Comparative Effectiveness of Different Macrolides

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Martian
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Comparative Effectiveness of Different Macrolides

Post by Martian » Tue 4 Sep 2007 22:05

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Comparative Effectiveness of Different Macrolides: Clarithromycin, Azithromycin, and Erythromycin

By William Bishai, MD, PhD

A recent feature article discussed the apparent clinical paradox of macrolide treatment success for the pneumococcus in spite of microbiologic resistance. This paradox may be explained by the fact that most macrolide pneumococcal resistance in the U.S. is of the intermediate level (MIC = 1-32 mcg/ml), and macrolides are known to be concentrated upon epithelial surfaces in the respiratory tract at levels exceeding the MIC of such moderately resistant strains. Therefore, there may be justification for moving toward a disease-specific macrolide MIC breakpoint of 8 or 16 ug/mL for pneumococcal sinusitis and pneumonia, rather than the current NCCLS standard of > 0.5 ug/mL for resistance. However, there are important differences in pharmacokinetics, pharmacodynamics, tissue concentrations, and activity against resistant strains that should considered in the selection of the appropriate macrolide agent for treating pneumococcal disease.

Pharmacokinetic properties of the macrolides

The major difference between erythromycin and the newer macrolides, clarithromycin and azithromycin, is the pharmacokinetic profile (Table 1). The oral bioavailability of erythromycin varies considerably between preparations. The bioavailability of clarithromycin is, in general, more than twice that of erythromycin, and the bioavailability of azithromycin is 1.5 times that of erythromycin. This improved absorption is related to increases in acid stability. Also, the elimination half-lives of azithromycin and clarithromycin are greater than that of erythromycin, with azithromycin having the longest half-life. The improved pharmacokinetic profile of the newer macrolides is important because these antibiotics exhibit time-dependent bacterial killing activity.

Another important difference is that peak serum concentrations of azithromycin are lower than those of the other two agents. This is because azithromycin accumulates to a greater degree in various host cells, which is reflected by its significantly larger volume of distribution. As a consequence, azithromycin has a lower serum area under the curve (AUC). The three macrolides are each moderately protein bound. Unlike most antibiotics that bind exclusively to albumin, the macrolides are bound to alpha-1-glycoproteins. Unlike the other macrolides, clarithromycin has an active metabolite, 14-hydroxy (OH)-clarithromycin. This metabolite has been shown to have an additive or synergistic effect against common respiratory tract pathogens including S. pneumoniae and H. influenzae (1).

Table 1. Pharmacokinetic profiles of the macrolides (following single oral 500 mg dose)
table1.png
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* 250 mg single-dose regimen
** 500 mg loading dose, then 250 mg daily
*** Multiple 500 mg dose regimens.
Adopted from review by Eisenberg and Barza (2).

In vitro microbiologic activity

A 1996 study by Ednie et al. compared the in vitro microbiologic activity of the macrolides for 120 pneumococcal isolates with varied penicillin resistance (3). Interestingly, all highly erythromycin-resistant strains with MICs > 64.0 ug/mL were also resistant to azithromycin and clarithromycin, underscoring the degree of cross-resistance across macrolide antibiotics. However, clarithromycin yielded MICs which were generally one or two dilutions lower than the other two macrolides for all strains. Another difference was that erythromycin was bactericidal at eight times the MIC, whereas the other compounds were bactericidal at only two times the MIC.

A later study which also examined in vitro macrolide activity against pneumococcal isolates demonstrated that erythromycin and clarithromycin had significantly greater bactericidal activity than azithromycin after only 4 hours exposure with concentrations equal to 10 times the MIC (4). These two macrolides also had greater post-antibiotic effects (PAEs) than azithromycin against the same strains.

Drug-host interactions

When virulence studies were performed by pre-treating pneumococcal strains with macrolides before inoculating them into immunocompetent mice, only erythromycin and azithromycin, but not clarithromycin resulted in significant decreases in post-antibiotic phase virulence (4). Virulence is a complex drug-host interaction presumed to be related, at least in part, to the capsular polysaccharide of the bacterium which performs an anti-phagocytic function. While the most important parameter for predicting the antimicrobial effects of an antibiotic is its bactericidal activity, the PAE and reductions in virulence may contribute to success with intermittent drug regimens.

An interesting drug-host interaction has been demonstrated for some macrolides, showing that the drug may have an immune-enhancing effect in addition to its direct antibacterial effect (5). It has been shown that macrolides enhance ciliary clearance and reduce levels of pro-inflammatory cytokines, which may reduce the recruitment of tissue-damaging mononuclear cells to the site of resolving infection and accelerate recovery. Such immunomodulatory abilities may significantly augment the activity of an antiobiotic—particularly in infections by drug-resistant strains.

