Mechanism of Action

The macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit.² The advanced macrolides have improved binding to ribosomes compared with erythromycin. Telithromycin, the ketolide, has a similar target site, but its structure allows for enhanced binding, even in the presence of ribosomal mutations.

Mechanisms of Resistance

There are three major mechanisms of bacterial resistance to macrolides: drug efflux, ribosomal mutations, and enzymatic inactivation. Active efflux, mediated by mef genes, and ribosomal methylation of the target site, mediated by erm genes, are the most clinically important resistance mechanisms.³ Organisms containing the mef gene commonly express low-level resistance that can often be overcome with larger doses of the antibiotic. In contrast, erm-containing organisms, expressing phenotypic macrolide-lincosamide-streptogramin B resistance, often express high-level resistance, rendering macrolides clinically ineffective.

Antimicrobial Spectrum of Activity

The macrolides have activity against many classes of bacteria but have only sporadic activity within each of these groups. Their primary microbiologic activity is directed against respiratory and intracellular pathogens (Table 123-1).^3–21

Pharmacokinetics

Erythromycin base is acid labile but still adequately absorbed from the gastrointestinal (GI) tract. Food can decrease absorption (Table 123-2).^1,34–42 More stable oral formulations have complexed erythromycin with salts or esters to form erythromycin estolate, stearate, and ethylsuccinate. Erythromycin lactobionate has also been formulated to allow for intravenous (IV) delivery. Peak concentrations are 0.73 µg/mL after 250 mg base orally and 10 µg/mL after 500 mg IV.^1,34 The half-life is 1 to 1.5 hours.³⁵ Like all macrolides, erythromycin is widely distributed throughout the body, with higher tissue and intracellular concentrations compared with plasma. Erythromycin is not found in the cerebrospinal fluid in normal volunteers, but low levels have been reported in patients with meningitis.³⁵ Erythromycin is metabolized by cytochrome P450 (CYP) enzymes in the liver and excreted as inactive metabolites, primarily in the feces.

Clarithromycin is well absorbed from the GI tract (bioavailability 52%-55%), with or without food. An IV lactobionate form is available in some countries. A peak concentration of 1.65 to 2.12 mg/mL is obtained after a 500-mg oral dose with a half-life of 3 to 5 hours.³⁷ Similar pharmacokinetics are observed after dosing with the oral suspension, even in critically ill patients.⁴³ An extended-release formulation is available that delays the time to peak concentrations, provides similar total drug exposure, and allows for once-daily dosing.³⁶ Clarithromycin is well distributed throughout the body, with respiratory tract tissue and fluid concentrations 3 to 30 times that of the plasma and alveolar macrophage concentrations 10² to 10³ higher than plasma.³⁷ Cerebrospinal fluid concentrations are unknown. Hepatic metabolism is the major metabolic pathway and leads to the formation of 14-hydroxy-clarithromycin, an active metabolite with greater activity than the parent compound.^24,37 Clarithromycin is extensively metabolized, with 18.4% and 4.4% of unchanged drug excreted in the urine and feces, respectively, after a 250-mg dose.³⁷ Dosing changes are required in patients with moderate to severe renal dysfunction.

Azithromycin is 37% bioavailable when administered orally but is also available in an IV formulation.^39,44 Food has little effect on bioavailability. Peak concentrations in the plasma after a 500-mg dose range from 0.4 µg/mL for the oral formulation to 3.6 µg/mL for the IV formulation.^38,39 An extended-release formulation of a single 2-g azithromycin dose shows a similar overall pharmacokinetic profile to standard oral dosing.⁴⁰ Azithromycin is unique in its extended half-life of 14 to 40 hours, thus providing low sustained plasma concentrations that persist after cessation of dosing.³⁹ Whereas plasma concentrations are very low, azithromycin attains very high concentrations in tissues (100 times plasma) and phagocytes (3000-7000 times plasma).³⁸ Little to no azithromycin can be recovered from the cerebrospinal fluid, but brain tissue concentrations well exceed those in the serum.⁴⁵ Azithromycin is minimally metabolized and largely excreted via the biliary tract into the feces.

Roxithromycin is well absorbed orally, with peak plasma concentrations of 6.6 to 7.9 µg/mL after a 150-mg oral dose, and a half-life of 8.4 to 15.5 hours.⁴¹ Fasting prior to dosing improves absorption. Tissue concentrations exceed those of the plasma. Roxithromycin is metabolized by multiple mechanisms, with the majority of the dose excreted in feces.^41,46

Telithromycin is 57% bioavailable, with peak plasma concentrations of 1.9 and 2.3 µg/mL after single or multiple 800-mg doses, respectively.⁴² The half-life of telithromycin is 7 to 10 hours. Like the macrolides, telithromycin achieves high concentrations in respiratory tissues, alveolar macrophages, and peripheral polymorphonuclear cells. Telithromycin is metabolized by CYP3A4 and non-CYP–related mechanisms. Fecal elimination of metabolites accounts for the majority of the excretion of telithromycin.

