chapter
Antibiotics – quinolones
Pages 6

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

ANTIBIOTICS – QUINOLONES

QUINOLONES DRUGS THAT PROLONG THE Q-T INTERVAL

QUINOLONES (especially moxifloxacin)

1. ANTIARRHYTHMICS – amiodarone, disopyramide, procainamide, propafenone 2. ANTIBIOTICS – macrolides (especially azithromycin, clarithromycin, parenteral erythromycin, telithromycin), quinupristin/ dalfopristin 3. ANTICANCER AND IMMUNOMODULATING DRUGS – arsenic trioxide 4. ANTIDEPRESSANTS – TCAs, venlafaxine 5. ANTIEMETICS – dolasetron 6. ANTIFUNGALS – fluconazole, posaconazole, voriconazole 7. ANTIHISTAMINES – terfenadine, hydroxyzine, mizolastine 8. ANTIMALARIALS – artemether with lumefantrine, chloroquine, hydroxychloroquine, mefloquine, quinine 9. ANTIPROTOZOALS – pentamidine isetionate 10. ANTIPSYCHOTICS – atypicals, phenothiazines, pimozide 11. BETA-BLOCKERS – sotalol 12. BRONCHODILATORS – parenteral bronchodilators 13. CNS STIMULANTS – atomoxetine

Risk of ventricular arrhythmias, particularly torsades de pointes

Additive effect; these drugs cause prolongation of the Q-T interval

Avoid co-administration

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – QUINOLONES

in those with epilepsy

Care in co-administering antiepileptics and NSAIDs in patients with epilepsy

CIPROFLOXACIN OPIOIDS 1. Effects of methadone ≠ by ciprofloxacin 2. ↓ levels of ciprofloxacin with opioids

1. Ciprofloxacin inhibits CYP1A2-, CYP2D6-and CYP3A4-mediated metabolism of methadone 2. Uncertain

1. Watch for ≠ effects of methadone 2. Avoid opioid premedication when ciprofloxacin is used as surgical prophylaxis

QUINOLONES ANTACIDS ↓ levels of these antibiotics ↓ absorption Separate quinolones and antacids by 2-6 hours. Separate tetracyclines and antacids by 2-3 hours

QUINOLONES ANTICANCER AND IMMUNOMODULATING DRUGS

NALIDIXIC ACID MELPHALAN Risk of melphalan toxicity Uncertain Avoid co-administration

CIPROFLOXACIN METHOTREXATE ≠ plasma concentrations of methotrexate, with risk of toxic effects of methotrexate, e.g. liver cirrhosis, blood dyscrasias which may be fatal, pulmonary toxicity, stomatitis. Haematopoietic suppression can occur abruptly. Other adverse effects include anorexia, dyspepsia, gastrointestinal ulceration and bleeding and pulmonary oedema

Ciprofloxacin ↓ renal elimination of methotrexate. Ciprofloxacin is known to cause renal failure and interstitial nephritis

Although the toxic effects of methotrexate are more frequent with high doses of methotrexate, it is necessary to do FBC, liver and renal function tests before starting treatment even with low doses, repeating these tests weekly until therapy is stabilized and thereafter every 2-3 months. Patients should be advised to report symptoms such as sore throat and fever immediately, and also any gastrointestinal discomfort. A profound drop in white cell or platelet counts warrants immediate stoppage of methotrexate therapy and initiation of supportive therapy. Consider a nonreacting antibiotic

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Mechanism Precautions Attributed to additive effects Avoid exposure of skin and eyes to

direct sunlight for 30 days after porfimer therapy

CIPROFLOXACIN CICLOSPORIN Ciprofloxacin may ↓ immunosuppressive effect (pharmacodynamic interaction)

Ciprofloxacin ↓ inhibitory effect of ciclosporin on IL-2 production to ↓ immunosuppressive effect

Avoid co-administration

NORFLOXACIN CICLOSPORIN ≠ plasma concentrations of ciclosporin, with risk of nephrotoxicity, myelosuppression, neurotoxicity and excessive immunosuppression, with risk of infection and posttransplant lymphoproliferative disease

Inhibition of CYP3A4-mediated metabolism of ciclosporin; these inhibitors vary in potency

Monitor plasma ciclosporin levels to prevent toxicity. Monitor renal function

NORFLOXACIN MYCOPHENOLATE Significant ↓ plasma mycophenolate concentrations (60% with rifampicin)

Inhibition of metabolism of mycophenolate

Avoid co-administration

QUINOLONES ANTICOAGULANTS – ORAL Occasional episodes of ≠ anticoagulant effect

Uncertain at present Monitor INR every 2-3 days

CIPROFLOXACIN ANTIDEPRESSANTS – DULOXETINE

≠ duloxetine levels, with risk of side-effects, e.g. arrhythmias

Inhibition of metabolism of duloxetine

Avoid co-administration

QUINOLONES ANTIDIABETIC DRUGS

QUINOLONES ACARBOSE, METFORMIN, NATEGLINIDE, REPAGLINIDE, PIOGLITAZONE, ROSIGLITAZONE, SULPHONYLUREAS

≠ risk of hypoglycaemic episodes Mechanism uncertain. Ciprofloxacin is a potent inhibitor of CYP1A2. Norfloxacin is a weak inhibitor of CYP1A2, but these may inhibit other CYP isoenzymes to varying degrees

