Macrolides: A Canadian Infectious Disease Society position paper

Can J Infect Dis. 2001 Jul-Aug; 12(4): 218–231.

PMCID: PMC2094825

Macrolides: A Canadian Infectious Disease Society position paper

S McKenna, BScPhm,¹ GA Evans, MD,² and Canadian Infectious Disease Society Antimicrobial Agents Committee^*

¹Department of Pharmacy Services, Kingston General Hospital, Kingston, Ontario;

²Division of Infectious Diseases, Department of Medicine, Queen's University, Kingston, Ontario;

^*Members: Drs Susan King, Toronto, Ontario; Coleman Rotstein, Hamilton, Ontario; Michel Laverdiere, Montreal, Quebec; Peter Phillips, Vancouver, British Columbia

Correspondence: GA Evans, Division of Infectious Diseases, Room 3013, Etherington Hall, Queen's University, 94 Stuart Street, Kingston, Ontario K7L 3N6. Telephone 613-533-6619, fax 613-533-6695, e-mail gae/at/post.queensu.ca

Declared conflicts: Dr Evans has received research support and speaking honoraria from Abbott Laboratories Ltd and Pfizer Canada Inc

Received April 23, 2001; Accepted April 23, 2001.

This article has been cited by other articles in PMC.

Abstract

Since the introduction of erythromycin in 1965, no new compounds from the macrolide antimicrobial class were licensed in Canada until the 1990s. Clarithromycin and azithromycin, since their introduction, have become important agents for treating a number of common and uncommon infectious diseases. They have become prime agents in the treatment of respiratory tract infections, and have revolutionized the management of both genital chlamydial infections, by the use of single-dose therapy with azithromycin, and nontuberculous mycobacterial infections, by the use of clarithromycin. The improvement of clarithromycin and azithromycin over the gastrointestinal intolerability of erythromycin has led to supplanting the use of the latter for many primary care physicians. Unfortunately, the use of these agents has also increased the likelihood for misuse and has raised concerns about a resultant increase in the rates of macrolide resistance in many important pathogens, such as Streptococcus pneumoniae. This paper reviews the pharmacology and evidence for the current indications for use of these newer agents, and provides recommendations for appropriate use.

Key Words: Azithromycin, Clarithromycin, Erythromycin, Macrolides, Review, Therapeutic use

Erythromycin A is a naturally occurring, microbiologically active compound of the macrolide class of antibiotics. Chemical modification of erythromycin A's 14-membered lactone ring has led to the formation of semisynthetic derivatives with not only improved bioavailability and tolerability, but also expanded spectrums of microbiological activity and improved pharmacokinetic profiles. Such modifications produced clarithromycin, classified as a macrolide because it retains the central 14-membered lactone ring (1,2), and azithromycin, classified as an azalide due to its 15-membered aglycone ring (1). The latter two compounds are the newest agents in the macrolide class licensed for use in Canada. Roxithromycin and dirithromycin are available in other countries.

These compounds are clinically active against Gram-positive and Gram-negative cocci, and Gram-negative bacilli (primarily Haemophilus influenzae, Legionella species, Moraxella catarrhalis, Campylobacter jejuni, Bordatella pertussis and Helicobacter pylori). Azalides such as azithromycin have exhibited superior activity against Gram-negative pathogens and are generally less active against Gram-positive pathogens. Intracellular pathogens such as Chlamydia species, Mycoplasma species, Ureaplasma species, Borrelia species and nontuberculous mycobacteria species show varying susceptibilities. On the basis of their microbial activity, both the macrolides and azalides have been shown to be clinically useful in the treatment of uncomplicated skin and soft tissue infections, upper and lower respiratory tract infections, sexually transmitted Chlamydia trachomatis infection and peptic ulcer disease. Additionally, the improved pharmacokinetic profiles and acid stability exhibited by the newer agents may lead to enhanced patient adherence through less frequent dosing and improved bioavailability in the presence of food.

