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J Grosset

Publications and source records attributed to J Grosset.

At least 19 recordsLinked to original sources
PubMed1995

Selection of clarithromycin-resistant Mycobacterium avium complex during combined therapy using the beige mouse model.

Sixteen weeks of treatment with clarithromycin (CLARI) alone displayed significant bactericidal activity against Mycobacterium avium complex infection in beige mice. Only two combined regimens, CLARI combined with an initial 4 or 8 weeks of amikacin (AMIKA), displayed activity greater than that displayed by CLARI alone. Four other combined regimens, CLARI combined with ethambutol (EMB), rifabutin (RBT), or both EMB and RBT during the entire 16 weeks of treatment or with AMIKA administered in an initial 2-week course showed bactericidal activity not significantly greater than that of CLARI alone. After 16 weeks of treatment, CLARI-resistant mutants were isolated from the majority of mice that had been treated with CLARI alone, CLARI-RBT, CLARI-EMB, or CLARI-EMB-RBT, as was the case for untreated controls, but the frequencies of occurrence of mutants were significantly greater in the groups treated with these combinations or CLARI alone. On the other hand, no CLARI-resistant mutants were isolated from the mice that had been treated with the combination of CLARI plus an initial 4 or 8 weeks of AMIKA and were isolated from only a tiny proportion of mice that had been treated with CLARI plus an initial 2 weeks of AMIKA. Therefore, only treatment with CLARI combined with an initial 4 or 8 weeks of AMIKA but not combined with RBT or EMB or both, could enhance the activity of the drug treatment and prevent the selection of CLARI-resistant mutants.

Amikacin↗
PubMed1995

Use of normal C57BL/6 mice with established Mycobacterium avium infections as an alternative model for evaluation of antibiotic activity.

Several murine models have been used to evaluate the activities of antimicrobial agents against Mycobacterium avium infection. The main model used is the beige mouse model, but beige mice are expensive and not easily available. Thus, we developed a model of infection in wild C57BL/6 mice. The drugs that exhibited some activity in a previous model of early infection were evaluated in a new model of established infection. Sparfloxacin (50 mg/kg of body weight), ethambutol (50 mg/kg), minocycline (25 mg/kg), and the inhibitor of the cortisol receptors RU-40555 (100 mg/kg) were compared with clarithromycin (50 mg/kg). Treatments were started 5 weeks after the inoculation and were continued for 21 days. Sparfloxacin and RU-40555, which exhibited a moderate activity in the model of early infection, were not effective in this model of established infection. Clarithromycin and combinations with clarithromycin kept their activities against M. avium infection, both in the spleen and in lungs. The present model of established infection of normal C57BL/6 mice is more relevant than the model of early infection for a stringent evaluation of drugs.

Animals↗
PubMed1995

Activities of roxithromycin against Mycobacterium avium infections in human macrophages and C57BL/6 mice.

The activity of roxithromycin against three clinical isolates of Mycobacterium avium was compared with that of clarithromycin both in a model of infection of human monocyte-derived macrophages and in a model of established infection of C57BL/6 mice. In the cell culture model, roxithromycin and clarithromycin were bactericidal for strains MO-1 and N-92159 and bacteriostatic for strain N-93043. For the three strains, the differences between the intracellular activities of roxithromycin and clarithromycin were not singificant after 7 days of treatment. Mice were infected with the MO-1 strain. Drugs were given by gavage at a dosage of 200 mg/kg of body weight 6 days per week for 16 weeks starting 5 weeks after infection. At the end of treatment, clarithromycin was more effective than roxithromycin in lungs; roxithromycin was as effective as clarithromycin in spleens. Thus, the activity of roxithromycin was comparable to that of clarithromycin both in vitro and in vivo.

Animals↗
PubMed1995

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis.

