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PubMed1998

Factors affecting solubility and penetration of clarithromycin through gastric mucus.

BACKGROUND: Factors influencing the pharmacokinetics of clarithromycin in gastric mucus are poorly defined. AIM: To determine: (i) whether the clinical formulation of clarithromycin (Biaxin granules and powdered Biaxin tablets) affects the water solvency of the antibiotic or changes the barrier properties of pig gastric mucus (PGM), thereby influencing the penetration of clarithromycin through the gastric mucus layer; and (ii) whether topically active anti-ulcer agents affect clarithromycin penetration through gastric mucus. METHODS: Solubility of clarithromycin in aqueous solution was studied at pH 7. PGM viscosities were determined using a falling ball microviscometer. Permeability of clarithromycin through PGM with and without added anti-ulcer drugs at pH 7 was monitored using a microfiltration device and an agar diffusion bioassay. RESULTS: Clarithromycin showed the poorest solubility at pH 7, whereas both Biaxin formulations demonstrated identical solubility of their antibiotic ingredient. Clarithromycin and both Biaxin formulations markedly increased mucin viscosity over the pH range 2-7. PGM markedly retarded the penetration of clarithromycin: unformulated clarithromycin and Biaxin tablets penetrated more rapidly through mucus than Biaxin granules. Pre-treatment of PGM with aluminium-magnesium-containing antacids (Riopan and Talcid preparations) decreased the rate of clarithromycin penetration, whereas Carafate and Peptobismol had no significant effect on mucus penetration of clarithromycin. CONCLUSIONS: The availability of clarithromycin in gastric mucus is significantly influenced by its clinical formulation, which affects its solubility as well as the viscous properties of mucus. Pulverized Biaxin tablets provide better local distribution of clarithromycin in mucus than Biaxin granules. Pre-treatment of mucus with anti-ulcer medications does not increase the penetration of clarithromycin through mucus.

Absorption↗
PubMed1995

In vitro and ex vivo activities of antimicrobial agents used in combination with clarithromycin, with or without amikacin, against Mycobacterium avium.

MICs of clarithromycin, amikacin, isoniazid, rifabutin, ciprofloxacin, sparfloxacin, ethambutol, and clofazimine were determined for six isolates of Mycobacterium avium complex (MAC) from AIDS patients both by the radiometric method and by an ex vivo model of infection in human macrophages. The median MICs in macrophages were similar or slightly lower than values found in broth, except for amikacin, which had slightly higher MICs inside the cells. Combinations of clarithromycin with other antimicrobial agents showed that clarithromycin-clofazimine and clarithromycin-rifabutin were synergistic on five of six strains while clarithromycin-amikacin and clarithromycin-isoniazid were antagonistic on one and two strains, respectively. The addition of amikacin made the combinations of clarithromycin-clofazimine and clarithromycin-ethambutol synergistic against all the MAC strains. In the macrophage model, the combination of clarithromycin-clofazimine (mean survival, 21%) and clarithromycin-rifabutin (mean survival, 29%) showed a strong reduction in viable counts compared with single drugs, while clarithromycin-amikacin was less active than single drugs alone. In general, the addition of amikacin did not improve the activity of the combinations, except for clarithromycin-isoniazid-amikacin (mean survival, 19%), which was significantly more active than either clarithromycin-isoniazid or clarithromycin-amikacin. The use of the macrophage model can suggest new combinations of antimicrobial agents with anti-MAC activity which, on the basis of their in vitro effectiveness, would probably be disregarded for assay in animal models.

Amikacin↗
PubMed1998

Molecular mechanisms of clarithromycin resistance in Helicobacter pylori.

Combination antibiotic therapy for Helicobacter pylori has now become the standard means of treating peptic ulcer diseases. Clarithromycin is a newly adopted antibiotic for H. pylori eradication. However, resistance to clarithromycin reduces the efficacy of clarithromycin-containing regimens. We explored mechanisms of clarithromycin resistance by evaluating H. pylori for macrolide resistance mechanisms reported in H. pylori and other bacteria. Degenerate polymerase chain reaction analysis of the H. pylori genome failed to yield products homologous to methylase, a drug inactivation enzyme, or efflux pumps. Clarithromycin selection in Escherichia coliNM522, transformed with an expression library that was constructed with genomic DNA from a clarithromycin-resistant strain of H. pylori, revealed six clones that conferred clarithromycin resistance consistently after retransformation. Southern hybridization and DNA sequencing revealed that four of the six clones contained the same locus. Comparison of DNA and amino acid sequences showed that the 1.3-kb DNA fragment had significant homology to the 3-oxoadipate CoA-transferase subunit A (yxjD) and subunit B (yxjE) of Bacillus subtilis. However, the clarithromycin inactivation assay and knockout mutation analysis showed that the gene increased clarithromycin resistance in E. coli, but not in H. pylori. In contrast, sequencing of the 23S rRNA gene in six clarithromycin-resistant H. pylori clinical isolates revealed an A to G transitional mutation at position 2515 of the 23S rRNA gene in all isolates. Natural transformation with the 23S rRNA gene from resistant strains conferred clarithromycin resistance in clarithromycin-sensitive strains. We conclude that the 23S rRNA mutation is sufficient to confer clarithromycin resistance and that it is the major mechanism of clarithromycin resistance in H. pylori.

