Azithromycin and clarithromycin

INTRODUCTION — Azithromycin and clarithromycin are derivatives of the older macrolide antibiotic erythromycin. They are used in the treatment of a variety of infections, including community-acquired respiratory tract infections and mycobacterial infections. The structural modifications made to erythromycin significantly changed the spectrum of activity, dosing, and administration of these newer agents.

The spectrum of activity, mechanisms of action and resistance, pharmacokinetics, interactions with other drugs, and adverse effects of these newer macrolide antibiotics will be reviewed here. The use of these drugs for community-acquired pneumonia and coronavirus disease 2019 (COVID-19) are discussed separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization" and "COVID-19: Management in hospitalized adults" and "COVID-19: Management of adults with acute illness in the outpatient setting".)

The macrolides are sometimes used for their anti-inflammatory effects. This is discussed in detail separately. (See "Chronic lung allograft dysfunction: Bronchiolitis obliterans syndrome", section on 'Treatment of BOS' and "Diffuse panbronchiolitis", section on 'Macrolide antibiotics' and "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Azithromycin'.)

MECHANISM OF ACTION AND CHEMICAL STRUCTURE — The antibacterial mechanism of action of the newer macrolides is similar to that of erythromycin. They bind to the 50S subunit of bacterial ribosomes, leading to inhibition of transpeptidation, translocation, chain elongation, and, ultimately, bacterial protein synthesis [1,2].

Clarithromycin has the same macrolide 14-membered lactone ring as erythromycin; the only difference is that, at position six, a methoxy group replaces the hydroxyl group [1]. Azithromycin, in comparison, has a 15-membered ring and a methyl-substituted nitrogen replacing the 9A carbonyl group. For this reason, azithromycin is more precisely referred to as an azalide rather than a macrolide [2-4].

These structural changes have made the newer macrolides more acid stable than erythromycin, providing improved oral absorption, tolerance, and pharmacokinetic properties. The newer macrolides also have a broader spectrum of antibacterial activity than erythromycin [1,2].

SPECTRUM OF ACTIVITY — Azithromycin and clarithromycin have a broader spectrum of activity than erythromycin that includes many gram-negative, atypical, and mycobacterial organisms as well as gram-positive organisms. These agents are therefore used in a variety of infections including infections of the respiratory tract, mycobacterial infections, and sexually transmitted diseases [5-9].

While azithromycin and clarithromycin are active against the above organisms, they may not be the preferred treatment in all cases. When treating such infections, the susceptibility of the organism should be confirmed when possible. It is also important to note that these macrolides are often used as part of a treatment regimen and not as single agents (eg, for the treatment of mycobacterial diseases).

Azithromycin — Azithromycin is active against many gram-positive organisms, including erythromycin-susceptible Streptococcus pneumoniae, Group A, B, C, and G streptococcus, and methicillin-susceptible Staphylococcus aureus [10]. Compared with erythromycin, azithromycin has expanded activity against susceptible gram-negative organisms, including Haemophilus spp, Moraxella catarrhalis, Escherichia coli, Salmonella spp, Yersinia enterocolitica, Shigella spp, Campylobacter jejuni, Vibrio cholerae, Neisseria gonorrhoeae, Helicobacter pylori, and Bordetella pertussis.  

Azithromycin is also active against several atypical organisms including Mycoplasma pneumoniae, Legionella pneumophila, Chlamydophila pneumoniae, Babesia microti, and Ureaplasma spp [11].

Due to its activity against Mycoplasma genitalium, Haemophilus ducreyi (Chancroid), Klebsiella granulomatis (granuloma inguinale), Chlamydia trachomatis, and Neisseria gonorrhoeae, azithromycin is also used in the treatment of sexually transmitted infections (STIs) [7,9].

Due to its activity against non-tuberculous mycobacteria, azithromycin is used as a primary part of treatment regimens for Mycobacterium avium complex infections and may also be used in treatment regimens for Mycobacterium abscessus infections, if susceptibility is confirmed (see "Mycobacterium avium complex (MAC) infections in persons with HIV" and "Treatment of Mycobacterium avium complex pulmonary infection in adults"), and other rapidly growing mycobacterial infections: M. chelonae and M. fortuitum [5,12]. (See "Rapidly growing mycobacterial infections: Mycobacteria abscessus, chelonae, and fortuitum".)