Pharmacodynamics

The macrolides and ketolides appear to have time-dependent antibacterial activity that is slowly bactericidal or bacteriostatic.^47,48 The relationship between drug concentration and bacterial effect that best explain drug activity is the free (unbound) drug area under the inhibitory curve (fAUC: MIC).^47,48 Differences in the pharmacokinetics of the individual agents and limited analyses do not allow absolute determination of the best dosing strategy. It should be noted that pharmacodynamic principles for antibacterials have generally been related to plasma concentrations.⁴⁹ As noted earlier, the plasma concentrations of the macrolides are usually lower than those of the tissues, where the majority of bacteria reside. Models looking at both epithelial lining fluid (a proxy for lung concentrations) and serum concentrations suggest that increasing bacterial resistance favors telithromycin in its ability to maintain favorable pharmacodynamics.⁵⁰

Immune Modulation

Increasing evidence suggests that antibacterial macrolides have antiinflammatory effects.^51–53 In vitro studies have suggested macrolide effects on a number of cellular mechanisms within human cells.⁵⁴ In addition to in vitro and animal models, clinical data suggest that macrolides may have activity in the treatment of inflammatory diseases including cystic fibrosis, diffuse panbronchiolitis, chronic sinusitis, and inflammatory skin diseases.^51,53 Azithromycin has been cautiously recommended for use in cystic fibrosis for its antiinflammatory effects in patients colonized with Pseudomonas spp.⁵⁵

Adverse Effects

Gastrointestinal effects (nausea and diarrhea) are the most common adverse events observed with macrolide therapy.^41,56 Erythromycin has the highest level of GI effects.¹ Nausea with erythromycin may occur after IV dosing, as erythromycin is secreted into the GI tract via the bile.⁵⁷ The advanced macrolides have a similar incidence of GI adverse events. A review of azithromycin safety data from over 4000 patients treated with the immediate-release formulation reported GI event rates of 4% for diarrhea and 3% for nausea.⁵⁸ Gastrointestinal side effects in patients receiving the 2-g extended release azithromycin formulation were higher, with 12% nausea and 4% diarrhea.⁵⁹ In 3800 patients receiving immediate-release clarithromycin, similar side-effect rates were observed for nausea (3.8%) and diarrhea (3.0%). Tolerability of the extended-release clarithromycin formulation was similar to those with the immediate-release product.³⁶ Roxithromycin was reported to have a 4% incidence of side effects in 32,405 patients, with 75% being mild to moderate GI events.⁴¹ From data in clinical trials, GI side effects were reported frequently with telithromycin (10.8% diarrhea, 7.9% nausea), although considerable variability was observed across studies.⁵⁶

More serious events associated with macrolide use include prolongation of the QT interval, with torsades de pointes. In vitro estimations of HERG blockade suggest that clarithromycin ≈ roxithromycin > erythromycin.⁶⁰ In contrast, erythromycin was found to have a higher proarrhythmic potential than clarithromycin and azithromycin in animal models.⁶¹ Torsades de pointes has been reported in patients receiving macrolides. Sudden cardiac death was observed with greater frequency in patients taking erythromycin than amoxicillin in a large database study.⁶² Although the relative ability of the macrolides to cause arrhythmias is difficult to ascertain, arrhythmias associated with clarithromycin use were reported more frequently than with erythromycin.⁶³

Severe hepatotoxicity associated with telithromycin was identified through post-marketing surveillance in the United States.⁶⁴ Forty-two cases were available for full review, with 5 patients dying or requiring liver transplants. Clinical features included short time to hepatoxicity (as short as 1-2 days), fever, abdominal pain, and ascites. As a result of this toxicity, telithromycin use has been limited to more severely infected individuals with a careful review of risks and benefits.

Prokinetic Activity

The intestinal prokinetic activity of the macrolides has been used to improve GI mobility. Erythromycin has been shown to improve gastric emptying in a dose-dependent manner.⁶⁵ However, concerns have been raised over the potential to increase bacterial resistance with non-antibacterial macrolide use.⁶⁶ In a comparative multidose trial in patients with enteral nutrition intolerability, erythromycin provided better results than metoclopramide, with both agents showing efficacy.⁶⁷ Optimal use of erythromycin as a prokinetic agent is not yet confirmed.^66–68

Drug-Drug Interactions

Drug-drug interactions must be evaluated when considering macrolide therapy. The macrolides have variable degrees of inhibition of CYP3A4 and are also substrates of this enzyme. The use of macrolides with other drugs metabolized by CYP3A4 may result in increases in the second drug concentrations. Erythromycin is the most potent inhibitor of CYP3A4, followed by moderate inhibition with clarithromycin and roxithromycin and little to no inhibition by azithromycin.⁶⁹ Erythromycin has been implicated in multiple drug interactions, including with benzodiazepines, carbamazepine, cyclosporine, digoxin, HMG-CoA inhibitors, tacrolimus, and theophylline. Case reports of interactions with warfarin have been documented for many of the macrolides.⁷⁰ Clarithromycin, although in vitro a less potent inhibitor of CYP3A4, has been associated with a similar scope of clinical interactions.⁷⁰ As expected by its limited CYP activity, few clinically important interactions have been reported with roxithromycin and azithromycin.^39,41,70

The pharmacodynamic interaction between macrolides and other drugs known to increase the QT interval must not be overlooked (see Adverse Effects).

Key Points