Amino Acid Sequence↗
PubMed2001

Pharmacokinetics and tolerability of extended-release clarithromycin.

BACKGROUND: Clarithromycin is a semisynthetic macrolide that exhibits broad-spectrum activity against gram-positive, gram-negative, and atypical respiratory tract and skin/skin structure pathogens, Mycobacterium species, and Helicobacter pylori. It is indicated for the treatment of a wide variety of respiratory and dermatologic infections in children and adults as well as prophylaxis and treatment of Mycobacterium avium complex infection and peptic ulcers due to H. pylori. OBJECTIVE: In this article, we review the results of 3 studies of the steady-state pharmacokinetic profiles of clarithromycin and 14(R)-hydroxy-clarithromycin after multiple oral once-daily doses of 500-mg extended-release (ER) clarithromycin tablets. We also review the drug tolerability in 2 phase III comparative clinical trials of immediate-release (IR) and ER clarithromycin conducted in adults with acute maxillary sinusitis (AMS) and acute exacerbation of chronic bronchitis (AECB). METHODS: In the 3 pharmacokinetic studies, multiple-dose regimens of clarithromycin IR (one 250-mg or 500-mg tablet twice daily) and clarithromycin ER (one or two 500-mg tablets once daily), administered to healthy male and female volunteers, were evaluated. The effect of administration in nonfasting versus fasting conditions was assessed as well. Tolerability information was collected from each adult patient enrolled in phase III efficacy studies conducted to support the application for US Food and Drug Administration approval for the treatment of AMS and AECB. Regimens evaluated were 500 mg IR clarithromycin tablets twice daily or 1000 mg (2 x 500 mg) ER clarithromycin tablets once daily for 7 days (AECB) or 14 days (AMS). RESULTS: Bioavailability of the ER clarithromyin tablet administered with food was equivalent to that of the reference IR tablet, based on area under the plasma concentration-time curve (AUC) for both parent compound and active metabolite. The bioavailability of the ER tablet was 30% lower (based on clarithromycin AUC) when administered under fasting versus nonfasting conditions. Compared with the IR tablet, administration of the ER tablet resulted in significantly lower (P < 0.05) clarithromycin peak plasma concentration (Cmax), delayed time to Cmax, and lower degree of concentration fluctuation, confirming its in vivo extended-release characteristics. The most frequently reported adverse events (AEs) in the phase III clinical trials were diarrhea, abnormal taste, and nausea and were generally mild or moderate. The incidence of AEs was comparable for the 2 formulations. The severity of gastrointestinal AEs was significantly less for the ER formulation than for the IR formulation (P = 0.018), as was the frequency of premature study discontinuation due to gastrointestinal AEs or abnormal taste (P = 0.004). CONCLUSIONS: The results from the 3 pharmacokinetic studies reviewed demonstrate the bioequivalence of the ER and IR formulations and support the use of this clarithromycin ER formulation in a once-daily dosing regimen in phase III clinical trials. The ER tablet should be taken with food to maximize bioavailability. The results of 2 phase III comparative clinical efficacy and safety trials of clarithromycin ER tablets versus IR tablets in AMS and AECB confirm the good tolerability of the ER formulation.

Adolescent↗
PubMed2002

Dose-dependent inhibition of CYP3A activity by clarithromycin during Helicobacter pylori eradication therapy assessed by changes in plasma lansoprazole levels and partial cortisol clearance to 6beta-hydroxycortisol.

