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Clarithromycin

A Review of its Antimicrobial Activity, Pharmacokinetic Properties and Therapeutic Potential

Abstract

Synopsis

Clarithromycin is an acid-stable orally administered macrolide antimicrobial drug, structurally related to erythromycin. It has a broad spectrum of antimicrobial activity, similar to that of ery-thromycin and inhibits a range of Gram-positive and Gram-negative organisms, atypical pathogens and some anaerobes. Significantly, clarithromycin demonstrates greater in vitro activity than erythromycin against certain pathogens including Bacteroides melaninogenicus, Chlamydia pneu-moniae, Chlamydia trachomatis, Mycobacterium chelonae subspecies — chelonae and — abscessus, Mycobacterium leprae, Mycobacterium marinum, Mycobacterium avium complex, Legionella spp. and, when combined with its 14-hydroxy metabolite, against Haemophilus influenzae. However, bacterial strains resistant to erythromycin are also generally resistant to clarithromycin. The antimicrobial activity of clarithromycin appears to be enhanced by the formation in vivo of the micro-biologically active 14-hydroxy metabolite. In combination, additive or synergistic activity against a variety of pathogens including Haemophilus influenzae, Moraxella catarrhalis, Legionella species (principally Legionella pneumophila) and various staphylococci and streptococci has been demonstrated. Clarithromycin has a superior pharmacokinetic profile to that of erythromycin, allowing the benefits of twice daily administration with the potential for increased compliance among outpatients where a more frequent regimen for erythromycin might otherwise be indicated.

The clinical efficacy of clarithromycin has been confirmed in the treatment of infections of the lower and upper respiratory tracts (including those associated with atypical pathogens), skin/soft tissues, and in paediatrics. Clarithromycin was as effective as erythromycin and other appropriate drugs including β-lactams (penicillins and cephalosporins) in some of the above infections. A most promising indication for clarithromycin appears to be in the treatment of immunocompromised patients infected with M. avium complex, M. chelonae sp. and Toxoplasma sp. Small initial trials in this setting reveal clarithromycin alone or in combination with other antimicrobials to be effective in the eradication or amelioration of these infections. Noncomparative studies have provided preliminary evidence for the effectiveness of clarithromycin in the treatment of infections of the urogenital tract, oromaxillofacial and ophthalmic areas. However, the promising in vitro and preliminary in vivo activity of clarithromycin against Mycobacterium leprae and Helicobacter pylori warrant further clinical trials to assess its efficacy in patients with these infections.

Despite the improved pharmacokinetic profile and in vitro antimicrobial activity of clarithro-mycin over erythromycin, comparative studies of patients with community-acquired infections reveal the 2 drugs to be of equivalent efficacy. However, clarithromycin demonstrates greater toler-ability, principally by inducing fewer gastrointestinal disturbances.

In conclusion, at this stage of its development clarithromycin appears to have a clinical profile which will make it a useful alternative to erythromycin, other macrolides and β-lactam antibiotics, for the treatment of community-acquired infections. Its activity against Mycobacteria including M. avium complex infection in AIDS patients may make it a first line option in this difficult to treat disease. Future comparative trials will help to further define its overall role in antimicrobial chemotherapy.

Antimicrobial Activity

Clarithromycin has an in vitro spectrum of activity broadly similar to that of erythromycin, although some significant differences in activity have been observed. Staphylococcus aureus and S. epidermidis strains susceptible to penicillin and/or erythromycin are also susceptible to clarithromycin. However, where these organisms show resistance to erythromycin, clarithromycin is inactive. Clarithromycin is active against streptococcus groups A, B, C (particularly) and G, and against S. bovis. It is more active than roxithromycin against group A streptococci and is more active than erythromycin and azithromycin against S. bovis and group G streptococci. S. pneu-moniae strains are also particularly susceptible to clarithromycin, except where these strains are resistant to erythromycin. Enterococci (streptococcus group D) are usually resistant to clarithromycin. Clarithromycin is the most potent macrolide tested against Bacillus species, and it is more active than azithromycin and clindamycin against Listeria monocytogenes. Clarithromycin shows poor overall activity against Corynebacterium species, although this finding is considered to reflect resistance by a subpopulation of isolates.

