poses serious problems for tuberculosis (TB) control and increases the demand for new therapies. Fluoroquinolone agents such as ciprofloxacin (CIP) and ofloxacin (OFL) are effective against TB, including disease caused by MDR strains (7,16). Of the recently developed fluoroquinolones, moxifloxacin (M) showed potent activity against M. tuberculosis in mice (9,11,18) but no studies have been performed with difficult-to-treat strains resistant to INH, RMP, and several other drugs. We therefore tested the activity of M, alone and in two-drug combinations with other agents, including the traditional second-line drugs capreomycin (CM), cycloserine (CS), para-aminosalicylic acid (PAS), ethionamide (ETH), and thiacetazone (TC) (6) and oxazolidinones (linezolid [LNZ]) (3), in mice infected with an MDR M. tuberculosis strain also resistant to all of the other first-line antituberculosis drugs. In order to evaluate a possible enhancement of the activity of M, a low dose of the drug (30 mg/kg) (9) was used.The MDR clinical isolate RM22, known to be resistant to RMP, INH, streptomycin (SM), ethambutol (EMB), pyrazinamide, and kanamycin (KM) (4), was used in this study. The mutation conferring resistance to RMP is TCG531TTG (Ser3Leu) in the rpoB gene (4, 15); the mutation conferring resistance to INH is AGC315ACC (Ser3Thr) in the katG gene (unpublished data). Comparative MICs of these and other drugs for isolate RM22 and for a susceptible M. tuberculosis strain, H37Rv (ATCC 27294), as determined by the twofold agar dilution technique on Middlebrook 7H11 agar (Difco Laboratories, Detroit, Mich.) (4-6, 13), are shown in Table 1. INH, CM, CS, PAS, EMB, SM, KM (Sigma Chemical Co., St. Louis, Mo.), and CIP (Bayer, Milan, Italy) were dissolved in distilled water; RMP (Sigma), rifapentine (RPT) (Aventis Pharma, Vitry-Alfortville, France), and rifabutin (RFB) (Pharmacia & Upjohn, Kalamazoo, Mich.) were dissolved in ethanol; OFL (Sigma), sparfloxacin (SPX) (Aventis), and M (Bayer) were dissolved in 0.1 M NaOH; and TC, ETH (Sigma), and LNZ (Pharmacia) were dissolved in dimethyl sulfoxide.Male BALB/c mice (Charles River, Calco, Como, Italy) were infected intravenously with 0.2-ml portions containing 5 ϫ 10 5 CFU of isolate RM22. One day after the infection, four mice were sacrificed and the numbers of CFU in the spleens and lungs were determined (untreated day 1 control). Organs were removed and homogenized in Middlebrook 7H9 broth (Difco). To enumerate CFU, appropriate dilutions of the homogenates were plated onto Midd...

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“…8 Recently, the Italian National Institute of Health (ISS) showed that, among second-line antitubercular drugs, only about 10% of the 46 drug-resistant strains of M tuberculosis isolated from Italian patients were resistant to capreomycin. 9 To overcome CS's toxic effects on kidneys, site-specific delivery systems can be employed. In particular, it has been demonstrated that entrapment of CS in multilamellar vesicles (MLVs) reduced renal toxicity, enhanced peptide penetration into tissues, and increased CS activity in a beige mouse model of M avium complex infection.…”

Section: Introductionmentioning

confidence: 99%

Unilamellar vesicles as potential capreomycin sulfate carriers: Preparation and physicochemical characterization

et al. 2003

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This increasing incidence of TB is attributable to several factors, the most important of which are the HIV epidemic and the lack of control of immigration from countries where TB is common. In fact, untreated HIV infection, leading to progressive immunodeficiency, increases susceptibility to TB, one of the main causes of death in populations with high HIV prevalence. 1-3The aim of this work was to evaluate unilamellar liposomes as new potential capreomycin sulfate (CS) delivery systems for future pulmonary targeting by aerosol administration. Dipalmitoylphosphatidylcholine, hydrogenated phosphatidylcholine, and distearoylphosphatidylcholine were used for liposome preparation. Peptide-membrane interaction was investigated by differential scanning calorimetry (DSC) and attenuated total internal reflection Fourier-transform infrared spectroscopy (ATIR-FTIR). Peptide entrapment, size, and morphology were evaluated by UV spectrophotometry, photocorrelation spectroscopy, and transmission electron microscopy, respectively. Interaction between CS and the outer region of the bilayer was revealed by DSC and ATIR-FTIR. DSPC liposomes showed enhanced interdigitation when the CS molar fraction was increased. Formation of a second phase on the bilayer surface was observed. From kinetic and permeability studies, CS loaded DSPC liposomes resulted more stable if compared to DPPC and HPC over the period of time investigated. The amount of entrapped peptide oscillated between 10% and 13%. Vesicles showed a narrow size distribution, from 138 to 166 nm, and a good morphology. These systems, in particular DSPC liposomes, could represent promising carriers for this peptide.

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Activity of 16 Antimicrobial Agents Against Drug-Resistant Strains ofMycobacterium tuberculosis

Cited by 34 publications

References 11 publications

Drug Resistance Evolution of a Mycobacterium tuberculosis Strain from a Noncompliant Patient

Drug Resistance Evolution of a Mycobacterium tuberculosis Strain from a Noncompliant Patient

Activities of Moxifloxacin Alone and in Combination with Other Antimicrobial Agents against Multidrug-Resistant Mycobacterium tuberculosis Infection in BALB/c Mice

Unilamellar vesicles as potential capreomycin sulfate carriers: Preparation and physicochemical characterization

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