OBJECTIVE: A 7-day triple therapy with lansoprazole, amoxicillin (INN, amoxicilline), and clarithromycin is widely used for eradication of Helicobacter pylori. Because clarithromycin is a potent inhibitor of cytochrome P450 (CYP) 3A, we investigated whether the standard triple therapy with clarithromycin would elicit clinically relevant CYP3A inhibition and alter CYP3A-mediated lansoprazole disposition in H pylori-positive patients. METHODS: Twenty H pylori-positive patients with peptic ulcer disease were randomly assigned to 2 groups: One group received 200 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days; the other group received 400 mg clarithromycin, 30 mg lansoprazole, and 750 mg amoxicillin at 8 am and 8 pm for 7 days. Ten healthy control subjects received 30 mg lansoprazole and 750 mg amoxicillin at 8 am and 8 pm for 7 days but did not receive clarithromycin. Urine samples were collected for 3 hours (from 8 am to 11 am) for urinary 6beta-hydroxycortisol and cortisol assay, and midpoint (at 9:30 am) plasma samples for cortisol assay were obtained from all participants before the drug therapy (day 0) and on day 7. In vivo CYP3A activity was assessed by the partial cortisol clearance by means of the formation of 6beta-hydroxycortisol (CL(cortisol-->6beta-hydroxycortisol)) and the urinary 6beta-hydroxycortisol/cortisol ratio. Additional plasma samples for lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone assay were obtained at 11 am on day 7. RESULTS: The groups of patients given 400 and 800 mg/day clarithromycin for H pylori eradication therapy showed 39% (from 2.20 +/- 1.29 to 1.35 +/- 0.88 mL/min [day 0 versus 7, mean +/- SD]; P <.05) and 68% (2.40 +/- 1.22 to 0.76 +/- 0.51 mL/min; P <.05) reductions in CL(cortisol-->6beta-hydroxycortisol), respectively. In contrast, the control subjects given lansoprazole and amoxicillin without clarithromycin showed no significant changes in CL(cortisol-->6beta-hydroxycortisol). The urinary 6beta-hydroxycortisol/cortisol ratio also decreased significantly (P <.05) in the patient groups but not in the control subjects. The mean 3-hour plasma lansoprazole levels elevated in proportion to the doses of clarithromycin: 385 +/- 338 ng/mL for the control subjects, 696 +/- 797 ng/mL for the H pylori-positive patients given 400 mg/day clarithromycin, and 947 +/- 806 ng/mL for the H pylori-positive patients given 800 mg/day clarithromycin (P <.05 versus the control subjects). No significant differences were observed among the groups in the mean plasma ratios of 5-hydroxylansoprazole or lansoprazole sulfone to lansoprazole. CONCLUSIONS: The 7-day H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole may elicit substantial inhibition of in vivo CYP3A activity. Although resultant elevations in plasma lansoprazole concentrations may be beneficial for H pylori eradication, caution must be exercised for possible drug interaction with a concomitantly administered CYP3A substrate (s) in patients undergoing H pylori eradication therapy with clarithromycin, amoxicillin, and lansoprazole.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1996

Clarithromycin resistance in Helicobacter pylori: prevalence in untreated dyspeptic patients and stability in vitro.

Susceptibilities to clarithromycin and metronidazole of 444 Helicobacter pylori isolates cultured from antral biopsies of 444 dyspeptic patients were determined by disc diffusion tests (15 mu g disc for clarithromycin, 5 mu g disc for metronidazole). Susceptibility of 46 of these isolates to erythromycin (5 mu g disc) was also tested. Minimal inhibitory concentrations (MICs) of clarithromycin for 42 selected isolates were determined by a plate dilution method. A zone diameter of 30 mm was defined as a 'cut-off' size differentiating susceptibility and resistance of the organism to clarithromycin, by comparing results obtained with the two methods. Of the 444 isolates, 424 (95.5%) were highly sensitive to clarithromycin, with zone diameters ranging from 30 to 98 mm. Twenty isolates (4.5%) were defined as resistant to clarithromycin, with zone diameters ranging between 6 and 28 mm. The incidence of clarithromycin resistance was similar in men and women and in different age groups, and was not significantly different between patients with peptic ulcer and non-ulcer dyspepsia. Among the 444 isolates, 168 (37.8%) were metronidazole resistant. There was cross resistance between clarithromycin and erythromycin, but not between clarithromycin and metronidazole. Stability of clarithromycin resistance was evaluated by the disc diffusion test and confirmed by the plate dilution method. Among the 20 clarithromycin-resistant isolates, nine (45%) reverted to be sensitive after 25 subcultures on drug-free agar. The findings in this study indicate that the incidence of clarithromycin-resistant H. pylori in untreated dyspeptic patients is low. Cross-resistance occurs between macrolides and resistance to clarithromycin in some strains is reversible.

Adult↗
PubMed1996

Ranitidine bismuth citrate plus clarithromycin is effective for healing duodenal ulcers, eradicating H. pylori and reducing ulcer recurrence. RBC H. pylori Study Group.

