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Clarithromycin

A Review of its Pharmacological Properties and Therapeutic Use in Mycobacterium avium-intracellulare Complex Infection in Patients with Acquired Immune Deficiency Syndrome

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Abstract

Synopsis

Results from noncomparative and placebo-controlled studies demonstrate the efficacy of clarithromycin in the treatment of disseminated Mycobacterium avium-intracellulare complex (MAC) infection in patients with acquired immune deficiency syndrome (AIDS), Whether given alone or in combination with other antimycobacterial treatments, doses of 500 to 2000mg (typically 1000mg) administered twice daily are effective in controlling bacteraemia in these patients. Clarithromycin has also been shown to improve clinical symptoms of infection and may improve quality of life in AIDS patients with MAC infection.

Clarithromycin is generally well tolerated when used in the doses typically required for the treatment of MAC infection (1000 or 2000 mg/day). Gastrointestinal disturbances are the most commonly occurring adverse events and occur most frequently at dosages of 4000 mg/day.

Thus, clarithromycin, as monotherapy or in combination with other antimycobacterial agents, is well tolerated and effectively eradicates MAC from the blood in the short term in patients with AIDS; however, short term monotherapy may lead to bacterial resistance, underscoring the importance of long term treatment with a combination of antimycobacterial agents. While the optimal combination regimen to prevent the development of resistance to antimycobacterial agents by MAC remains to be determined, clarithromycin will almost certainly be a valuable agent in any such combination.

Overview of Disease

Until recently, infection due to the intracellular bacteria Mycobacterium avium and Mycobacterium intracellulare was rarely observed and was generally restricted to pulmonary sites in patients with underlying pulmonary pathology. Disseminated disease is now common in patients with acquired immune deficiency syndrome (AIDS), and is the most frequently occurring bacterial infection in this patient population in the US. Patients with AIDS-related disseminated mycobacterial disease have a shorter median survival, and increased morbidity, compared with patients with AIDS who do not have mycobacterial disease; however, it is unclear whether shortened survival is attributable to the mycobacterial infection per se.

Overview of Pharmacology

The minimum inhibitory concentration of clarithromycin against MAC depends on both pH and the medium used for in vitro testing. At pH 7.4 clarithromycin is active against MAC in vitro, with minimum concentrations inhibitory to 90% of tested isolates ranging from 0.85 to 8 mg/L.

The minimum bactericidal concentration of clarithromycin against MAC ranged from ⩽6 to >256 mg/L; some investigators suggested clarithromycin would have bactericidal activity in vivo only if it accumulated within phagocytic cells. Clarithromycin does accumulate in leucocytes and polymorphonuclear cells and, at concentrations which are achievable in the serum, it appears that clarithromycin may have bactericidal activity against M. avium-intracellulare complex located within macrophages.

The 14-hydroxy metabolite of clarithromycin also has activity against MAC in vitro and against MAC growing within macrophages.

Clarithromycin is well absorbed after oral administration, but undergoes first-pass metabolism, principally to an active metabolite, reducing its systemic bioavailability. As the major metabolite of clarithromycin has some antimicrobial activity, the bioavailability of the parent compound may underestimate the bioavailability of active compounds. Tissue concentrations of clarithromycin are generally higher than those achieved in the serum, and clarithromycin penetrates into human phagocytic cells to a greater extent than does erythromycin.

Therapeutic Efficacy

Clarithromycin has been studied alone or in combination with other antimycobacterial drugs in the treatment of patients with AIDS and disseminated MAC infection, and initial results have been encouraging.

All 23 evaluable patients in 2 noncomparative studies responded clinically and had negative blood cultures for MAC after 8 weeks of combined antimycobacterial treatment, which included clarithromycin 2000 mg/day with either clofazimine or ciprofloxacin plus amikacin. Dose-ranging studies involving larger numbers of patients found clarithromycin in daily doses of 1000 to 2000mg to be effective in the treatment of MAC infection, although dosages of 1500 to 2000 mg/day may produce a therapeutic response more quickly or more effectively than dosages of ⩽1000 mg/day. Preliminary results of quality-of-life analyses using the Medical Outcomes Study (MOS)-HIV scale indicated that, compared with pretreatment values, clarithromycin produced significant improvements in quality-of-life parameters such as overall health, social functioning and energy level. Small placebo-controlled studies showed that clarithromycin 1000mg twice daily, with or without a 3-drug combination of isoniazid, ethambutol and clofazimine for 6 weeks, achieved consistent bacteriological and clinical response in patients with AIDS and disseminated MAC infection. However, relapse of AIDS-related MAC infection has been documented with clarithromycin, either when given as monotherapy or when used in combination with other antimycobacterial agents. More studies are required to establish the optimal therapeutic regimens for preventing the emergence of resistant organisms.

