Clarithromycin: Organs and Systems
Cardiovascular
QT interval prolongation and a ventricular dysrhythmia occurred in an HIV-positive 30-year-old man at the start of intravenous clarithromycin therapy 500 mg 12-hourly.
Intravenous clarithromycin caused thrombophlebitis in four patients when it was given inappropriately as a rapid bolus injection instead of a short infusion; the manufacturers have received other reports of similar reactions, even with infusions, but the incidence seems to be considerably lower than with erythromycin. In a prospective, non-randomized study, phlebitis occurred in 15 of 19 patients treated with intravenous erythromycin (incidence rate of 0.40 episodes/patient-day) and in 19 of 25 patients treated with intravenous clarithromycin (0.35 episodes/patient-day).
Respiratory
Bronchospasm with clarithromycin occurred in a 44-year-old woman who had no history of respiratory allergies but had had adverse drug reactions to general and regional anesthetics and to ceftriaxone. After the administration of a quarter of the therapeutic dose the patient had dyspnea, cough, and bronchospasm throughout the lung.
Nervous system
Adverse events on the nervous system due to clarithromycin have been observed in 3% of patients.
Progressive loss of strength and difficulty in swallowing and eye opening after the first dose of clarithromycin (2 g/day) occurred in a patient with cerebral toxoplasmosis and AIDS. This myasthenic syndrome resolved within 6 hours of withdrawal of clarithromycin and administration of pyridostigmine.
The authors postulated that this adverse effect may have been the consequence of neuromuscular blockade, through inhibition of the presynaptic release of acetylcholine.
Sensory systems
Eyes
Topical clarithromycin can cause self-resolving corneal deposits.
Ears
Ototoxicity was attributed to clarithromycin in a 76-year-old man 4 days after he started to take clarithromycin for atypical pulmonary tuberculosis. When the clarithromycin was withdrawn his hearing improved subjectively, but it worsened again on re-exposure.
Taste
Abnormal taste developed in 17 of 175 patients treated with clarithromycin 250 mg bd for 10 days for community-acquired pneumonia, compared with 3 of 167 patients treated with sparfloxacin. Mild to moderate gastrointestinal disturbances were the most common adverse events and were reported in 13 and 11% respectively.
Psychological, psychiatric
Two patients, a man aged 74 and a woman aged 56 years, developed delirium after taking clarithromycin.
Two patients (aged 21 and 33 years) with late-stage AIDS had acute psychoses shortly after taking clarithromycin (2 g/day) for MAC bacteremia. In both cases the psychosis resolved on withdrawal but recurred on rechallenge. In one case treatment with azithromycin was well tolerated.
Of cases of mania attributed to antibiotics and reported to the WHO, 28% were due to clarithromycin.
- A 77-year-old man who was HIV-negative developed mania after 6 days treatment with clarithromycin 1 g/day for a soft tissue infection; his mental state resolved on withdrawal.
- A 53-year-old Canadian lawyer taking long-term fluox-etine and nitrazepam developed a frank psychosis 1-3 days after starting to take clarithromycin 500 mg/day for a chest infection. His symptoms resolved on withdrawal of all three drugs, and did not recur with erythromycin or when fluoxetine and nitrazepam were restarted in the absence of antibiotics.
The symptoms may have been due to a direct effect of clarithromycin or else inhibition of hepatic cytochrome P450 metabolism, leading to fluoxetine toxicity. Clarithromycin occasionally causes hallucinations.
- Visual hallucinations with marked anxiety and nervousness occurred after the second dose of oral clarithromycin 500 mg in a 32-year-old woman. Clarithromycin was withdrawn and the symptoms disappeared a few hours later.
- Visual hallucinations developed in a 56-year-old man with chronic renal insufficiency and underlying aluminium intoxication maintained on peritoneal dialysis 24 hours after he started to take clarithromycin 500 mg bd for a chest infection, and resolved completely 3 days after withdrawal.
Hematologic
- Thrombotic thrombocytopenic purpura was reported in a 42-year-old man with no past medical history after he had just completed a 30-day course of clarithromycin 250 mg bd.
Gastrointestinal
Erythromycin acts as a motilin receptor agonist. This mechanism may be at least partly responsible for the gastrointestinal adverse effects of macrolides. Clarithromycin may act on gastrointestinal motility in a similar way. In dogs, clarithromycin caused contractions and discomfort, as did erythromycin. In healthy volunteers, oral clarithromycin 250 mg bd caused a statistically significant increase in the number of postprandial antral contractions and antral motility. A single oral dose of clarithromycin 3000 mg resulted in severe abdominal pain within 1 hour of administration in two patients.
