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PubMed1997

Susceptibility of penicillin-susceptible and -resistant pneumococci to dirithromycin compared with susceptibilities to erythromycin, azithromycin, clarithromycin, roxithromycin, and clindamycin.

Agar dilution with incubation in air and CO2 was used to determine the MICs of erythromycin, dirithromycin, azithromycin, clarithromycin, roxithromycin, and clindamycin for 79 penicillin-susceptible, 72 penicillin-intermediate, and 74 penicillin-resistant pneumococci (158 erythromycin-susceptible and 67 erythromycin-resistant pneumococci). MICs obtained in air were usually 1 to 3 dilutions lower than those obtained in CO2. In air, the respective MICs at which 50% (MIC50s) and 90% (MIC90s) of penicillin-susceptible, -intermediate, and -resistant strains are inhibited were as follows: erythromycin, 0.016 and 0.5, 0.03 and > 64, and 2 and > 64 microg/ml; dirithromycin, 0.03 and 0.5, 0.06 and > 64, and 8 and > 64 microg/ml; azithromycin, 0.03 and 0.5, 0.06 and > 64, and 2 and > 64 microg/ml; clarithromycin, 0.016 and 0.06, 0.03 and > 64, and 2 and > 64 microg/ml; roxithromycin, 0.06 and 2, 0.06 and > 64, and 2 and > 64 microg/ml; and clindamycin, 0.03 and 0.06, 0.06 and > 64, and 0.06 and > 64 microg/ml. The MICs of erythromycin, azithromycin, and dirithromycin were very similar; however, clarithromycin MICs were generally 1 to 2 dilutions lower and roxithromycin MICs were 1 to 2 dilutions higher than those of the other compounds tested. Strains resistant to one macrolide were resistant to all macrolides; however, not all macrolide-resistant strains were resistant to clindamycin, and 32 macrolide-resistant (MICs, > or = 28 microg/ml), clindamycin-susceptible (MICs, < or = 0.25 microg/ml) strains were encountered. Time-kill testing of six strains showed similar killing kinetics for all compounds, with 99.9% killing of all strains observed with the compounds only at or above the MIC after 24 h.

Aminoglycosides↗
PubMed1998

Explaining the bias in the 23S rRNA gene mutations associated with clarithromycin resistance in clinical isolates of Helicobacter pylori.

A single point mutation in the 23S rRNA gene of Helicobacter pylori is known to confer resistance to clarithromycin. Most prevalent among clarithromycin-resistant clinical H. pylori isolates are the mutations from A-2142 to G and A-2143 to G in the 23S rRNA gene. The bias in the 23S rRNA gene mutations conferring clarithromycin resistance may result from the higher MIC, stability of resistance, and growth rate found for the strains with the above-mentioned mutations.

Anti-Bacterial Agents↗
PubMed1998

Effect of grapefruit juice on clarithromycin pharmacokinetics.

To investigate whether grapefruit juice inhibits the metabolism of clarithromycin, 12 healthy subjects were given water or grapefruit juice before and after a clarithromycin dose of 500 mg in a randomized crossover study. Administration of grapefruit juice increased the time to peak concentration of both clarithromycin (82 +/- 35 versus 148 +/- 83 min; P = 0.02) and 14-hydroxyclarithromycin (84 +/- 38 min versus 173 +/- 85; P = 0.01) but did not affect other pharmacokinetic parameters.

Adult↗
PubMed1999

Mutations in 23S rRNA in Helicobacter pylori conferring resistance to erythromycin do not always confer resistance to clarithromycin.

Mutations conferring resistance to erythromycin or clarithromycin in Helicobacter pylori were studied. Mutation A2142G was consistently associated with clarithromycin MIC of > 256 micrograms/ml, whereas mutants carrying A2143G had MICs ranging from < or = 0.016 to > 256 micrograms/ml, suggesting that additional factors account for the observed multiple levels of resistance to clarithromycin.

Anti-Bacterial Agents↗
PubMed1999

Molecular investigation of the postantibiotic effects of clarithromycin and erythromycin on Staphylococcus aureus cells.

