Clarithromycin (Biaxin)

Clarithromycin

Clarithromycin is a semisynthetic macrolide antibiotic with a broader spectrum than that of erythromycins.

Uses

Clarithromycin is used orally for the treatment of pharyngitis and tonsillitis, mild to moderate respiratory tract infections (acute bacterial exacerbation of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia), uncomplicated skin and skin structure infections, and acute otitis media caused by susceptible organisms. Clarithromycin also is used orally in the treatment of disseminated infections caused by Mycobacterium avium complex (MAC) in patients with advanced human immunodeficiency virus (HIV) infection and for prevention of disseminated MAC infection (both primary and secondary prophylaxis) in HIV-infected individuals.

Oral clarithromycin is used in combination with amoxicillin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori infection and duodenal ulcer disease. Clarithromycin also is used orally in combination with omeprazole (dual therapy) or ranitidine bismuth citrate for the treatment of H. pylori infection in patients with an active duodenal ulcer.

Clarithromycin also has been used orally in other multiple-drug regimens (with or without amoxicillin, lansoproprazole, omeprazole, or ranitidine bismuth citrate) for the treatment of H. pylori infection associated with peptic ulcer disease.

Safety and efficacy of clarithromycin extended-release tablets have been established only for the treatment of certain respiratory tract infections in adults (acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, community-acquired pneumonia); safety and efficacy of the extended-release formulation of the drug have not been established for the treatment of other infections that are treated with clarithromycin conventional tablets or oral suspension. Current data from a limited number of controlled and uncontrolled clinical studies suggest that clarithromycin is as effective as erythromycin or a natural penicillin for the treatment of community-acquired respiratory infections and generally causes fewer adverse GI effects than erythromycin. Further studies and experience are needed to elucidate fully the efficacy and safety of clarithromycin relative to erythromycin and other anti-infective agents for the treatment of various infections.

Pending accumulation of such data and considering relative costs of therapy, erythromycin generally would be preferred for most infections in which oral macrolide therapy was indicated unless the patient is intolerant of erythromycin (e.g., secondary to GI toxicity), compliance with 3 or 4 times daily erythromycin dosing is considered a problem, or clarithromycin would be expected to be more effective than erythromycin or other less expensive anti-infectives.

Pharyngitis and Tonsillitis

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci) in adults and children.

Although clarithromycin generally is effective in the eradicating S. pyogenes from the nasopharynx, efficacy of the drug in the subsequent prevention of rheumatic fever has not been established. Because penicillin has a narrow spectrum of activity, is inexpensive, and generally effective, the US Centers for Disease Control and Prevention (CDC), American Academy of Pediatrics (AAP), American Academy of Family Physicians (AAFP), Infectious Diseases Society of America (IDSA), American Heart Association (AHA), American College of Physicians-American Society of Internal Medicine (ACP-ASIM), and others consider natural penicillins (i.e., 10 days of oral penicillin V or a single IM dose of penicillin G benzathine) the treatment of choice for streptococcal pharyngitis and tonsillitis and prevention of initial attacks (primary prevention) of rheumatic fever, although oral amoxicillin often is used instead of penicillin V in small children because of a more acceptable taste.

Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternatives. In a limited number of controlled, comparative studies, microbiologic and clinical response rates of approximately 90% or greater were achieved in patients 12 years of age or older who received oral therapy with either clarithromycin 250 mg every 12 hours, penicillin V 250 mg every 6 hours, or erythromycin 500 mg every 12 hours; most patients were treated for approximately 7-10 days. Comparable clinical and microbiologic response rates have been reported in children as young as 6 months of age who received clarithromycin 7.5 mg/kg (maximum dose: 250 mg) twice daily or penicillin V 13.3 mg/kg (maximum dose: 500 mg) 3 times daily as oral suspensions.

Respiratory Tract Infections

Although clarithromycin and its 14-hydroxy metabolite exhibit additive or synergistic antibacterial activity in vitro against H. influenzae, the drug has failed to eradicate this organism in some patients with respiratory tract infections (chronic bronchitis, mild to moderate community-acquired pneumonia) when used in an oral dosage of 250 mg twice daily. However, preliminary reports of a few studies in which oral clarithromycin 500 mg twice daily was used to treat mild to moderate pneumonia or exacerbations of chronic bronchitis caused by H. influenzae indicate that clinical and bacteriologic responses with clarithromycin therapy were comparable to those observed with second or third generation oral cephalosporin therapy (i.e., with cefuroxime axetil, cefaclor, or cefixime). Further comparative studies and experience are needed to elucidate fully the role of clarithromycin versus other anti-infective agents in the treatment of respiratory tract infections caused by H. influenzae infections.

Acute Exacerbations of Chronic Bronchitis

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of acute bacterial exacerbations of chronic bronchitis caused by Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, or Streptococcus pneumoniae in adults; clarithromycin (extended-release tablets) is used for the treatment of these infections in adults. Current data from a limited number of studies from which patients with b-lactamase-positive infections generally were excluded suggest similar clinical and microbiologic efficacy for oral clarithromycin and oral ampicillin in these infections.

Acute Sinusitis

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of acute maxillary sinusitis caused by H. influenzae, M. catarrhalis, or S. pneumoniae in adults or children; clarithromycin (extended-release tablets) is used for the treatment of these infections in adults. In one study in patients with acute maxillary sinusitis caused principally by S. pneumoniae or Haemophilus spp., oral therapy with clarithromycin 500 mg every 12 hours or amoxicillin 500 mg every 8 hours for 9-11 days resulted in clinical response in 91% of patients in each group, with similar microbiologic responses.

All microbiologic treatment failures in patients receiving clarithromycin involved Haemophilus spp. However, patients with b-lactamase-producing organisms were excluded from this study, and bacteriologic response rates may not be representative of those generally encountered in clinical practice. Limited data from another study in patients with acute maxillary sinusitis suggest that oral clarithromycin 500 mg every 12 hours or amoxicillin and clavulanate potassium 500 mg every 8 hours produce comparable clinical and bacteriologic responses. Further comparative studies of clarithromycin in patients with acute bacterial sinusitis are needed.

Community-Acquired Pneumonia

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of mild to moderate community-acquired pneumonia (CAP) caused by Mycoplasma pneumoniae, Chlamydia pneumoniae, or S. pneumoniae in adults and children; clarithromycin (conventional tablets, oral suspension) also is used in adults for the treatment of CAP caused by H. influenzae. In addition, clarithromycin (extended-release tablets) is used in adults for the treatment of CAP caused by H. influenzae, H. parainfluenzae, M. catarrhalis, M. pneumoniae, C. pneumoniae, or S. pneumoniae. Limited data in patients with CAP caused by these pathogens suggest that oral therapy with clarithromycin given twice daily generally is as effective as erythromycin given 2-4 times daily. Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens; therapy may then be changed (if possible) to a pathogen-specific regimen based on results of in vitro culture and susceptibility testing, especially in hospitalized patients.

The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation and whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., penicillin- or multidrug-resistant S. pneumoniae, enteric gram- negative bacilli, Ps. aeruginosa).

For both outpatients and inpatients, most experts recommend that an empiric regimen for the treatment of CAP include an anti-infective active against S. pneumoniae since this organism is the most commonly identified cause of bacterial pneumonia and causes more severe disease than many other common CAP pathogens. For information on recommendations of the IDSA and American Thoracic Society (ATS) regarding use of clarithromycin and other macrolides in empiric regimens for the inpatient or outpatient treatment of CAP, see Community-acquired Pneumonia under Uses: Respiratory Tract Infections, in the Erythromycins General Statement 8:12.12.04.

Acute Otitis Media

Clarithromycin (conventional tablets, oral suspension) is used for the treatment of acute otitis media (AOM) caused by H. influenzae, M. catarrhalis, or S. pneumoniae in children. Various anti-infectives, including oral amoxicillin, oral amoxicillin and clavulanate potassium, various oral cephalosporins (cefaclor, cefdinir, cefixime, cefpodoxime proxetil, cefprozil, ceftibuten, cefuroxime axetil, cephalexin), IM ceftriaxone, oral co-trimoxazole, oral erythromycin-sulfisoxazole, oral azithromycin, oral clarithromycin, and oral loracarbef, have been used in the treatment of AOM.

The AAP, CDC, and other clinicians state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of b-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice for treatment of uncomplicated AOM since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, and is well tolerated and inexpensive. Because S. pneumoniae resistant to amoxicillin also frequently are resistant to co-trimoxazole, clarithromycin, and azithromycin, these drugs may not be effective in patients with AOM who fail to respond to amoxicillin.

