Macrolide antibiotics interactions

Poehlsgaard J, Douthwaite S. Macrolide antibiotic interaction and resistance on the bacterial ribosome. Curr Opin Investig Drugs. 2003 4 140-148. 

As stated in Section II.B, macrolide antibiotics interact with peptidyltransferase by forming hydrogen bonds usually but occasionally hydrophobic bonds present in a 508 ribosomal subunit. That is why noncovalent interactions appear to be the key to the antibiotic flexibility and specificity observed between different macrolides and their derivatives and also probably to the solubility of the drugs in water. 

In terms of the basic principle of the secondary structure, E. coli 23S rRNA has six domains [166]. Macrolide antibiotics interact with two regions (in domains II and V) of 23S rRNA [166-168], and domain V plays a particularly important role on the occasion of translation, that is, during the peptidyltransferase reaction [26, 27, 98-100, 169]. 

Sirolimus is currently the only FDA-approved ToR inhibitor. One of its derivatives, everolimus, is in phase III clinical trials and has been approved for use in some European countries.30 Sirolimus is a macrolide antibiotic that has no effect on cal-cineurin phosphatase.11,31,32 Sirolimus inhibits T cell activation and proliferation by binding to and inhibiting the activation of the mammalian ToR, which suppresses cellular response to IL-2 and other cytokines (i.e., IL-4 and IL-15J.11,31 Studies have shown that sirolimus may be used safely and effectively with either cyclosporine or tacrolimus as a replacement for either azathioprine or mycophenolate mofetil.33 However, when using both sirolimus and cyclosporine as part of a patient s immunosuppressant therapy, because of a drug interaction between the two resulting in a marked increase in sirolimus concentrations, it is recommended to separate the sirolimus and cyclosporine doses by at least 4 hours. Sirolimus also can be used as an alternative agent for patients who do not tolerate calcineurin inhibitors due to nephrotoxicity or other adverse events.34... 

The macrolide antibiotic filipin interacts with 3-p-hydroxysterols such as cholesterol in the plasma membrane to form filipin-sterol complexes (59). Subsequently, the filamentous caveolin-l-coat rapidly disassembles, which... 

Drugs that may interact with rifabutin include the following Anticoagulants, azole antifungal agents, benzodiazepines, beta blockers, buspirone, corticosteroids, cyclosporine, delavirdine, doxycycline, hydantoins, indinavir, rifamycins, losartan, macrolide antibiotics, methadone, morphine, nelfinavir, quinine, quinidine, theophylline, aminophylline, tricyclic antidepressants, and zolpidem. 

Er hromycin Sulfisoxazole (Eryzole, Pediazole) [Anti-infective, Macrolide/Sulfonamide] Uses Upper lower resp tract bacterial Infxns H. influenzae otitis media in children Infxns in PCN-allergic pts Action Macrolide antibiotic w/ sulfonamide Dose Adults. Based on erythromycin content 400 mg erythromycin/1200 mg sulfisoxazole PO q6h Feds > 2 mo. 40-50 mg/kg/d erythromycin 150 mg/kg/d sulfisoxazole PO -s- q6h max 2 g/d erythromycin or 6 g/d sulfisoxazole x 10 d in renal impair Caution [C (D if near term), +] w/ PO anticoagulants, hypoglycemics, phenytoin, cyclosporine Contra Infants <2 mo Disp Susp SE GI upset Additional Interactions T Effects of sulfonamides W/ ASA, diuretics, NSAIDs, probenecid EMS See Erythromycin OD See Erythromycin... 

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. 

Maximal plasma concentrations occur 2 to 3 hours after oral administration of reboxetine (178). Reboxetine has linear pharmacokinetics over its clinically relevant dosing range and a half-life of approximately 12 hours. For this latter reason, a twice a day, equally divided dosing schedule was used during clinical trial development. Its clearance is reduced and half-life becomes longer as a function of advanced age (mean = 81 years of age) and renal and hepatic impairment ( 178, 322, 323). Reboxetine is principally metabolized by CYP 3A3/4 such that its dose should be reduced when used in combination with drugs that are substantial inhibitors of CYP (e.g., certain azole antifungals, certain macrolide antibiotics). Reboxetine itself, however, does not cause detectable inhibition of CYP 3A3/4 based on formal in vivo pharmacokinetic interaction studies as well as its own linear pharmacokinetics. 

With the important exception of additive effects when combined with other CNS depressants, including alcohol, BZDs interact with very few drugs. Disulfiram (see the section The Alcoholic Patient in Chapter 14) and cimetidine may increase BZD blood levels, and diazepam may increase blood levels of digoxin and phenytoin. Antacids may reduce the clinical effects of clorazepate by hindering its biotransformation to desmethyidiazepam. Coadministration of a BZD and another drug known to induce seizures may possibly increase seizure risk, especially if the BZD is abruptly withdrawn. Furthermore, as noted earlier, important interactions have been reported among nefazodone, erythromycin, troleandomycin, and other macrolide antibiotics, as well as itraconazole. In each case, metabolism is inhibited, and triazolam levels can increase significantly. 

Rapamycin, also known as sirolimus, is a new macrolide antibiotic that interacts with cellcycle regulating proteins and inhibits cell division. The main side effects are thrombocytopenia and hyperlipidaemia. There is also evidence that it causes interstitial pneumonitis, which may resolve on withdrawing the drug or dose reduction. The drug is currently being assessed for combination therapy with tacrolimus or cyclosporin. 

Mechanism-based inhibitors or suicide substrates seem to be particularly prevalent with CYP3A4. Such compounds are substrates for the enzyme, but metabolism is believed to form products that deactivate the enzyme. Several macrolide antibiotics, generally involving a tertiary amine function, are able to inhibit CYP3A4 in this manner (147,148). Erythromycin is one of the most widely used examples of this type of interaction, although there are other commonly prescribed agents that inactivate CYP3A4 (149-151), and a consideration of this phenomenon partially explains a number of interactions that are not readily explained by the conventional in vitro data (152). 

Ludden TM. Pharmacokinetic interactions of the macrolide antibiotics. Clin Pharmacokinet 1985 10 63-79. 

As a consequence, intramolecular and intermolecular interactions lead to unexpected chemical properties. In particular, those derivatives with lipophilic side chains tend to aggregate and behave like detergents even in dilute solutions. This property should be taken into account, when ansamycins are used at high concentrations in biological systems. The ansamysins do not contain lactone bonds in their ansa ring, which sets them clearly apart from the macrolide antibiotics. 

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