MECHANISMS OF ACTION AND RESISTANCE

Macrolides and azalides exert their antimicrobial activity by inhibiting translocation of aminoacyl transfer RNA through reversible binding to the 50S ribosomal subunit. In this manner, bacterial protein synthesis is inhibited (2). Generally, these agents are considered to be bacteriostatic. However, bactericidal activity has been demonstrated in vitro against certain strains of Streptococcus pyogenes and Streptococcus pneumoniae. Additionally, clarithromycin (and its active 14-hydroxy metabolite) and azithromycin have exhibited bactericidal activity against H influenzae (2). The antibacterial activity of clarithromycin and azithromycin is most likely enhanced by unique tissue distribution and elimination profiles, which result in high and sustained tissue levels relative to those produced with the use of erythromycin (3). These pharmacokinetics provide a probable explanation for the enhanced clinical activity of the newer agents against intracellular pathogens such as Chlamydia species (2,3).

Microbial resistance to macrolides and azalides may be either intrinsic or acquired in nature (4). At physiological pH, macrolides exhibit a low degree of ionization. The intrinsic resistance of the vast majority of Gram-negative bacilli and enterococci to these hydrophobic drugs is believed to be due to outer membrane impermeability (2). Acquired resistance occurs most frequently via either the induction of enzymes causing ribosomal methylation, a target site modification or active efflux. Ribosomal target site modification is mediated by one of a number of erm genes (ermA, ermB, ermC, ermTR). These genes modify the ribosome through methylation of a specific adenine residue in a conserved region of the 23S ribosome that interacts with macrolide, lincosamide and streptogramin type B antibiotics, conferring the so-called 'MLS_B' phenotype (5). Macrolide, lincosamide and streptogramin (MLS) resistance typically results in high levels of resistance to all macrolides leading to erythromycin minimum inhibitory concentrations (MICs) of 64 mg/L or greater. Active efflux of macrolides and azalides has been demonstrated in both staphylococci and streptococci, and generally confers low level resistance to these drugs (4,6). In Staphylococcus aureus, efflux is mediated through msrA and msrB genes encoding an adenosine triphosphate-dependent efflux pump, and results in both macrolide and streptogramin resistance or the MS phenotype. In S pneumoniae and S pyogenes, the genes mefE and mefA, respectively, encode for two transporter efflux pumps (MefE and MefA) that confer resistance only to macrolides and azalides (6). The latter is referred to as the M phenotype. Macrolide modification or inactivation (eg, Escherichia coli production of erythromycin esterase) does occur but is rare in S aureus, and has not been described in S pneumoniae or S pyogenes. Macrolide resistance rates in Canada remain low and have not exceeded 10% among isolates of S pneumoniae (6). In a 1999 Canadian study of 121 macrolide-resistant S pneumoniae isolates, 50.4% possessed the M phenotype (mefA), while 45.5% demonstrated MLS resistance (ermB). Both resistance genes were found in 3.3% of isolates, while neither genetic determinant was found in 0.8% (7). In North America, macrolide resistance in S pyogenes remains at less than 3% (6).

IN VITRO ACTIVITY

Table 1 lists published MICs of erythromycin, clarithromycin and its active metabolite, where relevant, and azithromycin, for pathogens of clinical interest. Streptococci are usually susceptible to the macrolides and azalides; however, erythromycin and clarithromycin are generally more active than azithromycin. As noted previously, susceptibility of staphylococcal strains is extremely variable due to several possible mechanisms of resistance.

TABLE 1

Published minimum inhibitory concentrations (mg/L) of erythromycin, clarithromycin (and 14-hydroxyclarithromycin [14-OH]) and azithromycin for pathogens of clinical interest

In certain cases, the in vivo activity of clarithromycin and azithromycin against Gram-negative and intracellular pathogens has been shown to be better than anticipated on the basis of in vitro data. For example, the activity of clarithromycin against H influenzae is enhanced in vivo by the microbiological activity of its metabolite, 14-hydroxyclarithromycin. Other factors that may confound the interpretation of in vitro MIC data include the postulated postantibiotic effect, the effect of serum and the variability of activity according to the pH at the site of action (2). Inherent difficulties in the determination of MICs for intracellular pathogens also emphasize the need for cautious interpretation (8).

