chapter
Antibiotics – macrolides
Pages 10

Be aware that the effects of alfentanil (especially when given as an infusion) may be prolonged by erythromycin

AZITHROMYCIN ANTACIDS ↓ levels of these antibiotics ↓ absorption Take azithromycin at least 1 hour before or 2 hours after an antacid. Take these cephalosporins at least 2 hours after an antacid. Separate quinolones and antacids by 2-6 hours. Separate tetracyclines and antacids by 2-3 hours

MACROLIDES ANTIBIOTICS

MACROLIDES RIFABUTIN ≠ rifabutin levels Inhibition of CYP3A4-mediated metabolism of rifabutin

Watch for early features of toxicity of rifabutin (warn patients to report painful eyes)

CLARITHROMYCIN, TELITHROMYCIN

RIFAMPICIN ↓ levels of these macrolides Rifampicins induce metabolism of these macrolides

Avoid co-administration for up to 2 weeks after stopping rifampicin

MACROLIDES ANTICANCER AND IMMUNOMODULATING DRUGS

CLARITHROMYCIN, ERYTHROMYCIN

BUSULFAN ≠ plasma concentrations of busulfan and ≠ risk of toxicity of busulfan such as veno-occlusive disease and pulmonary fibrosis

Macrolides are inhibitors of CYP3A4. Busulfan clearance may be ↓ by 25%, and the AUC of busulfan may ≠ by 1500 mol/L

Monitor clinically for veno-occlusive disease and pulmonary toxicity in transplant patients. Monitor busulfan blood levels as AUCs below 1500 mol/L per minute tends to prevent toxicity

ERYTHROMYCIN DOCETAXEL ≠ docetaxel levels Inhibition of CYP3A4-mediated metabolism of docetaxel is metabolized by enzymes that are moderately inhibited by erythromycin, leading to ≠ levels and possible toxicity

Cautious use or consider use of azithromycin, which has little effect on CYP3A4 and therefore is not expected to interact with docetaxel

DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES

Due to ↓ metabolism of doxorubicin by CYP3A4 isoenzymes due to inhibition of those enzymes

Monitor for ≠ myelosuppression, peripheral neuropathy, myalgias and fatigue

CLARITHROMYCIN, ERYTHROMYCIN

IFOSFAMIDE ↓ plasma concentrations of 4-hydroxyifosfamide, the active metabolite of ifosfamide, and risk of inadequate therapeutic response

Due to inhibition of the isoenzymatic conversion to active metabolites

Monitor clinically the efficacy of ifosfamide and ≠ dose accordingly

CLARITHROMYCIN, ERYTHROMYCIN

IMATINIB ≠ imatinib levels with ≠ risk of toxicity (e.g. abdominal pain, constipation, dyspnoea) and of neurotoxicity (e.g. taste disturbances, dizziness, headache, paraesthesia, peripheral neuropathy)

Due to inhibition of CYP3A4mediated metabolism of imatinib

Monitor for clinical efficacy and for the signs of toxicity listed, along with convulsions, confusion, signs of oedema (including pulmonary oedema). Monitor electrolytes, liver function and for cardiotoxicity

CLARITHROMYCIN, ERYTHROMYCIN

IRINOTECAN ≠ plasma concentrations of SN-38 (AUC by 100%) and ≠ toxicity of irinotecan, e.g. diarrhoea, acute cholinergic syndrome, interstitial pulmonary disease

Due to inhibition of the metabolism of irinotecan by CYP3A4 isoenzymes by macrolides

Peripheral blood counts should be checked before each course of treatment. Monitor lung function. Recommendation is to ↓ dose of irinotecan by 25%

CLARITHROMYCIN, ERYTHROMYCIN

VINCA ALKALOIDS – VINBLASTINE, VINCRISTINE, VINORELBINE

≠ adverse effects of vinblastine and vincristine

Inhibition of CYP3A4-mediated metabolism. Also inhibition of P-gp efflux of vinblastine

Monitor FBCs. Watch for early features of toxicity (pain, numbness, tingling in the fingers and toes, jaw pain, abdominal pain, constipation, ileus). Consider selecting an alternative drug

CLARITHROMYCIN, ERYTHROMYCIN

TOREMIFENE ≠ plasma concentrations of toremifene with clarithromycin and erythromycin

Due to inhibition of metabolism of toremifene by the CYP3A4 isoenzymes

Clinical relevance is uncertain. Necessary to monitor for clinical toxicities

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Mechanism Precautions

ERYTHROMYCIN, TELITHROMYCIN

ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity and excessive immunosuppression, with risk of infection and post-transplant lymphoproliferative disease