Comparison of intrapulmonary antibiotic concentrations

Two separate studies have compared the intrapulmonary steady-state concentrations of clarithromycin and azithromycin in healthy, non-smoking volunteers by bronchoalveolar lavage (6,7). Both drugs accumulate to a greater extent in intrapulmonary tissues than erythromycin. Even though azithromycin achieves a higher ratio of epithelial lining fluid (ELF)-to-serum concentration, these studies demonstrate that doses of clarithromycin result in greater absolute amounts of drug in ELF and alveolar macrophages. Ultimately, however, the more important consideration is whether pharmacodynamic parameters of the agents are optimized at the site of infection.

Pharmacodynamics of the macrolides

Since the macrolide antibiotics exhibit time-dependent, concentration-independent killing, serum concentrations above the MIC for at least 50% of the dosing interval, in general, achieves maximum bacteriologic cure rates. An important study by Stein & Schooley examined the serum pharmacodynamics of clarithromycin and azithromycin against isolates of S. pneumoniae (8). Azithromycin exhibited serum bactericidal activity (SBA) for at least 6 hours for strains up to a MIC of 0.5 ug/mL. Clarithromycin exhibited SBA for at least one-half of its recommended 12 hour dosing interval against strains with MICs up to 2.0 ug/mL, which is well above its current susceptibility breakpoint of 0.25 ug/mL. Since over 90% of strains in the U.S. have MICs less than or equal to 4.0 ug/mL, this data would predict bacteriologic eradication rates of approximately 90% for pneumococcal isolates with clarithromycin in clinical trials. This is consistent with the 92% success rate reported in a recent study of patients with lower respiratory tract infections (9).

Another group (10) has used different pharmacodynamic criteria for comparing these two antibiotics (see Table 2). This is based on data suggesting that ratio of serum AUC to MIC correlates with outcomes with azithromycin, whereas the proportion of the dosing interval in which serum concentrations exceed the MIC is most closely linked to outcome with clarithromycin (11). The criteria used were AUC/MIC greater than or equal to 25 and time above MIC greater than 40%, respectively. Based on serum concentrations, clarithromycin achieved its pharmacodynamic target in 76.9% of isolates, compared with 59.9% for azithromycin. The study also compared their activities based on concentrations in ELF. Based on ELF concentrations, clarithromycin achieved its target in 93.5% of isolates, compared with 74.6% for azithromycin. Against penicillin-resistant isolates, clarithromycin achieved its target in the ELF in 86.7% if cases and azithromycin in 28.3%.

Data from the Alexander project, a surveillance study of pneumococcal resistance, indicates a correlation between macrolide resistance and the increasing use of longer acting macrolide antibiotics such as azithromycin, although further study is required to investigate the causality of this correlation (12). Such data suggest, but do not prove, that the use of shorter half-life macrolides such as clarithromycin and erythromycin may be less likely to induce the development of macrolide resistance among S. pneumoniae.

Table 2. Pharmacodynamics of clarithromycin and azithromycin against S. Pneumoniae.
Percent of isolates against which the drug achieved its target
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Clarithromycin: target defined as concentration exceeding MIC for greater than 40% of dosing
interval. Azithromycin: target defined as AUC/MIC ratio >= 25.

Data from Kays and Denys (10).

Clinical trials and beyond

A limited number of clinical trials have investigated the comparative efficacy of macrolides in treating lower respiratory infections. A 1994 phase IV, investigator-blinded, multicenter randomized trial by Spiritus et al., demonstrated that clarithromycin therapy resulted in a higher clinical success rate than erythromycin, and also had the most rapid time to resolution of symptoms, and the lowest cost of healthcare resources utilized (13). This was consistent with retrospective data suggesting that clarithromycin was more cost-effective than both erythromycin (14, 15). A 1998 randomized, multicenter study comparing azithromycin and clarithromycin in the treatment of adults with mild to moderate community-acquired pneumonia from all causes, demonstrated equal efficacy and tolerability of these two agents (16). However, it is difficult to compare the clinical effectiveness of these two agents specifically for treating pneumococcal infections. No large clinical trials have compared these two agents head-to-head for treating respiratory infections with pneumococci of varied macrolide resistance profiles. Klepser et al. have used a neutropenic mouse model to address this issue (17). They infected mice rendered neutropenic by cyclophosphamide with nineteen different pneumococcal isolates and then treated the mice with different doses of azithromycin or clarithromycin. Mice infected with isolates demonstrating the ermB resistance phenotype (MLSB phenotype, or high-level macrolide resistance with MIC90 values of ≥ 64 ug/ml) had similar mortality with both antibiotics compared to untreated controls. In contrast, mice infected with isolates bearing the mefA-efflux resistance phenotype (M phenotype, or low-level macrolide resistance with MIC90 values of 1 - 32 ug/ml) had significantly improved survival with clarithromycin, responding in a manner similar to those infected with fully susceptible isolates. Interestingly, this effect was not observed in mice treated with azithromycin.