Mycoplasma pneumoniae is generally susceptible to the aforementioned macrolides and azithromycin. Both clarithromycin and azithromycin are active against certain pathogens involved in sexually transmitted disease; namely, C trachomatis and Haemophilus ducreyi.

Organisms of the Mycobacterium avium complex (MAC) are susceptible to both clarithromycin and azithromycin. Other nontuberculous mycobacteria, including Mycobacterium kansasii, Mycobacterium simae, Mycobacterium xenopi and Mycobacterium malmoense, have been shown to be susceptible in vitro to both azithromycin and clarithromycin in a beige mouse model of infection (9). Clarithromycin has been shown to possess broad in vitro activity against many nontuberculous mycobacteria, including Mycobacterium scrofulaceum, Mycobacterium szulgai, M xenopi, Mycobacterium fortuitum complex and Mycobacterium marinum (10). Neither new macrolide nor related compounds possess significantly important clinical activity against Mycobacterium tuberculosis.

Clarithromycin exhibits the greatest activity against H pylori, whereas both clarithromycin and azithromycin are active against Borrelia burgdorferi. Clarithromycin and azithromycin are each more active than erythromycin against Legionella pneumophila.

PHARMACOKINETICS

The oral bioavailability of erythromycin is variable, and depends on the presence of food and formulation administered. Erythromycin degrades rapidly in the presence of acid to form products devoid of antimicrobial activity. Unlike erythromycin, clarithromycin and azithromycin are stable in the presence of acid. Both are readily absorbed after oral administration. Food delays the time to peak serum concentrations of clarithromycin but does not affect the extent of absorption (bioavailability of 55%) (2,11). The bioavailability of azithromycin is approximately 37%; however, food can decrease this value by as much as 50%.

Erythromycin attains a peak serum concentration (C_max) of 1.8 mg/L approximately 1.7 h after oral administration (12). Clarithromycin reaches a C_max of 2.1 mg/L after a similar period of time. The peak concentration of azithromycin is 0.4 mg/L, achieved approximately 2.5 h after oral administration. Erythromycin and azithromycin are also available commercially in parenteral formulations. At steady state, the C_max of parenteral erythromycin, administered in 500 to 1000 mg doses four times daily, is approximately 10 to 17 mg/L (13). Azithromycin, administered in 500 mg doses intravenously once daily, reaches a steady state C_max of 3 mg/L (14).

Clarithromycin and azithromycin are more extensively distributed than erythromycin (volume of distribution of erythromycin = 0.64 L/kg; volume of distribution of clarithromycin = 3.4 L/kg; volume of distribution of azithromycin = 23 L/kg) (11). High concomitant serum concentrations are maintained with clarithromycin, while low serum concentrations with concomitant high and persistent tissue concentrations occur with azithromycin. Peak clarithromycin concentrations in the lung have been shown to exceed that in plasma by sixfold. Two- to sixfold tissue to plasma clarithromycin concentrations also occur in the nasal mucosa and tonsils (2). Similarly, azithromycin tissue concentrations are 10- to 100-fold higher than those in plasma (15). In comparison, erythromycin exhibits a tissue to plasma concentration ratio of only 0.5- to fivefold (10). Azithromycin becomes highly concentrated in various cells (eg, polymorphonuclear leukocytes, monocytes, alveolar macrophages and fibroblasts) and is subsequently released slowly into the extracellular space. In adults, a single oral 500 mg dose of azithromycin has been shown to produce tissue drug concentrations that are in excess of the minimum inhibitory concentration for many pathogens at sites of infection (bronchial epithelial lining fluid, sputum and bronchial mucosa) for up to 96 h postdose (12). Tonsillar levels exceed plasma concentrations by over 150-fold up to 84 h after two oral doses of 250 mg every 12 h (16).

Clarithromycin and azithromycin exhibit 45% to 50% and 7% to 50% protein binding, respectively, in human serum compared with 65% to 90% for erythromycin base (17). Due to the saturable nature of azithromycin binding, increased free drug concentrations are noted with increased total serum drug concentrations (12).