In tests with 18 drug-susceptible strains of Mycobacterium tuberculosis, the MIC at which 50% of the strains are inhibited by levofloxacin (LVFX) was one dilution less than that at which 50% of the strains are inhibited by ofloxacin (OFLO), but the MICs at which 90% of the strains are inhibited were similar. The in vivo activity of LVFX against M. tuberculosis was compared with the activities of isoniazid, OFLO, and sparfloxacin (SPFX). Mice were inoculated intravenously with 1.74 x 10(6) CFU of H37Rv, and treatments began the next day and were carried out six times weekly for 4 weeks. The severity of infection and effectiveness of treatment were assessed by survival rate, spleen weights, gross lung lesions, and enumeration of CFU in the spleen. In terms of CFU counts, the ranking of the anti-M. tuberculosis activities of the treatments used ran in the following order: LVFX (300 mg/kg of body weight) = SPFX (100 mg/kg) > isoniazid > SPFX (50 mg/kg) > OFLO (300 mg/kg) = LVFX (150 mg/kg) > OFLO (150 mg/kg) = LVFX (50 mg/kg). It seems, therefore, that the in vivo activity of LVFX is comparable to that produced by a twofold-greater dosage of OFLO. It is assumed that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg daily, which is equivalent to 300 mg of LVFX per kg in mice. Because LVFX displayed powerful bactericidal activity, promising effects against human tuberculosis may be achieved if patients are treated with the maximal clinically tolerated dosage of LVFX.

Animals↗
PubMed1995

Characterization of the Triticum durum Desf. chloroform-methanol-soluble protein family.

The CM (chloroform-methanol-soluble) proteins are low-molecular-weight cysteine-rich proteins that are found in wheat and barley endosperms. A cDNA clone encoding a Triticum durum (T. durum) CM3 protein has been isolated from a mid-maturation seed cDNA library. The T. durum CM3 protein is synthesized as a precursor including a signal peptide (SP) of 25 residues. Northern blot analysis shows that in developing seed the highest level of CM3 protein mRNA is detected at mid-maturation. The hybridization patterns obtained by Southern blot analysis indicated that T. durum CM proteins are encoded by a small multigene family. The similarity between the wheat and barley CM proteins encoded by homologous chromosomes is much higher than that between each of the three members of the T. durum family. All CM proteins contain ten cysteine residues organized in a conserved cysteine motif.

Amino Acid Sequence↗
PubMed1994

Chloroquine does not enhance the activity of clarithromycin against multiplication of Mycobacterium avium within human macrophages.

SETTING: Chloroquine, an alkalinizing lysosomotropic agent, enhances the intracellular activity of antibiotics against Mycobacterium tuberculosis or Coxiella burnetii. OBJECTIVE: To determine if chloroquine modifies the activity of clarithromycin, less effective at acidic pH, against intracellular Mycobacterium avium. DESIGN: The activity of clarithromycin (4 micrograms/ml) against the MO-1 strain of M. avium was evaluated within human macrophages in presence of chloroquine (5 micrograms/ml). The minimal inhibitory concentration of clarithromycin for the strain was 2 micrograms/ml. RESULTS: While clarithromycin alone did decrease the intracellular infection at day 7 of culture (P < 0.01), chloroquine alone did not impede the intracellular growth of M. avium, and did not enhance the activity of clarithromycin. CONCLUSION: Chloroquine should not improve clarithromycin treatment against M. avium infection.

Cells, Cultured↗
PubMed1994

Selection of a gyrA mutant of Mycobacterium tuberculosis resistant to fluoroquinolones during treatment with ofloxacin.

A strain of Mycobacterium tuberculosis resistant to ofloxacin was selected in a patient with a long history of multidrug-resistant tuberculosis eventually treated by ofloxacin combined with other second-line drugs. A mutation in the gyrA gene was hypothesized to be the mechanism of acquired resistance to ofloxacin in this strain. Chromosomal DNA of strains MTB1, isolated before treatment and susceptible to ofloxacin (MIC, 1 microgram/mL), and MTB2, isolated during treatment and resistant to ofloxacin (MIC, 32 micrograms/mL), was amplified by polymerase chain reaction (PCR) using two oligonucleotide primers highly homologous to DNA sequences flanking the quinolone resistance-determining region in gyrA of mycobacteria. Comparison of the nucleotide sequences of the 150-bp fragments obtained by PCR revealed a point mutation in MTB2 leading to the substitution of histidine for aspartic acid at a position corresponding to residues involved in quinolone resistance in Escherichia coli (Asp87), Staphylococcus aureus (Glu88), and Campylobacter jejuni (Asp90).