Based on observations made in dogs and rabbits, clarithromycin is significantly less potent than azithromycin and erythromycin as an agonist for stimulation of smooth muscle contraction. Therefore, a lower rate of gastrointestinal adverse events would be expected with clarithromycin.
Pseudomembranous colitis is relatively rarely seen with macrolides, but has been reported with clarithromycin.
Liver
Abnormal liver function tests and hepatomegaly have been described with clarithromycin; in 4291 patients, the frequency of increased alanine transaminase activity was 5%. Clarithromycin was also associated with cholestatic hepatitis.
To date, at least nine cases of hepa-totoxicity have been described in HIV-negative patients taking clarithromycin 1-2 g/day for chronic lung disease due to M. avium or Mycobacterium abscessus. The pattern of liver enzyme abnormality was primarily cholestatic, and the patients were typically elderly (all but one aged over 60 years), or of low weight.
Only three patients were symptomatic, and the liver function abnormalities resolved on withdrawal. Subsequent rechallenge was successful in four patients, unsuccessful in one, and not performed in four. There was some dispute as to whether toxicity was dose-related or not, but it is wise to recommend that elderly patients should receive an initial daily dose of 1 g in this disease setting.
Although cholestatic hepatitis has been typically described in association with erythromycin, newer macro-lides are not totally free of this risk. A gradual increase in bilirubin and transaminases has been reported during treatment of a Mycobacterium chelonae infection with clarithromycin. These alterations were quickly reversible after withdrawal, but re-appeared on re-exposure to clarithromycin 1 g.
- Fatal drug-induced cholestasis associated with clarithromycin 500 mg bd for 3 days has been reported in a 59-year-old woman with diabetes mellitus and chronic renal insufficiency.
- Idiosyncratic drug-induced fatal fulminant hepatic failure has been reported in a 40-year-old woman with end-stage renal insufficiency taking clarithromycin 500 mg bd.
Skin
Clarithromycin has been associated with fixed drug eruptions and hypersensitivity reactions. In one case a clarithromycin-induced fixed drug eruption was reproduced by oral provocation, whereas patch tests on both unaffected and residual pigmented skin were negative.
- A 31-year-old woman developed Stevens-Johnson syndrome after she had taken oral erythromycin 333 mg tds for otitis media. After two doses she developed oral ulcers, tongue swelling, and a generalized erythematous rash. The diagnosis was confirmed histologically. She recovered slowly after withdrawal of erythromycin.
- Roxithromycin-induced generalized urticaria and tachycardia with a positive prick test and a cross-reaction to erythromycin and clarithromycin has been reported in a 31-year-old woman.
Clarithromycin can cause phototoxicity.
Clarithromycin: Side Effects
See also Macrolide antibiotics Clarithromycin is a commonly used macrolide antibiotic and is a regular part of regimens for the eradication of Helicobacter pylori, often in combination with a nitromidazole antibiotic as well, in addition to a proton pump inhibitor. Variable rates of adverse events (4-30%) have been reported with clarithromycin.
Comparative studies
In a double-blind, multicenter trial in 328 patients with H. pylori infection and non-ulcer dyspepsia, omeprazole 20 mg bd, amoxicillin 1 g bd, and clarithromycin 500 mg bd were compared with omeprazole alone. The rate of success and quality of life were similar in both groups. There were no serious adverse events. However, there were 12 withdrawals in the group given omeprazole and antibiotics and two in the group given omeprazole alone.
Diarrhea occurred in 63 patients in those given omeprazole and antibiotics and in ten patients given omeprazole alone. In another double-blind, placebo-controlled trial eradication of H. pylori (omeprazole 20 mg, amoxicillin 1 g, and clarithromycin 500 mg bd) in long-term users of non-steroidal anti-inflammatory drugs with past or current peptic ulcer or troublesome dyspepsia led to impaired healing of gastric ulcers and did not affect the rate of peptic ulcers or dyspepsia over 6 months.