For additional information regarding treatment of AOM and information regarding prophylaxis of recurrent AOM, treatment of persistent or recurrent AOM, and treatment of otitis media with effusion (OME), see Uses: Otitis Media in the Aminopenicillins General Statement 8:12.16.08. In controlled clinical trials of therapy for children with otitis media in areas of the US where the rate of b-lactamase-producing bacteria is high, clarithromycin therapy was compared with cephalosporin therapy alone or other antibiotic therapy with a concomitant b-lactamase inhibitor. In these studies, the combined clinical success rate (i.e., cure plus improvement) for clarithromycin therapy ranged from 88-91%, while that for the comparison therapies was 91%. The overall clinical success rate (i.e., presumed bacterial eradication/clinical cure outcomes) for clarithromycin ranged from 81-83%, while that for the comparison agents ranged from 73-97%. In all studies, the adverse effects associated with any therapy were principally GI related (e.g., diarrhea, vomiting), with a similar or lower incidence of effects occurring in the clarithromycin-treated group as compared with group treated with the comparison agent.

Skin and Skin Structure Infections

Clarithromycin (conventional tablets, oral suspension) is used in adults and children for the treatment of uncomplicated skin and skin structure infections caused by Staphylococcus aureus or Streptococcus pyogenes. Some data in adults and children suggest that oral clarithromycin has efficacy comparable to that of oral erythromycin or an oral cephalosporin (e.g., cefadroxil) in treating various bacterial skin and skin structure infections (e.g., impetigo, cellulitis). Further comparative studies are needed to determine the relative efficacy of clarithromycin versus other anti-infective agents in treating various skin and skin structure infections, and other drugs (e.g., an oral penicillinase-resistant penicillin or cephalosporin) generally are preferred for the treatment of these infections.

Mycobacterial Infections

Mycobacterium avium Complex (MAC) Infections

Primary Prevention of Disseminated MAC Infection

Clarithromycin (conventional tablets, oral suspension) is used to prevent Mycobacterium avium complex (MAC) bacteremia and disseminated infections (primary prophylaxis) in patients with advanced HIV infection.

The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) state that either clarithromycin or azithromycin is the preferred drug for primary prevention of disseminated MAC infection in adults and pediatric patients.

Results of a limited number of controlled studies in patients with HIV infection and absolute helper/inducer (CD4+, T4+) T-cell counts less than 100/ mm indicate that clarithromycin used alone is more effective than placebo in preventing disseminated MAC disease; clarithromycin prophylaxis also has been shown to reduce mortality in at least one placebo-controlled study. In a randomized, double-blind study in patients with acquired immunodeficiency syndrome (AIDS) and baseline median CD4+ counts of 25-30 cells/mm3, the risk of MAC infection (defined as at least one positive culture for MAC bacteria from blood or another normally sterile site) was reduced by 69% in patients receiving clarithromycin 500 mg twice daily compared with that in patients receiving placebo (6 versus 16% incidence of MAC infection with clarithromycin or placebo prophylaxis, respectively). On an intent-to-treat basis, the 1- year cumulative incidence of MAC bacteremia was 5% for patients receiving clarithromycin and 19.% for patients receiving placebo.

Clarithromycin-resistant MAC isolates developed in 11 of 19 clarithromycin recipients who developed MAC infection compared with none of the 53 placebo recipients in whom MAC bacteremia developed. Despite this higher incidence of clarithromycin resistance, clarithromycin prophylaxis was associated with reduced mortality compared with placebo, particularly during the first 12 months of the study. During a follow-up period of about 10 months, the incidence of mortality with clarithromycin prophylaxis was 32% versus 41% with placebo, a 26% reduction.

The incidences of hospitalization and of certain complications of HIV infection (e.g., pneumonia, giardiasis) also were reduced in patients receiving clarithromycin prophylaxis. Patients receiving clarithromycin also showed reductions in the manifestations of disseminated MAC disease, including fever, night sweats, weight loss, and anemia.

Although the incidence of adverse effects attributed to the study drug was higher in patients receiving clarithromycin (42%) than in those receiving placebo (26%), taste perversion (11 versus 2% with clarithromycin or placebo, respectively) and rectal disorders (8 versus 3%, respectively) were the only adverse effects that occurred more frequently with clarithromycin than with placebo. The incidence of severe adverse effects was similar with clarithromycin (7%) and placebo (6%), and discontinuance of clarithromycin prophylaxis because of adverse events (principally headache, nausea, vomiting, depression and taste perversion) was required in 18% of patients receiving the drug compared with 17% of those receiving placebo.

The USPHS/IDSA recommends that primary prophylaxis against MAC disease be given to HIV-infected adults and adolescents (13 years or older) who have CD4+ T-cell counts less than 50/mm3. Severely immunocompromised HIV-infected children younger than 13 years of age also should receive primary prophylaxis against MAC disease according to the following age-specific CD4+ T-cell counts: children 6-13 years of age, less than 50 cells/mm3; children 2- 6 years of age, less than 75 cells/mm3; children 1-2 years of age, less than 500 cells/mm3; and infants younger than 1 year of age, less than 750 cells/mm3. The USPHS/IDSA states that either azithromycin or clarithromycin is the preferred agent for primary prophylaxis; alternatively, if these drugs cannot be tolerated, rifabutin may be used.

There is evidence from placebo-controlled studies that concomitant use of clarithromycin and rifabutin for primary prophylaxis is no more effective than clarithromycin used alone and the combination regimen appears to be associated with an increased incidence of adverse effects. Therefore, the USPHS/IDSA does not recommend concomitant use of clarithromycin and rifabutin for primary MAC prophylaxis. Although the combination of azithromycin and rifabutin is more effective than azithromycin alone for primary MAC prophylaxis, the USPHS/IDSA currently does not recommend this combination regimen because of additional cost, increased incidence of adverse effects, and absence of a difference in survival in patients receiving the combination compared with azithromycin prophylaxis alone.

Current evidence indicates that primary MAC prophylaxis can be discontinued with minimal risk of developing disseminated MAC disease in HIV- infected adults and adolescents who have responded to highly active antiretroviral therapy (HAART) with an increase in CD4+ T-cell counts to greater than 100/mm3 that has been sustained for at least 3 months. The USPHS/IDSA states that discontinuance of primary prophylaxis against MAC is recommended in adults and adolescents meeting these criteria because prophylaxis in these individuals appears to add little benefit in terms of disease prevention for MAC or bacterial infections, and discontinuance reduces the medication burden, the potential for toxicity, drug interactions, selection of drug-resistant pathogens, and cost. However, the USPHS/IDSA states that primary MAC prophylaxis should be restarted in adults and adolescents if CD4+ T-cell counts decrease to less than 50-100/mm3.

The safety of discontinuing MAC prophylaxis in children whose CD4+ T-cell counts have increased as a result of highly active antiretroviral therapy has not been studied to date. HIV-infected pregnant women are at risk for MAC disease, and primary prophylaxis against the infection should be given to such women who have T- cell counts less than 50/mm3. However, some clinicians may choose to withhold prophylaxis during the first trimester of pregnancy because of general concerns regarding drug administration during this period.

Of the available agents, the USPHS/IDSA considers azithromycin the drug of choice for MAC prophylaxis in HIV-infected pregnant women because of the drug’s safety profile in animal studies and anecdotal information on safety in humans. Clarithromycin has demonstrated adverse effects on pregnancy outcome and/or embryo-fetal development in animals and should be used during pregnancy only in clinical circumstances where no alternative therapy is appropriate. (See Cautions: Pregnancy, Fertility, and Lactation.). HIV-infected patients who develop MAC disease while receiving prophylaxis for the infection require treatment with multiple drugs since monotherapy results in drug resistance and clinical failure. (See Treatment and Prevention of Recurrence of Disseminated MAC Infection, under Management of Other Mycobacterial Diseases: Mycobacterium avium Complex [MAC] Infections, in the Antituberculosis Agents General Statement 8:16.04.)

Treatment and Prevention of Recurrence of Disseminated MAC Infection

Clarithromycin (conventional tablets, oral suspension) is used in the treatment of disseminated infections caused by MAC and for prevention of recurrence (secondary prophylaxis) of disseminated MAC infection. Although clarithromycin has been effective when used alone for the treatment of MAC, most authorities recommend the use of multiple-drug regimens that include clarithromycin or azithromycin for the treatment or secondary prevention of these infections. Many clinicians consider the combination of clarithromycin or azithromycin and ethambutol (with or without rifabutin) the best available treatment for disseminated MAC infection.

