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PubMed2000

Ranitidine bismuth citrate can help to overcome Helicobacter pylori resistance to clarithromycin in vivo.

BACKGROUND: Helicobacter pylori eradication usually fails when clarithromycin is used against resistant strains. OBJECTIVE: The objective of this study was to test whether the apparent synergy found in vitro between ranitidine bismuth citrate (RBC) and clarithromycin also exists in vivo against resistant strains. METHODS: H. pylori was cultured and clarithromycin susceptibility was determined before and after treatment, from duodenal ulcer patients receiving RBC and clarithromycin or omeprazole and clarithromycin for 2 weeks in a multicenter randomized clinical trial. RESULTS: The overall eradication rate was 88.7% in the RBC group (71 patients) and 52.7% in the omeprazole group (74 patients). The demographic characteristics of the two groups were not different. Clarithromycin-resistant strains were isolated in 22 cases (15.1%). A difference between the eradication rates of susceptible and resistant strains was found in the omeprazole group but not in the RBC group. After treatment, resistance to clarithromycin developed in three of the seven strains (42.3%) cultured from the patients of the RBC group, compared with 11 of the 26 strains (42%) of the omeprazole group. That is, clarithromycin-resistant strains were found in 6% and 27% in the RBC group and the omeprazole group, respectively, on considering the global results. CONCLUSION: A synergy between RBC and clarithromycin may exist in vivo and, while clarithromycin resistance is increasing, it is an argument for using RBC in triple therapies.

Adult↗
PubMed2002

Pharmacokinetic evaluation of high pulmonary disposition of clarithromycin after systemic administration.

1. The distribution characteristics of clarithromycin to the lung were investigated in vivo and in isolated lung perfusion experiments. The in-vivo integration plot analysis showed that the pulmonary uptake and extracellular distribution in the lung were significantly higher for clarithromycin than for erythromycin. 2. In the rat lung single-pass perfusion study, the pulmonary extraction ratio (E(ss)) of clarithromycin at steady-state was significantly higher than that of erythromycin, and the E(ss) of clarithromycin tended to decrease as the inflow concentration increased, suggesting the involvement of carrier-mediated transport in the pulmonary disposition of clarithromycin. 3. The outflow patterns of clarithromycin or erythromycin at various inflow concentrations were simultaneously analysed based on a pharmacokinetic model, which consists of the non-specific binding site, the specific binding site and the subsequent uptake process. The parameters obtained suggested that clarithromycin would have the higher affinity and higher capacity for the specific binding site, and the higher equilibrium constant for the non-specific binding site than erythromycin. 4. The simulation study using those parameters demonstrated that clarithromycin could be bound to the specific binding site and subsequently taken up more extensively than erythromycin. 5. A multiple-indicator dilution study also indicated that clarithromycin was more readily associated and extracted with the lung than with erythromycin. In the inhibition study, it was suggested that the pulmonary uptake of clarithromycin could be ascribed not only to the non-specific binding depending on its lipophilic nature, but also in part to some specialized mechanisms such as organic cation transporters.

Animals↗
PubMed1998

Clarithromycin resistance and susceptibility patterns of Mycobacterium avium strains isolated during prophylaxis for disseminated infection in patients with AIDS.

A randomized, placebo-controlled trial was conducted to evaluate the efficacy of clarithromycin in the prevention of disseminated Mycobacterium avium complex (MAC) infection in patients with AIDS; special attention was given to the development of clarithromycin resistance. The median time to documented MAC bacteremia was 199 days for placebo-treated patients, 217 days for clarithromycin-treated patients infected with clarithromycin-susceptible MAC, and 385 days for clarithromycin-treated patients infected with clarithromycin-resistant MAC. Most of the patients with clarithromycin-resistant isolates (91%) had a baseline CD4 T-cell count of < 20/microL, while these low counts occurred in only 25% of patients having clarithromycin-susceptible breakthrough isolates. The emergence of clarithromycin resistance did not affect the total period of survival. Resistance to clarithromycin in breakthrough MAC isolates emerges most likely when the patient is extremely immunodeficient at the time of initiation of the preventative therapy.

AIDS-Related Opportunistic Infections↗
PubMed1991

A comparative safety and efficacy study of clarithromycin and erythromycin stearate in community-acquired pneumonia.