Tolerability

Data from patients with AIDS receiving clarithromycin 500 to 2000mg twice daily for the treatment of disseminated MAC infection suggest that adverse events, particularly gastrointestinal problems, are dosage-related. An unpublished analysis revealed that gastrointestinal adverse events occurred with a similar frequency in patients receiving clarithromycin 1000 or 2000 mg/day, but occurred considerably more often in patients receiving 4000 mg/day. Similarly, patients receiving clarithromycin 4000 mg/day were more likely to have their treatment with clarithromycin discontinued because of drug-related adverse gastrointestinal events. Furthermore, the drug was well tolerated in other trials using similar dosage regimens in this clinical setting. Other adverse events associated with higher clarithromycin dosages have included minor temporary elevations in liver function test parameters and dysphoric sensations.

Pooled data from phase II/III clinical trials undertaken in 3437 patients, the majority of whom had respiratory tract infections, demonstrated that clarithromycin 250 to 500mg twice daily is well tolerated with few severe adverse events. Approximately 20% of clarithromycin recipients reported 1 or more adverse event, the most frequent of which were gastrointestinal problems. Overall, 3% of patients receiving clarithromycin discontinued treatment due to adverse events. Furthermore, discontinuation of therapy because of adverse effects was less likely with clarithromycin than with older macrolides (3 vs 6%).

Dosage and Administration

The most common dosage of clarithromycin used in clinical trials undertaken in patients with AIDS and disseminated MAC infection has been 1000mg twice daily either alone or in combination with other antimycobacterial agents. Efficacy appears to be dosage-related, but dosages of between 1000 and 2000 mg/day were effective in this patient population.

Dosage reduction may be required in the presence of severe renal impairment, and in elderly patients dosages should be based on bodyweight and renal function and may need to be reduced to 1000 mg/day.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Lee B. Barradell, Greg L. Plosker & Donna McTavish

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  1. Lee B. Barradell
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  2. Greg L. Plosker
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  3. Donna McTavish
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Various sections of the manuscript reviewed by: B.A. Brown, Department of Microbiology, University of Texas Health Center, Tyler, Texas, USA; B. Dautzenberg, Service de Pneumologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; F. de Lalla, Divisione Malattie Infettive, Ospedale Civile San Bortolo, Vicenza, Italy; L.B. Heifets, Mycobacteriology Department, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado, USA; C.R. Horsburgh Jr, Department of Health & Human Services, Division of HIV/AIDS, National Center for Infectious Diseases, Atlanta, Georgia, USA; J. Hoy, Fairfield Hospital, Fairfield, Victoria, Australia; M. Ishiguro, Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan; H. Koga, Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan; C. Perronne, Hôpital Claude-Bernard, Paris, France; B. Ruf, Second Department of Internal Medicine, Rudolf Virchow University Hospital (Wedding), Freie Universität Berlin, Berlin, Federal Republic of Germany; R.J. Wallace Jr, Department of Microbiology, University of Texas Health Center, Tyler, Texas, USA; R. Wise, Department of Medical Microbiology, Dudley Road Hospital, Birmingham, England; M.J. Wood, Department of Infection & Tropical Medicine, Birmingham Heartlands Hospital, Birmingham, England; A.W. Wu, School of Hygiene and Public Health, Health Services Research and Development Center, Johns Hopkins University, Baltimore, Maryland, USA.

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Barradell, L.B., Plosker, G.L. & McTavish, D. Clarithromycin. Drugs 46, 289–312 (1993). https://doi.org/10.2165/00003495-199346020-00007

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