The ATS recommends therapy that includes either clarithromycin or azithromycin combined with ethambutol and rifabutin for the treatment of disseminated MAC infection in HIV-infected patients. Limited data from comparative trials suggest that concomitant use of ethambutol and clarithromycin may decrease emergence of clarithromycin-resistant MAC; 220 however, inclusion of clofazimine in multiple-drug regimens containing clarithromycin (e.g., with or without ethambutol) does not add to the efficacy (e.g., in terms of prevention of clarithromycin resistance) of such regimens and may even be associated with reduced survival. Therefore, clofazimine should not be used for the treatment of disseminated MAC disease.

The choice of the drug regimen for the treatment of disseminated MAC infection should be made in consultation with an expert, and this regimen usually should be continued for the duration of the patient’s life if such therapy is associated with clinical and microbiologic improvement unless immune recovery has occurred as the result of potent antiretroviral therapy.

Clarithromycin appears to be one of the most active single agents against MAC; however, monotherapy with clarithromycin has been associated with clinical and bacteriologic relapse and the development of clarithromycin-resistant MAC isolates. Randomized studies in adults and children infected with HIV and MAC who had peripheral blood absolute helper/inducer (CD4+, T4+) T-cell counts less than 100/mm3 (with most patients having such T-cell counts less than 50/mm3), demonstrated that oral monotherapy with clarithromycin (0.5-2 g twice daily in adults, 3.75-15 mg/kg twice daily in children) resulted in clinical and laboratory improvement of the MAC infection. In 52-61% of treated patients in these studies, colony counts of MAC in sequential blood cultures decreased or became absent within 29-54 days; patients also experienced decreases in the incidence of fever, night sweats, weight loss, diarrhea, splenomegaly, and hepatomegaly.

However, effects of clarithromycin monotherapy were not sustained; only 8-25% of treated patients maintained negative blood cultures for 12 weeks or longer and median duration of clinical improvement was 2-6 weeks. In addition, development of drug resistance has been reported after 2-7 months of clarithromycin monotherapy.

High clarithromycin dosages (e.g., 1 or 2 g twice daily) for the treatment of disseminated MAC infection have been associated with reduced survival in some studies compared with that in patients receiving clarithromycin 500 mg twice daily; while these findings are not fully understood, dosages exceeding 500 mg twice daily currently are not recommended in HIV-infected patients with disseminated MAC infection. In randomized studies in HIV-infected patients who had peripheral blood absolute helper/inducer (CD4+, T4+) T-cell counts less than 100/mm3 (with most patients having such T-cell counts less than 50/mm3), median survival was 199-249 or 179-215 days in adults receiving clarithromycin dosages of 0.5 or 1 g twice daily, respectively. Higher dosages (e.g., 1-2 g twice daily) of clarithromycin were associated with better bacteriologic improvement during the first 4 weeks of therapy; median time to achieve negative blood culture was 54, 41, or 29 days in patients receiving 0.5, 1, or 2 g of the drug twice daily, respectively.

However, no substantial differences in the time required to achieve negative blood cultures were observed later in therapy. Although the optimum regimen for treatment of disseminated MAC infection in HIV-infected patients remains to be established, currently available data suggest that multiple-drug regimens containing a macrolide (e.g., clarithromycin, azithromycin) are superior to non-macrolide regimens.

Results of a randomized, comparative study in patients with AIDS and MAC bacteremia demonstrated improved functional status, decreased weight loss, and increased survival in patients receiving a 3-drug, clarithromycin-containing regimen compared with a 4-drug regimen that did not include a macrolide antibiotic. In this study, MAC bacteremia was cleared in 69% of evaluable patients receiving clarithromycin (1 g twice daily), ethambutol (approximately 15 mg/kg daily), and rifabutin (300 or 600 mg daily) compared with 29% of those receiving rifampin (600 mg daily), ethambutol (approximately 15 mg/kg daily), clofazimine (100 mg daily), and ciprofloxacin (750 mg twice daily).

Median survival was 8.6 months with the clarithromycin-containing regimen versus 5.2 months for the 4-drug regimen. The dosage of rifabutin used in the 3-drug regimen was reduced from 600 to 300 mg daily in the latter part of the study following an unacceptably high incidence of uveitis in patients receiving this regimen.

However, although the 600-mg dosage of rifabutin was more effective in clearing MAC bacteremia than the 300-mg dosage, the 3-drug regimen that included rifabutin 300 mg daily was still more effective than the 4-drug, non-macrolide regimen. In another randomized, comparative study in adults with HIV infection and MAC bacteremia who had peripheral blood absolute helper/inducer (CD4+, T4+) T-cell counts less than 100/mm3, treatment success (defined as the patient being alive, having either no fever or a reduction of 1°C or more in initial body temperature, and having negative blood cultures for M. avium complex) was similar at 2 and 6 months in patients receiving a 3-drug regimen consisting of clarithromycin (1 g twice daily for 8 weeks, then 500 mg twice daily), rifabutin (450 mg daily), and ethambutol (1. g daily) or a 2-drug regimen consisting of clarithromycin (1 g twice daily for 8 weeks, then 500 mg twice daily) and clofazimine (200 mg daily for 8 weeks, then 100 mg daily) for at least 26 weeks; however, the 3-drug regimen was associated with fewer relapses of MAC bacteremia and a decrease in the emergence of clarithromycin-resistant MAC strains.

To prevent recurrence of MAC disease in HIV-infected adults, adolescents, or children who have previously been treated for an acute episode of MAC infection, the USPHS/IDSA recommends a regimen consisting of clarithromycin given with ethambutol (with or without rifabutin) for long-term suppressive or chronic maintenance therapy (secondary prophylaxis); alternatively, a regimen of azithromycin given with ethambutol (with or without rifabutin) can be used.

The USPHS/IDSA considers azithromycin and ethambutol the preferred regimen for secondary prophylaxis of disseminated MAC infection in pregnant women. Secondary MAC prophylaxis generally is administered for life in adults and adolescents unless immune recovery has occurred as a result of potent antiretroviral therapy.

Limited data indicate that secondary MAC prophylaxis can be discontinued in adults and adolescents who have immune recovery in response to potent antiretroviral therapy.

Based on these data and more extensive cumulative data on safety of discontinuing secondary prophylaxis for other opportunistic infections, the USPHS/IDSA states that it may be reasonable to consider discontinuance of secondary MAC prophylaxis in adults and adolescents who have successfully completed at least 12 months of MAC therapy, have remained asymptomatic with respect to MAC, and have CD4+ T-cell counts exceeding 100/mm3 as the result of potent antiretroviral therapy and this increase has been sustained (e.g., for 6 months or longer). Some experts would obtain a blood culture for MAC (even in asymptomatic patients) prior to discontinuing secondary MAC prophylaxis to substantiate that the disease is no longer active.

The USPHS/IDSA recommends that secondary MAC prophylaxis be restarted in adults of adolescents if CD4+ T-cell counts decrease to less than 100/mm3. The safety of discontinuing secondary MAC prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been studied and children with a history of disseminated MAC should receive lifelong secondary prophylaxis.

Limited evidence suggests additional benefits of clarithromycin for prophylaxis of disseminated MAC infection in patients with HIV infection, including prevention of other infections and a reduced risk of HIV-related cancers. In a large randomized, placebo-controlled study in HIV-infected adults with peripheral blood absolute helper/inducer (CD4+, T4+) T-cell counts less than 100/mm3 in whom prophylaxis with clarithromycin (500 mg twice daily) reduced the incidence of disseminated MAC, the incidences of Pneumocystis carinii pneumonia, community-acquired pneumonia, Giardia lamblia infection, and some neoplastic diseases (e.g., Kaposi’s sarcoma) also were reduced.

Treatment of Pulmonary MAC Infection

Clarithromycin has been included in multiple-drug regimens for the treatment of Mycobacterium avium complex (MAC) pulmonary infections. The ATS and some clinicians currently recommend that therapy for MAC pulmonary infections in HIV-negative patients consist of at least 3 drugs, including clarithromycin (500 mg twice daily) or azithromycin (250 mg daily or 500 mg 3 times weekly), rifabutin (300 mg daily) or rifampin (600 mg daily), and ethambutol (25 mg/kg daily for 2 months, then 15 mg/kg daily). For patients with a small body mass and/or who are older than 70 years of age, clarithromycin 250 mg twice daily or azithromycin 250 mg 3 times weekly may be better tolerated.

