Drug Interactions between amoxicillin / clarithromycin / lansoprazole and ceftriaxone

GENERALLY AVOID: Coadministration of ceftriaxone with lansoprazole has been associated with prolongation of the QT interval and increased risk of ventricular arrhythmia, cardiac arrest, and death in hospitalized patients. The precise mechanism of interaction has not been established, although ceftriaxone and lansoprazole in combination have been shown in patch-clamp electrophysiologic experiments to block the human ether-a-go-go-related gene (hERG) potassium channel at clinically relevant concentrations, which is a common mechanism for drug-induced QT prolongation. In a single-center retrospective cohort study consisting of 380,000 patients, investigators found the combination of ceftriaxone and lansoprazole was associated with significant prolongation of the corrected QT (QTc) interval, and patients treated with the combination were 1.4 times more likely to have a QTc interval greater than 500 msec relative to treatment with either drug alone. On average, QTc intervals were 12 msec longer in men and 9 msec longer in women who were receiving ceftriaxone and lansoprazole concurrently compared with patients receiving either drug alone. These observations were not reported for cefuroxime and lansoprazole, the negative control used in the study. In another retrospective cohort study of 31,152 patients receiving ceftriaxone therapy with a proton pump inhibitor (PPI) in 13 hospitals in Ontario, Canada, over a 7 year period, concomitant use of lansoprazole (n=3747; 12%) was associated with adjusted absolute risk increases of 1.7% for ventricular arrhythmia or cardiac arrest and 7.4% for all-cause in-hospital mortality compared with use of other PPIs (n=27,405; 88%). Overall, ventricular arrhythmia or cardiac arrest occurred in 126 patients (3.4%) in the lansoprazole group and 319 patients (1.2%) in the other PPI group, while in-hospital mortality occurred in 746 patients (19.9%) in the lansoprazole group and 2762 patients (10.1%) in the other PPI group. However, these events could not be definitively linked to QTc interval prolongation, since QTc intervals on electrocardiograms were not captured in the study. The interaction was also independently reported in a patient receiving ceftriaxone 2 gm/day for pneumonia who developed QTc prolongation following the addition of lansoprazole 30 mg/day for epigastralgia. The patient's QTc interval was 422 msec on admission and 417 msec three days after starting ceftriaxone, but increased to 475 msec after two days of combined treatment despite no changes in electrolytes, echocardiography findings, or further drug use. Two days after lansoprazole was stopped and replaced with pantoprazole, QTc returned to normal at 424 msec while ceftriaxone was continued.

MANAGEMENT: Until more information is available, prescribers should consider avoiding the concomitant use of ceftriaxone and lansoprazole when possible, particularly in the elderly and patients with underlying risk factors for QT prolongation such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). Patients coadministered these medications should have renal function, serum electrolytes, and electrocardiograms monitored.

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MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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