Beta-lactam antibiotics
In a multicenter, double-blind, randomized comparison of cefprozil, 500 mg bd for 5 days and clarithromycin 500 mg bd for 10 days in 295 subjects with an acute exacerbation of chronic bronchitis, the most common adverse effects of clarithromycin were nausea (8%), diarrhea (12%), taste disturbance (8%), and dry mouth (5%). Clarithromycin (250 mg bd for 10 days) was as effective as cefuroxime axetil (250 mg bd for 10 days) in the treatment of acute maxillary sinusitis in a randomized, double-blind, multicenter study in 370 patients; 10% of patients in each group had adverse events.
Other macrolides
The incidence of disseminated Mycobacterium avium complex (MAC) infection has increased dramatically with the AIDS epidemic. Treatment regimens for patients with a positive culture for MAC from a sterile site should include two or more drugs, including clarithromycin.
Prophylaxis against disseminated MAC should be considered for patients with a CD4 cell count of less than 50 x 106/1. In a randomized, open trial in 37 patients with HIV-associated disseminated MAC (Mycobacterium avium complex) infection, treatment with clarithromycin + ethambutol produced more rapid resolution of bacteremia, and was more effective at sterilization of blood cultures after 16 weeks than azithro-mycin + ethambutol. In a direct comparison of clarithromycin with erythro-mycin stearate, the rate of adverse events was 19% in 96 patients taking clarithromycin and 35% in 112 patients taking erythromycin.
Most of the adverse events associated with clarithromycin affect the gastrointestinal tract (7%). In a prospective, single-blind, randomized study of a 7-day course of clarithromycin (7.5 mg/kg bd) and a 14-day course of erythromycin (13.3 mg/kg tds) in 153 children with pertussis, the incidence of treatment-emergent drug-related adverse events was significantly higher with erythromycin than with clarithromycin (62 versus 45%). Three subjects given erythromycin withdrew prematurely because of adverse events: one because of a rash; one with vomiting and diarrhea; and one with vomiting, abdominal pain, and rash.
Quinolones
In a multicenter, double-blind, randomized comparison of trovafloxacin 200 mg and clarithromycin 500 mg bd in 176 subjects with acute exacerbations of chronic bronchitis, the most common adverse effects of clarithromycin were nausea (3%), diarrhea (4%), and taste disturbances (4%).
Tetracyclines
Clarithromycin (0.75-2 g/day), minocycline (200 mg/ day), and clofazimine (100 mg/day) for 15 months were investigated as treatment of MAC lung disease in 30 HIV-negative patients. Eight patients did not complete the study owing to deviations from protocol or adverse effects. Persistently negative cultures were found in 14 of the other patients. There were three cases of hepatic disturbances and three of ototoxicity, which required a reduction in clarithromycin dosage after a short interruption of treatment.
Antibiotic Biaxin and Metallic Taste
Question from Barry
I have been prescribed Biaxin for my Bronchitis. I am experiencing the metallic Taste. How long does this last? Does it go away quickly when I stop taking the drug? Also the label says I should continue for one full week. But in the data I found on line there is no mention of continuing full term. So if I feel like it cured me, can I just stop?
Dear Barry:
The metallic taste is a common side effect with the antibiotic Biaxin. It will usually go away after you discontinue the medication. In general you should always take an antibiotic until it is completed. For example, if your doctor prescribed it for 10 days, take it for the entire time. Even though you may feel good, the longer duration of therapy will insure that you do not get a recurrence of your infection.
Clarithromycin: Drug-Drug Interactions
Antifungal imidazoles
In three patients with pulmonary MAC and aspergillosis infections, itraconazole was suggested to increase the plasma concentration of clarithromycin as well as the clarithromycin:14-hydroxyclarithromycin ratio. This effect may have been due to inhibition of CYP3A4 by itraconazole.
Antihistamines
Toxic effects of terfenadine and astemizole have been reported in patients taking concomitant macrolides, especially clarithromycin, typically resulting in prolongation of the QT interval and cardiac dysrhythmias (torsade de pointes).
Cisapride
Cisapride can prolong the QT interval, with a risk of ventricular dysrhythmias. Clarithromycin increases serum concentrations of cisapride. This potentially dangerous interaction can result in QT interval prolongation and dysrhythmias such as torsade de pointes.
- Torsade de pointes occurred in a 77-year-old woman taking cisapride and clarithromycin.
Warnings have been issued by the manufacturers to avoid concomitant administration.
Colchicine
- Fatal colchicine intoxication occurred in a 67-year-old man who had taken clarithromycin 500 mg bd for 4 days.