The ATS states that the addition of streptomycin given intermittently (2 or 3 times weekly) for at least 2 months may be considered for patients with extensive disease. Studies evaluating the efficacy and tolerability of azithromycin- and clarithromycin-containing regimens given intermittently (i.e., 3 times weekly) for the treatment of MAC pulmonary infections currently are ongoing. The optimal duration of therapy for MAC pulmonary disease has not been established. (See Treatment of Pulmonary and Localized Extrapulmonary MAC Infections, under Management of Other Mycobacterial Diseases: Mycobacterium avium complex [MAC] Infections, in the Antituberculosis Agents General Statement 8:16.04.)

Other Mycobacterial Infections

Clarithromycin has been used successfully in the treatment of various other mycobacterial infections; however, further experience and study are needed to establish the role of clarithromycin therapy in the treatment of these infections. The ATS350 and other clinicians suggest that clarithromycin can be used as an alternative agent for the treatment of infections caused by M. kansasii.

Although a regimen of isoniazid, rifampin, and ethambutol usually is recommended for the treatment of pulmonary or extrapulmonary infections caused by M. kansasii, the ATS states that clarithromycin is a reasonable alternative in patients who are unable to tolerate one of these drugs or when retreatment is necessary. It also has been suggested that clarithromycin may be substituted for rifampin for the treatment of M. kansasii infections in HIV-infected individuals who are receiving indinavir and therefore cannot receive concomitant rifampin.

Although M. kansasii generally are susceptible to clarithromycin in vitro, clinical experience is limited and efficacy of the drug for the treatment of infections caused by this organism has not been established. The ATS suggests that use of clarithromycin can be considered for the treatment of cutaneous infections caused by M. abscessus or M. chelonae; however, treatment of these infections should be based on results of in vitro susceptibility testing.

Although there is some evidence that clarithromycin monotherapy may be effective for the treatment of cutaneous M. chelonae infections in adults, preliminary studies indicate that monotherapy with macrolides is insufficient to produce microbiologic cure for pulmonary M. abscessus infection. In an open, noncomparative trial evaluating clarithromycin in cutaneous (disseminated) infection caused by M. chelonae in a limited number of patients with immunosuppression secondary to disease (e.g., organ transplant, autoimmune disease) or drug therapy (e.g., corticosteroids, cyclophosphamide), clarithromycin (0.5-1 g twice daily for 6 months) resolved the infection in all patients completing therapy; 82% of patient who completed therapy had complete remission of the infection.

Although clarithromycin appears to be highly effective, further study and long-term follow-up are needed to establish the role of clarithromycin therapy in the treatment of M. chelonae infections. The ATS suggests that clarithromycin monotherapy (500 mg twice daily for at least 3 months) is one of several acceptable regimens for the treatment of cutaneous infections caused by M. marinum. In a case report of 2 patients (one HIV-infected, one HIV-seronegative) clarithromycin at a dosage of 2 g daily (with or without concomitant ethambutol therapy) caused resolution of cutaneous M. marinum infection; there was no evidence of recurrence at 6- 24 months after treatment. Limited in vitro and in vivo studies suggest that clarithromycin has bactericidal activity against M. leprae, and the drug has been used with some success in multiple-drug regimens for short periods in a few patients with leprosy.

Helicobacter pylori Infection

Clarithromycin (conventional tablets) is used in combination with amoxicillin and lansoprazole or omeprazole (triple therapy) for the treatment of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis) infection in patients with duodenal ulcer disease (active or up to 1-year history of duodenal ulcer).

Clarithromycin also is used in combination with omeprazole (dual therapy) or ranitidine bismuth citrate for the treatment of H. pylori infection in patients with an active duodenal ulcer.

Clarithromycin also has been used orally in other multiple-drug regimens (with or without amoxicillin, omeprazole, lansoprazole, or ranitidine bismuth citrate) for the treatment of H. pylori infection associated with peptic ulcer disease. While some evidence indicates that combined therapy with 2 drugs (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti-H. pylori therapy), the American College of Gastroenterology (ACG) and some clinicians currently recommend anti-H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) because of enhanced H. pylori eradication rates, decreased treatment failures due to resistance, and shorter treatment periods compared with those apparently required with 2-drug regimens.

Pathogenesis

Current epidemiologic and clinical evidence supports a strong association between gastric infection with H. pylori and the pathogenesis of duodenal and gastric ulcers; with the exception of ulcers associated with gastrinoma (Zollinger-Ellison syndrome) or use of NSAIAs, almost all cases of duodenal ulcer and most cases of gastric ulcer are associated with H. pylori infection. 278

Although H. pylori eradication (generally defined as the absence of H. pylori organisms in the stomach documented at least 1 month after completion of anti-H. pylori therapy) reduces ulcer relapse rates, other factors appear to be essential for the development of peptic ulcer because most individuals with H. pylori infection do not develop peptic ulcers, and such ulcers are healed by various other therapies despite the presence of the organism in the stomach.

Once acquired, H. pylori infection may persist for decades or even for life, causing chronic inflammation, although most infected individuals reportedly are asymptomatic.

Since type B active chronic gastritis is caused by H. pylori infection and may eventually progress to chronic atrophic gastritis, a well- recognized risk factor for gastric carcinoma, long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. However, whether eradication of H. pylori ultimately will reduce the incidence of gastric carcinoma remains to be established, and most clinicians currently do not advocate the use of anti-H. pylori therapy solely as a potential means of lowering the risk of gastric cancer given the prevalence of H. pylori infection in the general population and the potential costs and complications of current treatment regimens.

Although H. pylori eradication (generally defined as the absence of H. pylori organisms in the stomach documented at least 1 month after completion of anti-H. pylori therapy) reduces ulcer relapse rates, other factors appear to be essential for the development of peptic ulcer because most individuals with H. pyloriinfection do not develop peptic ulcers, and such ulcers are healed by various other therapies despite the presence of the organism in the stomach.

Once acquired, H. pylori infection may persist for decades or even for life, causing chronic inflammation, although most infected individuals reportedly are asymptomatic. Since type B active chronic gastritis is caused by H. pylori infection and may eventually progress to chronic atrophic gastritis, a well- recognized risk factor for gastric carcinoma, long-term H. pylori infection also has been implicated as a risk factor for gastric cancer. However, whether eradication of H. pylori ultimately will reduce the incidence of gastric carcinoma remains to be established, and most clinicians currently do not advocate the use of anti-H. pylori therapy solely as a potential means of lowering the risk of gastric cancer given the prevalence of H. pylori infection in the general population and the potential costs and complications of current treatment regimens.

Therapeutic Regimens

Conventional antiulcer therapy with H2-receptor antagonists, proton-pump inhibitors, sucralfate, and/or antacids heals ulcers but generally is ineffective in eradicating H. pylori, and such therapy is associated with a high rate of ulcer recurrence (e.g., 60-100% per year). Several useful therapeutic regimens for H. pylori-associated peptic ulcer disease have been identified, and the ACG, the National Institutes of Health (NIH), and most clinicians currently recommend that all patients with initial or recurrent duodenal or gastric ulcer and documented H. pylori infection receive anti-infective therapy for treatment of the infection.

The optimum regimen for treatment of H. pylori infection has not been established; however, combined therapy with 3 drugs that have activity against H. pylori (e.g., a bismuth salt, metronidazole, and tetracycline or amoxicillin) has been effective in eradicating the infection, resolving associated gastritis, healing peptic ulcer, and preventing ulcer recurrence in many patients with H. pylori-associated peptic ulcer disease.

Although such 3-drug regimens typically have been administered for 10-14 days, current evidence principally from studies in Europe suggests that 1 week of such therapy provides H. pylori eradication rates comparable to those of longer treatment periods. Other regimens that combine one or more anti-infective agents (e.g., clarithromycin, amoxicillin) with a bismuth salt and/or an antisecretory agent (e.g., omeprazole, lansoprazole, H2-receptor antagonist) also have been used successfully for H. pylori eradication, and the choice of a particular regimen should be based on the rapidly evolving data on optimal therapy, including consideration of the patient’s prior exposure to anti-infective agents, the local prevalence of resistance, patient compliance, and costs of therapy.

