Erythromycin toxicity

Theophylline serum levels can be increased by erythromycin. Toxicity may develop in those patients whose serum ieveis are at the higher end of the therapeutic range unless the dosage is reduced. The onset may be delayed for several days, and not all patients demonstrate this interaction. Erythromycin levels may possibly fall to subtherapeutic concentrations. 

Cyclosporine, tacrolimus Ketoconazole, erythromycin, etc. CYP3A4 Cydosporine/tacrolimus toxicity... 

The lincosamides, another group of anti-infectives, are effective against many gram-positive organisms, such as streptococci and staphylococci. However, because of their high potential for toxicity, the lincosamides are usually used only for the treatment of serious infections in which penicillin or erythromycin (a macrolide) is not effective... 

The effects of buspirone are decreased when the drug is administered with fluoxetine Increased serum levels of buspirone occur if the drug is taken with erythromycin or itraconazole Should any of these combinations be required, the dosage of buspirone is decreased to 2.5 mg BID, and the patient is monitored closely. Venlafaxine blood levels increase with a risk of toxicity when administered witii MAOIs or cimetidine There is an increased risk of toxicity when trazodone is administered with the phenothiazines and decreased effectiveness of trazodone when it is administered with carbamazepine Increased serum digoxin levels have occurred when digoxin is administered with trazodone There is a risk for increased phenytoin levels when phenytoin is administered witii trazodone... 

Erythromycin is considered the optimal drug for treatment of Campylobacter infections. The rate of resistance of Campylobacter to erythromycin remains low. Other advantages of this drug include ease of administration, low cost, lack of major toxicity, and narrow spectrum of activity.14 The recommended dosage for adults is 250 mg orally four times daily or 500 mg orally twice daily for 5 to 7 days. For very ill patients, treatment with gentamicin, imipenem, cefotaxime, or chloramphenicol is indicated, but susceptibility tests should be performed. 

Certain medications (e.g., cimetidine, diltiazem, erythromycin, fluoxetine, fluvoxamine, isoniazid, itraconazole, ketoconazole, nefazodone, propoxyphene, and verapamil) added to carbamazepine therapy may cause carbamazepine toxicity. 

Macrolides, both erythromycin and others, inhibit the synthesis of bacterial proteins. The primary mechanisms of protein synthesis are identical in humans and bacteria. However, there is a significant difference that allows a specific antibiotic to exhibit selective toxicity with respect to bacteria. 

The macrolide antibacterials (including erythromycin, clarithromycin and telithromycin) are often implicated in interactions, most frequently as a result of inhibition of the CYP3A4 enzyme system in the liver and enterocytes. Erythromycin inhibits the metabolism of carbamazepine, ciclosporin and theophylline significant increases in serum levels and features of toxicity have been documented. Careful clinical and pharmacokinetic monitoring are required in a patient taking any of these drugs who requires concomitant erythromycin. 

The metabolism of ciclosporin is inhibited by diltiazem, verapamil, azole antifungal agents, erythromycin and clarithromycin with resultant potential for renal, hepatic and CNS toxicity. These interactions have been investigated as a cost saving device in organ transplant recipients, with the aim of using a lower dose of ciclosporin to achieve immunosuppression. 

Carbamazepine also can induce the enzymes that metabolize other anticonvulsant drugs, including phenytoin, primidone, phenobarbital, valproic acid, clonazepam, and ethosuximide, and metabolism of other drugs the patient may be taking. Similarly, other drugs may induce metabolism of carbamazepine the end result is the same as for autoinduction, and the dose of carbamazepine must be readjusted. A common drug-drug interaction is between carbamazepine and the macrolide antibiotics erythromycin and trolean-domycin. After a few days of antibiotic therapy, symptoms of carbamazepine toxicity develop this is readily reversible if either the antibiotic or carbamazepine is discontinued. 

B) Exhibit decreased metabolism of erythromycin, with potential toxicity... 

Macrolides bind to the SOS ribosomal subunit of bacteria but not to the SOS mammalian ribosome this accounts for its selective toxicity. Binding to the ribosome occurs at a site near peptidyltransferase, with a resultant inhibition of translocation, peptide bond formation, and release of oligopeptidyl tRNA. However, unlike chloramphenicol, the macrolides do not inhibit protein synthesis by intact mitochondria, and this suggests that the mitochondrial membrane is not permeable to erythromycin. 

Nefazodone substantially decreases the clearance rate for triazolam, which results in a 400% increase in triazolam s serum levels (131). Erythromycin can also interfere with the metabolism of triazolam, resulting in decreased clearance and increased plasma levels, possibly causing toxicity. Troleandomycin and other macrolide antibiotics, such as clarithromycin, flurithromycin, josamycin, midecamycin, or roxithromycin, also may inhibit triazolam s metabolism (132). The coadministration of itraconazoie and triazolam can produce a marked elevation of triazolam plasma levels associated with statistically significant impairment of psychomotor tests and a prolongation of other effects (e.g., amnesia, lethargy, and confusion) for hours after awakening ( 133). 

BZD hypnotics such as midazolam and triazolam are primarily metabolized via the P450 3A3/4 microenzyme system. Other BZDs often used as hypnotics, such as diazepam, can also be metabolized by CYP 33/4 and CYP 2C19. Any drugs that act as inhibitors or inducers of these isoenzymes could increase or decrease BZD levels, respectively (350). Thus, ketoconazole, macrolide antibiotics (e.g., erythromycin), SSRIs (e.g., fluoxetine-norfluoxetine and fluvoxamine), and other antidepressants (especially nefazodone) may decrease clearance and increase BZD levels to potentially toxic ranges. Conversely, rifampacin, CBZ, and dexamethasone may increase clearance and decrease BZD levels to potentially subtherapeutic ranges. 

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

Erythromycin Prevents bacterial protein synthesis by binding to the 50S ribosomal subunit Bacteriostatic activity against susceptible bacteria Community-acquired pneumonia t pertussis corynebacterial, and chlamydial infections Oral, IV hepatic clearance (half-life 1.5 h) dosed every 6 h cytochrome P450 inhibitor Toxicity Gastrointestinal upset, hepatotoxicity, QTC prolongation... 

Metronidazole plus a luminal amebicide is the treatment of choice for amebic colitis and dysentery. Tetracyclines and erythromycin are alternative drugs for moderate colitis but are not effective against extraintestinal disease. Dehydroemetine or emetine can also be used, but are best avoided because of toxicity. 

FIGURE 6—18. The antidepressants fluoxetine, fluvoxamine, and nefazodone are all inhibitors of CYP450 3A4. More potent inhibitors of this enzyme include the nonpsychotropic drugs ketoconazole, erythromycin, and protease inhibitors. If a 3A4 inhibitor is given with cisapride or astemazole, levels of these substrates can rise to toxic levels. Thus, fluoxetine, fluvoxamine, and nefazodone cannot be given with cisapride or astemazole. 

Rhabdomyolysis due to a short course of erythromycin in a 73-year-old man who had taken lovastatin for 7 years was accompanied by signs of multiple organ toxicity so severe as to mimic sepsis (13). 

Wong PW, Dillard TA, Kroenke K. Multiple organ toxicity from addition of erythromycin to long-term lovastatin therapy. South Med J 1998 91(2) 202-5. 

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