The efficacy and tolerance of clarithromycin and erythromycin stearate in the treatment of community-acquired pneumonia were compared in a multicentre, double-blind randomized trial. Two hundred and eight adult patients were randomized to receive either clarithromycin 250 mg 12-hourly (96 patients) or erythromycin stearate 500 mg 6-hourly (112 patients), each for 14 days. One hundred and eight patients were evaluable for efficacy, 64 receiving clarithromycin and 44 erythromycin stearate. There was no significant difference between the two groups in terms of clinical cure (52% for clarithromycin, 40% for erythromycin) or clinical success (clinical cure and improvement; 89% for clarithromycin, 98% for erythromycin stearate), or radiological response (90% for both groups). An intention-to-treat analysis, including all patients entering the study revealed significant differences in favour of clarithromycin. The clinical cure rate after two weeks of treatment was 45% in those who received clarithromycin compared with 25% in the erythromycin stearate group (P = 0.003), whilst improvement in cough was observed in 97% and 80% of patients receiving clarithromycin and erythromycin stearate, respectively (P = 0.07). Adverse effects, mainly gastrointestinal, caused discontinuation of treatment in 4% (4/96) patients in the clarithromycin group in comparison with 19% (21/112) treated with erythromycin stearate (P less than 0.01). These results demonstrate that clarithromycin twice daily is at least as effective as four times daily erythromycin stearate for the treatment of community-acquired pneumonia and is better tolerated.

Adult↗
PubMed2002

Pharmacokinetics of lansoprazole, amoxicillin and clarithromycin after simultaneous and single administration.

In a randomized, double-blind, placebo-controlled, four-way crossover study, possible influences of the triple therapy with amoxicillin, clarithromycin and the proton pump inhibitor lansoprazole on the pharmacokinetics of each of the drugs and the active 14-OH-clarithromycin metabolite were assessed. Twelve Helicobacter pylori-negative healthy male volunteers (age 27 +/- 4.3 years; creatinine clearance 7.0 +/- 2.0 L/h) were given lansoprazole 30 mg, amoxicillin 1 g and clarithromycin 500 mg, alone and in triple combination. Drug elimination intervals were at least 9 days between the dosing periods. The study medication was administered twice daily for 4 days. On the fifth day of each period, drugs were only given once in the morning, and blood and urine samples were collected for 12 h. The concentrations of the three substances administered, and 14-OH-clarithromycin, were determined by validated HPLC methods. Alterations in the serum kinetics were found for lansoprazole and the active 14-OH-clarithromycin metabolite (all data expressed as mean +/- S.D.). For lansoprazole, the elimination half-life (t(1/2)) was significantly prolonged (1.46 versus 1.7 h, P < 0.05) and the area under the concentration-time curve from 0 to 8 h (AUC(0-8)) was significantly increased (3.65 versus 4.59 mg.h/L, P < 0.05) by combination of the drugs. For 14-OH-clarithromycin, the peak concentration (C(max)) was 0.95 versus 1.18 mg/L and the AUC from 0 to 12 h (AUC(0-12)) was 8.3 versus 10.5 mg.h/L (augmented significantly, P < 0.05). The amoxicillin concentrations were slightly elevated by concomitant administration of lansoprazole and clarithromycin but without statistical significance (11.1 versus 12.6 mg/L). For clarithromycin, the time to maximum concentration of drug in serum (T(max)) was increased (2.73 versus 3.31 h, P < 0.05), whereas AUC and C(max) remained unchanged. Simultaneous administration of lansoprazole, amoxicillin and clarithromycin increases the serum concentrations of lansoprazole and the active 14-OH-clarithromycin metabolite significantly. These effects were not so pronounced as to have any therapeutic influence, making dosage adjustment unnecessary.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed2004

High prevalence rate of Helicobacter pylori resistance to clarithromycin during long-term multiple antibiotic therapy for chronic respiratory disease caused by non-tuberculous mycobacteria.