The kinetics of recovery after inhibition of growth by erythromycin and clarithromycin were examined in Staphylococcus aureus cells. After inhibition for one mass doubling by 0.5 microg of the antibiotics/ml, a postantibiotic effect (PAE) of 3 and 4 h duration was observed for the two drugs before growth resumed. Cell viability was reduced by 25% with erythromycin and 45% with clarithromycin compared with control cells. Erythromycin and clarithromycin treatment reduced the number of 50S ribosomal subunits to 24 and 13% of the number found in untreated cells. 30S subunit formation was not affected. Ninety minutes was required for resynthesis to give the control level of 50S particles. Protein synthesis rates were diminished for up to 4 h after the removal of the macrolides. This continuing inhibition of translation was the result of prolonged binding of the antibiotics to the 50S subunit as measured by 14C-erythromycin binding to ribosomes in treated cells. The limiting factors in recovery from macrolide inhibition in these cells, reflected as a PAE, are the time required for the synthesis of new 50S subunits and the slow loss of the antibiotics from ribosomes in inhibited cells.

Anti-Bacterial Agents↗
PubMed2000

Effects of fluconazole and clarithromycin on rifabutin and 25-O-desacetylrifabutin pharmacokinetics.

Ten human immunodeficiency virus-infected patients were given rifabutin in addition to fluconazole and clarithromycin. There was a 76% increase in the area under the concentration-time curve of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together with rifabutin. Patients should be monitored for adverse effects of rifabutin administered concomitantly with clarithromycin and/or fluconazole.

Adult↗
PubMed2000

Regional differences in metronidazole resistance and increasing clarithromycin resistance among Helicobacter pylori isolates from Japan.

The patterns of antibiotic resistance in Helicobacter pylori were assessed in two different regions in Japan. Overall, prevalences of resistance to metronidazole and clarithromycin were 12.4 and 12.9%, respectively. While there was no difference in clarithromycin resistance, the prevalence of metronidazole resistance was significantly higher in Kyoto (23.8%) than in Sapporo (8.1%). From 1996 to 1999, the prevalence of metronidazole resistance did not change but the prevalence of clarithromycin resistance doubled (from 9.1 to 18.7%).

Adult↗
PubMed2002

Effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on Chlamydia pneumoniae in a continuous-infection Model.

Persistent infections with Chlamydia pneumoniae have been implicated in the development of chronic diseases, such as atherosclerosis and asthma. Although azithromycin, clarithromycin, and levofloxacin are frequently used for the treatment of respiratory C. pneumoniae infections, little is known about the dose and duration of therapy needed to treat a putative chronic C. pneumoniae infection. In this study, we investigated the effect of prolonged treatment with azithromycin, clarithromycin, or levofloxacin on the viability of C. pneumoniae and cytokine production in an in vitro model of continuous infection. We found that a 30-day treatment with azithromycin, clarithromycin, and levofloxacin at concentrations comparable to those achieved in the pulmonary epithelial lining fluid reduced but did not eliminate C. pneumoniae in continuously infected HEp-2 cells. All three antibiotics decreased levels of interleukin-6 (IL-6) and IL-8 in HEp-2 cells, but this effect appeared to be secondary to the antichlamydial activity, as the cytokine levels correlated with the concentrations of microorganisms. The levels of IL-1beta, IL-4, IL-10, tumor necrosis factor alpha, and gamma interferon were too low to assess the effect of antibiotics. These data suggest that the dosage and duration of antibiotic therapy currently being used may not be sufficient to eradicate a putative chronic C. pneumoniae infection.

Anti-Bacterial Agents↗
PubMed2002

Helicobacter pylori primary resistance to metronidazole and clarithromycin in Brazil.

Helicobacter pylori resistance to metronidazole was detected in 107 (52.97%) of 202 strains. Twenty (9.85%) strains, 18 of them harboring 23S ribosomal DNA mutations, were resistant to clarithromycin. Metronidazole resistance was associated with female gender. Resistance to metronidazole and resistance to clarithromycin were associated. Increasing clarithromycin resistance rates were observed over time.

Anti-Bacterial Agents↗
PubMed2002

Pharmacodynamic effects of nitroimidazoles alone and in combination with clarithromycin on Helicobacter pylori.

Pharmacodynamic studies of Helicobacter pylori exposed to metronidazole and tinidazole alone and in combination with clarithromycin were performed by bioluminescence assay of intracellular ATP. The pharmacodynamic parameter control-related effective regrowth time (CERT) was used. CERT is defined as the time required for the resumption of logarithmic growth and a return of the level of growth to the preexposure inoculum in the test culture minus the corresponding time in the control culture. CERT measures the combined effects of the initial level of killing and postantibiotic effect. The incubation times and drug concentrations were chosen according to their half-lives and their clinically achievable concentrations. The study shows that the parameter CERT is useful for the testing of antibiotic combinations. The CERTs induced by clarithromycin, metronidazole, and tinidazole alone and in the combinations tested were concentration dependent, with no maximum response, indicating that the use of high doses may be preferable. The combinations with the highest concentrations induced synergistic effects and prevented regrowth. The use of tinidazole in combination with clarithromycin proved to give the longest CERTs, indicating that this is the most effective combination.