Clarithromycin may have inhibited colchicine metabolism and caused a rise in colchicine concentration.
Digoxin
Clarithromycin has been reported to cause digoxin toxicity. Two different mechanisms are involved, inhibition of the renal excretion of digoxin and alteration of intestinal flora, which reduces the presystemic hydrolysis of digoxin.
- A 70-year-old woman taking digoxin for atrial fibrillation developed nausea, vomiting, and dizziness 2 days after starting to take clarithromycin. Her serum digoxin concentration was 3.9 µg/ml (target range 0.5-2).
Disulfiram
Fatal toxic epidermal necrolysis and fulminant hepatitis occurred shortly after the start of treatment with clarithromycin in a 47-year-old man who was taking disulfiram.
- A 47-year-old man with a history of chronic alcoholism took disulfiram 250 mg/day for 1 month. He then took clarithromycin 500 mg bd and paracetamol 500 mg tds and 1 week later noticed non-pruritic cutaneous macu-lopapular lesions on his legs, extending to the rest of his body, excluding the palms and soles. Previous drug therapy was withdrawn. A skin biopsy showed toxic epidermal necrolysis. During the next several days the skin lesions worsened. Cutaneous blisters became evident, initially covering less than 10% of the body surface, but then extending all over the body. The serum bilirubin concentration was 359 µmol/l (direct bilirubin 213 µmol/l), the partial thromboplastin time longer than 200 seconds, and the prothrombin time 26 seconds. He developed septic shock and, despite supportive measures, died.
Ergot alkaloids
In patients with ergotamine toxicity, vasoconstriction can lead to frank ischemia. Clarithromycin interferes with ergotamine metabolism.
- A 41-year-old woman developed worsening lower leg pain, pallor, and a sensation of coolness aggravated by exertion; there was severe vasospasm in the legs. She had taken a caffeine + ergotamine formulation for migraine for many years and had recently been given clarithromycin 500 mg bd for flu-like symptoms.
HIV nucleoside reverse transcriptase inhibitors
Clarithromycin reduced the peak concentration and AUC of zidovudine at steady state by about 12%, possibly as a result of reduced zidovudine absorption. However, if the two drugs were taken at least 2 hours apart, the pharmacokinetics of zidovudine were unaffected.
In 12 HIV-positive patients there was no statistically significant difference in concentrations of didanosine when clarithromycin was added.
Midazolam
In an open, randomized, crossover, pharmacokinetic and pharmacodynamic study in 12 healthy volunteers who took clarithromycin 250 mg bd for 5 days, azithromycin 500 mg/day for 3 days, or no pretreatment, followed by a single dose of midazolam (15 mg), clarithromycin increased the AUC of midazolam by over 3.5 times and the mean duration of sleep from 135 to 281 minutes. In contrast, there was no change with azithromycin, suggesting that it is much safer for co-administration with midazolam.
Omeprazole
In 21 healthy volunteers, clarithromycin (400 mg bd) for 3 days before omeprazole (20 mg/day) significantly inhibited the metabolism of omeprazole.
Pimozide
Clarithromycin inhibits the metabolism of pimozide, pimozide plasma concentrations increase, and there is an increased risk of cardiotoxicity through prolongation of the QT interval and fatal ventricular dysrhythmias.
Rifamycins
Clarithromycin is one of the core drugs for Mycobacterium avium complex infections in both HIV-infected and non-infected patients. For this indication, doses of up to 2000 mg/day are used, typically in combination with other drugs.
The interaction of clarithromycin with the rifamycins is complex. Clarithromycin inhibits CYP3A4, while both rifampicin and rifabutin induce P450 cytochromes, including CYP3A4, resulting in enhanced metabolism of drugs. The changes in serum concentrations of clarithromycin and its metabolite in the presence of the enzyme inducers rifampicin and rifabutin suggest that metabolism of clarithromycin by CYP3A4 is increased.
After the addition of rifampicin, peak serum concentrations of clarithromycin fell markedly, from a mean of 5.8-2.5 µg/ml. At the same time the ratio of the serum concentrations of clarithromycin and its 14-OH metabolite was reversed from 3.3:1 to 1:2.7. There were similar, although less marked, changes after the addition of rifabutin 600 mg/day to a regimen that included clarithromycin 1000 mg/day.