BACKGROUND: Helicobacter pylori resistance to clarithromycin, probably due to the frequent use of this antibiotic for the treatment of other diseases, is the greatest obstacle against its eradication. AIM: To clarify the prevalence of clarithromycin-resistant H. pylori in patients with non-tuberculous mycobacterial lung disease receiving multiple antibiotic treatment, including clarithromycin. METHODS: We enrolled 88 patients with non-tuberculous mycobacterial lung disease; 29 underwent upper gastrointestinal endoscopy for the diagnosis of H. pylori infection prior to treatment, and 60 underwent it during treatment. The diagnosis of H. pylori infection was confirmed by histological examination, urease test and microaerobic bacterial culture. The minimum inhibitory concentration of clarithromycin was determined and the DNA was analysed for each of the isolated H. pylori strains. RESULTS: Patients during the treatment had a high prevalence rate of clarithromycin-resistant H. pylori (100%). Analysis of DNA of the clarithromycin-resistant H. pylori isolates revealed point mutations at A2142G or A2143G. Moreover, a linear correlation was found between the total cumulative dose of clarithromycin and the minimum inhibitory concentration. CONCLUSION: All patients with non-tuberculous mycobacterial lung disease being treated long-term with multiple antibiotics, including clarithromycin, harboured clarithromycin-resistant H. pylori in the stomach. Therefore, eradication of H. pylori before commencement of long-term therapy including clarithromycin should be recommended.

Anti-Bacterial Agents↗
PubMed1989

Comparative pharmacokinetics of clarithromycin (TE-031), a new macrolide antibiotic, and erythromycin in rats.

Clarithromycin (TE-031) is a newly synthesized macrolide with high stability in acidic conditions. In the present study, the pharmacokinetics of [N-methyl-14C]clarithromycin were compared with those of [N-methyl-14C]erythromycin in rats by radioassay and bioassay. Both radioactivity and bioactivity of [14C]clarithromycin in plasma and tissues were found to be significantly higher than those of [14C]erythromycin at the same oral dose of 20 mg/kg (body weight). Among the tissues, the peak level of [14C]clarithromycin in the lung was especially high. Levels of radioactivity and bioactivity amounted to 15 and 73 times the corresponding levels of [14C]erythromycin. In the urine, bioactivity recovered after administration of [14C]clarithromycin was sevenfold higher than that for [14C]erythromycin. This accounted for about 60 and 20% of the total radioactivity in the urine for [14C]clarithromycin and [14C]erythromycin, respectively. An examination of metabolites in the urine for [14C]clarithromycin revealed appreciable amounts of bioactive unchanged clarithromycin. These results indicate that clarithromycin has pharmacokinetic properties superior to those of erythromycin. The desirable properties of clarithromycin include high levels in plasma resulting from its high stability in gastric acid; a high tissue affinity, especially to the lung; and favorable urinary excretion.

Administration, Oral↗
PubMed1994

Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice.

Bacteremic infection caused by organisms of the Mycobacterium avium complex (MAC) is common in patients with AIDS. We evaluated both clarithromycin and dapsone alone and in combination for the treatment and prevention of disseminated MAC disease in beige mice. In the therapeutic model, C57BL/6 beige mice were infected intravenously with strain 101 of MAC (serovar 1). After 1 week postinfection, mice were given clarithromycin (200 mg/kg of body weight per day) and dapsone (15 mg/kg of body weight per day) alone or in combination by gavage. Treatment with clarithromycin resulted in a significant reduction in bacteremia and the numbers of CFU of MAC in the liver and spleen. Treatment with dapsone had no effect on the mycobacterial counts in blood, liver, or spleen, and the combination of dapsone with clarithromycin was no better than clarithromycin as a single agent. Clarithromycin and dapsone were used to prevent systemic disease in beige mice infected orally with MAC 101. Clarithromycin prophylaxis was associated with a significant reduction in the numbers of bacteria in the liver, spleen, and appendix compared with those in controls. Prophylaxis with dapsone resulted in a mild reduction in the numbers of MAC in the spleen but not in the other tissues. Clarithromycin both treats and prevents MAC disease in beige mice. Dapsone has no therapeutic effect, but it does have a slight prophylactic effect, and in combination with clarithromycin it does not abrogate the effect of clarithromycin.

Animals↗
PubMed2002

In vitro selection of resistance in Haemophilus influenzae by amoxicillin-clavulanate, cefpodoxime, cefprozil, azithromycin, and clarithromycin.