Inhibition of CYP3A4-mediated metabolism of ciclosporin; these inhibitors vary in potency. Clarithromycin and telithromycin are classified as potent inhibitors

Avoid co-administration with clarithromycin and telithromycin. Consider alternative antibiotics but need to monitor plasma ciclosporin levels to prevent toxicity

CLARITHROMYCIN, ERYTHROMYCIN

CORTICOSTEROIDS ≠ adrenal suppressive effects of corticosteroids, which may ≠ risk of infections and produce an inadequate response to stress scenarios

Due to inhibition of metabolism of corticosteroids

Monitor cortisol levels and warn patients to report symptoms such as fever and sore throat

CLARITHROMYCIN, ERYTHROMYCIN

SIROLIMUS ≠ sirolimus levels Inhibition of metabolism of sirolimus

Avoid co-administration

MACROLIDES TACROLIMUS ≠ plasma concentrations of tacrolimus, with risk of toxic effect

Clarithromycin, erythromycin and telithromycin inhibit CYP3A4mediated metabolism of tacrolimus. Azithromycin, if at all, mildly inhibits CYP3A4; a marked ≠ in tacrolimus levels is attributed to inhibition of P-gp

Be aware and monitor tacrolimus plasma concentrations

MACROLIDES ANTICOAGULANTS – ORAL Occasional episodes of ≠ anticoagulant effect

Uncertain at present Monitor INR every 2-3 days

MACROLIDES ANTIDEPRESSANTS

ERYTHROMYCIN MAOIs – PHENELZINE Report of fainting and severe hypotension on initiation of erythromycin

Attributed to ≠ absorption of phenelzine due to rapid gastric emptying caused by erythromycin

Be aware

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES

Possibly inhibition of CYP3A4mediated metabolism of reboxetine

Avoid co-administration

TELITHROMYCIN ST JOHN’S WORT ↓ telithromycin levels Due to induction of CYP3A4mediated metabolism of telithromycin

Avoid co-administration for up to 2 weeks after stopping St John’s wort

ERYTHROMYCIN, CLARITHROMYCIN, TELITHROMYCIN

ANTIDIABETIC DRUGS – REPAGLINIDE

Likely to ≠ plasma concentrations of repaglinide and ≠ risk of hypoglycaemic episodes. ≠ risk of gastrointestinal side-effects with clarithromycin

Due to inhibition of CYP3A4 isoenzymes, which metabolize repaglinide. These drugs vary in potency as inhibitors (clarithromycin is a potent inhibitor) and ≠ plasma concentrations varies. Clarithromycin ≠ plasma concentrations by 60%. However, the alternative pathway – CYP2C8 – is unaffected by these inhibitors

MACROLIDES ANTIEMETICS – APREPITANT

≠ aprepitant levels Inhibition of CYP3A4-mediated metabolism of aprepitant

Use with caution. Clinical significance unclear; monitor closely

MACROLIDES ANTIEPILEPTICS

TELITHROMYCIN BARBITURATES ↓ levels of these drugs, with risk of therapeutic failure

Induction of hepatic metabolism 1. Avoid co-administration of telithromycin for up to 2 weeks after stopping phenobarbital 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ dose as required

TELITHROMYCIN CARBAMAZEPINE ↓ levels of these drugs, with risk of therapeutic failure

Induction of hepatic metabolism 1. Avoid co-administration of telithromycin for up to 2 weeks after stopping carbamazepine 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ dose as required

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Mechanism Precautions

Inhibition of metabolism Monitor carbamazepine levels

TELITHROMYCIN PHENYTOIN ↓ levels of these drugs, with risk of therapeutic failure

Induction of hepatic metabolism 1. Avoid co-administration of telithromycin for up to 2 weeks after stopping phenytoin 2. With the other drugs, monitor for ↓ clinical efficacy and ≠ dose as required

CLARITHROMYCIN PHENYTOIN ≠ phenytoin levels Inhibited metabolism Monitor phenytoin levels ERYTHROMYCIN VALPROATE ≠ valproate levels Inhibited metabolism Monitor levels

CLARITHROMYCIN, ERYTHROMYCIN, TELITHROMYCIN

ANTIFUNGALS – ITRACONAZOLE, KETOCONAZOLE, VORICONAZOLE

≠ plasma concentrations of itraconazole, ketoconazole and voriconazole, and risk of toxic effects