Adult↗
PubMed1994

Effectiveness of various antimicrobial agents against Mycobacterium avium complex in the beige mouse model.

The results of five chemotherapeutic experiments in beige mice infected with organisms of the Mycobacterium avium complex are presented. After monotherapy with various antimicrobial agents for 4 weeks, only clarithromycin, amikacin, and ethambutol displayed definite bactericidal effects; sparfloxacin and clofazimine showed modest bacteriostatic effects; and rifampin and rifabutin were totally inactive against the isolate tested. After treatment for 4 weeks, the large quantities of clofazimine that had accumulated in the organs of mice seriously interfered with the enumeration of the CFU and assessment of the efficacy of the treatment. The in vitro synergistic effects of drug combinations against M. avium complex were not confirmed in beige mice. In combination with clarithromycin, amikacin could prevent the selection of clarithromycin-resistant mutants, whereas minocycline could not.

Animals↗
PubMed1993

Efficacy of granulocyte colony-stimulating factor and RU-40555 in combination with clarithromycin against Mycobacterium avium complex infection in C57BL/6 mice.

We compared the activities of two different biological-response modifiers with that of clarithromycin against Mycobacterium avium complex infection in C57BL/6 mice. Mice were pretreated daily with clarithromycin (50 mg/kg of body weight subcutaneously [s.c.]), RU-40555 (100 mg/kg s.c.), or granulocyte colony-stimulating factor (G-CSF) at low dose (15 micrograms/kg intraperitoneally [i.p.]) or high dose (300 micrograms/kg i.p.) 3 days before intravenous challenge with 2.5 x 10(7) CFU of the MO-1 strain of M. avium complex. Mice were treated daily until sacrifice at day 1, 8, 15, or 21 after challenge, and the numbers of CFU were measured per gram of tissue in lung and spleen. Compared at day 21 with control treatment, clarithromycin significantly decreased the level of infection in spleen (P < 0.0001) and lungs (P < 0.0001). Compared with control treatment, G-CSF at low dose had no activity, but G-CSF in combination with clarithromycin was more effective than clarithromycin alone in spleen (P < 0.05) and lungs (P < 0.015). The high dose of G-CSF was as effective as the low dose. RU-40555 alone had no beneficial activity. The RU-40555-clarithromycin combination was more effective than control treatment in spleen (P = 0.0001) and lungs (P < 0.0005) and more effective than clarithromycin alone in spleen (P < 0.009) but not in lungs. Thus, our experiments suggest that clarithromycin alone or in combination with G-CSF should be further evaluated for the prophylaxis of M. avium complex infection.

Acquired Immunodeficiency Syndrome↗
PubMed1993

A simple and rapid technique for the detection of rifampin resistance in Mycobacterium leprae.

The rifampin resistance of Mycobacterium leprae is due to missense mutations in the rpoB gene encoding the beta-subunit of the essential enzyme RNA polymerase. A rapid and very simple method has been developed to detect rifampin resistance in small numbers of M. leprae present in biopsies. It involves polymerase chain reaction amplification of a defined region of the rpoB gene followed by single-strand conformational polymorphism analysis (PCR-SSCP). The reliability of the method has been tested on a sample of known drug-resistant and susceptible isolates of M. leprae.

Alleles↗
PubMed1992

Activities of WIN-57273, minocycline, clarithromycin, and 14-hydroxy-clarithromycin against Mycobacterium avium complex in human macrophages.