Abilities of amoxicillin-clavulanate, cefpodoxime, cefprozil, azithromycin, and clarithromycin to select resistant mutants of Haemophilus influenzae were tested by multistep and single-step methodologies. For multistep studies, 10 random strains were tested: 5 of these were beta-lactamase positive. After 50 daily subcultures in amoxicillin-clavulanate, MICs did not increase more than fourfold. However, cefprozil MICs increased eightfold for one strain. Clarithromycin and azithromycin gave a >4-fold increase in 8 and 10 strains after 14 to 46 and 20 to 50 days, respectively. Mutants selected by clarithromycin and azithromycin were associated with mutations in 23S rRNA and ribosomal proteins L4 and L22. Three mutants selected by clarithromycin or azithromycin had alterations in ribosomal protein L4, while five had alterations in ribosomal protein L22. Two mutants selected by azithromycin had mutations in the gene encoding 23S rRNA: one at position 2058 and the other at position 2059 (Escherichia coli numbering), with replacement of A by G. One clone selected by clarithromycin became hypersusceptible to macrolides. In single-step studies azithromycin and clarithromycin had the highest mutation rates, while amoxicillin-clavulanate had the lowest. All resistant clones were identical to parents as observed by pulsed-field gel electrophoresis. The MICs of azithromycin for azithromycin-resistant clones were 16 to >128 micro g/ml, and those of clarithromycin for clarithromycin-resistant clones were 32 to >128 micro g/ml in multistep studies. For strains selected by azithromycin, the MICs of clarithromycin were high and vice versa. After 50 daily subcultures in the presence of drugs, MICs of amoxicillin-clavulanate and cefpodoxime against H. influenzae did not rise more than fourfold, in contrast to cefprozil, azithromycin, and clarithromycin, whose MICs rose to variable degrees.

Amino Acid Sequence↗
PubMed2006

Effect of clarithromycin on the pharmacokinetics of cabergoline in healthy controls and in patients with Parkinson's disease.

Cabergoline is used in the treatment of Parkinson's disease (PD). Clarithromycin is a potent inhibitor of CYP3A4 and P-glycoprotein and is often co-administered with cabergoline in usual clinical practice. We studied the effect of clarithromycin co-administration on the blood concentration of cabergoline in healthy male volunteers and in PD patients. Study 1: Ten healthy male volunteers were enrolled and were randomized to take a single oral dose of cabergoline (1 mg/day) for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Study 2: Seven PD patients receiving stable cabergoline doses were enrolled. They were evaluated for the plasma cabergoline concentration before and after the addition of clarithromycin 400 mg/day for 6 days, and again 1 month after discontinuation of clarithromycin. The dose and duration of clarithromycin were decided according to usual clinical practice. In healthy male volunteers, mean Cmax and AUC(0-10 h) of cabergoline increased to a similar degree during co-administration of clarithromycin. Mean plasma cabergoline concentration over 10 h post-dosing increased 2.6-fold with clarithromycin co-administration. In PD patients, plasma cabergoline concentration increased 1.7-fold during clarithromycin co-administration. Co-administration with clarithromycin may increase the blood concentration of cabergoline in healthy volunteers and in PD patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Pharmacokinetics of clarithromycin extended-release (ER) tablets in patients with AIDS.

BACKGROUND: Clarithromycin is a key agent in effective antimycobacterial therapy and prophylaxis for AIDS-related disseminated Mycobacterium avium complex (dMAC) infection. Immediate-release (IR) clarithromycin tablets are dosed at 500 mg bid for these indications. A new extended-release (ER) tablet of clarithromycin has been developed and approved at a dosing interval of once every 24 hours for treatment of respiratory tract bacterial infections. However, the pharmacokinetics of clarithromycin ER in AIDS patients with or at risk for dMAC has not been previously investigated. METHOD: We conducted a randomized, crossover trial in which 14 AIDS patients received clarithromycin ER, 1000 mg once daily, and clarithromycin IR, 500 mg bid, each for 1 week, with pharmacokinetic sampling at the end of each week. RESULTS: The mean of the individual AUC ratios for clarithromycin ER vs. IR was 1.09 (90% CI, 0.94-1.24). Adverse events were no more severe or frequent with clarithromycin ER than IR. CONCLUSION: Clarithromycin ER is a once-daily regimen that is as well tolerated as standard bid IR clarithromycin dosing and has average bioequivalence to the IR formulation in patients with AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Efficacy and safety of clarithromycin compared to cefixime as outpatient treatment of lower respiratory tract infections.