AIM: To compare the efficacy of the coadministration of ranitidine bismuth citrate plus the antibiotic clarithromycin, with ranitidine bismuth citrate alone or clarithromycin alone for the healing of duodenal ulcers, eradication of H. pylori and the reduction of ulcer recurrence. METHODS: This two-phase, randomized, double-blind, placebo-controlled, multicentre study consisted of a 4-week treatment phase followed by a 24-week post-treatment observation phase. Patients with an active duodenal ulcer were treated with either ranitidine bismuth citrate 400 mg b.d. for 4 weeks plus clarithromycin 500 mg t.d.s. for the first 2 weeks; ranitidine bismuth citrate 400 mg b.d. for 4 weeks plus placebo t.d.s. for first 2 weeks; placebo b.d. for 4 weeks plus clarithromycin 500 mg t.d.s. for the first 2 weeks; or placebo b.d. for 4 weeks plus placebo t.d.s. for the first 2 weeks. RESULTS: Ulcer healing rates after 4 weeks of treatment were highest with ranitidine bismuth citrate plus clarithromycin (82%) followed by ranitidine bismuth citrate alone (74%; P = 0.373), clarithromycin alone (73%; P = 0.33) and placebo (52%; P = 0.007). Ranitidine bismuth citrate plus clarithromycin provided significantly better ulcer symptom relief compared with clarithromycin alone or placebo (P < 0.05). The coadministration of ranitidine bismuth citrate plus clarithromycin resulted in significantly higher H. pylori eradication rates 4 weeks post-treatment (82%) than did treatment with either ranitidine bismuth citrate alone (0%; P < 0.001), clarithromycin alone (36%; P = 0.008) or placebo (0%; P < 0.001). Ulcer recurrence rates 24 weeks post-treatment were lower following treatment with ranitidine bismuth citrate plus clarithromycin (21%) compared with ranitidine bismuth citrate alone (86%; P < 0.001), clarithromycin alone (40%; P = 0.062) or placebo (88%; P = 0.006). All treatments were well tolerated. CONCLUSIONS: The coadministration of ranitidine bismuth citrate plus clarithromycin is a simple, well-tolerated and effective treatment for active H. pylori-associated duodenal ulcer disease. This treatment regimen effectively heals duodenal ulcers, provides effective symptom relief, eradicates H. pylori infection and reduces the rate of ulcer recurrence. The eradication of H. pylori infection in patients with recently healed duodenal ulcers is associated with a significant reduction in the rate of ulcer recurrence.

Adolescent↗
PubMed1995

Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state.

This study was conducted to determine (i) the effect of omeprazole on steady-state concentrations of clarithromycin and 14-(R)-hydroxyclarithromycin in plasma and gastric mucosa, (ii) the effect of clarithromycin on steady-state concentrations of omeprazole in plasma, and (iii) the effect of clarithromycin on the suppression of gastric acid secretion by omeprazole. Twenty healthy, Helicobacter pylori-negative male subjects completed this three-period, double-blind, randomized crossover study. In period 1, all subjects received 40 mg of omeprazole each morning for 6 days. Twenty-four-hour gastric pH monitoring took place on days -1 and 6. Pharmacokinetic sampling took place on day 6. In periods 2 and 3, subjects were randomly assigned to receive either 40 mg of omeprazole or omeprazole placebo daily for 6 days plus clarithromycin (500 mg) every 8 h for 5 days with a single 500-mg dose on day 6. Gastric tissue and mucus samples were obtained via endoscopy on day 5. Gastric pH monitoring and pharmacokinetic sampling took place on day 6. Two-week washout intervals separated the three study periods. Clarithromycin increased mean omeprazole area under the concentration-time curve from 0 to 24 h from 3.3 +/- 2.0 to 6.3 +/- 4.5 micrograms.h/ml (P < 0.05) and harmonic mean half-life from 1.2 to 1.6 h (P < 0.05) but did not significantly alter the effect of omeprazole on gastric pH. Mean clarithromycin area under the concentration-time curve from 0 to 8 h increased from 22.9 +/- 5.5 (placebo) to 26.4 +/- 5.7 micrograms.h/ml (omeprazole) (P < 0.05) when clarithromycin was administered with omeprazole. Analysis of variance revealed that mean concentrations of clarithromycin in tissue and mucus were statistically significantly higher when clarithromycin was given with omeprazole than when clarithromycin was given with placebo (P <0.001). Mean maximum observed concentrations of clarithromycin in the gastric fundus increased from 20.8 +/- 7.6 (placebo) to 24.3 +/- 6.4 micrograms/g (omeprazole), and those in the gastric mucous from 4.2 +/- 7.7 placebo to 39.3 +/- 32.8 micrograms/g (omeprazole). Similar increases were observed for the 14-(R)-hydroxyclarithromycin. These results show that omeprazole increases concentrations of clarithromycin in gastric tissue and mucus and may provide a mechanism for synergy between clarithromycin ad omeprazole that explains the excellent eradication of H. pylori seen in clinical trials.

Adolescent↗
PubMed1999

Clinical pharmacokinetics of clarithromycin.