Overall, clarithromycin is either active or moderately active against Campylobacter species, but is notably more active than erythromycin, azithromycin and roxithromycin against Helico-bacter pylori. Haemophilus infiuenzae is either susceptible or resistant to clarithromycin and erythromycin but is susceptible or moderately susceptible to its primary metabolite, 14-hydroxy clarithromycin, in vitro. Indeed, 14-hydroxy clarithromycin is almost 3-fold more active than the parent compound against this organism. In contrast H. parainfluenzae is resistant to clarithromycin and erythromycin, although the activity of 14-hydroxy clarithromycin against this organism was not determined. Furthermore, despite the implications of these findings there are indications that Haemophilus species are susceptible to clarithromycin in the clinical setting. Combined laboratory data indicate that Neisseria gonorrhoeae strains (including those producing β-lacta-mase) are susceptible to clarithromycin and other macrolides although less so than to azithromycin and clindamycin. Overall, N. meningitidis is moderately susceptible to clarithromycin and erythromycin. Clarithromycin is particularly active against Bordetella pertussis, Bordetella par-apertussis and Borrelia burgdorferi, and is more active than erythromycin against the latter organism. Moraxella (Branhamella) catarrhalis (including β-lactamase producing strains) and strains of the Legionella genus (principally L. pneumophila) are susceptible to clarithromycin, which was the most active of the macrolides tested against L. pneumophila. Pasteurella multocida is more susceptible to clarithromycin than to erythromycin.

Clinical isolates of Bacteroides species were generally resistant to clarithromycin and erythromycin, although B. melaninogenicus is particularly susceptible to clarithromycin as is Pro-pionibacterium acnes. Clarithromycin was moderately active against Clostridium species and it was the most active macrolide tested against Eubacterium species. Peptococcus species show varying sensitivities to clarithromycin, although against combined isolates of the Peptococcus/Pep-tostreptococcus genera clarithromycin was moderately active.

Clarithromycin was the most potent of the macrolides tested against Chlamydia trachomatis and C. pneumoniae (TWAR), and produced potent inhibition of Mycoplasma pneumoniae. Isolates of Ureaplasma urealyticum were generally susceptible to clarithromycin, although other strains are resistant. Mycoplasma hominis is resistant to clarithromycin and erythromycin.

Clarithromycin is active against Mycobacterium chelonae subspecies -chelonae and -abscessus and is generally moderately active against M. fortuitum-fortitum and Mycobacterium avium complex (MAC), consistently showing greater activity than other macrolides. Clarithromycin also shows activity against other mycobacterium species including Mycobacterium marinum, Myco bacterium kansaii and Mycobacterium fortuitum-peregrinum. The metabolic function of M leprae was similarly inhibited by clarithromycin and standard antileprotic drugs. Clarithromycin is inactive against M. tuberculosis and, like azithromycin, appears to have parasitostatic activity against Toxoplasma gondii.

In general, bacterial strains resistant to erythromycin are also resistant to clarithromycin, although bacterial strains resistant to penicillin class drugs are susceptible to clarithromycin where macrolide resistance is absent. The combination of clarithromycin plus its 14-hydroxy metabolite demonstrates additive or synergistic activity against H. influenzae, M. catarrhalis, Legionella species, and some streptococci and staphylococci.

Clarithromycin is bactericidal against a variety of organisms including H. influenzae, L. pneu- mophila, S. pneumoniae and M. avium complex, and demonstrated a postantibiotic effect against H. influenzae, S. aureus, S. pyogenes and β-haemolytic Streptococci.

Clarithromycin produces its antimicrobial effect by inhibition of intracellular protein synthesis. It is widely distributed throughout the body, is highly concentrated in tissues, organs (particularly the lung) and leucocytes, and enhances phagocytosis. Clarithromycin causes significant morphological changes in the cell wall of M. avium complex leading to cytoplasmic vacuolation.

Clarithromycin produces good antimicrobial activity in experimental models of infection induced by a variety of Gram-positive and Gram-negative bacteria (including L. pneumophila and H. influenzae) and other organisms including M. avium complex and M. leprae.