BACKGROUND: Clarithromycin is a new acid-stable, 14-membered macrolide active against many of the organisms responsible for lower respiratory tract infections. It has been administered to over 5,000 patients worldwide and has been shown to be a safe and effective treatment for acute bacterial exacerbations of chronic bronchitis and bacterial pneumonia when given twice daily (250 to 500 mg). Cefixime is an amino-thiazolyl cephalosporin with an extended spectrum of antibacterial activity inhibiting beta-lactamase-producing respiratory pathogens. It has a long half-life, allowing once-daily administration. METHODS: This randomized, double-blind multicenter study compared clarithromycin and cefixime as treatment for patients with community-acquired lower respiratory tract infections (n = 213). Patients had bacterial pneumonia (clarithromycin, 19 percent; cefixime, 21 percent) or acute bacterial exacerbation of chronic bronchitis or asthmatic bronchitis (clarithromycin, 81 percent; cefixime, 79 percent). Patients received 500 mg of clarithromycin twice daily (n = 103) or 400 mg of cefixime once daily (n = 110) for 7 to 14 days. RESULTS: Clinical cure or improvement occurred in 86 percent of the clarithromycin-treated patients and 88 percent of the cefixime-treated patients. When only patients with identified infections with Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae were considered, clinical success rates were 97 percent for clarithromycin and 96 percent for cefixime; the rate of bacteriologic eradication was 91 percent for clarithromycin and 90 percent for cefixime. Adverse events occurred in 29 percent of the clarithromycin-treated patients and 23 percent of the cefixime-treated patients. CONCLUSIONS: This study demonstrates that clarithromycin and cefixime are effective treatments for pneumonia and acute bacterial exacerbations of bronchitis of mild to moderate severity caused by the most common infecting organisms.

Adult↗
PubMed2006

Pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar cells of foals.

OBJECTIVE: To determine pharmacokinetics of clarithromycin and concentrations in body fluids and bronchoalveolar (BAL) cells of foals. ANIMALS: 6 healthy 2-to 3-week-old foals. PROCEDURES: In a crossover design, clarithromycin (7.5 mg/kg) was administered to each foal via IV and intragastric (IG) routes. After the initial IG administration, 5 additional doses were administered IG at 12-hour intervals. Concentrations of clarithromycin and its 14-hydroxy metabolite were measured in serum by use of high-performance liquid chromatography. A microbiologic assay was used to measure clarithromycin activity in serum, urine, peritoneal fluid, synovial fluid, CSF, pulmonary epithelial lining fluid (PELF), and BAL cells. RESULTS: After IV administration, elimination half-life (5.4 hours) and mean +/- SD body clearance (1.27 +/- 0.25 L/h/kg) and apparent volume of distribution at steady state (10.4 +/- 2.1 L/kg) were determined for clarithromycin. The metabolite was detected in all 6 foals by 1 hour after clarithromycin administration. Oral bioavailability of clarithromycin was 57.3 +/- 12.0%. Maximum serum concentration of clarithromycin after multiple IG administrations was 0.88 +/- 0.19 microg/mL. After IG administration of multiple doses, clarithromycin concentrations in peritoneal fluid, CSF, and synovial fluid were similar to or lower than concentrations in serum, whereas concentrations in urine, PELF, and BAL cells were significantly higher than concentrations in serum. CONCLUSIONS AND CLINICAL RELEVANCE: Oral administration of clarithromycin at 7.5 mg/kg every 12 hours maintains concentrations in serum, PELF, and BAL cells that are higher than the minimum inhibitory concentration (0.12 microg/mL) for Rhodococcus equiisolates for the entire 12-hour dosing interval.

Administration, Oral↗
PubMed2000

Relationship between eradication therapy and clarithromycin-resistant Helicobacter pylori in Japan.