The elimination half-lives of erythromycin, clarithromycin and azithromycin are 2 h, 4 h and 68 h, respectively, after administration of a single 500 mg oral dose (11). Clarithromycin undergoes extensive hepatic metabolism, and there is a substantial first pass effect. The major metabolic pathway is hydroxylation, which results in the formation of the active 14-hydroxyl metabolite. Both unchanged clarithromycin and its metabolites are eliminated in the feces and the urine. Clarithromycin's pharmacokinetics are nonlinear due to a saturable metabolism; therefore, increased half-life and decreased metabolic clearance occur with increased doses (2). Azithromycin is primarily eliminated unchanged, principally, in the feces and, to a lesser extent, in the urine (12).

CLINICAL TRIALS

Respiratory tract infections:

Several randomized clinical trials have shown clarithromycin and azithromycin to be as effective as erythromycin and other conventional antibiotics in the treatment of upper and lower respiratory tract infections (Table 2).

TABLE 2

Comparative clinical trials: Respiratory tract infections

Upper respiratory tract infections:

Clinical response to clarithromycin and azithromycin therapy was found to be similar to the response found with the use of penicillin V in the treatment of group A beta-hemolytic streptococcal pharyngitis in children (18-20) and adults (21). However, bacteriological cure rates were variable. Compared with penicillin V, eradication rates were higher in clarithromycin-treated groups and lower in azithromycin-treated groups. One study found azithromycin 10 mg/kg daily for three days to be clinically inferior to penicillin V 50,000 U/kg/day administered in two divided doses for 10 days in children with group A beta-hemolytic streptococcal pharyngitis (22). Clinical response rates comparable with that of penicillin V have been reported using azithromycin 12 mg/kg/day daily for five days (23,24).

Acute maxillary sinusitis in adults appears to respond equally well to clarithromycin 500 mg orally twice daily, amoxicillin 500 mg orally three times daily or amoxicillin (combined with clavulanate) 500 mg orally three times daily (25,26). Similarly, an open-label, noncomparative study for this indication demonstrated the effectiveness of azithromycin 500 mg orally on the first day followed by 250 mg orally for four more days (27). Azithromycin 500 mg orally for three days was found to be clinically as effective as amoxicillin/clavulanate 500 mg administered three times daily for 10 days in the treatment of nonsevere, acute maxillary or ethmoidal sinusitis (28).

Clinical response to therapy with azithromycin or amoxicillin/clavulanate was found to be equivalent in the treatment of acute otitis media in paediatric patients (29). However, bacteriological failures with azithromycin recently have been demonstrated. Amoxicillin/clavulanate therapy was associated with higher middle ear fluid bacterial pathogen eradication rates and increased likelihood of clinical improvement in culture-positive patients compared with azithromycin (30). Similarly, bacteriological failure has been demonstrated in a study comparing azithromycin with cefaclor (31). Clinical cure or improvement has been documented in trials comparing clarithromycin and amoxicillin (32,33), amoxicillin/clavulanate (34,35) or cefaclor (36).

Acute exacerbations of chronic bronchitis:

Studies of the treatment of mild to moderate acute exacerbations of chronic bronchitis in adults have demonstrated acceptable clinical response rates to clarithromycin administered for five to 10 days or cefaclor for seven days (37,38). Clarithromycin 500 mg has also been compared with oral ciprofloxacin 500 mg, each administered twice daily for 14 days in the treatment of acute bacterial exacerbations of bronchitis. Ciprofloxacin therapy was associated with a longer infection-free interval (median 142 days versus 51 days for clarithromycin, P=0.15). There were trends toward better clinical response and bacteriological response rates with ciprofloxacin than with clarithromycin (90% versus 82% [not significant] and 91% versus 77% [P=0.01], respectively) (39). This finding is in contrast to an earlier trial that demonstrated similar clinical success and overall bacteriological response rates in patients treated with oral clarithromycin 500 mg or ciprofloxacin 750 mg twice daily (40). Compared with cefixime as a seven- to 14-day outpatient treatment, both therapies were found to be effective for the treatment of mild to moderate pneumonia and acute bacterial exacerbations of chronic bronchitis caused by H influenzae, M catarrhalis or S pneumoniae in adults (41). Comparison of clarithromycin with cefaclor for the same indication showed similar favourable clinical response and bacteriological eradication rates in both groups (42). An open-label study employing clarithromycin (250 mg orally twice daily for 10 days) or azithromycin (500 mg orally once daily for three days) for the treatment of lower respiratory tract infections, including acute bronchitis, acute infective exacerbations of chronic bronchitis and pneumonia, showed similar effectiveness for both drugs (43). Azithromycin has also been shown to have a statistically significant higher overall clinical response rate than amoxicillin/clavulanate for the treatment of acute tracheobronchitis or acute infectious exacerbations of chronic bronchitis (44).

