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 10 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 NSAIDs 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 [ ].

Cardiovascular

Clarithromycin caused modest but significant prolongation of the QT _c interval in 28 children with respiratory tract infections after 24 hours of treatment (mean prolongation 22 ms; 95% CI = 14, 30); in seven cases the QT _c interval was over 440 ms, and in one case it was over 460 ms [ ].

• 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.

Pulmonary infiltration with eosinophilia occurred in a 17-year old youth who took clarithromycin 500 mg bd for 7 days; clarithromycin was immediately withdrawn, and he quickly recovered [ ].

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

Psychiatric

Two patients, a man aged 74 and a woman aged 56 years, developed delirium after taking clarithromycin [ ].

• A 63-year-old woman took clarithromycin for a community-acquired pneumonia and had an episode of agitation and delirium; she recovered when the clarithromycin was stopped [ ].

• 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 fluoxetine 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 [ ]. Clarithromycin can cause abdominal pain, but less often than erythromycin [ ].

In a randomized comparison of oral telithromycin 800 mg/day for 5 or 7 days and oral clarithromycin 500 mg bd for 10 days in 575 patients, 257 (45%) had at least one treatment-related adverse event [ ]. The most frequent adverse effects were gastrointestinal (diarrhea, nausea, and dysgeusia). None of the patients taking clarithromycin withdrew because of gastrointestinal events.

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 [ , ].