Azithromycin use has also been reported in the treatment of select Pseudomonas aeruginosa infections. The mechanism of action for this organism is not definitively known but may be related to suppression of the inflammatory response, biofilm, and/or direct antibacterial effects [13]. The use of azithromycin for pseudomonal infections in patients with cystic fibrosis is discussed separately. (See "Cystic fibrosis: Antibiotic therapy for chronic pulmonary infection" and "Cystic fibrosis: Overview of the treatment of lung disease".)

Clarithromycin — Clarithromycin and it’s active metabolite 14-hydroxyclarithromycin have a similar spectrum of activity to azithromycin, with broad gram-positive, gram-negative, atypical, and antimycobacterial activity [10]

Clarithromycin is somewhat more active than azithromycin in vitro against wildtype S. pneumoniae and has similar activity against M. pneumoniae, C. pneumoniae, and Legionella pneumophilia [10]. Like azithromycin, clarithromycin has activity against Ureaplasma urealyticum and B. pertussis.

Clarithromycin is generally not used for STIs because it is less active than azithromycin against some organisms (M. genitalium) and because the pharmacokinetics and tolerance favor azithromycin. (See "Treatment of Chlamydia trachomatis infection" and "Approach to the patient with genital ulcers".)

RESISTANCE — Mechanisms of resistance to azithromycin or clarithromycin are the same as or similar to those of erythromycin. Alterations in ribosomal ribonucleic acid (RNA) can confer complete cross-resistance among erythromycin, azithromycin, and clarithromycin in gram-positive organisms.

Acquired macrolide resistance is an increasing problem. As with resistance to other drugs, antibiotic use has been associated with development of resistance. This relationship was directly demonstrated in a randomized double-blind trial in which 224 healthy volunteers were assigned to azithromycin, clarithromycin, or placebo; the end point was the development of pharyngeal carriage of macrolide-resistant streptococci [14]. The proportion of macrolide-resistant streptococci was 26 to 30 percent at baseline. Both macrolides significantly increased the proportion of macrolide-resistant streptococci compared with placebo, peaking at day 4 to 8, with a mean increase of about 50 percent (to an absolute proportion of over 80 percent) compared with a 4 percent increase with placebo. The increase in resistance was greater with azithromycin, a possible reflection of its much longer half-life. Clarithromycin resistance among M. avium complex and M. abscessus has also been reported [15,16].

Two main mechanisms of acquired macrolide resistance have been described [17-19]:

●Methylases encoded by the acquired erm (erythromycin ribosome methylase) genes (ermA, ermB, ermC) alter the macrolide-binding site on the bacterial ribosomal RNA, usually conferring a high degree of macrolide resistance [20]. In a study of selected resistance in volunteers, clarithromycin but not azithromycin selected for this type of resistance [14]. This mechanism usually also confers resistance to clindamycin.

●Active macrolide efflux pumps, encoded by the mef (macrolide efflux) msrA and msrB genes, confer a low to moderate degree of macrolide resistance [20-22].

In North America, efflux pump resistance mechanisms are more common, whereas the ribosomal modification mechanism is more common in Europe [23].

These mechanisms are both due to acquired genes and are responsible for erythromycin resistance in most gram-positive cocci (eg, S. aureus, S. pneumoniae, other streptococci). (See "Resistance of Streptococcus pneumoniae to the macrolides, azalides, and lincosamides".)

In contrast with the mechanisms of acquired resistance, intrinsic resistance exhibited by Enterobacterales, Pseudomonas spp, and Acinetobacter spp is due to decreased permeability of the outer cell envelope. Resistance to macrolides due to mutation of native chromosomal genes is uncommon because many bacteria have multiple copies of the ribosomal RNA genes that encode the macrolide-binding sites on the ribosome, and mutations of multiple gene copies are infrequent. Mycobacteria are an exception. Because they have a single chromosomal copy of the ribosomal RNA gene, selection of mutational resistance can occur readily.