Pertussis:

Only two clinical trials have been published that have evaluated the use of either azithromycin or clarithromycin for the treatment of pertussis in children (45,46). Small numbers of subjects in each trial make it difficult to recommend these agents as first-line therapy. It is likely that the newer agents are equivalent to standard therapy, such as erythromycin, for this infection.

Community-acquired pneumonia:

The empirical treatment of community-acquired pneumonia (CAP) with the macrolides has been well studied. Clarithromycin 250 mg orally bid has been shown to be just as effective as erythromycin 500 mg orally four times daily as a seven- to 14-day therapy for this condition in adults (47,48). Oral azithromycin has also compared favourably with oral clarithromycin (49) and oral erythromycin (50) for the treatment of CAP. More recently, azithromycin (500 mg intravenously once daily for two days followed by 500 mg orally once daily; total duration of seven to 10 days) was compared with the combination of cefuroxime (750 mg intravenously every 8 h for two to seven days followed by 500 mg orally twice daily; total duration seven to 10 days) and erythromycin (500 to 1000 mg intravenously or orally every 6 h; total duration up to 21 days) in hospitalized patients (51). Clinical cure rates were similar (91% in each group, P=0.95). Another open-label trial comparing intravenous-to-oral azithromycin therapy with cefuroxime therapy with the addition of erythromycin therapy, if deemed necessary by the clinician, has been published (52). Clinical cure or improvement was noted in 77% of the azithromycin group and 74% of the cefuroxime with or without erythromycin group (not significant). Until further information is available, the treatment of patients with bacteremic S pneumoniae pneumonia with azithromycin monotherapy should be undertaken with caution due to low serum concentrations relative to beta-lactam agents. An open-label study in 25 patients using a three-day course of the azalide reported that a patient with S pneumoniae bacteremia and pneumonia failed to respond to antibiotic therapy and died in respiratory failure (53).

The effectiveness of azithromycin for CAP has also been studied in children. Clinical response was similar when azithromycin was compared with amoxicillin/clavulanate (age five years or younger) or erythromycin estolate (age older than five years) (90.6% and 87.1%, respectively) (54). Chlamydia pneumoniae and M pneumoniae eradication was at least as successful with azithromycin as with the comparator antimicrobial (81% and 100% for azithromycin versus 100% and 57% for amoxicillin/clavulanate, respectively).

Skin and skin structure infections:

The efficacy of clarithromycin in the treatment of mild to moderate skin and skin structure infections has been assessed in adults and children. Clarithromycin (500 mg twice daily for five to 14 days) produces clinical response rates comparable with erythromycin (250 mg four times daily for less than 14 days) and cefadroxil (500 mg twice daily for five to 14 days) (55). Similarly, children treated with clarithromycin 7.5 mg/kg (maximum 500 mg) twice daily responded equally well to cefadroxil 15 mg/kg (maximum 1000 mg) twice daily (56).

Azithromycin (500 mg orally on the first day followed by 250 mg for four more days) has been shown to be as effective as oral erythromycin (500 mg four times daily for seven days) (57,58), cephalexin (500 mg twice daily for 10 days) (59,60) and cloxacillin (500 mg twice daily for seven days) (58) in the treatment of mild to moderate acute bacterial infections of skin or soft tissue in adults. In children aged six months to 12 years, therapy with azithromycin 10 mg/kg for three days was shown to be as effective as cefaclor 20 mg/kg/day in three divided doses for the treatment of mild to moderate dermatological conditions and abscesses (61).