Clarithromycin↗
PubMed2004

Antipneumococcal activities of two novel macrolides, GW 773546 and GW 708408, compared with those of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin.

The MICs of GW 773546, GW 708408, and telithromycin for 164 macrolide-susceptible and 161 macrolide-resistant pneumococci were low. The MICs of GW 773546, GW 708408, and telithromycin for macrolide-resistant strains were similar, irrespective of the resistance genotypes of the strains. Clindamycin was active against all macrolide-resistant strains except those with erm(B) and one strain with a 23S rRNA mutation. GW 773546, GW 708408, and telithromycin at two times their MICs were bactericidal after 24 h for 7 to 8 of 12 strains. Serial passages of 12 strains in the presence of sub-MICs yielded 54 mutants, 29 of which had changes in the L4 or L22 protein or the 23S rRNA sequence. Among the macrolide-susceptible strains, resistant mutants developed most rapidly after passage in the presence of clindamycin, GW 773546, erythromycin, azithromycin, and clarithromycin and slowest after passage in the presence of GW 708408 and telithromycin. Selection of strains for which MICs were >/=0.5 microg/ml from susceptible parents occurred only with erythromycin, azithromycin, clarithromycin, and clindamycin; 36 resistant clones from susceptible parent strains had changes in the sequences of the L4 or L22 protein or 23S rRNA. No mef(E) strains yielded resistant clones after passage in the presence of erythromycin and azithromycin. Selection with GW 773546, GW 708408, telithromycin, and clindamycin in two mef(E) strains did not raise the erythromycin, azithromycin, and clarithromycin MICs more than twofold. There were no change in the ribosomal protein (L4 or L22) or 23S rRNA sequences for 15 of 18 mutants selected for macrolide resistance; 3 mutants had changes in the L22-protein sequence. GW 773546, GW 708408, and telithromycin selected clones for which MICs were 0.03 to >2.0 microg/ml. Single-step studies showed mutation frequencies <5.0 x 10(-10) to 3.5 x 10(-7) for GW 773546, GW 708408, and telithromycin for macrolide-susceptible strains and 1.1 x 10(-7) to >4.3 x 10(-3) for resistant strains. The postantibiotic effects of GW 773546, GW 708408, and telithromycin were 2.4 to 9.8 h.

Anti-Bacterial Agents↗
PubMed2004

Activities of two novel macrolides, GW 773546 and GW 708408, compared with those of telithromycin, erythromycin, azithromycin, and clarithromycin against Haemophilus influenzae.

The MIC at which 50% of strains are inhibited (MIC(50)) and the MIC(90) of GW 773546, a novel macrolide, were 1.0 and 2.0 microg/ml, respectively, for 223 beta-lactamase-positive, beta-lactamase-negative, and beta-lactamase-negative ampicillin-resistant Haemophilus influenzae strains. The MIC(50)s and MIC(90)s of GW 708408, a second novel macrolide, and telithromycin, an established ketolide, were 2.0 and 4.0 microg/ml, respectively, while the MIC(50) and MIC(90) of azithromycin were 1.0 and 2.0 microg/ml, respectively. The MIC(50) and MIC(90) of erythromycin were 4.0 and 8.0 microg/ml, respectively; and those of clarithromycin were 4.0 and 16.0 microg/ml, respectively. All compounds except telithromycin were bactericidal (99.9% killing) against nine strains at two times the MIC after 24 h. Telithromycin was bactericidal against eight of the nine strains. In addition, both novel macrolides and telithromycin at two times the MIC showed 99% killing of all nine strains after 12 h and 90% killing of all strains after 6 h. After 24 h, all drugs were bactericidal against four to seven strains when they were tested at the MIC. Ten of 11 strains tested by multistep selection analysis yielded resistant clones after 14 to 43 passages with erythromycin. Azithromycin gave resistant clones of all strains after 20 to 50 passages, and clarithromycin gave resistant clones of 9 of 11 strains after 14 to 41 passages. By comparison, GW 708408 gave resistant clones of 9 of 11 strains after 14 to 44 passages, and GW 773546 gave resistant clones of 10 of 11 strains after 14 to 45 passages. Telithromycin gave resistant clones of 7 of 11 strains after 18 to 45 passages. Mutations mostly in the L22 and L4 ribosomal proteins and 23S rRNA were detected in resistant strains selected with all compounds, with alterations in the L22 protein predominating. Single-step resistance selection studies at the MIC yielded spontaneous resistant mutants at frequencies of 1.5 x 10(-9) to 2.2 x 10(-6) with GW 773546, 1.5 x 10(-9) to 6.0 x 10(-4) with GW 708408, and 7.1 x 10(-9) to 3.8 x 10(-4) with telithromycin, whereas the frequencies were 1.3 x 10(-9) to 6.0 x 10(-4) with erythromycin and azithromycin and 2.0 x 10(-9) to 2.0 x 10(-3) with clarithromycin. Alterations in the L22 protein (which were predominant) and the L4 protein were present in mutants selected by the single-step selection process. The postantibiotic effects of GW 773546, GW 708408, and telithromycin for seven H. influenzae strains were 6.6 h (range, 5.2 to 8.8 h), 4.7 h (range, 2.6 to 6.9 h), and 6.4 h (range, 3.8 to 9.7 h), respectively. The results of in vitro studies obtained with both novel macrolides were similar to those obtained with telithromycin and better than those obtained with older macrolides.