Pharmacokinetic Properties

Clarithromycin is well absorbed from the gastrointestinal tract, although it undergoes substantial first pass metabolism reducing systemic bioavailability to 55% after a 250mg dose in healthy volunteers. Maximum clarithromycin plasma concentrations (Cmax) in healthy ‘Western’ volunteers were 0.62 to 0.84 mg/L and 1.77 to 1.89 mg/L following single dose administration of clarithromycin 250 and 500mg, respectively. Marginally higher values were recorded in Japanese volunteers administered clarithromycin 200 or 400mg. In these studies the time to reach Cmax(tmax) was about 3 hours, irrespective of ethnic origin. The areas under the plasma concentration-time curves (AUC) were about 4 and 11 mg/L · h for doses of 250 and 500mg in ‘Western’ volunteers, but were approximately doubled in Japanese volunteers givęn 200 or 400mg.

Clarithromycin undergoes rapid biotransformation to produce the microbiologically active 14-hydroxy (R) metabolite, which achieves peak plasma concentrations of 0.4 and 0.8 mg/L within 3 hours of administering clarithromycin 250 or 500mg. In ‘Western’ volunteers AUC values for the 14-hydroxy metabolite were 3.1 to 4.9 and 6.1 to 6.9 mg/L·h following administration of clarithromycin 250 or 500mg, respectively. The presence of food does not appear to have a clinically significant effect on the pharmacokinetic parameters of clarithromycin. With continued administration of clarithromycin 250mg twice daily, steady-state is usually attained after 5 doses with Cmax for the parent and 14-hydroxy metabolite of 1 and 0.6 mg/L, respectively. Steady-state maximum plasma concentrations of 2.4 to 3.5 mg/L for clarithromycin and 0.7 to 0.8 mg/ L for the metabolite are achieved with a 500mg dose. Oral administration of clarithromycin 200mg resulted in a Cmax 3-fold greater, and an AUC 5-fold greater than those for erythromycin 200mg.

Clarithromycin appears to be widely distributed throughout the body, generally achieving higher concentrations in tissues and organs (including the lung and tonsils) than in blood. Indeed, reported values for volume of distribution have been large — 226 to 266L in ‘Western’ volunteers and 115 to 138L in Japanese volunteers. At concentrations representative of those achieved clinically, clarithromycin was 42 to 70% bound to human plasma protein.

The primary metabolic pathways for clarithromycin are oxidative N-demethylation and hy-droxylation, which are saturable resulting in nonlinear kinetics. The principal metabolite of clarithromycin is the 14-hydroxy derivative, which is mainly excreted with the parent drug via urinary mechanisms. The elimination half-life (t1/2β) for clarithromycin ranged from 2.6 to 4.4 hours and the plasma clearance from 42 to 64 L/h when administered in doses of 250 to 500mg to ‘Western’ volunteers. Values for t1/2β were very similar in Japanese volunteers, but total body clearance was much lower’(22 to 24 L/h). In ‘Western’ children, the pharmacokinetic profile of clarithromycin is consistent with that seen in adults. Limited data in Japanese children reveal AUC and t1/2β values to be about half those in Japanese adults receiving similar doses. A reduction in urinary clearance in the elderly and patients with severe renal insufficiency is associated with an increase in AUC, Cmax and/or t1/2β. Mild-to-severe hepatic impairment does not significantly affect the pharmacokinetics of clarithromycin, although reduced metabolite formation may occur with severe liver impairment.

Therapeutic Efficacy

Clarithromycin is effective in the treatment of several types of infection when administered as a 250 or 500mg dose twice daily in ‘Western’ adult patients, or in lower divided doses in Japanese adults. In noncomparative studies, the clinical success rate for clarithromycin in ‘Western’ patients with lower respiratory tract infections was 94 to 99%, whereas the clinical efficacy (excellent plus good responses) derived from Japanese studies ranged from 86 to 91%, except in bronchiectasis (58%). Bacterial eradication rates in Japanese studies ranged from 70 to 94% for the most commonly isolated pathogens. In comparative studies of ‘Western’ patients with pneumonia, acute bronchitis or acute exacerbations of chronic bronchitis, clarithromycin produced clinical cure rates of 47 to 96%, clinical success rates of 76 to 100% and bacteriological eradication rates of 57 to 100%. In these studies, the clinical efficacy of clarithromycin was at least comparable with that of erythromycin, josamycin, roxithromycin, ampicillin, cefaclor, cefuroxime and/or ce-fixime. The clinical efficacy of clarithromycin in Japanese patients with pneumonia, bronchitis or bronchiectasis, was also equivalent to that of cefaclor (77 vs 67%) but greater than that of midecamycin acetate (90 vs 74%), bacteriological eradication rates in these studies showing similar trends for the various drugs.