Since clarithromycin is expected to be widely used to treat Helicobacter pylori infection in the near future, it is important to investigate the relationship between resistance to clarithromycin and the regimens of eradication therapy. We investigated: (1) the usefulness of susceptibility tests prior to eradication therapy, and (2) the rate of acquisition of H. pylori resistance to clarithromycin after treatment failure. Drug susceptibility tests to clarithromycin and amoxicillin were conducted by Dry Plate Test or E-test. The subjects in the first part of this study included 112 patients with H. pylori infection who received triple therapy with various combinations of drugs, including clarithromycin. The eradication rate in patients with clarithromycin-susceptible H. pylori was significantly higher than that in patients with clarithromycin-resistant H. pylori. The second part of this study included 21 patients in whom H. pylori was not eradicated by triple therapy and 12 patients in whom H. pylori was not eradicated with dual therapy including clarithromycin. Of the 33 patients showing non-eradication. 90.9% of those treated with dual therapy and 35.7% of those treated with triple therapy acquired secondary resistance of H. pylori to clarithromycin. We conclude that it is important to conduct drug susceptibility tests prior to treatment of H. pylori infection. Since the incidence of acquiring clarithromycin resistance was significantly higher in the patients showing non-eradication, it is important to choose a regimen with a higher eradication rate, such as triple therapy.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMedDate not supplied

Randomized comparison of once-daily ceftibuten and twice-daily clarithromycin in the treatment of acute exacerbation of chronic bronchitis.

In an evaluator-blind, parallel-group, multicenter study, the efficacy and tolerability of ceftibuten 400 mg capsules once daily were compared with clarithromycin 500 mg twice daily for 7-14 days in the treatment of 309 patients with acute exacerbation of chronic bronchitis (AECB). Clinical (n = 262) and microbiological (n = 71) assessments were conducted before treatment, during days 4-6 of treatment, and at 0-6 and 7-21 days after treatment. Clinical efficacy success rates (cure/improvement) at the end of treatment (0-6 days) were 91.0% for ceftibuten and 93.0% for clarithromycin. In the intent-to-treat population, the overall clinical assessment showed a success rate of 77.6% (121/156) in the ceftibuten group and 78.4% (120/153) in the clarithromycin group (95% confidence interval, -10.8 to +9.0%). One patient in each of the ceftibuten and clarithromycin groups had a microbiological relapse and became a treatment failure. The overall success rate was 84.3% for ceftibuten and 86.7% for clarithromycin (C.I. -11.7%, +6.9). Overall eradication of the target pathogens (Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae) was 84.8% for ceftibuten and 89.5% for clarithromycin. Eradication rates for ceftibuten at 0-6 days post treatment were 95.2% (H. influenzae), 87.5% (M. catarrhalis), and 100% (S. pneumoniae), compared with 85.7%, 100% and 100%, respectively, for clarithromycin. Significantly fewer patients in the ceftibuten group experienced treatment-related adverse events than in the clarithromycin group (5.3 vs 21.9%; p < 0.001). This difference was due to a large number of patients in the clarithromycin group reporting taste perversion (12.6%) or gastrointestinal adverse events (9.9%). Given its tolerability and efficacy profiles, and the advantage of once-daily administration, ceftibuten provides a rational alternative for the treatment of AECB.

Acute Disease↗
PubMed1999

Effect of adding clofazimine to combined clarithromycin-ethambutol therapy for Mycobacterium avium complex septicemia in AIDS patients.

This study compared the efficacies of clarithromycin-ethambutol and clarithromycin-ethambutol-clofazimine for the treatment of Mycobacterium avium complex (MAC) in AIDS patients. Thirty-four patients were randomized into two groups to receive clarithromycin 2 g/day and ethambutol 20 mg/kg/day, with or without clofazimine 200 mg/day. The evaluation was based primarily on blood cultures becoming negative after 2 months of therapy, but survival at 12 months and clinical evolution were also assessed. Inclusions were prematurely stopped because of a communication reporting increased mortality associated with clofazimine. At 2 months, the blood cultures of 55% of the clarithromycin-ethambutol group patients versus 81% of the clarithromycin-ethambutol-clofazimine group were negative; this difference is not significant (P=0.42). Only one relapse was observed during the study. No clarithromycin-resistant strain was isolated. No apparent difference in either survival or clinical evolution was observed in this small number of patients (median survival, 144 days in the clarithromycin-ethambutol group and 236 days in the clarithromycin-ethambutol-clofazimine group, P=0.44). The clarithromycin-ethambutol combination appears to be an effective and well-tolerated first-line therapy against MAC infections in AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed1998

The influence of cisapride and clarithromycin on QT intervals in healthy volunteers.

