Macrolide tolerances

Stahhnau R, Lode H. Macrolides tolerability aud iuter-actious with other drugs. Auti-iufective Drugs Chemother 1996 14 155-62. 

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... 

Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Intravenous erythromycin (3 mg/kg) is beneficial in some patients with gastroparesis however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy. 

Macrolides Erythromycin useful in diabetic gastroparesis but tolerance develops... 

Epigastric distress This side effect is common and can lead to poor patient compliance for erythromycin. The new macrolides seem to be better tolerated by the patient gastrointestinal problems are their most common side effects. 

The use of cisapride and its benefit to harm balance in children has been reviewed (25). Overall it is well tolerated. The most common adverse effects are diarrhea, abdominal cramps, borborygmi, and colic. Serious adverse events are rare and include isolated cases of extrapyramidal reactions, seizures in epileptic patients, cholestasis, QT interval prolongation and ventricular dysrhythmias, anorexia, and enuresis. Interactions of cisapride with other drugs are similar to those reported in adults. Co-administration of drugs that inhibit CYP3A4, such as imidazoles, macrolide antibiotics, the antidepressant nefazodone, and protease inhibitors such as ritonavir, are contraindicated. Furthermore, co-administration of anticholinergic drugs can compromise the beneficial effects of cisapride. 

The gastrointestinal adverse effects are the most common untoward effects of the macrolides (Table 2). Nausea and vomiting associated with abdominal pain and occasionally diarrhea can be minor and transitory or, in a small percentage of patients, become severe enough to result in premature withdrawal. The rate of these adverse effects varies among the different antibiotics. In general, newer macrolides, such as azithromycin, clarithromycin, or roxithromycin, are better tolerated and cause fewer adverse effects than erythromycin. 

In spite of its in vitro activity against H. pylori, dirithromycin has not been effective in eradicating this organism in vivo, even in combination with metronidazole or proton pump inhibitor [133]. Dirithromycin is well tolerated, with gastrointestinal discomfort as the most frequently reported adverse effect [134]. The incidence and nature of abnormal clinical laboratory evaluation are similar to those of other macrolides, and these infrequent test abnormalities do not result in clinical manifestations, even in elderly patients [135]. 

For skin and soft tissue infections, roxithromycin is an effective and well-tolerated therapy for erysipelas and acne [162, 163]. As with other macrolide antibiotics, its immunomodulatory effects make it useful as an adjunctive therapy of psoriasis vulgaris [164]. Despite its in vitro activity against Borrelia burgdorferi, monotherapy with this macrolide was not effective for the treatment of Lyme borrelio-sis [165]. However, a small, nonrandomized, open prospective clinical study of 17 patients with confirmed late Lyme disease (stage n/III) showed a 76% complete recovery rate from a therapeutic combination of roxithromycin 300 mg... 

Nelfinavir mesylate is a peptidomimetic drug that is effective in HIV-1 and HIV-2 wild-type and ZDV-resistant strains, with median effective dose concentrations ranging from 9 to 60 nM (95% effective dose, 0.04 mg/mL) (98). After IV administration, the elimination half-life of nelfinavir was approximately 1 hour. In combination with D4T, nelfinavir reduced HIV viral load by approximately 98% after 4 weeks. It is well tolerated when used with azole antifungals (ketoconazole, fluconazole, or itraconazole) or macrolide antibiotics (erythromycin, clarithromycin, or azithromycin) however, it causes diarrhea and other side effects common to nonnucleoside drugs. Following oral administration, nelfinavir peak levels in plasma ranged from 0.34 mg/mL (10 mg/kg in the dog) to 1.7 mg/mL (50 mg/kg in the rat). In the dog, nelfinavir was slowly absorbed, and bioavailability was 47%. The drug appeared to be metabolized in the liver, and the major excretory route was in feces. 

Cp2TiMe2 and WOCI4 or WCle is an effective catalytic system for the metathesis of olefins. Importantly, the system tolerates carboxylic esters, and this enabled it to be used to effect the key steps in syntheses of civetone and other macrolides. Unsaturated ketones or acetals are not suitable substrates. 

The concerns over selection for resistance in commensal bacteria have been borne out in clinical studies where the majority of patients carry resistant organisms after treatment over a period of months. While macrolide resistance has become so common that this in itself is tolerable in certain settings, the fact that macrolide resistance is often carried on multi-resistance plasmids makes it more problematic. The official consensus has, therefore, been to avoid the promotion of macrolides for inflammation. However, in certain indications their use is so beneficial that concerns over resistance have been put aside by individual practitioners. 

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