Current data suggest that eradication of H. pylori infection using regimens consisting of 1 or 2 anti-infective agents with a bismuth salt and/or an H2-receptor antagonist or proton-pump inhibitor (e.g., omeprazole, lansoprazole) is cost effective compared with intermittent or continuous maintenance therapy with an H2-receptor antagonist (considering the costs associated with ulcer recurrence, including endoscopic or other diagnostic procedures, physician visits, and/or hospitalization). The ACG and some clinicians currently state that an H. pylori eradication rate of approximately 90% with a 1-week treatment period represents a realistic goal of therapy for H. pylori infection. However, some clinicians state that results of 1-week anti-H. pylori regimens in Europe generally have been superior to those conducted in the US to date and that additional US studies with these regimens are needed to confirm the efficacy of 1-week regimens in the US.

Although high eradication rates have been achieved with standard 3-drug, bismuth-based regimens (e.g., bismuth-metronidazole-tetracycline or bismuth- metronidazole-amoxicillin), such regimens typically involve administration of many tablets/capsules and have been associated with a relatively high (although variable) incidence of adverse effects. In addition, the efficacy of these regimens generally is unacceptable in patients with H. pylori strains resistant to the imidazole anti-infective (e.g., metronidazole) component. Current evidence suggests that inclusion of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) in anti-H. pylori regimens containing 2 anti-infectives enhances effectiveness, and limited data suggest that such regimens retain good efficacy despite imidazole (e.g., metronidazole) resistance.

Therefore, the ACG and many clinicians currently recommend 1 week of therapy with a proton-pump inhibitor and 2 anti-infective agents (usually clarithromycin and amoxicillin or metronidazole), or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor, for treatment of H. pylori infection. Although few comparative studies have been performed, such regimens appear to provide high (e.g., 85-90%) H. pylori eradication rates, are well tolerated, and may be associated with better patient compliance than more prolonged therapy. The ACG states that in a cost-sensitive environment, an alternative regimen consisting of a bismuth salt, metronidazole, and tetracycline for 14 days is a reasonable choice in patients who are compliant and in whom there is a low expectation of metronidazole resistance (no prior exposure to the drug and a low regional prevalence of resistance).

Current data suggest that modification of bismuth-metronidazole-tetracycline regimens by substituting clarithromycin for metronidazole or amoxicillin (but not ampicillin) for tetracycline also results in effective therapy, but the substitution of either amoxicillin or another tetracycline derivative (i.e., doxycycline) for tetracycline hydrochloride in such regimens reduces efficacy. While azithromycin has been used in a limited number of multiple-drug regimens (e.g., with tetracycline, metronidazole, bismuth salts, and/or omeprazole) for the treatment of Helicobacter pylori infection and peptic ulcer disease, such combination regimens generally have been associated with a high incidence of adverse effects (principally GI effects) or low H. pylori eradication rates (e.g., 50-70%).

Additional controlled, comparative studies and long-term follow-up are needed to determine optimal drug regimens for H. pylori-associated peptic ulcer and to elucidate the effects of H. pylori eradication on potential long- term complications of peptic ulcer disease such as GI bleeding and gastric carcinoma. Current evidence suggests that eradication of H. pylori by anti-infective agents may be facilitated by increased gastric pH, and many clinicians recommend concomitant treatment with antisecretory agents (e.g., omeprazole, lansoprazole, H2-receptor antagonists) to enhance ulcer healing and symptom relief while allowing relatively short (e.g., 1-week) treatment periods in patients with active peptic ulcer disease.

Eradication rates of almost 100% have been reported with addition of omeprazole to a 3-drug anti-H. pylori regimen. Therapy with an antisecretory drug and a single anti-infective agent (i.e., “dual therapy”) also has been used successfully for treatment of H. pylori infection. However, rates of H. pylori eradication have varied considerably in some studies using combined therapy with 2 drugs (e.g., amoxicillin and omeprazole) depending on dosage, timing of administration, and possibly the age of the patient.

An analysis of pooled data from a number of studies in which combined therapy with omeprazole and either amoxicillin or clarithromycin was used indicate H. pylori eradication rates averaging approximately 55-62% with amoxicillin-omeprazole and 67-75% with clarithromycin-omeprazole therapy. In 4 randomized, controlled trials in patients with active duodenal ulcer, combined therapy with clarithromycin (500 mg 3 times daily for 14 days) and omeprazole (40 mg daily for 14 days followed by either 20 or 40 mg daily for an additional 14 days) was successful in eradicating H. pylori (defined as 2 negative tests for H. pylori 4 weeks after the end of treatment) in 64-83% of patients compared with 0-1% of patients receiving omeprazole alone or (in 2 trials) 31-39% of patients receiving clarithromycin alone.

Ulcer healing rates at 4 weeks averaged 94-100% with clarithromycin-omeprazole treatment, 88- 99% with omeprazole alone, and (in 2 trials) 64-71% with clarithromycin alone. In addition, follow-up evaluations at 6 months in patients whose ulcers were healed demonstrated a reduction in ulcer recurrence in patients in whom H. pylori was eradicated. In 2 other randomized, controlled trials in patients with active duodenal ulcer, eradication of H. pylori (defined as 2 negative tests for H. pylori 4 weeks after the end of anti-H. pylori treatment) was achieved in 72 or 71% of patients receiving 2 weeks of combined therapy with clarithromycin (500 mg 2 or 3 times daily, respectively) and ranitidine bismuth citrate (400 mg twice daily) followed by 2 weeks of monotherapy with ranitidine bismuth citrate (400 mg 2 times daily).

Follow-up evaluations demonstrated a twofold reduction in the risk of ulcer recurrence within 6 months of completing treatment in patients in whom H. pylori was eradicated compared with those in whom the infection was not eradicated. The contribution, if any, of bismuth citrate to the healing effects of ranitidine alone was not evaluated in these studies.

While some studies demonstrate that certain 2-drug anti-H. pylori regimens (e.g., clarithromycin-omeprazole, ranitidine bismuth citrate-omeprazole, amoxicillin-omeprazole) can successfully eradicate H. pylori infection and prevent recurrence of duodenal ulcer at least in the short term (e.g., at 6 months following completion of anti-H. pylori therapy), 3-drug regimens appear to be associated with higher H. pylori overall eradication rates than dual-therapy combinations. In 2 randomized, controlled trials in patients with H. pylori infection and duodenal ulcer disease (i.e., active ulcer or history of an ulcer within 1 year) who received triple therapy for 14 days with clarithromycin (500 mg twice daily), amoxicillin (1 g twice daily), and lansoprazole (30 mg twice daily), H. pylori was eradicated (defined as 2 negative tests for H. pylori by culture or histology 4-6 weeks after the end of anti-H. pylori treatment) in 92 or 86% of evaluable patients (86 or 83% of patients, respectively, by intent- to-treat analysis); while dual therapy with lansoprazole (30 mg 3 times daily) and amoxicillin (1 g 3 times daily) for 14 days produced H. pylori eradication in 77 or 66% of evaluable patients (70 or 61% of patients, respectively, by intent-to-treat analysis).

Therapy with the 3-drug combination was more effective than all possible dual-therapy combination regimens with these drugs (i.e., lansoprazole-amoxicillin, lansoprazole-clarithromycin, and amoxicillin-clarithromycin).

In 3 randomized, double-blind trials in patients with H. pylori infection and duodenal ulcer disease (active ulcer or a history of duodenal ulcer in the previous 5 years) who were treated for 10 days, triple therapy with clarithromycin (500 mg twice daily), amoxicillin (1 g twice daily), and omeprazole (20 mg twice daily) eradicated H. pylori (defined as 2 negative and no positive tests for H. pylori as assessed by CLOtest®, histology, and/or culture) in 77, 78, or 90% of evaluable patients (69, 73, or 83% of patients, respectively, by intent- to-treat analysis); dual therapy with clarithromycin and amoxicillin eradicated H. pylori infection in 43, 41, or 33% of evaluable patients (37, 36, or 32% of patients, respectively, by intent-to-treat analysis). In 2 of these studies, patients receiving the triple-therapy regimen for eradication of H. pylori continued omeprazole 20 mg daily for an additional 18 days.

The ACG and some clinicians currently state that anti-H. pylori regimens consisting of at least 3 drugs (e.g., 2 anti-infective agents plus a proton-pump inhibitor) are recommended because of enhanced H. pylori eradication rates, decreased failures secondary to resistance, and shorter treatment periods (e.g., 1 week) compared with those apparently required with 2-drug regimens (e.g., 10-14 days). Additional randomized, controlled studies comparing various anti-H. pylori regimens are needed to clarify optimum drug combinations, dosages, and duration of treatment for H. pylori infection.