M. abscessus and M. fortuitum organisms have a clinically important inducible macrolide-resistance gene (erm) that may not be detected on routine susceptibility testing [24-26]. (See "Microbiology of nontuberculous mycobacteria".)

Increasing resistance to azithromycin has been described in patients with syphilis, and it is therefore generally not recommended for this infection; the frequency of resistance varies with geographic area [27]. (See "Syphilis: Treatment and monitoring".)

Despite relatively high rates of in vitro macrolide-resistant S. pneumoniae, studies of hospitalized patients with community-acquired pneumonia (CAP) have shown improved outcomes when macrolides are included in combination antibiotic regimens. Macrolides have immunomodulatory and antiinflammatory effects that reduce interleukin 8 and tumor necrosis factor-alpha, which may in part explain the benefit [28-30]. The use of macrolides as part of a combination regimen for the treatment of CAP in hospitalized patients is discussed in detail separately. (See "Treatment of community-acquired pneumonia in adults who require hospitalization".)

METABOLISM AND PHARMACOKINETICS — Clarithromycin and azithromycin have improved oral absorption, longer serum half-lives, and better tissue and intracellular penetration than erythromycin.

Acid stability and food — Azithromycin and clarithromycin are stable at gastric pH. As a result, their bioavailability is better than that of erythromycin base (25 percent), and enteric coating is not required. The immediate-release tablet formulations and oral suspensions can be taken with or without food [1,4,31]. In contrast, azithromycin extended-release suspension should be taken on an empty stomach, and clarithromycin extended-release tablets should be administered with food.

The bioavailability of oral azithromycin tablets is 37 percent [32]. Despite this, serum concentrations are quite low, due to wide tissue distribution and high intracellular concentrations [33]. A regimen of 500 mg on day 1 followed by 250 mg/day for nine days leads to an average plasma azithromycin concentration of 0.21 mcg/mL [2-4,34,35]. The oral bioavailability of the clarithromycin immediate-release tablets (dosed every 12 hours) is approximately 50 percent; the mean steady-state peak serum concentration following 500 mg orally every 12 hours is 2 to 3 mcg/mL [36].

Tissue and intracellular penetration — Azithromycin and clarithromycin penetrate well into most tissues and fluids, which correlates with their clinical efficacy in a variety of infection sites [10]. Because these antibiotics also concentrate in tissues, epithelial lining fluid and alveolar macrophage concentrations are usually higher than plasma levels [1,4].

Azithromycin concentrates in tissues to a greater extent than clarithromycin (and erythromycin) [1,36]. Levels in sputum and lung are 10 to 100 times those in the plasma; alveolar macrophage and neutrophil concentrations are also higher [2,4,36]. In comparison, clarithromycin levels in the lung are only six to eight times higher than the plasma concentration [35]. These differences in intracellular penetration and plasma concentration make comparison of the activity of these agents by traditional, in vitro methods (such as minimum inhibitory concentration) difficult. The clinical significance of the better tissue penetration but lower plasma levels of azithromycin is not definitively known. High levels of azithromycin persist in tissues for extended periods, which is beneficial for dosing regimens and adherence, but may facilitate selection for the resistance seen with the agent.

Active metabolites — Azithromycin is excreted in the bile and then the feces, with very little unchanged drug appearing in the urine [2,4]. Several azithromycin metabolites have been identified, but none is known to be biologically active [4,37].

Clarithromycin is hydroxylated, N-demethylated, and hydrolyzed in the liver, utilizing the cytochrome P450 enzyme system. The major metabolite, 14-hydroxy-clarithromycin, is microbiologically active [1,2], and it is more active than the parent compound against some species. As an example, among H. influenzae isolates from patients with community-acquired pneumonia, the concentration at which 90 percent of organisms are inhibited (MIC₉₀) of the 14-OH metabolite was 3 mcg/mL compared with 9 mcg/mL for the parent compound [38]. This active clarithromycin metabolite is another variable that makes a comparison between clarithromycin and azithromycin difficult in vitro. Twenty to 30 percent of clarithromycin is excreted unchanged in the urine [39].

