Experimental Evaluation of Efficacy

Trnka, L; Mison, Petr; Bartmann, K; Otten, H.

doi:10.1007/978-3-642-72873-0_2

Cited by 9 publications

(13 citation statements)

References 35 publications

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“…In vitro studies of exposure of proliferating bacilli to isoniazid concentrations of 1-2 mg/mL found a decrease in viable cfu counts to ∼1% of the original population within 3-4 days. This in vitro killing was also dependent on active mycobacterial growth and, above a certain optimum level, was also concentration independent [16]. Our results also lend support to the designation of a 2-h isoniazid concentration of ∼3 mg/mL as the lower limit of the normal range [17].…”

Section: Discussionsupporting

confidence: 75%

The Influence of Human N-Acetyltransferase Genotype on the Early Bactericidal Activity of Isoniazid

Donald

Sirgel

Venter

et al. 2004

Clinical Infectious Diseases

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The elimination of isoniazid is subject to the influence of the N-acetyltransferase 2 (NAT2) genotype, and individuals may be homozygotic slow, heterozygotic fast, or homozygotic fast acetylators of isoniazid. The early bactericidal activity (EBA) of an antituberculosis agent can be determined by quantitative culture of Mycobacterium tuberculosis in sputum samples obtained from patients with pulmonary tuberculosis during the first days of treatment. In these studies, the EBA of isoniazid during the first 2 days of treatment was determined for 97 patients with sputum smear-positive pulmonary tuberculosis following isoniazid doses of < or =37.5 mg, 75 mg, 150 mg, 300 mg, and 600 mg. The NAT2 genotype was determined in 70 patients, and the association between EBA and genotype was examined in this subgroup. Similarly, the relationship between EBA and isoniazid serum concentration was evaluated in 87 patients. The mean EBA of isoniazid increased with dose, but it levelled off between doses of 150 mg (mean EBA, 0.572) and 300 mg (mean EBA, 0.553). Significant differences were found in the mean EBA of isoniazid between the homozygous slow acetylator group and the heterozygous fast acetylator group and between the homozygous slow acetylator group and the homozygous fast acetylator group, but not between the heterozygous fast acetylator group and the homozygous fast acetylator group. The EBA appeared to reach a maximum at a 2-h isoniazid concentration of 2-3 microg/mL. These data confirm a significant effect of NAT2 genotype on the EBA of isoniazid over a range of doses.

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Section: Discussionsupporting

confidence: 75%

The Influence of Human N-Acetyltransferase Genotype on the Early Bactericidal Activity of Isoniazid

Donald

Sirgel

Venter

et al. 2004

Clinical Infectious Diseases

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“…Some support for this view comes from the knowledge that CM, which is absorbed subcutaneously in mice (17), was effective both in vivo and in vitro. The good concordance of the in vitro and in vivo activities of ETH may also be due to the good distribution of the drug (17). Compared with the day 1 CFU count, significant bactericidal effects of ETH and M-ETH were observed.…”

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confidence: 99%

“…The remaining mice were allocated either to untreated groups or to various drugtreated groups (six mice per group). The following drugs were administered by gavage five times weekly: ETH at 100 mg/kg (10), CS at 300 mg/kg (10), TC at 60 mg/kg (8), PAS at 750 mg/kg (17), and LNZ at 50 mg/kg (3). CM was administered subcutaneously at 150 mg/kg (10).…”

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confidence: 99%

“…The inactivity of PAS, TC, and CS alone (which are active against the strain in vitro) may be related to the capacity of these drugs to penetrate and persist in mouse cells: PAS and TC are known to penetrate mouse cells poorly (12,17), while the rate of CS excretion in mice is high (2,14,17). Some support for this view comes from the knowledge that CM, which is absorbed subcutaneously in mice (17), was effective both in vivo and in vitro. The good concordance of the in vitro and in vivo activities of ETH may also be due to the good distribution of the drug (17).…”

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confidence: 99%

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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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“…1) from Streptomyces griseus cultures, this antibiotic has been studied widely. Streptomycin was one of the first antibiotics used clinically; but now, because of its toxic effect on the eighth cranial nerve, causing vertigo and deafness (4), it has been replaced in the treatment of many infectious diseases, although it is still one of the antibiotics of choice in the treatment of tuberculosis (18).…”

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confidence: 99%

Synthesis of active nitroguaiacol ether derivatives of streptomycin

Abad

Amils

1990

Antimicrob Agents Chemother

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The synthesis, purification, and biological properties of nitroguaiacol ether derivatives of streptomycin and their corresponding radioactive reduced products were examined. These derivatives are biologically active against gram-positive and gram-negative eubacteria and they are also photoreactive because of the presence of the nitroguaiacol group in the molecule. We demonstrated that these derivatives can be used as streptomycin analogs in photoaffinity labeling of the macromolecular structures related to the mode of action of the antibiotic.

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Experimental Evaluation of Efficacy

Cited by 9 publications

References 35 publications

The Influence of Human N-Acetyltransferase Genotype on the Early Bactericidal Activity of Isoniazid

The Influence of Human N-Acetyltransferase Genotype on the Early Bactericidal Activity of Isoniazid

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

Synthesis of active nitroguaiacol ether derivatives of streptomycin

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