OBJECTIVE: Recently a few cases of long QT syndrome were reported during treatment with cisapride. In most of these cases, risk factors for cardiac arrhythmias or pharmacologic interactions might have been involved, and the role of cisapride remained unclear. Macrolides such as clarithromycin potentially interact with the metabolic elimination of cisapride and have overlapping indication areas. We therefore studied whether combined treatment with clarithromycin and cisapride leads to pharmacokinetic changes and increased QT intervals. METHODS: The study was an open, randomized, 2-way crossover study with washout periods of 1 week. Twelve healthy volunteers were recruited. Treatments were cisapride (10 mg 4 times a day) for 10 days with concomitant clarithromycin (500 mg twice a day) from days 6 through 10, or clarithromycin (500 mg twice a day) for 10 days combined with cisapride (10 mg 4 times a day) from days 6 through 10. Frequent ECG recordings were performed for 24 hours before drug treatment (baseline). After 5 days of monotherapy and combination therapy, frequent ECG recordings and assessments of plasma drug levels were performed for 24 hours. RESULTS: Clarithromycin alone was associated with a minimal increase in QTc intervals. Monotherapy with 10 mg cisapride 4 times a day led to a concentration-dependent QTc elevation, amounting to 6 ms during steady state. Combination of cisapride and clarithromycin caused an average QTc increase of 25 ms above pretreatment values and 3-fold increases in cisapride concentrations. CONCLUSIONS: QTc elevations after cisapride or clarithromycin alone remained within the normal range of diurnal variation. Coadministration of cisapride and clarithromycin produced a substantial QT prolongation. The data support the recently purported interaction between cisapride and clarithromycin and thus the filed contraindication to combine these drugs.

Adult↗
PubMed1999

Effect of clarithromycin on the pharmacokinetics and pharmacodynamics of pimozide in healthy poor and extensive metabolizers of cytochrome P450 2D6 (CYP2D6).

BACKGROUND: The use of pimozide is associated with prolongation of the QT interval and fatal ventricular arrhythmia. We recently reported 2 fatal cases in patients taking pimozide and clarithromycin and we have shown that clarithromycin inhibits CYP3A-mediated metabolism of pimozide in vitro. In this study, we examined the effect of clarithromycin on pimozide pharmacokinetics and QT interval changes in a total of 12 healthy subjects (7 men and 5 women), documented as extensive metabolizers or poor metabolizers of CYP2D6. METHODS: In a randomized, double-blind placebo-controlled crossover design, subjects were given a single 6-mg oral dose of pimozide after 5 days of treatment with clarithromycin (500 mg twice a day) or a placebo pill. Blood samples were obtained before and for 96 hours after pimozide administration, and plasma pimozide and clarithromycin concentrations were measured by HPLC. Electrocardiograms for the analysis of the QTc intervals were recorded immediately before each blood sample. RESULTS: Pimozide significantly lengthened QTc interval in the first 20 hours in both the placebo-treated groups (delta QTcmax = 13.3 +/- 5.3 ms; P = .003) and clarithromycin-treated groups (delta QTcmax = 15.7 +/- 9.5 ms; P = .005) compared with baseline values. This is consistent with an effect of the parent drug. Clarithromycin caused a significant increase in the peak plasma concentration (P = .015), terminal elimination half-life (P = .003), and area under the plasma concentration-time curve (P = .024) and a decrease in the clearance (P = .029) of pimozide. Mean QTcmax observed within 20 hours of pimozide administration was significantly greater in the clarithromycin-treated group (23.8 +/- 12.2 ms; P = .0397) than in the placebo-treated group (16.8 +/- 6 ms). There was no significant effect of CYP2D6 or gender on the pharmacokinetics or pharmacodynamics of pimozide. CONCLUSIONS: A single 6-mg oral dose of pimozide resulted in measurable QT interval changes. Clarithromycin inhibited CYP3A-mediated pimozide metabolism and the resulting elevation in plasma concentrations may increase the risk of pimozide cardiotoxicity.

Adult↗