Upper respiratory tract infections (including those of the middle ear), also responded well to clarithromycin. Thus, in noncomparative ‘Western’ studies (employing dosages of 250 or 500mg twice daily), clinical success rates of 84 to 97% were recorded. In noncomparative Japanese trials, clinical efficacy rates of 62 to 87% were recorded, whilst bacteriological eradication rates of 75 to 94% were noted for the most commonly isolated organisms (S. aureus, S. pyogenes and S. pneumoniae). In comparative studies in ‘Western’ patients with streptococcal pharyngitis, clarithromycin therapy produced clinical cure in 80 to 96% of patients, clinical success in 95 to 100% of patients and bacteriological eradication rates of 88 to 100%. Patients with acute maxillary sinusitis also responded well to treatment with clarithromycin as evidenced by clinical cure rates of 58 to 69%, clinical success rates of 85 to 95% and bacteriological eradication rates of 89 to 92%. Clarithromycin was considered equally effective as erythromycin or phenoxymethyl penicillin in treating pharyngitis and as effective as amoxicillin (with or without clavulanic acid) in treating acute maxillary sinusitis. Clarithromycin also demonstrated efficacy equivalent to that of josamycin in the treatment of acute tonsillitis and acute suppurative otitis media in Japanese patients. In the treatment of tonsillitis, clinical efficacy and bacteriological eradication rates of 87 and 99% were noted for clarithromycin. Clarithromycin was less effective in the treatment of suppurative otitis media, as evidenced by clinical efficacy and bacteriological eradication rates of 63%.

In the treatment of skin and soft tissue infections, clarithromycin was associated with an overall efficacy rate of 74% and bacteriological eradication rates of ⩾86% in Japanese noncomparative studies. Furthermore, in a Japanese comparative study, clarithromycin and erythromycin were similarly effective (clinical response rates 83 vs 79% and bacteriological eradication rates 92 vs 93%). Clarithromycin was also shown to be equally effective as erythromycin or cefadroxil in ‘Western’ patients with skin and soft tissue infections. Clinical success rates of 95 and 96% were noted for clarithromycin and comparator drugs, respectively, while bacteriological eradication rates were identical for the two groups (92%).

In Japanese noncomparative studies, the clinical efficacy of clarithromycin in the treatment of infections of the urogenital tract ranged from 48 to 92% (depending on the causative pathogen), with the greatest responses elicited in those with chlamydial (92%) or ureaplasmic infections (85%). Oromaxillofacial and ophthalmic infections responded with efficacy rates of 74 to 89%.

In preliminary studies of Mycobacterium avium complex infection in AIDS patients, clarithromycin, either alone or in combination with other antimicrobial drugs, has been shown to reduce or eradicate the pathogen from blood samples, and this has been associated with clinical improvement. Clarithromycin has also shown promising activity in immunocompromised patients with disseminated Mycobacterium chelonae — chelonae infection or toxoplasma encephalitis.

Clarithromycin has a proven efficacy in the treatment of paediatric infections in Japanese and ‘Western’ patients. Thus, in Japanese noncomparative studies where clarithromycin suspension was usually given at a dosage of 10 to 15 mg/kg bodyweight twice or 3 times daily, excellent plus good clinical response rates of 80 to 97% were recorded for Japanese children with impetigo, infections of the respiratory tract or gastrointestinal tract. In ‘Western’ comparative studies, clarithromycin 7.5 mg/kg twice daily (maximum 250mg twice daily) in suspension was considered as effective as phenoxymethylpenicillin for streptococcal pharyngitis, amoxicillin (with or without clavulanic acid) for acute otitis media, cefadroxil or erythromycin for skin or skin structure infections and amoxicillin for lower respiratory tract infections.

Preliminary studies have shown clarithromycin to be effective in the treatment of infection with Helicobacter pylori and in the treatment of leprosy.