Clarithromycin is a macrolide antibacterial that differs in chemical structure from erythromycin by the methylation of the hydroxyl group at position 6 on the lactone ring. The pharmacokinetic advantages that clarithromycin has over erythromycin include increased oral bioavailability (52 to 55%), increased plasma concentrations (mean maximum concentrations ranged from 1.01 to 1.52 mg/L and 2.41 to 2.85 mg/L after multiple 250 and 500 mg doses, respectively), and a longer elimination half-life (3.3 to 4.9 hours) to allow twice daily administration. In addition, clarithromycin has extensive diffusion into saliva, sputum, lung tissue, epithelial lining fluid, alveolar macrophages, neutrophils, tonsils, nasal mucosa and middle ear fluid. Clarithromycin is primarily metabolised by cytochrome P450 (CYP) 3A isozymes and has an active metabolite, 14-hydroxyclarithromycin. The reported mean values of total body clearance and renal clearance in adults have ranged from 29.2 to 58.1 L/h and 6.7 to 12.8 L/h, respectively. In patients with severe renal impairment, increased plasma concentrations and a prolonged elimination half-life for clarithromycin and its metabolite have been reported. A dosage adjustment for clarithromycin should be considered in patients with a creatinine clearance < 1.8 L/h. The recommended goal for dosage regimens of clarithromycin is to ensure that the time that unbound drug concentrations in the blood remains above the minimum inhibitory concentration is at least 40 to 60% of the dosage interval. However, the concentrations and in vitro activity of 14-hydroxyclarithromycin must be considered for pathogens such as Haemophilus influenzae. In addition, clarithromycin achieves significantly higher drug concentrations in the epithelial lining fluid and alveolar macrophages, the potential sites of extracellular and intracellular respiratory tract pathogens, respectively. Further studies are needed to determine the importance of these concentrations of clarithromycin at the site of infection. Clarithromycin can increase the steady-state concentrations of drugs that are primarily depend upon CYP3A metabolism (e.g., astemidole, cisapride, pimozide, midazolam and triazolam). This can be clinically important for drugs that have a narrow therapeutic index, such as carbamazepine, cyclosporin, digoxin, theophylline and warfarin. Potent inhibitors of CYP3A (e.g., omeprazole and ritonavir) may also alter the metabolism of clarithromycin and its metabolites. Rifampicin (rifampin) and rifabutin are potent enzyme inducers and several small studies have suggested that these agents may significantly decrease serum clarithromycin concentrations. Overall, the pharmacokinetic and pharmacodynamic studies suggest that fewer serious drug interactions occur with clarithromycin compared with older macrolides such as erythromycin and troleandomycin.

Animals↗
PubMed1992

Clarithromycin. A review of its antimicrobial activity, pharmacokinetic properties and therapeutic potential.

Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of erythromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneumoniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies--chelonae and--abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the microbiologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated. The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including beta-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections. Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithromycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater tolerability, principally by inducing fewer gastrointestinal disturbances.(ABSTRACT TRUNCATED AT 400 WORDS)

Aged↗
PubMedDate not supplied

Effects of clarithromycin and its metabolites on the mixed function oxidase system in hepatic microsomes of rats.

Clarithromycin and its metabolites have been examined for their abilities to induce specific form(s) of cytochrome P-450 and metabolite complex formation in rats. Pretreatment of rats with clarithromycin,N-demethyl clarithromycin, clarithromycin N-oxide, and decladinosyl clarithromycin resulted in 48-75% decreases in the amount of 2C11 and 100-600% increases in the amount of 3A1. Clarithromycin and N-demethyl clarithromycin, but not decladinosyl clarithromycin, produced a metabolite complex with cytochrome P-450 in vivo. Activities of testosterone 2 beta- and 6 beta-hydroxylases were increased by administration of clarithromycin and N-demethyl clarithromycin when these activities were measured in the presence of ferricyanide, but not significant induction was observed when measured in the absence of ferricyanide. Clarithromycin N-oxide treatment resulted in the increase in hydroxylation of testosterone not only at the 2 beta- and 6 beta-positions (430 and 190%, respectively), but also at 7 alpha-position (60%), regardless of the presence or absence of ferricyanide. In vitro experiments with hepatic microsomes of dexamethasone-pretreated rats indicated that the metabolites that were modified at the tertiary amino group more efficiently produced the metabolite complex with cytochrome P-450 compared with the parent compound. In contrast, decladinosyl and hydroxylated metabolites had similar or lower capacities for metabolite complex formation than did the parent compound. Clarithromycin and its N-modified metabolites were able to induce 3A1 and form a metabolite complex with cytochrome P-450 in vivo in varying extents. Decladinosyl clarithromycin has a weak inducibility of 3A1 and did not form a metabolite complex with cytochrome P-450 in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Inhibition of human intestinal wall metabolism by macrolide antibiotics: effect of clarithromycin on cytochrome P450 3A4/5 activity and expression.