It appears that both azithromycin and clarithromycin have advantages over erythromycin primarily afforded by their improved pharmacokinetic profiles and superior tolerability. However, in an era of increasing macrolide resistance, predominately due to increases in the prevelance of the intermediate-level mefA-efflux resistance phenotype, it is important to select the most potent antimicrobial agent of this class for treating pneumococcal infections. Since clinical trial data comparing the macrolides directly are lacking, the comparative pharmacologic attributes and animal model performance of azithromycin and clarithromycin have been reviewed. The macrolides, particularly azithromycin and clarithromycin remain popular choices for treating respiratory infections and have been endorsed by the IDSA, the ATS, and the CDC in recent community acquired pneumonia guidelines. As drug resistant strains of pneumococci increase in prevalence, it will become important to validate these apparent pharmacologic and animal model differences among the macrolides through well-controlled randomized clinical trials.

References

Hoover et al. Clarithromycin in vitro activity enhanced by its major metabolite, 14-hydroxy clarithromycin. Diag Microbiol Infect Dis. 1992; 15:259-266.

Eisenberg E, Barza M. Azithromycin and clarithromycin. Curr Clin Top Infect Dis. 1994;14:52-79.

Ednie et al. Comparative activities of clarithromycin, erythromycin, and azithromycin against penicillin-susceptible and penicillin-resistant pneumococci. Antimicrob Agents and Chemother. 1996 Aug; 40(8):1950-1952.

Fuursted et al. Comparative study of bactericidal activities, postantibiotic effects, and effects on bacterial virulence of penicillin G and six macrolides against streptococcus pneumoniae. Antimicrob Agents and Chemother. 1997 April; 41(4):781-784.

Martin SJM, and Sahloff EG. Clarithromycin has immune-enhancing effects on whole human blood against macrolide-resistant Streptococcus pneumoniae. Intl. J. Antimicrob. Agents 2001; 17 (Suppl. 1): S37.

Hardy et al. Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin, its major metabolite in humans. Antimicrob Agents and Chemother. 1990 July; 34(7):1407-1413.

Patel et al. Comparison of bronchopulmonary pharmacokinetics of clarithromycin and azithromycin. Antimicrob Agents and Chemother. 1996 Oct; 40(10):2375-2379.

Stein GE, Schooley S. Comparative serum bactericidal activity of clarithromycin and azithromycin against macrolide-sensitive and resistant strains of streptococcus pneumoniae. Diag Microb and Infect Dis. 2000 Oct; 39:181-185.

Gotfried MH. Comparison of bacteriologic eradication of streptococcus pneumoniae by clarithromycin and reports of increased antimicrobial resistance. Clin Ther. 2000; 22:2-14.

Kays MB, Denys GA. In vitro activity and pharmacodynamics of azithromycin and clarithromycin against Streptococcus pneumoniae based on serum and intrapulmonary pharmacokinetics. Clin Ther. 2001; 23(3):413-424.

Drusano GL, Craig WA. Relevance of pharmacokinetics and pharmacodynamics in the selection of antibiotics for respiratory tract infections. J Chemother. 1997; 9(Suppl 3):38-44.

Baquero F. Evolving resistance patterns of streptococcus pneumoniae: a link with long-acting macrolide consumption? J Chemother 1999 Feb; 11(Suppl 1):35-43.

Spiritus et al. Cost savings of clarithromycin compared with erythromycin or cefaclor in the treatment of lower respiratory tract infection: results of a randomized, multicenter study. Amer Jour of Man Care. 1998 Oct; 4(Suppl 10):S562-S570.

Quenzer et al. Pharmacoeconomic analysis of selected antibiotics in lower respiratory tract infection. Amer Jour of Man Care. 1997 July; 3:1027-1036.

Ober NS. Respiratory tract infections: consider the total cost of care. Drug Benefit Trends. 1998; Suppl 10:S23-S29.

O'Doherty B, Muller O. Randomized, multicentre study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of adults with mild to moderate community-acquired pneumonia. Azithromycin Study Group. Eur J Clin Microbiol Infect Dis. 1998 Dec; 17(12):828-833.

Klepser M, Hoffmann H, Petzold CR, Doern G. Efficacy of clarithromycin and azithromycin against Streptococcus pneumoniae with various macrolide resistance mechanisms in a neutropenic murine respiratory infection model. Intl. J. Antimicrob Agents 2001; 17 (Suppl. 1): S157.

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