The activities of the fluoroquinolone WIN-57273, 14-OH clarithromycin (a human metabolite of clarithromycin), and minocycline against two virulent strains of Mycobacterium avium complex were evaluated in a model of intracellular infection and compared with that of clarithromycin. Human monocyte-derived macrophages were infected at day 6 of culture. Intracellular CFU at 60 min and intracellular and supernatant CFU on days 4 and 7 were counted after inoculation. The concentrations used, which were equal to peak levels in serum, were 3 micrograms of WIN-57273 per ml (MICs for the two strains, 1 microgram/ml), 4 microgram of 14-OH clarithromycin per ml (MICs, 8 and 2 micrograms/ml, respectively, at pH 7.4), 4 micrograms of minocycline per ml (MICs, 64 and 32 micrograms/ml, respectively), and 4 micrograms of clarithromycin per ml (MICs, 2 and 0.5 micrograms/ml, respectively, at pH 7.4). On day 7, compared with controls, WIN-57273, minocycline (P less than 0.02), clarithromycin, or different combinations of clarithromycin and the other drugs (P less than 0.001) slowed the intracellular replication of strain MO-1. 14-OH clarithromycin (P less than 0.02), clarithromycin (P less than 0.02), 14-OH clarithromycin plus clarithromycin (P less than 0.01), clarithromycin plus minocycline, or clarithromycin plus minocycline plus 14-OH clarithromycin (P less than 0.001) slowed the intracellular replication of strain LV-2. WIN-57273 was less effective than clarithromycin against strain MO-1 (P less than 0.05). Clarithromycin plus 14-OH clarithromycin plus minocycline (P less than 0.02) was more effective than clarithromycin alone against strain LV-2. Thus, clarithromycin plus minocycline, which corresponds in humans to three active molecules, may exhibit a better efficacy than clarithromycin in this model.

Anti-Infective Agents↗
PubMed1992

Sparfloxacin, ethambutol, and cortisol receptor inhibitor RU-40 555 treatment for disseminated Mycobacterium avium complex infection of normal C57BL/6 mice.

Sparfloxacin (50 mg/kg of body weight given subcutaneously each day), alone or in combination with ethambutol (50 mg/kg given subcutaneously each day), was examined for its therapeutic efficacy against experimental infection induced with the Mycobacterium avium complex in normal C57BL/6 mice. In addition, the potential anti-infective role of RU-40 555 (100 mg/kg given intraperitoneally each day), a drug that inhibits the cortisol receptors, was examined in the same model. Treatments were started 24 h after intravenous bacterial challenge and were continued for 21 days. Compared with controls, sparfloxacin or ethambutol decreased the CFU counts in spleens and lungs (P < 0.001). The sparfloxacin plus ethambutol combination was more effective than sparfloxacin alone in spleens (P < 0.001) but not in lungs. The sparfloxacin plus ethambutol plus RU-40 555 combination was more effective than the sparfloxacin plus ethambutol combination in spleens and lungs (P < 0.001). Thus, in this model, RU-40 555 enhanced the antibacterial activities of the antibiotics tested. Results of the study showed that normal C57BL/6 mice infected with the M. avium complex can be used for the evaluation of antimicrobial agents.

Animals↗
PubMed1992

Selection of resistant mutants of Mycobacterium avium in beige mice by clarithromycin monotherapy.

Beige mice were inoculated intravenously with 10(7.90) CFU of Mycobacterium avium 101. Among the untreated control mice, when the mean CFU per spleen increased to a level greater than 10(8), small numbers of organisms resistant to clarithromycin (CLARI) were isolated from some of the spleens; the frequency of CLARI-resistant mutants was estimated to be between 10(-8) and 10(-9). In mice treated with 200 mg of CLARI per kg of body weight six times weekly, however, CLARI-resistant organisms were isolated from the spleens of all mice examined after treatment for 8 weeks; the mean CFU per spleen and the frequency of resistant mutants were significantly greater than those of control mice and increased further after treatment for 16 weeks. The MICs of CLARI against the resistant organisms isolated from both control and treated mice were > or = 512 micrograms/ml.

Animals↗