Anti-Bacterial Agents↗
PubMed2005

Effect of CYP3A1(23) induction on clarithromycin pharmacokinetics in rats with diabetes mellitus.

After intravenous and oral administration of clarithromycin at a dose of 20 mg/kg of body weight to rats with diabetes mellitus induced by alloxan (DMIA) and diabetes mellitus induced by streptozotocin (DMIS), the area under the curve values were significantly smaller than those of respective control rats. The in vitro intrinsic clearance values for the disappearance of clarithromycin were significantly faster in both rats with DMIA and rats with DMIS than in control rats. The above data suggested that metabolism of clarithromycin increased in both types of diabetic rat due to an increase in the expression and mRNA level of CYP3A1(23) in the rats.

Alloxan↗
PubMed2003

Effect of clarithromycin on inflammatory markers in patients with atherosclerosis.

Atherosclerosis can to a certain extent be regarded as an inflammatory disease. Also, inflammatory markers may provide information about cardiovascular risk. Whether macrolide antibiotics, especially clarithromycin, have an anti-inflammatory effect in patients with atherosclerosis is not exactly known. To study this phenomenon, a placebo-controlled, randomized, double-blind study was performed. A total of 231 patients with documented coronary artery disease received a daily dose of either 500 mg of slow-release clarithromycin or placebo until the day of surgery. Levels of inflammatory markers (C-reactive protein, interleukin-2 receptor [IL-2R], IL-6, IL-8, and tumor necrosis factor alpha) were assessed during the preoperative outpatient visit, on the day of surgery, and 8 weeks after surgery. Also, changes in the levels of inflammatory markers between visits were determined by delta calculations. Baseline patient characteristics were balanced between the two treatment groups: the average age was 66 years (standard deviation [SD] = 9.0), 79% of the patients were male, and the average number of tablets used was 16 (SD = 9.3). The inflammatory markers of the groups as well as the delta calculations were not significantly changed. Treatment with clarithromycin did not influence the inflammatory markers in patients with atherosclerosis.

Aged↗
PubMed1988

Variability of clarithromycin and erythromycin susceptibility tests with Haemophilus influenzae in four different broth media and correlation with the standard disk diffusion test.

Four separate laboratories performed antimicrobial susceptibility tests with 40 Haemophilus influenzae isolates, each tested in triplicate. Erythromycin and a new macrolide, clarithromycin (A-56268; TE-031), were tested by the disk diffusion method, by the agar dilution procedure in two different media, and by broth microdilution tests in four different media. Erythromycin MICs for 90% of the strains were 16 micrograms/ml in Mueller-Hinton broth with 3% lysed horse blood and NAD, 4.0 micrograms/ml in hemophilus test medium, and 2.0 micrograms/ml in supplemented Schaedler broth or in the fastidious broth medium from Beckman Instruments, Inc. Clarithromycin MICs were generally 1 doubling dilution greater than erythromycin MICs in each of the media. Erythromycin disk tests corresponded best with MICs determined in the fastidious broth medium. In that same medium, clarithromycin MICs were about 1 doubling dilution greater than what would be expected from the results of disk tests. Because there were fewer growth failures, hemophilus test medium is recommended for microdilution tests with H. influenzae. Incubation of all tests for a full 24 h without an increased CO2 atmosphere was needed to achieve maximal precision of the tests. Interlaboratory and intralaboratory reproducibility of all tests was satisfactory.