Duration of Therapy

The minimum duration of therapy required to eradicate H. pylori infection in peptic ulcer disease has not been fully established. In a randomized trial in patients with H. pylori infection and duodenal ulcer disease, 10 days of therapy with clarithromycin (500 mg twice daily), amoxicillin (1 g twice daily), and lansoprazole (30 mg twice daily) was as effective in eradicating H. pylori as 14 days of therapy with this drug regimen; H. pylori eradication was achieved in 85% of evaluable patients with the 14-day regimen compared with 84% of those receiving the 10-day regimen (82 versus 81% of patients, respectively, by intent-to-treat analysis).

In patients with uncomplicated ulcers who receive a proton-pump inhibitor (e.g., omeprazole) plus 2 anti-infective agents or a proton-pump inhibitor and bismuth-tetracycline-metronidazole, the ACG and many clinicians state that treatment for longer than 1 week probably is not necessary. However, more prolonged anti-infective and/or antisecretory therapy is recommended for patients with complicated, large, or refractory ulcers; therapy in such patients should be continued at least until successful eradication of H. pylori has been confirmed.

Resistant and Recurrent Infection

The optimum method of treating patients who fail to respond to currently recommended anti-H. pylori regimens is unknown. However, clarithromycin or metronidazole should not be used subsequently in patients with H. pylori infection who fail therapy that includes these drugs since resistance commonly emerges during such unsuccessful therapy. Rapid development of resistance by H. pylori to certain drugs (e.g., metronidazole, clarithromycin and other macrolides, quinolones) has occurred when these drugs were used as monotherapy or as the only anti-infective agent in anti-H. pylori regimens.

Resistance commonly emerges during therapy with clarithromycin or metronidazole when eradication of H. pylori is not achieved; therefore, prior exposure to these anti-infectives predicts resistance in individual patients and should be considered when selecting anti-H. pylori treatment regimens. Clarithromycin-containing regimens should not be used for eradication of H. pylori in patients with known or suspected clarithromycin-resistant isolates because of reduced efficacy in such patients.

Some clinicians state that the same anti-infective regimen should not be used for retreatment of H. pylori infection even if antibiotic resistance has not developed. In clinical trials in patients who received clarithromycin as the sole anti-infective agent in combination regimens for H. pylori infection, some H. pylori isolates demonstrated an increase in clarithromycin MICs over time, indicating decreased susceptibility and increasing resistance to the drug. Agents that do not induce resistance in H. pylori include amoxicillin, tetracycline, and bismuth; 1 or 2 of these drugs generally are included in regimens that contain metronidazole or clarithromycin.

The ACG states that possible regimens for treatment of metronidazole-resistant H. pylori infections include bismuth-clarithromycin-tetracycline or omeprazole-amoxicillin-clarithromycin. In patients who develop clarithromycin resistance, the ACG suggests potential alternative therapy consisting of omeprazole, a bismuth salt, metronidazole, and tetracycline; or omeprazole, amoxicillin, and metronidazole.

A regimen consisting of amoxicillin (1 g twice daily), rifabutin (300 mg daily), and a proton-pump inhibitor (pantoprazole 40 mg twice daily) for one week reportedly was effective in eradicating H. pylori (according to the results of a 13C urea breath test) in about 79% of patients who had failed at least 2 prior courses of anti-H. pylori therapy. Some clinicians also suggest that a 3-drug, furazolidone-containing regimen could be used in patients with metronidazole- or clarithromycin-resistant H. pyloriinfection. The most common cause of ulcer recurrence after anti-infective therapy for H. pylori infection is failure to eradicate the organism since reinfection with H. pylori in developed countries appears to occur very infrequently.

The ACG and some clinicians state that diagnostic confirmation of H. pylori eradication is important in patients with complicated, giant, or refractory ulcers but is controversial or generally not needed in those with uncomplicated ulcers who remain asymptomatic after anti-infective therapy. If diagnostic tests for H. pylori are used, such tests should be performed at least 1 month or, preferably, longer after discontinuance of anti-H. pylori therapy to minimize the potential for false-negative test results attributable to suppression rather than eradication of the organism.

Therapy in Children

Combined therapy with 1 or 2 anti-infective agents (e.g., generally amoxicillin with or without metronidazole) and bismuth subsalicylate in children with H. pylori infection and associated peptic ulcer disease appears to promote healing and reduces ulcer recurrence.

Although the prevalence of H. pylori infection is lower in children than in adults, the organism reportedly has been identified in approximately 50% of children with gastritis or gastric ulcers and in 60% of those with duodenitis or duodenal ulcers. Limited data suggest that therapy with H2-receptor antagonists or a single antibiotic is associated with a high risk of disease recurrence; in addition, reinfection with H. pylori has been reported to be more common in children than in adults. Because the prevalence of H. pylori infection and the incidence of H. pylori-associated gastroduodenal inflammation are much lower in children than in adults, H. pylori is more likely to be associated with peptic ulcer disease when found in a child.

Therefore, some clinicians have recommended that children with symptoms suggesting gastroduodenal inflammation that do not respond to antacid therapy should be evaluated for the presence of H. pylori and, if the organism is found, given therapy aimed at eradicating the infection. In a study in a limited number of children (mean age: 12. years) with H. pylori-associated duodenal ulcer, treatment with a 6-week regimen of bismuth subsalicylate and amoxicillin, or these 2 drugs plus metronidazole in cases of initial treatment failure, resulted in endoscopically proved eradication of the organism in 100% of patients at long- term (mean: 6.5 months) follow-up.

Nonulcer Dyspepsia

Although it has been suggested that patients with nonulcer dyspepsia and concomitant H. pylori infection also may benefit from eradicative therapy for H. pylori, evidence from several well-designed clinical trials has been conflicting regarding an association between this organism and nonulcer dyspepsia. Nevertheless, while therapy for H. pylori eradication in such patients generally is not routinely recommended, some evidence suggests that initial anti-H. pylori therapy may be a cost-effective management strategy compared with initial endoscopy for patients with simple dyspepsia who are H. pylori-positive on noninvasive (e.g., serologic) testing.

Lyme Disease

Clarithromycin (500 mg twice daily for 21 days) has been used with apparent success (based on a 6-month follow-up period) in a limited number of patients with early Lyme disease. However, some evidence in patients with early Lyme disease suggests that other macrolides (e.g., azithromycin, erythromycin) may be less effective than penicillins or tetracyclines, and the IDSA, AAP, and other clinicians recommend that macrolide antibiotics not be used as first-line therapy for early Lyme disease. Oral doxycycline or oral amoxicillin is recommended as first-line therapy for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree atrioventricular (AV) heart block; alternatively, oral cefuroxime axetil has been used.

The IDSA and other clinicians state that macrolide antibiotics should be reserved for patients who are intolerant of doxycycline, amoxicillin, and cefuroxime axetil and that patients treated with macrolides should be monitored closely. For more detailed information on the manifestations of Lyme disease and the efficacy of various anti-infective regimens in early or late Lyme disease, see Lyme Disease in Uses: Spirochetal Infections, in the Tetracyclines General Statement 8:12.24.

Cryptosporidiosis

It has been reported that use of clarithromycin or rifabutin in HIV-infected adults for prevention of MAC infection may also decrease the incidence of cryptosporidiosis is these patients. The severity of symptoms of cryptosporidiosis in HIV-infected individuals appears to depend on the CD4+ T-cell count, and fulminant infections usually have occurred in those with CD4+ T-cell counts less than 50/mm3.

No anti-infective agent has been found to reliably eradicate Cryptosporidium, although several drugs (e.g., paromomycin, azithromycin, nitazoxanide [not commercially available in the US]) appear to suppress the infection. Some clinicians suggest that asymptomatic and immunocompetent individuals with cryptosporidiosis can be treated with supportive care only (i.e., oral or IV fluids and electrolyte replacement to correct dehydration) until spontaneous recovery occurs.

These clinicians suggest that the best treatment for cryptosporidiosis in HIV-infected individuals is improvement in immune function through the use of potent antiretroviral agents; when this is not possible or effective, standard treatment is use of an anti-infective agent in conjunction with an antidiarrheal agent.