These antibiotics are inhibitors of metabolism of itraconazole by the CYP3A4. Erythromycin is a weaker inhibitor than clarithromycin. The role of clarithromycin and erythromycin as inhibitors of P-gp is not known with certainty. Ketoconazole is a potent inhibitor of P-gp

Monitor LFTs closely. Azithromycin does not cause this effect

ERYTHROMYCIN, CLARITHROMYCIN

ANTIGOUT DRUGS – COLCHICINE

Cases of colchicine toxicity when macrolides added

Uncertain; macrolides may inhibit hepatic metabolism of colchicine. Clarithromycin and erythromycin both inhibit intestinal P-gp, which may ≠ bioavailability of colchicine

Monitor FBC and renal function closely

MACROLIDES ANTIMIGRAINE DRUGS

MACROLIDES ERGOT DERIVATIVES ≠ ergotamine/methysergide levels, with risk of toxicity

Inhibition of CYP3A4-mediated metabolism of the ergot derivatives

Avoid co-administration

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES

heaviness, pressure or tightness of any part of body including the throat and chest, dizziness

Almotriptan is metabolized mainly by CYP3A4 isoenzymes. Most CYP isoenzymes are inhibited by clarithromycin to varying degrees, and since there is an alternative pathway of metabolism by MAOA, the toxicity responses will vary between individuals

Avoid co-administration

CLARITHROMYCIN, ERYTHROMYCIN

ANTIMUSCARINICS – TOLTERODINE

≠ tolterodine levels Inhibition of CYP3A4-mediated metabolism

Avoid co-administration (manufacturers’ recommendation)

ERYTHROMYCIN ANTIPARKINSON’S DRUGS – BROMOCRIPTINE, CABERGOLINE

≠ bromocriptine and cabergoline levels

Inhibition of metabolism Monitor BP closely and watch for early features of toxicity (nausea, headache, drowsiness)

ERYTHROMYCIN ANTIPSYCHOTICS – CLOZAPINE

≠ clozapine levels, with risk of clozapine toxicity

Clozapine is metabolized by CYPIA2, which is moderately inhibited by erythromycin. Erythromycin is a potent inhibitor of CYP3A4, which has a minor role in the metabolism of clozapine. This may lead to ↓ clearance and therefore ≠ levels of clozapine

Cautious use advised

MACROLIDES ANTIVIRALS

CLARITHROMYCIN NNRTIs 1. ↓ efficacy of clarithromycin but ≠ efficacy and adverse effects of the active metabolite 2. A rash occurs in 46% of patients when efavirenz is given with clarithromycin

1. Uncertain: possibly due to altered CYP3A4-mediated metabolism 2. Uncertain

1. Clinical significance unknown; no dose adjustment is recommended when clarithromycin is co-administered with nevirapine, but monitor LFTs and activity against Mycobacterium avium intracellulare complex closely 2. Consider alternatives to clarithromycin for patients on efavirenz

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Mechanism Precautions

Possibly involves altered P-gp transport

Watch for signs of azithromycin toxicity

CLARITHROMYCIN, ERYTHROMYCIN

PROTEASE INHIBITORS Possibly ≠ adverse effects of macrolide with atazanavir, ritonavir (with or without lopinavir) and saquinavir

Inhibition of CYP3A4-and possibly CYP1A2-mediated metabolism. Altered transport via P-gp may be involved. Amprenavir and indinavir are also possibly ≠ by erythromycin

Consider alternatives unless there is Mycobacterium avium intracellulare infection; if combined, ↓ dose by 50% (75% in the presence of renal failure with a creatinine clearance of 30 mL/min)

MACROLIDES ANXIOLYTICS AND HYPNOTICS

ERYTHROMYCIN, CLARITHROMYCIN, TELITHROMYCIN

MIDAZOLAM, TRIAZOLAM, POSSIBLY ALPRAZOLAM

≠ BZD levels Inhibition of CYP3A4-mediated metabolism

↓ dose of BZD by 50%; warn patients not to perform skilled tasks such as driving for at least 10 hours after the dose of BZD

MACROLIDES BUSPIRONE ≠ buspirone levels Inhibition of CYP3A4-mediated metabolism

Warn patients to be aware of additional sedation

MACROLIDES BRONCHODILATORS

MACROLIDES LEUKOTRIENE RECEPTOR ANTAGONISTS – ZAFIRLUKAST

↓ zafirlukast levels Induction of metabolism Watch for poor response to zafirlukast

AZITHROMYCIN, CLARITHROMYCIN, ERYTHROMYCIN

THEOPHYLLINE 1. ≠ theophylline levels 2. Possibly ↓ erythromycin levels when given orally