Whether these changes in serum clarithromycin concentrations are relevant to its antimicrobial activity is unknown, since prediction of clinical efficacy based on serum concentrations of clarithromycin is probably not justified, given that the macrolides accumulate to a large degree in tissues and macrophages.
In patients with Mycobacterium avium complex infections taking rifabutin or rifampicin the addition of clarithromycin resulted in rifamycin-related adverse events in 77% of patients. These included uveitis, especially at rifabutin doses of 600 mg/day or more, neutropenia, nausea, vomiting, diarrhea, and abnormal liver enzyme activities. In addition, diffuse polyarthralgia (19%) was observed. Since inhibition of cytochrome P450 by clarithromycin can interfere with rifabutin metabolism, as illustrated by a report of a significant increase in the AUC of rifabutin during treatment with clarithromycin, the authors recommended using rifabutin in a dosage of 300 mg/day in regimens that include a macrolide.
The effects of fluconazole and clarithromycin on the pharmacokinetics of rifabutin and 25-O-desacetylrifabu-tin have been studied in ten HIV-infected patients who were given rifabutin 300 mg qds in addition to fluconazole 200 mg qds and clarithromycin 500 mg qds. There was a 76% increase in the plasma AUC of rifabutin when either fluconazole or clarithromycin was given alone and a 152% increase when both drugs were given together. The authors concluded that patients should be monitored for adverse effects of rifabutin when it is co-administered with fluconazole or clarithromycin.
Sulfonylureas
Severe hypoglycemia occurred in two elderly men with type 2 diabetes mellitus and mild to moderate impaired renal function, who took clarithromycin 1000 mg/day for respiratory infections, in addition to a sulfonylurea (glibenclamide 5 mg/day in one case and glipizide 15 mg/day in the other). Both developed severe hypoglycemia within 48 hours of starting clarithromycin.
Tacrolimus
Clarithromycin can increase the steady-state concentrations of drugs that depend primarily on CYP3A metabolism.
- Steady-state tacrolimus concentrations rose in a 32-year-old African-American man who took clarithromycin 500 mg bd for 4 days.
- In two women aged 37 and 69, acute and reversible tacrolimus nephrotoxicity developed after the addition of clarithromycin for an upper respiratory tract infection.
Theophylline and other xanthines
Inhibition of cytochrome P450 activity by clarithromycin affects the metabolism of theophylline. However, the results of several studies of the effect of clarithromycin on theophylline concentrations are conflicting. While the total body clearance of theophylline fell and plasma theophylline concentrations increased by 18%, mean theophylline concentrations remained within the target range. Based on these data it is wise to monitor serum theophylline concentrations in patients taking high dosages of theophylline or in patients with theophylline concentrations in the upper target range who start to take clarithromycin.
Warfarin
Increases in International Normalized Ratio (INR) have been detected in patients who have previously been stabilized on warfarin when they were simultaneously given clarithromycin. In one case this caused a suprachoroidal hemorrhage.
| Dosage forms of Clarithromycin: | |||
|---|---|---|---|
| Clarithromycin 100% powder | Biaxin Bid 250 mg Tablet | Mylan-Clarithromycin 500 mg Tablet | Pms-Clarithromycin 500 mg Tablet |
| Ratio-Clarithromycin 500 mg Tablet | Sandoz Clarithromycin 500 mg Tablet | Biaxin Xl 500 mg Extended-Release Tablet | Biaxin Bid 500 mg Tablet |
| Clarithromycin 250 mg tablet | Clarithromycin 500 mg tablet | Clarithromycin er 500 mg tablet | Clarithromycin 500 mg 24 Hour tablet |
| Biaxin 500 mg tablet | Biaxin 250 mg tablet | Biaxin xl 500 mg tablet | Biaxin XL 500 mg 24 Hour tablet |
| Clarithromycin 125 mg/5ml Suspension 50ml Bottle | Clarithromycin 125 mg/5ml Suspension 100ml Bottle | Clarithromycin 250 mg/5ml Suspension 50ml Bottle | Clarithromycin 250 mg/5ml Suspension 100ml Bottle |
| Biaxin 60 250 mg tablet Bottle | Biaxin 25 mg/ml Suspension | Biaxin 50 mg/ml Suspension | |
Synonyms of Clarithromycin:
CLA, Clarithromycine, Clathromycin
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Therapeutic classes of Clarithromycin:
Anti-Bacterial Agents, Macrolides, Other Macrolides, Protein Synthesis Inhibitors
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