BACKGROUND: Clarithromycin increases both hepatic and intestinal availability of the selective cytochrome P450 (CYP) 3A probe midazolam. This study was designed to identify determinants of variability in the extent of intestinal wall CYP3A inhibition by clarithromycin, such as CYP3A5 genotype, and the mechanism of inhibition. METHODS: Ten healthy volunteers received 500 mg oral clarithromycin twice a day for 7 days. Before and after administration of clarithromycin, small-bowel mucosal biopsy specimens were obtained endoscopically. Intestinal CYP3A activity was determined from the rate of 1'-hydroxymidazolam and 4-hydroxymidazolam formation by incubation of small-bowel homogenate with midazolam (25 micromol/L) and NADPH for 5 minutes. Intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid was quantified by real-time reverse transcriptase-polymerase chain reaction. Intestinal CYP3A4 and CYP3A5 protein concentrations were determined by immunoblotting. Serum and homogenate concentrations of midazolam, clarithromycin, and metabolites were determined by liquid chromatography-mass spectrometry. CYP3A5 genotype was determined by real-time polymerase chain reaction. RESULTS: The formation of 1'-hydroxymidazolam (1.36 +/- 0.46 pmol . min(-1) . mg(-1) at baseline versus 0.35 +/- 0.16 pmol . min(-1) . mg(-1) after administration) and 4-hydroxymidazolam (0.39 +/- 0.12 pmol . min(-1) . mg(-1) at baseline versus 0.12 +/- 0.05 pmol . min(-1) . mg(-1) after administration) was significantly (P < .001) reduced after clarithromycin administration. Clarithromycin administration did not result in a significant change in intestinal CYP3A4 and CYP3A5 messenger ribonucleic acid and protein expression. All subjects had detectable serum clarithromycin concentrations after 7 days of clarithromycin (3.71 +/- 2.43 micromol/L). The mean concentration of clarithromycin in the intestinal biopsy homogenate was 1.2 +/- 0.7 nmol/L (range, 0.42-2.39 nmol/L). Compared with CYP3A5 nonexpressers, subjects with at least 1 CYP3A5*1 allele (CYP3A5 expressers) had greater inhibition of intestinal CYP3A activity after treatment with clarithromycin. There was a strong linear relationship between the decrease in intestinal CYP3A activity and baseline catalytic activity (R(2) = 0.9). CONCLUSION: Baseline intestinal activity of CYP3A4 was a key determinant of variability of the inhibitory effect of clarithromycin among individuals. CYP3A5*1 alleles were associated with greater baseline intestinal CYP3A activity and, therefore, greater extent of inhibition. The primary in vivo mechanism was not rapidly reversible competitive or irreversible inhibition but was likely formation of metabolic intermediate complexes.

Administration, Oral↗
PubMed1999

Sparfloxacin versus clarithromycin in the treatment of community-acquired pneumonia.

Community-acquired pneumonia remains a significant health concern despite the availability of effective antibiotics. This randomized, double-masked, double-dummy, multicenter comparative trial was undertaken to compare the efficacy and safety of sparfloxacin with those of clarithromycin in the treatment of community-acquired pneumonia. In 54 centers throughout the United States, 342 patients aged > or = 18 years with community-acquired pneumonia were enrolled in this trial. A total of 167 patients, 98 males and 69 females with a mean age of 51.0 years (range, 18-87), received a 400-mg loading dose of sparfloxacin on the first day, followed by 200 mg once daily for a total of 10 days. A total of 175 patients, 85 males and 90 females with a mean age of 51.3 years (range, 18-91), received clarithromycin 250 mg twice daily for 10 days. In the intent-to-treat population, 133 (79.6%) patients in the sparfloxacin group and 145 (82.9%) in the clarithromycin group were cured or improved (the 95% confidence interval [CI] for the differences in success rate between sparfloxacin and clarithromycin was -11.5% to 5.1%). Success rates for the per-protocol patients were 88.7% (133/150) in the sparfloxacin group and 88.9% (144/162) in the clarithromycin groups (95% CI, -7.2% to 6.8%). There were no significant differences in success rate between treatment groups based on age > or = 65 years. The overall bacteriologic response rates in the bacteriologically assessable population were 97.0% (64/66 isolates) in the sparfloxacin group and 91.4% (74/81 isolates) in the clarithromycin group. Recurrence occurred in 6.0% of per-protocol patients in the sparfloxacin group and 6.3% of patients in the clarithromycin group. The overall frequency of adverse events was 56.3% in the sparfloxacin group and 65.1% in the clarithromycin group. Gastrointestinal disturbances were the most common adverse event in both groups. Abnormal taste related to study drug was reported by 17 patients (9.7%) treated with clarithromycin, versus 3 patients (1.8%) treated with sparfloxacin (P = 0.002). Photosensitivity reactions were reported in 10 patients (6.0%) treated with sparfloxacin, versus 1 patient (0.6%) treated with clarithromycin (P = 0.002). QT-interval prolongation was documented in 4 patients (2.4%) in the sparfloxacin group and no patients in the clarithromycin group. Thus sparfloxacin was as well tolerated and as effective as clarithromycin in the treatment of community-acquired pneumonia.

Adult↗
PubMed2000

High prevalence of Helicobacter pylori infection with dual resistance to metronidazole and clarithromycin in Hong Kong.