1. Inhibition of CYP2D6-mediated metabolism of theophylline (macrolides and quinolones – isoniazid not known) 2. ↓ bioavailability; uncertain mechanism

1. Monitor theophylline levels before, during and after co-administration 2. Consider an alternative macrolide

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – MACROLIDES

adverse effects of verapamil (bradycardia and ↓ BP) with both erythromycin and clarithromycin

Erythromycin inhibits CYP3A4metabolism of felodipine and verapamil. Clarithromycin and erythromycin inhibit intestinal P-gp, which may ≠ bioavailability of verapamil

Monitor PR and BP closely; watch for bradycardia and ↓ BP. Consider ↓ dose of calcium channel blocker during macrolide therapy

MACROLIDES CARDIAC GLYCOSIDES – DIGOXIN

Digoxin concentrations may be ≠ by the macrolides

Uncertain; postulated that macrolides inhibit P-gp in both the intestine (≠ bioavailability) and kidney (↓ clearance). It is possible that alterations in intestinal flora may also have a role

Monitor digoxin levels; watch for digoxin toxicity

CLARITHROMYCIN, TELITHROMYCIN

CNS STIMULANTS – MODAFINIL

≠ plasma concentrations of modafinil, with risk of adverse effects

Due to inhibition of CYP3A4, which has a partial role in the metabolism of modafinil

Be aware. Warn patients to report dose-related adverse effects, e.g. headache anxiety

ERYTHROMYCIN DIURETICS – POTASSIUMSPARING

≠ eplerenone results in ≠ risk of hypotension and hyperkalaemia

Eplerenone is primarily metabolized by CYP3A4; there are no active metabolites. Erythromycin moderately inhibits CYP3A4, leading to ≠ levels of eplerenone

Eplerenone dosage should not exceed 25 mg daily

ERYTHROMYCIN H2 RECEPTOR BLOCKERS – CIMETIDINE

≠ efficacy and adverse effects of erythromycin, including hearing loss

≠ bioavailability Consider an alternative antibiotic, e.g. clarithromycin. Deafness was reversible with cessation of erythromycin

MACROLIDES IVABRADINE 1. Risk of arrhythmias with erythromycin 2. Possible ≠ levels with clarithromycin and telithromycin

1. Additive effect 2. Uncertain Avoid co-administration

Mechanism Precautions

SIMVASTATIN

atorvastatin and simvastatin; the risk of myopathy ≠10x when erythromycin is co-administered with a statin

Macrolides inhibit CYP3A4mediated metabolism of atorvastatin and simvastatin. Also, erythromycin and clarithromycin inhibit intestinal P-gp, which may ≠ bioavailability of statins

Avoid co-administration of macrolides with atorvastatin or simvastatin (temporarily stop the statin if the patient needs macrolide therapy). Manufacturers also recommend that patients are warned to look for the early signs of rhabdomyolysis when other statins are co-ingested with macrolides

ERYTHROMYCIN ROSUVASTATIN ↓ rosuvastatin levels with erythromycin

Uncertain Avoid chronic co-administration

ERYTHROMYCIN OESTROGENS Reports of ↓ contraceptive effect Possibly alteration of the bacterial flora necessary for recycling ethinylestradiol from the large bowel, although not certain in every case

Advise patients to use additional contraception for the period of antibiotic intake and for 1 month after stopping the antibiotic

ERYTHROMYCIN PARASYMPATHOMIMETICS – GALANTAMINE

≠ galantamine levels Inhibition of CYP3A4-mediated metabolism of galantamine

Be aware; watch for ≠ side-effects from galantamine

ERYTHROMYCIN, CLARITHROMYCIN

PERIPHERAL VASODILATORS – CILOSTAZOL

Cilostazol levels ≠ by erythromycin and possibly clarithromycin

Erythromycin and clarithromycin inhibit CYP3A4-mediated metabolism of cilostazol

Avoid co-administration

MACROLIDES PHOSPHODIESTERASE TYPE 5 INHIBITORS

≠ phosphodiesterase type 5 inhibitor levels with erythromycin, and possibly clarithromycin and telithromycin

Inhibition of metabolism ↓ dose of these phosphodiesterase inhibitors (e.g. start vardenafil at 5 mg)

CLARITHROMYCIN PROTON PUMP INHIBITORS – OMEPRAZOLE

≠ efficacy and adverse effects of both drugs

≠ plasma concentration of both drugs

No dose adjustment recommended. Interaction considered useful for Helicobacter pylori eradication

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