Pertussis

It has been suggested that clarithromycin may be effective for the treatment of pertussis and can be considered an alternative agent for the treatment of infections caused by Bordetella pertussis. However, the AAP states that erythromycin is considered the drug of choice for the treatment of the catarrhal stage of pertussis and to reduce the communicability of the disease and efficacy of other macrolides (azithromycin, clarithromycin) has not been proven to date.

Toxoplasmosis

Clarithromycin has been used in conjunction with pyrimethamine for the treatment of encephalitis caused by Toxoplasma gondii in a few patients with AIDS. Further controlled studies and experience are needed or are ongoing to determine the potential role of clarithromycin in the treatment of this infection. The USPHS/IDSA states that use of clarithromycin for primary or secondary prophylaxis of toxoplasmosis in HIV-infected individuals cannot be recommended based on current data.

Prevention of Bacterial Endocarditis

Clarithromycin has been recommended for prevention of a-hemolytic (viridans group) streptococcal endocarditis in penicillin-allergic adults and children with congenital heart disease, rheumatic or other acquired valvular heart dysfunction (even after valvular surgery), prosthetic heart valves (including bioprosthetic or allograft valves), surgically constructed systemic pulmonary shunts or conduits, hypertrophic cardiomyopathy, mitral valve prolapse with valvular regurgitation and/or thickened leaflets, or previous bacterial endocarditis (even in the absence of heart disease) who undergo dental procedures that are likely to result in gingival or mucosal bleeding (e.g., dental extractions; periodontal procedures such as scaling, root planing, probing, and maintenance; dental implant placement or reimplantation of avulsed teeth; root-filling procedures; subgingival placement of antibiotic fibers or strips; initial placement of orthodontic bands; intraligamentary local anesthetic injections; routine professional cleaning) or minor upper respiratory tract surgery or instrumentation (e.g., tonsillectomy, adenoidectomy, bronchoscopy with a rigid bronchoscope).

The AHA recognizes that its current recommendations for prevention of bacterial endocarditis are empiric, since no controlled efficacy studies have been published, and that prophylaxis of endocarditis is not always effective. However, the AHA, the ADA, and most clinicians generally recommend routine use of prophylactic anti-infectives in patients at risk for bacterial endocarditis. A national registry established by the AHA in the early 1980s analyzed 52 cases of apparent failure of anti-infective prophylaxis against bacterial endocarditis; only 6 (12%) cases had received AHA-recommended prophylactic regimens. When selecting anti-infectives for prophylaxis of recurrent rheumatic fever or prophylaxis of bacterial endocarditis, the current recommendations published by the AHA should be consulted.

Dosage and Administration

Reconstitution and Administration

Clarithromycin conventional tablets and oral suspension are administered orally and may be given without regard to meals. Clarithromycin oral suspension may be administered with milk.

Clarithromycin extended-release tablets should be taken with food. Clarithromycin granules for oral suspension should be reconstituted at the time of dispensing by adding the amount of water specified on the bottle to provide a suspension containing 125 or 250 mg of clarithromycin per 5 mL of suspension. The water should be added in two portions and the suspension agitated well after each addition. The suspension should be agitated well just prior to each use.

Dosage

Safety and efficacy of clarithromycin extended-release tablets have been established for the treatment of acute bacterial exacerbations of chronic bronchitis, acute maxillary sinusitis, and community-acquired pneumonia (CAP) in adults; safety and efficacy of the extended-release formulation of the drug have not been established for the treatment of other infections that are treated with clarithromycin conventional tablets or oral suspension.

Pharyngitis and Tonsillitis

The usual oral dosage of clarithromycin conventional tablets or oral suspension for the treatment of pharyngitis and tonsillitis in adults is 250 mg every 12 hours for 10 days. The usual oral dosage of clarithromycin for the treatment of pharyngitis and tonsillitis in children is 7.5 mg/kg every 12 hours for 10 days.

Respiratory Tract Infections

For the treatment of acute exacerbations of chronic bronchitis caused by Haemophilus influenzae or H. parainfluenzae in adults, the usual dosage of clarithromycin conventional tablets or oral suspension is 500 mg every 12 hours for 7-14 days or 7 days, respectively.

The usual adult dosage of clarithromycin conventional tablets or oral suspension for the treatment of acute bacterial exacerbations of chronic bronchitis caused by Moraxella catarrhalis or Streptococcus pneumoniae is 250 mg every 12 hours for 7-14 days. For the treatment of acute bacterial exacerbations of chronic bronchitis due to these organisms, the usual adult dosage of clarithromycin extended-release tablets is 1 g (two 500-mg extended-release tablets) every 24 hours for 7 days. T he usual oral dosage of clarithromycin conventional tablets or oral suspension for the treatment of acute maxillary sinusitis in adults is 500 mg every 12 hours for 14 days.

The usual oral dosage of clarithromycin extended-release tablets for the treatment of acute maxillary sinusitis in adults is 1 g (two 500- mg extended-release tablets) every 24 hours for 14 days. Children receiving clarithromycin for the treatment of acute maxillary sinusitis should receive 7.5 mg/kg every 12 hours for 10 days.

For the treatment of community-acquired pneumonia (CAP) in adults, the usual dosage of clarithromycin conventional tablets or oral suspension is 250 mg every 12 hours; therapy is continued for 7-14 days for infections caused by Chlamydia pneumoniae, Mycoplasma pneumoniae, or S. pneumoniae or 7 days for infections caused by H. influenzae. The usual adult dosage of clarithromycin extended-release tablets for the treatment of CAP caused by H. influenzae, H. parainfluenzae, M. catarrhalis, S. pneumoniae, C. pneumoniae, or M. pneumoniae is 1 g (two 500 mg extended-release tablets) every 24 hours for 7 days. Children receiving clarithromycin for the treatment of CAP should receive 7.5 mg/kg every 12 hours for 10 days.

Acute Otitis Media

The usual oral dosage of clarithromycin for the treatment of acute otitis media in children is 7.5 mg/kg every 12 hours for 10 days. Skin and Skin Structure Infections The usual dosage of clarithromycin conventional tablets or oral suspension for the treatment of uncomplicated skin and skin structure infections in adults is 250 mg every 12 hours for 7-14 days; the usual clarithromycin dosage in children is 7.5 mg/kg every 12 hours for 10 days.

Mycobacterium Avium Complex (MAC) Infections

Primary Prevention of Disseminated MAC Infection

For primary prevention of disseminated Mycobacterium avium complex (MAC) infection (primary prophylaxis) in individuals with human immunodeficiency virus (HIV) infection, adults and adolescents should receive 500 mg of clarithromycin (conventional tablets or oral suspension) every 12 hours and children should receive 7.5 mg/ kg (maximum 500 mg) every 12 hours. The manufacturer states that no studies of clarithromycin prophylaxis of MAC infection have been conducted in pediatric patients and that clarithromycin dosages recommended for primary prophylaxis in children are derived from studies involving treatment of MAC infection in pediatric patients.

The Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/ IDSA) recommends primary prophylaxis against disseminated MAC infection in HIV-infected adults and adolescents with CD4+ T-cell counts less than 50/ mm.

Although consideration can be given to discontinuing such prophylaxis in adults and adolescents when there is immune recovery in response to potent antiretroviral therapy and an increase in CD4+ T-cell count to greater than 100/ mm has been sustained for at least 3 months, the USPHS/IDSA states that primary MAC prophylaxis should be restarted if the CD4+ T-cell count decreases to less than 50-100/mm3.

The safety of discontinuing primary MAC prophylaxis in children whose CD4+ T-cell counts have increased as a result of highly active antiretroviral therapy has not been studied to date.

Treatment and Prevention of Recurrence of Disseminated MAC Infection

For the treatment of disseminated MAC infection, adults and adolescents should receive 500 mg of clarithromycin (conventional tablets or oral suspension) every 12 hours. Clarithromycin dosages higher than 500 mg twice daily are not recommended since such dosages have been associated with reduced survival in clinical studies in patients with disseminated MAC disease. Children should receive 7.5 mg/kg (maximum 500 mg) every 12 hours for treatment of prevention of recurrence. Clarithromycin should be used in combination with other antimycobacterial drugs that have in vitro activity against MAC or have produced clinical benefit in patients with disseminated MAC disease.

Infections and also see Treatment and Prevention of Recurrence of Disseminated MAC Infection, under Management of Other Mycobacterial Diseases: Mycobacterium avium Complex [MAC] Infections, in the Antituberculosis Agents General Statement 8:16.04.)