Clarithromycin↗
PubMed1996

Metronidazole and clarithromycin resistance in Helicobacter pylori determined by measuring MICs of antimicrobial agents in color indicator egg yolk agar in a miniwell format. The Gastrointestinal Physiology Working Group of Universidad Peruana Cayetano Heredia and the Johns Hopkins University.

Resistance of Helicobacter pylori to metronidazole often causes failure of commonly used combination drug treatment regimens. We determined the MICs of metronidazole and clarithromycin against 18 H. pylori strains from Peru using tetrazolium egg yolk (TEY) agar. The MIC results obtained by agar dilution with petri dishes were compared with the results found through a miniwell format. The results of the two protocols for measuring drug susceptibility differed by no more than 1 dilution in all cases. On TEY agar, bright-red H. pylori colonies were easy to identify against a yellow background. Sixty-one percent (11 of 18) of the strains were resistant to metronidazole (MIC, > or = 4 micrograms/ml) and 50% (9 of 18) were resistant to clarithromycin (MIC, > or = 0.125 micrograms/ml), whereas none (0 of 5) of the strains tested were resistant to tetracycline (MIC, > or = 1 micrograms/ml). Thus, the prevalence of metronidazole and clarithromycin resistance in Peru is higher than that in developed regions of the world. The miniwell plate with TEY agar allows easy H. pylori colony identification, requires about one-third less of the costly medium necessary for petri dish assaying, conserves space, and yields MICs equivalent to those with agar dilution in petri dishes.

Agar↗
PubMed2001

Influence of variations in test methods on susceptibility of Haemophilus influenzae to ampicillin, azithromycin, clarithromycin, and telithromycin.

The National Committee for Clinical Laboratory Standards standard broth microdilution method for testing the susceptibility of Haemophilus influenzae to ampicillin, azithromycin, clarithromycin, and telithromycin was evaluated by altering one variable at a time. Variables that were tested included age of colony for inoculum preparation, inoculum density, test medium, incubation atmosphere, and incubation time. For the macrolide, azalide, and ketolide agents, incubation in 5 to 7% CO(2) most significantly affected the MICs, producing nearly twofold increases for clarithromycin and telithromycin and a greater than threefold increase for azithromycin. For ampicillin, a 10-fold increase in inoculum density increased the geometric mean MICs for beta-lactamase-negative strains from 1. 50 to 2.45 microg/ml. In addition, 206 H. influenzae strains were tested for their susceptibilities to the same drugs by the broth microdilution tests in two media, as well as by agar dilution tests, disk diffusion tests, and Etests, on six different agar media. The three standard methods with Haemophilus test medium (HTM) compared favorably with each other except for a high minor discrepancy rate (27%) by the disk diffusion test with ampicillin and clarithromycin. Agar dilution test MICs on the five comparative media were generally higher than those on HTM agar but were only rarely more than one twofold concentration higher. Etest MICs of azithromycin and telithromycin were more than twofold higher than agar dilution and broth microdilution MICs on HTM; ampicillin Etest MICs were nearly twofold lower. The use of media other than HTM agar appears to have a minimal effect on susceptibility test results for the ketolide, azalide, or macrolide drugs that we tested against H. influenzae.

Ampicillin↗
PubMed2001

Clarithromycin-susceptible and -resistant Helicobacter pylori isolates with identical randomly amplified polymorphic DNA-PCR genotypes cultured from single gastric biopsy specimens prior to antibiotic therapy.

Of the Helicobacter pylori populations from 976 patients, six contained clarithromycin-resistant as well as -susceptible colonies. In each heterogeneous H. pylori population, resistant H. pylori colonies harbored identical 23S ribosomal DNA (rDNA) mutations associated with clarithromycin resistance, while the susceptible H. pylori colonies all had wild-type 23S rDNA. The resistant and susceptible colonies of each of the heterogeneous H. pylori populations had identical randomly amplified polymorphic DNA-PCR genotypes. In conclusion, evaluation of antimicrobial susceptibility can be misinterpreted if only a single colony from the primary H. pylori population is used to test for clarithromycin susceptibility.

Anti-Bacterial Agents↗