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – QUINOLONES

Both hyperglycaemia and hypoglycaemia

Altered glycaemic control requires frequent monitoring

Mechanism for hypoglycaemia is not known

CIPROFLOXACIN ANTIEPILEPTICS – PHENYTOIN Variable effect on phenytoin levels Unknown Monitor phenytoin levels

CIPROFLOXACIN, LEVOFLOXACIN, NALIDIXIC ACID, NORFLOXACIN

ANTIGOUT DRUGS – PROBENECID

≠ ciprofloxacin, nalidixic acid and norfloxacin levels

Uncertain Watch for ≠ incidence of side-effects. Moxifloxacin, ofloxacin and sparfloxacin do not seem to interact and could be used as alternative therapy

QUINOLONES ANTIMIGRAINE DRUGS – ZOLMITRIPTAN

Possible ↓ plasma concentrations of zolmitriptan, with risk of inadequate therapeutic efficacy

Possibly induced metabolism of zolmitriptan

Be aware of possibility of ↓ response to triptan and consider ≠ dose if effect is considered to be due to interaction

CIPROFLOXACIN ANTIPARKINSON’S DRUGS – ROPINIROLE

≠ ropinirole levels Inhibition of CYP1A2-mediated metabolism

Watch for early features of toxicity (nausea, drowsiness)

CIPROFLOXACIN ANTIPSYCHOTICS – CLOZAPINE, OLANZAPINE

≠ clozapine levels and possibly ≠ olanzapine levels

Ciprofloxacin inhibits CYP1A2; clozapine is primarily metabolized by CYP1A2, while olanzapine is partly metabolized by it

Watch for the early features of toxicity to these antipsychotics. ↓ dose of clozapine and olanzapine may be required

QUINOLONES ANTIVIRALS

QUINOLONES DIDANOSINE ↓ efficacy of ciprofloxacin and possibly levofloxacin, moxifloxacin, norfloxacin and ofloxacin with buffered didanosine

Cations in the buffer of didanosine preparation chelate and adsorb ciprofloxacin. Absorption of the other quinolones may be ↓ by the buffered didanosine formulation, which raises gastric pH

Give the antibiotic 2 hours before or 6 hours after didanosine. Alternatively, consider using the entericcoated formulation of didanosine, which does not have to be given separately

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Mechanism Precautions Unknown; possibly additive side-

effect Avoid combination in patients with past medical history of epilepsy. Consider an alternative antibiotic

QUINOLONES BRONCHODILATORS – 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

CIPROFLOXACIN CALCIUM ↓ antibiotic levels ↓ absorption Separate doses by at least 2 hours CIPROFLOXACIN, NORFLOXACIN

DAIRY PRODUCTS ↓ norfloxacin levels, with risk of therapeutic failure

The calcium from dairy products is thought to form an insoluble chelate with norfloxacin, leading to ↓ absorption from the gut

Dairy products should be avoided for 1-2 hours before and after taking norfloxacin. Alternatively, moxifloxacin, enoxacin, lomefloxacin and ofloxacin can be used as alternative therapies as they show minimal interaction

QUINOLONES DRUG DEPENDENCE THERAPIES – BUPROPION

≠ risk of seizures. This risk is marked in elderly people, in patients with a history of seizures, with addiction to opiates/cocaine/ stimulants, and in diabetics treated with oral hypoglycaemics or insulin

Bupropion is associated with a dose-related risk of seizures. These drugs, which lower seizure threshold, are individually epileptogenic. Additive effects occur when they are combined

Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis)

QUINOLONES IRON – ORAL ↓ plasma concentrations of these drugs, with risk of therapeutic failure

Iron chelates with and ↓ their absorption

Separate doses of other drugs as much as possible and monitor their effects

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DRUGS TO TREAT INFECTIONS ANTIBIOTICS – QUINOLONES

Tizanidine is a substrate for CYP1A2. Ciprofloxacin is a potent inhibitor of CYP1A2 and is thought to inhibit the presystemic metabolism, resulting in ≠ absorption and levels of tizanidine

Avoid co-administration

CIPROFLOXACIN PERIPHERAL VASODILATORS – PENTOXIFYLLINE

Ciprofloxacin may ≠ pentoxifylline levels

Uncertain; likely to be due to inhibition of hepatic metabolism

Warn patients of the possibility of adverse effects of pentoxifylline

CIPROFLOXACIN SEVELAMER ↓ plasma concentrations of ciprofloxacin

↓ absorption Separate doses as much as possible

CIPROFLOXACIN SODIUM BICARBONATE ↓ solubility of ciprofloxacin in the urine, leading to ≠ risk of crystalluria and renal damage

≠ urinary pH caused by sodium bicarbonate can result in ↓ ciprofloxacin solubility in the urine

If both drugs are used concomitantly, the patient should be well hydrated and be monitored for signs of renal toxicity

QUINOLONES STRONTIUM RANELATE ↓ levels of these antibiotics ↓ absorption Avoid co-administration QUINOLONES SUCRALFATE ↓ levels of these antibiotics ↓ absorption of these antibiotics Give the antibiotics at least 2 hours

before sucralfate

CIPROFLOXACIN THYROID HORMONES – LEVOTHYROXINE

↓ levels of levothyroxine and possible therapeutic failure

The mechanism has not been elucidated, the concurrent administration of ciprofloxacin with levothyroxine may interfere with the absorption of levothyroxine and result in lower than expected levels

The interaction may be minimized by separating dosing of the two agents; ciprofloxacin should be taken several hours before or after taking levothyroxine

CIPROFLOXACIN ZINC ↓ antibiotic levels ↓ absorption Separate doses by at least 2 hours