DOSING AND ADMINISTRATION — Compared with clarithromycin, azithromycin is typically given for a shorter period because of the long intracellular half-life (40 to 68 hours) and slow release from tissue sites. Thus, for many infections, a once-daily 5-day regimen is as effective as 10-day courses of the other macrolides.

The 2 g extended-release oral suspension of azithromycin (Zmax) has an even shorter regimen, as it is given as a single dose due to its long half-life [40]. Unlike azithromycin tablets and immediate-release suspension, the extended-release suspension should be taken one hour before or two hours after food. It must be consumed within 12 hours of being reconstituted.

Additional information on dosing and administration can be found in the Lexicomp drug monographs. (See "Azithromycin (systemic): Drug information" and "Clarithromycin: Drug information".)

SPECIAL POPULATIONS

Renal insufficiency — Azithromycin dosing does not require adjustment with decreased creatinine clearance. In patients with a creatinine clearance below 30 mL/minute, the dose of clarithromycin should be reduced by half or the dosing interval should be doubled.

Pregnancy — Although we have the most experience in pregnant females with erythromycin, azithromycin is now the most used macrolide in pregnant females.

Some studies have shown a potential association between macrolide use during pregnancy and congenital anomalies or other adverse outcomes [41-43], while other studies have not [44-48]. Additional research is needed to evaluate azithromycin- and clarithromycin-specific exposures and risks and potential confounding factors, including indication, trimester, dose, and follow-up.  

Azithromycin — Azithromycin is commonly used in pregnancy, although its safety, particularly during the first trimester, is unclear. While some studies suggest that azithromycin may be associated with congenital anomalies, this association is not consistently seen across studies and it is uncertain if the association is causal [37,49].

In one population-based cohort study evaluating over 100,000 children for a median of 5.8 years following birth, maternal azithromycin use during first trimester was associated with an increased risk of major medical malformations when compared with penicillin (adjusted risk ratio 1.55, 95% CI 1.19-2.03) [41]. However, results were not controlled for antibiotic indication. In two other studies, patients with cervical chlamydial infection received a 1 g dose of azithromycin and were followed for efficacy and toxicity [44,45]. Teratogenic effects were not noted, although it is not clear if neonatal examination and follow-up were required. In another study, 123 pregnant women taking azithromycin were prospectively followed along with two groups of matched controls [46]. The incidence of major malformations was similar in the azithromycin-exposed and -unexposed groups and was not more than the 1 to 3 percent that would be expected in the general population. However, all three of the malformations occurred in the infants of mothers who received five days of azithromycin for upper respiratory tract infections and the study was underpowered to detect a difference between the azithromycin-exposed and -unexposed groups.

Clarithromycin — Clarithromycin should not be used in pregnant females except in circumstances in which no alternative therapy is appropriate [50]. No adequate and well-controlled trials in pregnant females have been performed but teratogenic effects (including cleft palate, cardiovascular anomalies, and fetal growth restriction) have occurred in monkeys, rats, mice, and rabbits with plasma clarithromycin concentrations 2 to 17 times the levels normally achieved in humans.

ADVERSE REACTIONS — Azithromycin and clarithromycin, like erythromycin have been associated with gastrointestinal (GI) side effects, hepatoxicity, QT prolongation, and other cardiovascular events. Among these agents, azithromycin is generally most well tolerated, followed by clarithromycin and erythromycin.

The following provides a brief summary of some of the major adverse effects associated with azithromycin and clarithromycin. Details about specific adverse effects or interactions may be obtained by using the drug interactions program included within UpToDate.

Hepatotoxicity

Azithromycin — Postmarketing reports have identified various hepatic abnormalities in patients receiving azithromycin, including abnormal liver function tests, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure; some of these cases have resulted in death [51,52]. Azithromycin is therefore contraindicated in patients with a history of cholestatic jaundice or hepatic dysfunction associated with prior azithromycin use. It should be discontinued immediately if signs or symptoms of hepatitis occur.