BACKGROUND: Metronidazole resistance is a common problem in most Asian countries, and clarithromycin has been widely used in Hong Kong. AIM: To determine the prevalence of Helicobacter pylori strains resistant to metronidazole and clarithromycin in Hong Kong and to assess the effect on eradication rates. Also to determine the genetic mutation in relation to phenotypic divergence in clarithromycin-resistant strains. METHODS: H. pylori were cultured from gastric biopsies obtained from 87 patients during upper endoscopy. Minimal inhibitory concentrations of metronidazole and clarithromycin were determined by Etest and agar dilution methods. Mutations in clarithromycin-resistant strains were identified by polymerase chain reaction and restriction analysis. Random amplified polymorphic DNA fingerprinting was performed on clarithromycin-resistant and susceptible isolates. RESULTS: The prevalences of H. pylori strains resistant to metronidazole and clarithromycin were 49.4% and 10.8%, respectively, in Hong Kong. Dual resistance to metronidazole and clarithromycin were found in 7. 2% of patients. The agreement between E-test and agar dilution methods was determined by error-rate bound analysis as 95.4% for metronidazole and 100% for clarithromycin. Dual resistant strains reduced the eradication rate to 66.7%. Among clarithromycin-resistant strains tested, all were due to A2144G point mutation in 23S rRNA gene. Random amplified polymorphic DNA fingerprinting suggested various phenotypically mixed populations. CONCLUSIONS: The prevalence of metronidazole-resistant H. pylori strains remained static whilst the prevalence of clarithromycin-resistant strains was not rare in Hong Kong. An alarming 7.2% of patients were resistant to both the antimicrobials, which had a definite impact on treatment success. All cases of resistance to clarithromycin were due to A2144G mutation in 23S rRNA of H. pylori.

Adolescent↗
PubMed1999

Twice-daily versus thrice-daily clarithromycin in combination with ranitidine bismuth citrate in the eradication of Helicobacter pylori.

BACKGROUND: Ranitidine bismuth citrate (RBC), 400 mg bid for 4 weeks, plus clarithromycin, 500 mg tid, is a regimen approved by the US Food and Drug Administration for the eradication of Helicobacter pylori in patients with duodenal ulcers. Proof that the clarithromycin portion of the regimen could be given twice daily without loss of efficacy would reduce cost and improve patient compliance. The objective of this study was to compare the H. pylori eradication rates in patients who had duodenal ulcer and were randomly assigned to 4 weeks of treatment with RBC, 400 mg bid, in conjunction with 2 weeks of therapy with either clarithromycin, 500 mg tid, or clarithromycin, 500 mg bid. PATIENTS AND METHODS: Patients who had a duodenal ulcer and were H. pylori-positive by at least two tests were randomly assigned to (1) RBC, 400 mg bid for 4 weeks, plus clarithromycin, 500 mg tid for 2 weeks, or (2) RBC, 400 mg bid for 4 weeks, plus clarithromycin, 500 mg bid for 2 weeks. H. pylori eradication was assessed 4 weeks after completion of RBC plus clarithromycin. RESULTS: Three hundred eighty-three patients from 78 centers had a duodenal ulcer and were H. pylori-positive. The modified intent-to-treat (MITT) and the per-protocol (PP) eradication rates were statistically equivalent between the twice-daily (65% MITT, 74% PP) and thrice-daily (63% MITT, 73% PP) clarithromycin treatment regimens. Incidence and types of adverse events did not differ between the two groups. CONCLUSIONS: For eradicating H. pylori in patients with duodenal ulcer, clarithromycin, 500 mg bid for 2 weeks, with RBC, 400 mg bid for 4 weeks, is equivalent to clarithromycin, 500 mg tid with RBC. The potential enhancement of patient compliance, reduced cost of clarithromycin, and equivalent efficacy would support the use of twice-daily clarithromycin in triple-therapy regimens with RBC.

Adult↗
PubMed1991

The in-vitro and disc susceptibility testing of clarithromycin and its 14-hydroxy metabolite.

The in-vitro antibacterial activity of clarithromycin, its 14-hydroxy metabolite and a combination containing clarithromycin and the 14-hydroxy metabolite in a ratio of three parts of the former to one part of the latter were compared with erythromycin by determination of MICs. Disc susceptibility testing was also performed using discs containing 6 micrograms clarithromycin, 6 micrograms clarithromycin with 2 micrograms 14-hydroxy-clarithromycin, 3 micrograms clarithromycin and 3 micrograms clarithromycin with 1 microgram 14-hydroxy-clarithromycin. This was to determine a suitable disc content and minimum zone diameter to distinguish between sensitive and resistant strains using a breakpoint of 4 mg/l clarithromycin. Clarithromycin showed similar activity to erythromycin against Streptococcus pneumoniae and Haemophilus influenzae, although the 14-hydroxy metabolite was more active against H. influenzae. The clarithromycin/14-hydroxy metabolite combination was most active against beta-haemolytic streptococci (Groups A-C) (mode MIC 0.06 mg/l). The parent compound and the combination were similarly active against Staphylococcus aureus (MIC50 0.12 mg/l). Branhamella catarrhalis was more susceptible to clarithromycin (MIC90 0.06) than to erythromycin (MIC90 0.25 mg/l). Activities of all compounds against S. epidermidis and enterococci were similar but against Neisseria species erythromycin was the more active compound. The 6 micrograms clarithromycin disc strength was found to give the most consistent results for all isolates. Using a breakpoint of 4 mg/l, minimum zone diameters indicative of sensitivity were as follows: 16 mm for staphylococci, 17 mm for respiratory pathogens and 11 mm for streptococci and Neisseria spp.