Sexually transmitted diseases:

Several clinical trials have demonstrated the effectiveness of azithromycin for the treatment of sexually transmitted chlamydial infections. A single 1000 mg dose of oral azithromycin was shown to be effective and well tolerated compared with doxycycline 100 mg orally twice daily for seven days in men treated for either uncomplicated gonococcal urethritis and/or urethritis caused by C trachomatis and Ureaplasma urealyticum (62). Similarly, other trials have shown chlamydial cervicitis and nongonococcal urethritis to respond equally well to either azithromycin or doxycycline (63,64) and clarithromycin 250 mg orally twice daily for seven days or doxycycline (65). However, in the latter trial, doxycycline was more effective than clarithromycin in eradicating U urealyticum. Treatment of chlamydial infection in pregnant women and their sexual partners with single-dose azithromycin has been shown to be superior to therapy with standard course erythromycin for women, combined with tetracycline for their sexual partners. The proportion of positive cultures for C trachomatis at four weeks was significantly lower in women and partners randomized to single dose azithromycin (4.5%) than in those randomized to standard dose erythromycin or tetracycline (21.1%) (66). In this same study, adverse effects were significantly less in the azithromycin group (7.4%) compared with the group receiving erythromycin (38.8%) or tetracycline (28.6%).

Nontuberculous mycobacterial infections:

MAC prophylaxis and therapy:

Clarithromycin and azithromycin have been studied in the prophylaxis and treatment of HIV-infected patients with MAC infections. Clarithromycin reduced the incidence of disseminated infection by 10% and improved survival (hazard ratio 0.75, P=0.026) in patients with advanced AIDS compared with a placebo (67). Clarithromycin when used as a monotherapy has also been shown to be as effective as when used in combination with rifabutin for primary prophylaxis in HIV-infected patients (68). A comparison of azithromycin (1200 mg once weekly) alone, rifabutin (300 mg daily) alone or both for MAC prophylaxis showed that the combination produced the lowest cumulative incidence of disseminated MAC infection (2.8%) at one year of prophylactic therapy (69).

Clarithromycin in doses of 500 to 1000 mg twice daily has been demonstrated to eradicate MAC bacteremia and improve symptomatology (70,71). In disseminated MAC, however, macrolide monotherapy can lead to drug resistance (72). Therefore, the use of combination therapy is advocated (73). The addition of ethambutol to macrolide-containing regimens for MAC bacteremia has been shown to decrease the emergence of resistance (74). A clarithromycin-based three-drug regimen was superior to a four-drug regimen without clarithromycin in resolving MAC bacteremia and increasing survival rates in patients with AIDS (75). Most recently, a trial demonstrated that a combination of clarithromycin and ethambutol was superior to azithromycin and ethambutol for the treatment of MAC bacteremia in HIV-infected patients (76). Median time to clearance of bacteremia was significantly faster in the clarithromycin group (4.38 weeks versus longer than 16 weeks in the azithromycin group). Bacteremia resolved in a greater proportion of patients randomized to the clarithromycin group at 16 weeks (85.7% versus 37.5%). However, it is possible that, in this study, the dose of azithromycin (600 mg once daily) studied was too low.

Infections with other nontuberculous mycobacteria:

Clarithromycin therapy in combination with other agents may be effective for the treatment of nontuberculous, non-MAC mycobacterial infections. If required due to protease inhibitor drug interactions, clarithromycin or rifabutin may be added to isoniazid and ethambutol instead of rifampin for the treatment of M kansasii pulmonary disease. This recommendation is based on the excellent in vitro susceptibility of M kansasii to clarithromycin (77). Excellent in vitro susceptibility to clarithromycin has also led to this agent being recommended as one of the treatments for cutaneous infections with M marinum, for pulmonary infections with M xenopi and for cutaneous or pulmonary infections with Mycobacterium abscessus or M fortuitum (77). Clarithromycin is also recommended for the treatment of cervical lymphadenitis caused by nontuberculous mycobacteria in patients with extensive disease or poor response to surgical excision (77). Long term clarithromycin monotherapy has been shown to be effective for the treatment of cutaneous infection with M chelonae in an open-label, noncomparative trial (78). Promising results were also observed in a small trial assessing improvement in clinical and laboratory parameters; patients with previously untreated Mycobacterium leprae infection received clarithromycin monotherapy (79).