Tolerability

Analysis of 4291 ‘Western’ patients revealed an adverse event rate of 19.6% for clarithromycin, the most common occurrences being nausea, diarrhoea, abdominal pain, dyspepsia and headache. In excess of 90% of these adverse events were either mild or moderate in severity. The adverse event rate for clarithromycin was similar to that of common β-lactam antimicrobials, although in comparison with pooled data for other macrolides (erythromycin, josamycin and roxithro-mycin), clarithromycin caused substantially fewer gastrointestinal effects, particularly when compared with erythromycin alone. Premature discontinuation of therapy due to adverse events for clarithromycin (3 to 3.5%) was similar to that with β-lactam antimicrobials (2.7 to 3.5%) but was significantly less than that with other macrolides considered together (5.9%). Increased trans-aminase levels were recorded for patients treated with clarithromycin or other macrolides. However, the incidence of elevated aspartate aminotransferase and alanine aminotransferase was significantly lower (about 2-fold) for clarithromycin compared with other macrolides, especially josamycin.

Dosage and Administration

The recommended oral dosage of clarithromycin in adult ‘Western’ patients with various community-acquired infections (excluding M. avium complex) is 250 to 500mg twice daily for 7 to 14 days. Preliminary data suggest that clarithromycin 1 to 2 g/day is suitable for the treatment of AIDS patients with M. avium complex. ‘Western’ paediatric clinical studies employed a clarithromycin dosage of 7.5 mg/kg bodyweight twice daily (maximum 250mg twice daily) for 5 to 10 days. In adult Japanese patients the recommended dosage for clarithromycin is 400mg twice daily, whereas in Japanese children it is 10 to 15 mg/kg bodyweight in 2 or 3 divided daily doses. It is recommended that the duration of treatment be adjusted depending on the nature and severity of the infection, however, the duration in most Japanese clinical studies has been 7 to 14 days.

Pharmacokinetic studies indicate that dosage adjustment is appropriate in the presence of severe renal impairment. However, in the absence of this condition, dosage adjustment is not necessary in mild to severe hepatic impairment or for the elderly.

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Various sections of the manuscript reviewed by: P.M. Aldons, Prince Charles Hospital, Chermside, Queensland, Australia; C. A. Benson, Section of Infectious Disease, Rush-Presbyterian-St Luke’s Medical Center, Chicago, Illinois, USA; F. Fraschini, Dipartimento Di Farmacologia Chemoterapia E Tossicologia Medica, Universita Degli Studi Di Milano, Milano, Italy; M.J. Gevaudan, Laboratoire de Microbiologie Hygiene et Epidemiologie Hospitalieres, Centre Hospitalier Regional et Universitaire de Marsaille, Hopital Salvator, Marsaille, France; D.R.P. Guay, College of Pharmacy, University of Minnesota, St Paul, Minnesota, USA; K. Hara, Second Department of Internal Medicine, Nagasaki School of Medicine, Nagasaki, Japan; P. Karma, Department of ENT, University Central Hospital, Haartmaninkatu, Helsinki, Finland; S. Kohno, Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan; R. W. Lacey, Department of Microbiology, University of Leeds, Leeds, England; L.A. Mandell, Division of Infectious Diseases, McMaster University, Henderson General Hospital, Hamilton, Ontario, Canada; H.C. Neu, Division of Infectious Diseases, College of Physicians and Surgeons of Columbia University, New York, New York, USA; D. Pastel, Department of Pharmacy, Cedars-Sinai Medical Center, Los Angeles, California, USA; F. Vogel, Medizinische Klinik 111, Kliniken des Main-TaunusKreises, Lindenstrasse 10, Hofheim am Taunus, Federal Republic of Germany; R. Wise, Department of Medical Microbiology, Dudley Road Hospital, Birmingham, England; M.I. Wood, Department of Infection and Tropical Medicine, East Birmingham Hospital, Birmingham, England.

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Peters, D.H., Clissold, S.P. Clarithromycin. Drugs 44, 117–164 (1992). https://doi.org/10.2165/00003495-199244010-00009

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Keywords

  • Erythromycin
  • Clarithromycin
  • Azithromycin
  • Roxithromycin
  • Clinical Success Rate