Bacteria↗
PubMed1998

Molecular basis of clarithromycin activity against Mycobacterium avium and Mycobacterium smegmatis.

Clarithromycin, the 6-O-methyl derivative of erythromycin, is approved for treatment of Mycobacterium avium infections and for prophylaxis in patients at risk. Since clarithromycin is more active against mycobacteria than the parent compound, erythromycin, we evaluated the interaction of erythromycin and clarithromycin with cells and ribosomes isolated from M. avium and Mycobacterium smegmatis. The MIC of clarithromycin was 32 and 64 times lower than that of erythromycin for M. smegmatis and M. avium, respectively. The cellular uptake rate for clarithromycin was two- to five-fold faster than for erythromycin, and cell-associated clarithromycin reached a plateau two-fold higher than that of erythromycin after 3 h. Energy was not required for uptake. Fractionation of cell-associated clarithromycin yielded 12% in the walls, 21% bound to ribosomes, with the remainder being lost during work-up. In addition, three- to six-fold more clarithromycin was associated with the isolated cell integument compared with erythromycin. The Kd for clarithromycin binding to ribosomes was 2.9- and 3.5-fold tighter for M. smegmatis and M. avium, respectively, than for erythromycin, due mainly to a slower off-rate. The log partition coefficients of the non-ionized form (log Pu) for clarithromycin and erythromycin were 3.24 and 2.92, respectively. Thus clarithromycin is more hydrophobic than erythromycin. This would favour more rapid diffusion within and across hydrophobic regions of the cell integument, since once a solute saturates a membrane the net flux across the membrane must equal the net flux within the membrane as dictated by diffusion. We conclude that the lower MIC of clarithromycin for M. avium and M. smegmatis is due to a combination of increased cellular uptake, the major factor, possibly through a peripheral hydrophobic layer, and increased binding affinity to ribosomes.

Anti-Bacterial Agents↗
PubMed2004

Two dosages of clarithromycin for five days, amoxicillin/clavulanate for five days or penicillin V for ten days in acute group A streptococcal tonsillopharyngitis.

BACKGROUND: Short course antimicrobial therapy is suggested for group A streptococcal tonsillopharyngitis. METHODS: The bacteriologic and clinical efficacies of clarithromycin [30 or 15 mg/kg/day twice daily (b.i.d.)] or amoxicillin/clavulanate (43.8/6.2 mg/kg/day b.i.d.) for 5 days or penicillin V (30 mg/kg/day 3 times a day) for 10 days were compared. In a randomized, open label, parallel group, multicenter study, 626 children (2-16 years old) with tonsillopharyngitis were enrolled; 537 were evaluable for efficacy. Follow-up evaluations were performed at 4-8 and 21-28 days after therapy. RESULTS: At enrollment, 26% of the Streptococcus pyogenes isolates were clarithromycin-nonsusceptible. All regimens had an apparently similar clinical efficacy. The long term S. pyogenes eradication rates were 102 of 123 (83%) with amoxicillin/clavulanate and 88 of 114 (77%) with penicillin V. In the 30- and 15-mg/kg/day clarithromycin groups, eradication occurred in 71 of 86 (83%) and 59 of 80 (74%) of the clarithromycin-susceptible isolates (P = 0.33), and in 4 of 28 (14%) and 5 of 26 (19%) of the clarithromycin-resistant isolates, respectively (clarithromycin-susceptible versus -resistant, P < 0.0001). Both clarithromycin dosages were well-tolerated. CONCLUSIONS: In group A streptococcal tonsillopharyngitis, 5 days of clarithromycin or amoxicillin/clavulanate treatment had clinical efficacy comparable with that of 10 days of penicillin V treatment; however, amoxicillin/clavulanate and penicillin V were bacteriologically more effective than clarithromycin because of its failure to eradicate the clarithromycin-resistant S. pyogenes isolates. The 5-day clarithromycin regimens are not recommended for treatment of streptococcal tonsillopharyngitis in areas where in vitro resistance of group A streptococci to clarithromycin is common.

Acute Disease↗