Peptic ulcer disease and H pylori infection:

The association of H pylori with peptic ulcer disease is now well established. There have been six published meta-analyses on regimens for H pylori eradication (80-85). All have shown that three drug regimens using clarithromycin and a proton pump inhibitor in combination with amoxicillin or metronidazole have eradication rates between 80% to 90% assessed by intention-to-treat analysis. In one meta-analysis examining the role of high versus low dose clarithromycin administered with a proton pump inhibitor and amoxicillin or metronidazole, the best treatment results by intention-to-treat analysis were seen with 500 mg twice daily compared with 250 mg twice daily (amoxicillin, 86.6% versus 78.2%; metronidazole, 88.3% versus 86.7%) (82). Azithromycin for H pylori infection has not been as well studied as clarithromycin and is not currently recommended.

ADVERSE EFFECTS

Erythromycin is one of the safest antibiotics in clinical use. Gastrointestinal upset is the most common adverse event associated with macrolide therapy and is dose-related (Table 3). Macrolides act as gastric prokinetic agents through stimulation of motilin receptors in the gastrointestinal tract. It is believed that erythromycin's high affinity for these receptors, relative to that of clarithromycin and azithromycin, results in the higher incidence of gastrointestinal upset observed during therapy with this macrolide (86). The incidence of significant gastrointestinal effects (ie, nausea, diarrhea, abdominal pain and vomiting) is reported to be 20% to 35% with erythromycin and 10% to 15% for clarithromycin or azithromycin (87). Venous irritation and phlebitis occur commonly with parenteral erythromycin therapy, and may be minimized with a reduction in the concentration and/or infusion rate (88). Parenteral azithromycin appears to be better tolerated with an incidence of infusion site reactions of 3% to 6% (14). Other adverse effects reported during clinical trials with a frequency of less than 2% include headache, hepatic dysfunction, changes in neutrophil or leukocyte counts, and skin rash. Taste perversion has been reported in patients receiving clarithromycin therapy at a frequency of 2%. Bilateral, sensorineural ototoxicity has been reported with each of the macrolide derivatives. It is typically reversible with drug discontinuation and appears to be related to high serum concentrations arising from aggressive dosing, or hepatic or renal dysfunction (13,89).

TABLE 3

Frequency of gastrointestinal adverse effects of macrolides at recommended doses

DRUG INTERACTIONS

Several pharmacokinetic drug interactions have been documented with erythromycin, an inhibitor of the cytochrome P450 (subset CYP3A) enzyme system through inactivation by the formation of an inactive complex (Table 4). The clearance of theophylline, carbamazepine, nonsedating antihistamines (ie, terfenadine, astemizole and, potentially, loratidine), ergot alkaloids, cyclosporine and warfarin may decrease if erythromycin is administered concomitantly. Clinically significant toxicity may ensue. Clarithromycin forms microsomal complexes to a lesser extent, and azithromycin does not appear to inactivate cytochrome P450 at all. Clarithromycin may cause clinically significant increases in carbamazepine, terfenadine and theophylline concentrations via inhibition of CYP3A-mediated metabolism (2). Concomitant use should be avoided or monitored closely. Azithromycin appears to have no clinically significant pharmacokinetic effect on drugs metabolized by cytochrome P450 (90).

TABLE 4

Potential clinically significant drug interactions involving erythromycin, clarithromycin and azithromycin

When physical complexes are formed with antacids or food, there may be a reduction in the bioavailability of erythromycin. Food and antacids do not appear to cause a clinically significant interaction when administered with clarithromycin. However, peak azithromycin serum levels may be reduced when administered as a capsule or oral suspension concomitantly with food or antacids (14). Therefore, this drug is recommended for administration on an empty stomach in the absence of antacids.