Gastrointestinal toxicity — Azithromycin and clarithromycin are better tolerated than erythromycin, which may in part be related to the greater stability of the drugs and the lack of formation of the anhydrohemiketal degradation product thought to be responsible for some of the GI side effects associated with erythromycin [35,53]. Nonetheless, GI side effects remain common causes of discontinuation of azithromycin and clarithromycin. Rates of nausea, vomiting, diarrhea, and abdominal pain are generally 1 to 14 percent, but nausea rates as high as 28 percent have been reported with clarithromycin [8,54]. Abdominal cramping with subsequent loose stools is common with high doses of oral azithromycin [4,35] and may be related to stimulation of motilin. Azithromycin and clarithromycin, like erythromycin, have a dose-related effect on motilin receptors and can thereby stimulate the smooth muscle of the gastrointestinal tract. In fact, these drugs have been used clinically to stimulate gastric motility [55-58].

The intravenous formulation of azithromycin also causes gastrointestinal side effects including nausea (4 to 7 percent), vomiting (1.4 percent), diarrhea (4 to 9 percent), and abdominal pain (2 to 3 percent).

Patients can often tolerate these GI side effects and complete the treatment course. When that is not the case, and when appropriate clinically and feasible without reducing efficacy or adherence, we may try to reduce the dose or split the daily dose into smaller increments (eg, azithromycin 600 mg twice a day once weekly rather than 1200 mg as a single dose once weekly) for M. avium complex prophylaxis) [59].

Intolerance due to these GI symptoms with one drug does not necessarily predict intolerance to the other. Some patients, for example, have intolerable side effects with clarithromycin but not azithromycin, and vice versa.

Dysgeusia, on the other hand, is a relatively frequent complaint in patients who are treated with clarithromycin but is rare with azithromycin. If a dose reduction or change to azithromycin is not clinically appropriate, masking the taste with gum, hard candy, or ice chips can be attempted, although this usually does not reduce symptoms significantly.

QT interval prolongation and cardiovascular events — All macrolides have been associated with QT interval prolongation [60-68]. Before giving one of these agents, it is important for clinicians to determine if a patient is at risk for torsades de pointes (eg, history of a long QT interval, taking other medications that can prolong the QT interval (table 1), drug interactions, older age, electrolyte abnormalities) [69]. While it is prudent for clinicians to assess the risk of torsades de pointes when considering a macrolide for patients at risk for cardiovascular events [70], the potential for alternative antibiotics, including levofloxacin, to prolong the QT interval must also be considered. Similarly, the potential benefit seen in patients taking macrolides for certain indications should also be considered [71]. (See "Acquired long QT syndrome: Definitions, pathophysiology, and causes", section on 'Incidence' and "Fluoroquinolones", section on 'QT interval prolongation'.)

Macrolides have also been associated with increased cardiovascular and all-cause mortality [65,72-78]. However, this association has not been consistently demonstrated across studies [71,73,79-83]. Discrepancies among studies may be due to differences in patient populations (eg, age, presence of underlying cardiovascular disease, or certain P-glycoprotein polymorphisms), the severity of infections being treated, study methodologies, and other variables [84].

Because of potential for adverse cardiac events, the US Food and Drug Administration (FDA) has issued warnings about the use of azithromycin and clarithromycin:

●In 2013, the FDA issued a warning about the risk of QT interval prolongation and potentially fatal torsades de pointes among patients taking azithromycin [70]. The warning is based on a retrospective cohort study that showed that patients taking a five-day course of azithromycin had an increased risk of cardiovascular mortality (hazard ratio [HR] 2.88, 95% CI 1.79-4.63) and all-cause mortality (HR 1.85, 95% CI 1.25-2.75) when compared with propensity-matched controls who did not receive antibiotics [85]. The risk of cardiovascular death was also greater than that observed in propensity-matched controls taking either amoxicillin or ciprofloxacin; a nonstatistically significant increased risk was detected when comparing azithromycin with levofloxacin. Overall, the degree of risk appeared to be higher in patients with known cardiovascular disease and correlated with underlying disease severity.

