Drug Interactions between amoxicillin / omeprazole / rifabutin and ketoconazole

GENERALLY AVOID: Coadministration with rifamycins may significantly decrease the plasma concentrations of itraconazole, levoketoconazole and ketoconazole. The proposed mechanism is accelerated clearance of the azoles due to induction of CYP450 3A4-mediated metabolism by rifamycins. Pharmacokinetic studies and case reports have demonstrated that rifampin can reduce itraconazole and ketoconazole systemic exposure by at least 80% and sometimes even to undetectable levels. Treatment failure has been reported. Rifabutin, a less potent CYP450 3A4 inducer, has been found in one study to decrease itraconazole systemic exposure by 74%. Conversely, itraconazole, levoketoconazole and ketoconazole are potent inhibitors of CYP450 3A4 and may substantially increase the plasma levels of rifabutin and its pharmacologically active metabolite, 25-O-desacetylrifabutin. This may increase the risk of adverse effects such as leukopenia, uveitis, arthralgia, joint disorder, and skin discoloration. By contrast, itraconazole reportedly has no effect on rifampin pharmacokinetics. Ketoconazole has been found in some studies to decrease rifampin plasma levels, but interaction is apparently minimized when they are given 12 hours apart.

MANAGEMENT: The manufacturers recommend that itraconazole and ketoconazole not be used concomitantly or within 2 weeks of treatment with rifamycins, unless the benefits outweigh the risk of potentially reduced antifungal efficacy. If coadministration is required, the antifungal activity should be monitored and the azole dosage increased as necessary. With rifabutin, however, consideration should also be given to the potential for increased risk of rifabutin toxicity, particularly when the azole dosage is increased. Therapeutic drug monitoring for rifabutin is therefore advisable, and the dosage adjusted if needed. In addition, a complete blood count should be performed at least weekly and as clinically indicated to monitor for development of neutropenia. Levoketoconazole manufacturer recommends avoiding its concomitant use or within 2 weeks of treatment with rifamycins.

GENERALLY AVOID: Inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) may decrease the gastrointestinal absorption of the azole antifungal agents, itraconazole (capsules only) and ketoconazole, both of which require an acidic environment for dissolution. By increasing gastric pH and reducing the acidity, proton pump inhibitors can decrease bioavailability of the azoles by 75% to 80%. Additionally, ketoconazole (a potent CYP450 3A4 inhibitor) may increase serum omeprazole levels. The metabolism of omeprazole includes hydroxylation catalyzed by CYP450 2C19 and, to a minor extent, sulfoxidation by CYP450 3A4. In a study involving ten subjects, ketoconazole 100 mg to 200 mg daily resulted in a marked inhibition of the formation of the omeprazole sulfone in both extensive and poor metabolizers of CYP450 2C19. In poor metabolizers, a doubling of omeprazole levels was observed. No adverse effects were reported by any of the subjects.

MANAGEMENT: In general, the concomitant use of these drugs is not recommended. If coadministration is necessary, an acidic pH may be produced with two capsules of glutamic acid hydrochloride administered 15 minutes before the azole dose. Administration with an acidic beverage such as Coca-Cola(R) may also help. Additionally, an increase of the antifungal dosage may be required. However, clinicians should still consider the possibility of a reduced or subtherapeutic antifungal effect. It may be appropriate to switch to itraconazole oral solution or an agent like fluconazole whose absorption is not affected by stomach pH.