DOSING AND ADMINISTRATION

The recommended dosages and recommendations regarding dosing adjustment in renal and/or hepatic failure are presented in Table 5. Estimated drug acquisition costs for total regimen are also provided. Only erythromycin and azithro-mycin are available in parenteral forms for intravenous administration. Parenteral azithromycin therapy may be a useful alternative to parenteral erythromycin when a reduction in fluid administration or frequency of administration is desired. A dosing comparison of these agents is provided in Table 6.

TABLE 5

Oral dosing of select macrolides and azalides

TABLE 6

Parenteral dosing of erythromycin and azithromycin

CONCLUSIONS AND RECOMMENDATIONS

The macrolide clarithromycin and the azalide azithromycin offer potential therapeutic and tolerability advantages over erythromycin. For the majority of patients treated (eg, those suffering from community-acquired respiratory tract infections), these drugs offer a more tolerable gastrointestinal adverse event profile and a simpler dosing regimen. The antimicrobial spectrum and clinical trial evidence support the use of either azithromycin or clarithromycin as first-line agents or alternatives to erythromycin in the treatment of CAP in the ambulatory setting. Both agents are acceptable for the treatment of hospitalized patients with CAP in combination with second- or third-generation cephalosporins. The introduction of azithromycin injection offers an alternative to parenteral erythromycin in this setting. The extended antimicrobial coverage of clarithromycin versus MAC and other nontuberculous mycobacteria is clinically relevant. For peptic ulcer disease caused by H pylori, triple-drug regimens containing clarithromycin are considered first-line therapy. In the treatment of uncomplicated genital tract chlamydial infection and nongonococcal urethritis, single dose azithromycin is now the standard. For the treatment of skin and skin structure infections, more effective and less expensive agents exist, rendering these agents to second-line status.

The evidence cited in these recommendations has been classified into five levels, which have been used in the development of other clinical practice guidelines (91).

Level I evidence is based on randomized, controlled trials (or meta-analysis of such trials) of adequate size to ensure a low risk of incorporating false-positive or false-negative results.
Level II evidence is based on randomized, controlled trials that are too small to provide level I evidence. These may show either positive trends that are not statistically significant or no trends, and are associated with a high risk of false-negative results.
Level III evidence is based on nonrandomized, controlled or cohort studies, case series, case-controlled studies or cross-sectional studies.
Level IV evidence is based on the opinion of respected authorities or that of expert committees as indicated in published consensus conferences or guidelines.
Level V evidence expresses the opinion of those individuals who have written and reviewed these guidelines, based on their experience, knowledge of the relevant literature and discussion with their peers.

Taking into account the differences in drug acquisition cost and spectrums of activity between erythromycin, clarithromycin and azithromycin, the following recommendations are made.

First-line therapy

CAP in ambulatory patients (in combination with beta-lactam if modifying risk factors) (Level I)
CAP in hospitalized patients in combination with beta-lactam (Level I)
Single-dose treatment of uncomplicated nongonococcal urethritis or cervicitis (azithromycin 1 g orally) (Level I)
For eradication of H pylori infection in combination with a proton pump inhibitor and either amoxicillin or metronidazole (clarithromycin 500 mg twice daily) (Level I)
For treatment of infection with MAC (clarithromycin in combination with ethambutol with or without rifabutin) (Level I)
For treatment of infection caused by susceptible nontuberculous mycobacteria (clarithromycin in combination with other agents) (Level IV)
For prophylaxis of infection with MAC in HIV-infected patients azithromycin 1200 mg once weekly (with or without rifabutin) (Level I)

Alternate therapy

For treatment of infection with MAC (azithromycin in combination with ethambutol with or without rifabutin) (Level II)
For prophylaxis of infection with MAC in HIV-infected patients (clarithromycin) (Level II)
For patients experiencing or who have a history of severe gastrointestinal adverse effects while receiving any oral erythromycin formulation or conventional beta-lactam antibiotics (eg, penicillins and cephalosporins) for community-acquired respiratory tract infections (Level III)
For patients who are likely to be nonadherent with standard erythromycin or conventional beta-lactam antibiotic regimen (Level IV)
For prophylaxis of bacterial endocarditis for dental, oral, respiratory or gastrointestinal endoscopic procedures in patients with a history of beta-lactam hypersensitivity as recommended by the American Heart Association (92) (Level IV)

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