●In 2017, the FDA issued a warning about increased mortality risk among patients with coronary artery disease who were taking clarithromycin [50,86]. The warning is based on a 10-year follow-up study of a randomized trial evaluating 4373 patients with stable coronary heart disease who received either clarithromycin or placebo for the treatment of atherosclerosis [74,87]. Patients who received clarithromycin had an increased risk of all-cause mortality (HR 1.10, 95% CI 1.02-1.38) over a 10-year period and increased risk of cardiovascular mortality during the first three years of follow-up (HR 1.42, 95% CI 1.09-1.84). In addition, some [62,63,74,88,89] but not all [75,90] epidemiologic studies evaluating clarithromycin for the treatment of underlying bacterial infections have shown an increased risk of cardiovascular mortality.

●In 2021, the FDA issued a warning about increased risk of acute cardiovascular death among all patients taking azithromycin, especially within the first five days of use [91]. The warning was based on observational studies [80], including one that showed increased risk of acute cardiovascular mortality with azithromycin compared with amoxicillin exposure (HR 1.71, 95% CI 1.06-2.76) [78]. However, causality has not been established.

Other — Severe reactions are rare but possible with any macrolide. These include anaphylaxis, Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS), pseudomembranous colitis, and exacerbations of myasthenia gravis [50,92]. A severe reaction to azithromycin may persist for several days due to its long half-life. Irreversible hearing loss has been reported with azithromycin, clarithromycin, and erythromycin [93-95]. Reversible hearing loss has also been reported following macrolide use, especially when they have been given at high doses [96-99].

An increased risk of cancer relapse and death was seen in hematopoietic stem cell transplant recipients who received long-term (two years) azithromycin for prevention of bronchiolitis obliterans [100]. This prompted early discontinuation of the study and an August 2018 FDA safety alert recommending against long-term prophylactic azithromycin in patients with blood or lymphatic cancers [101]. An increased rate of cancer relapse was also seen in hematopoietic stem cell transplant patients with acute lymphoblastic leukemia and acute myeloid leukemia or myelodysplastic syndrome receiving long-term azithromycin, and second neoplasms were seen in hematopoietic stem cell patients treated for bronchiolitis obliterans [102,103]. In contrast, cancer relapse rates and death were not increased in patients who received azithromycin for treatment of established moderate to severe chronic graft-versus-host disease or in allogenic stem cell transplant patients being treated for bronchiolitis obliterans [104,105].

DRUG INTERACTIONS — The macrolides have a variety of drug interactions, many of which are mediated by inhibition of hepatic cytochrome CYP (P450) 3A enzymes [106]. In contrast with clarithromycin and erythromycin, azithromycin is a much weaker inhibitor of the CYP3A4 hepatic microsomal enzyme so there are many fewer azithromycin-related, clinically significant drug-drug interactions. However, because azithromycin is a weak CYP3A4 inhibitor and a potent inhibitor of the P-glycoprotein drug transporter, clinically important drug interactions have also been reported with azithromycin, albeit less often. As examples, concomitant azithromycin may increase the risk of statin-associated rhabdomyolysis, including in patients with the heterozygous SLCO1B1 polymorphism, which decreases hepatic uptake of simvastatin [107,108]. Clarithromycin was associated with a higher risk of hemorrhage than azithromycin in patients over age 66 taking the direct-acting anticoagulants, dabigatran, apixaban, and rivaroxaban [109]. In another study, fatalities were reported in patients receiving clarithromycin and colchicine; specific colchicine dose reduction recommendations have been published [110,111].

In a population-based retrospective cohort study of older adults (mean age 76 years), coprescribing clarithromycin with a calcium channel blocker (compared with azithromycin plus a calcium channel blocker) was associated with a small but statistically significant increase in risk of hospitalization with acute kidney injury (absolute risk increase 0.22 percent, 95% CI 0.16-0.27 percent) [112]. Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (absolute risk increase 0.04 percent, 95% CI 0.02-0.07 percent) and all-cause mortality (absolute risk increase 0.43 percent, 95% CI 0.35-0.51 percent). Although the risks associated with the combined use of clarithromycin and calcium channel blockers appear to be small, they should be considered when deciding whether to use these agents in combination in older patients or other patients at risk for acute kidney injury.

Drug interactions that can occur as a result of additive pharmacologic effects should also be considered when prescribing macrolides. For example, both azithromycin and the antihistamine cetirizine can cause QTc prolongation. When combined for the treatment of upper respiratory tract infections, the prolongation over the first four days of therapy can be significant [113].

Details about specific interactions may be obtained by using the drug interactions program included within UpToDate.

SUMMARY

●Overview − Azithromycin and clarithromycin are azalide and macrolide antibiotics that are used in the treatment of several infections, including community-acquired respiratory tract infections, sexually transmitted infections, and mycobacterial infections. They are derivatives of the older macrolide antibiotic erythromycin. (See 'Introduction' above.)

●Mechanism of action − Their mechanism of action is similar to that of erythromycin. They bind to the 50S subunit of bacterial ribosomes, leading to inhibition of transpeptidation, translocation, chain elongation, and, ultimately, bacterial protein synthesis. (See 'Mechanism of action and chemical structure' above.)

●Chemical structure − Structural changes make azithromycin and clarithromycin more acid stable than erythromycin, providing improved oral absorption, tolerance, and pharmacokinetic properties. (See 'Mechanism of action and chemical structure' above.)

●Spectrum of activity − Azithromycin and clarithromycin also have a broader spectrum of activity than erythromycin and include activity against respiratory tract pathogens such as susceptible strains of Streptococcus pneumoniae, Haemophilus spp, Moraxella catarrhalis, and atypical pneumonia pathogens as well as against various other pathogens including some gram-positive and gram-negative bacteria and Mycobacterium avium complex. (See 'Spectrum of activity' above.)

●Antibiotic resistance mechanisms − Two main mechanisms of acquired macrolide resistance have been described:

•Methylases encoded by the erm (erythromycin ribosome methylase) genes (ermA, ermB, ermC) alter the macrolide-binding site on the bacterial ribosomal RNA, usually conferring a high degree of macrolide resistance as well as resistance to clindamycin.

•Active macrolide efflux pumps, encoded by the mef (macrolide efflux) msrA and msrB genes, confer a low to moderate degree of macrolide resistance. These mechanisms are responsible for erythromycin resistance in most gram-positive cocci (eg, Staphylococcus aureus, S. pneumoniae, other streptococci). In contrast with the mechanisms of acquired resistance, intrinsic resistance exhibited by Enterobacterales, Pseudomonas spp, and Acinetobacter spp is due to decreased permeability of the outer cell envelope. (See 'Resistance' above.)

●Use in pregnancy − Azithromycin is commonly used in pregnancy, although its safety, particularly during the first trimester, is unclear. Some but not all observational studies suggest azithromycin may be associated with congenital anomalies, however, it is uncertain if this association is causal. Clarithromycin should not be used in pregnant females except in circumstances in which no alternative therapy is appropriate. (See 'Pregnancy' above.)

●Adverse reactions − Multiple adverse events have been associated with azithromycin and clarithromycin. Gastrointestinal intolerance is common and substantially more pronounced with clarithromycin. Both agents can cause QT prolongation, and each has been associated with cardiovascular events, though causality is not determined. Additional adverse events, including exacerbation of myasthenia gravis and hearing loss, are detailed above. (See 'Adverse reactions' above.)

●Drug interactions − Azithromycin and clarithromycin have a variety of drug-drug interactions, many of which are mediated by inhibition of hepatic cytochrome CYP (P450) 3A enzymes and P-glycoprotein. In contrast with clarithromycin and erythromycin, azithromycin is a weak hepatic cytochrome P450 enzyme inhibitor, leading to fewer documented drug interactions (see 'Drug interactions' above). Specific interactions with other medications may be determined using the drug interaction program included with UpToDate.