For long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence of disseminated MAC in HIV-infected individuals who responded to treatment, the USPHS/IDSA recommends that adults and adolescents receive clarithromycin in a dosage of 500 mg twice daily in conjunction with ethambutol (15 mg/kg once daily) with or without rifabutin (300 mg once daily). For prevention of MAC recurrence in HIV-infected infants and children, the USPHS/IDSA recommends clarithromycin in a dosage of 7.5 mg/kg (maximum 500 mg) twice daily in conjunction with ethambutol (15 mg/kg [maximum 900 mg] once daily) with or without rifabutin (5 mg/kg [maximum 300 mg] once daily). Secondary MAC prophylaxis in HIV-infected individuals usually is continued for life therapy.

However, the USPHS/IDSA states that consideration can be given to discontinuing secondary MAC prophylaxis in adults and adolescents when there is immune recovery in response to potent antiretroviral therapy (see Treatment and Prevention of Recurrence of Disseminated MAC Infection under Mycobacterial Infections: Mycobacterium avium Complex [MAC] Infections in Uses) but states that such prophylaxis should be restarted if CD4+ T-cell counts decrease to less than 100/mm3. The safety of discontinuing secondary MAC prophylaxis in children receiving potent antiretroviral therapy has not been studied to date and HIV-infected children with a history of disseminated MAC should receive lifelong secondary prophylaxis.

Helicobacter pylori Infection

When used in combination with omeprazole (40 mg daily in the morning for 14 days) for the treatment of H. pylori infection in adults with duodenal ulcer disease (active or up to 1-year history), the recommended dosage of clarithromycin (conventional tablets or oral suspension) is 500 mg 3 times daily for 14 days; an additional 14 days of omeprazole monotherapy (20 mg daily in the morning) is recommended for ulcer healing and symptom relief in patients with an active duodenal ulcer at the time treatment is initiated to complete 28 days of therapy.

When used in combination with ranitidine bismuth citrate (400 mg twice daily for 14 days) the recommended dosage of clarithromycin (conventional tablets or oral suspension) for the treatment of H. pylori infection and duodenal ulcer is 500 mg 2 or 3 times daily for 14 days; an additional 14 days of ranitidine bismuth citrate monotherapy (400 mg twice daily) is then administered to complete 28 days of therapy.

When used in combination with amoxicillin (1 g twice daily for 10 or 14 days) and lansoprazole (30 mg twice daily for 10 or 14 days), the recommended dosage of clarithromycin (conventional tablets or oral suspension) for the treatment of H. pylori infection and duodenal ulcer in adults is 500 mg twice daily for 10 or 14 days. When used in combination with amoxicillin (1 g twice daily for 10 days) and omeprazole (20 mg twice daily for 10 days), the recommended dosage of clarithromycin (conventional tablets or oral suspension) for the treatment of H. pylori infection and duodenal ulcer disease (active or up to 1-year history of duodenal ulcer) in adults is 500 mg twice daily for 10 days.

An additional 18 days of omeprazole monotherapy (20 mg daily) is recommended for ulcer healing and symptom relief in patients with an active duodenal ulcer at the time therapy is initiated.

Multiple-drug regimens currently recommended by the American College of Gastroenterology (ACG) and many clinicians for the treatment of H. pylori infection consist of a proton-pump inhibitor (e.g., omeprazole, lansoprazole) and 2 anti-infective agents (e.g., clarithromycin and amoxicillin or metronidazole) or a 3-drug, bismuth-based regimen (e.g., bismuth-metronidazole-tetracycline) concomitantly with a proton-pump inhibitor; when clarithromycin has been used in these regimens, dosages of 250 mg twice daily to 500 mg 3 times daily (generally 500 mg 2 or 3 times daily) have been used. While the minimum duration of therapy required to eradicate H. pylori infection with these 3- or 4-drug regimens has not been fully elucidated, the ACG and many clinicians state that treatment for longer than 1 week probably is not necessary.

However, more prolonged therapy is recommended for patients with complicated, large, or refractory ulcers; therapy in such patients should be continued at least until successful eradication of H. pylori has been confirmed. (See Helicobacter pylori Infection, in Uses.)

Lyme Disease

For the treatment of early localized or early disseminated Lyme disease associated with erythema migrans (but without neurologic involvement or third-degree AV heart block) in patients who are allergic to or intolerant of amoxicillin, doxycycline, and cefuroxime axetil, the Infectious Diseases Society of America (IDSA) suggests an oral clarithromycin dosage of 500 mg (conventional tablets or oral suspension) twice daily for 14-21 days in adults and 7.5 mg/kg (maximum dose: 500 mg) twice daily for 14-21 days in children.

Dosage in Renal and Hepatic Impairment

Clarithromycin generally may be used without dosage adjustment in patients with hepatic impairment and normal renal function. However, in patients with creatinine clearances less than 30 mL/minute with or without hepatic impairment, the dosage should be halved or the dosing interval for clarithromycin doubled.

An initial clarithromycin dose of 500 mg (conventional tablets or oral suspension) followed by 250 mg twice daily has been suggested for adults with creatinine clearances less than 30 mL/minute when a usual dosage of 500 mg twice daily would have been used in adults with normal renal function; a dosage of 250 mg (conventional tablets or oral suspension) daily has been suggested for such patients when a usual dosage of 250 mg twice daily would have been used in individuals with normal renal function.

Cautions

Clarithromycin generally is well tolerated. In clinical studies, most adverse effects were mild and transient; only about 1% of reported effects were described as severe.

Limited data from comparative studies suggest that the overall incidence of adverse effects with oral clarithromycin therapy is similar to or lower than that with oral erythromycin. As with oral erythromycin, the most common adverse effects of oral clarithromycin involve the GI tract. The manufacturer states that fewer than 3% of patients receiving oral clarithromycin in clinical studies discontinued therapy because of adverse effects. In clinical trials in patients who received combined therapy with clarithromycin and omeprazole for the treatment of H. pylori infection and associated duodenal ulcer, most adverse effects reported with such combined therapy were mild to moderate in severity.

However, discontinuance of therapy because of adverse effects was required in 3.5% of these patients. In clinical trials in which dual therapy with clarithromycin and omeprazole or ranitidine bismuth citrate or triple therapy with clarithromycin, amoxicillin, and lansoprazole or omeprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, no adverse effects peculiar to these drug combinations were observed.

The most frequently reported adverse effects in patients receiving clarithromycin, amoxicillin, and lansoprazole were diarrhea (7% of patients), headache (6% of patients), and taste perversion (5% of patients). The incidence of adverse effects reported with the clarithromycin- amoxicillin-lansoprazole regimen given for 14 days was similar to that reported with the same regimen given for 10 days. The most frequently reported adverse effects in patients receiving triple therapy with clarithromycin, amoxicillin, and omeprazole were diarrhea (14%), taste perversion (10%), and headache (9%).

Triple therapy with these drugs was not associated with a higher incidence of adverse effects than dual therapy. The most frequently reported adverse effects in patients receiving clarithromycin and ranitidine bismuth citrate were taste disturbance (8-11%), diarrhea (4-5%), and nausea and vomiting (3-5%).

GI Effects

Diarrhea, nausea, and abnormal taste were reported in 3-6% of patients receiving oral clarithromycin in clinical studies, while dyspepsia and abdominal discomfort occurred in 2% of patients receiving the drug.

Oral candidiasis, glossitis, stomatitis, vomiting, flatulence, diaper dermatitis, constipation, tongue discoloration, anorexia, pancreatitis, and laryngismus also have been reported. Tooth discoloration, usually reversible with professional dental cleaning, has been reported in patients receiving clarithromycin.

Results of studies in animals indicate that clarithromycin causes less stimulation of GI smooth muscle motility than erythromycin, and some clinical studies suggest that clarithromycin may cause adverse GI effects less frequently than oral erythromycin. In patients with community-acquired pneumonia, adverse GI effects were reported less frequently in patients receiving clarithromycin (13%) than in those receiving oral erythromycin as the base or stearate salt (32%). In these studies, discontinuance of therapy because of adverse effects (e.g., vomiting, nausea diarrhea, abdominal pain) reportedly was required in 4% of patients receiving clarithromycin versus 17% of those receiving erythromycin as the base or stearate salt.

Similar differences in the development of adverse GI effects were seen in comparative studies of clarithromycin versus amoxicillin and clavulanate potassium; 21% of patients receiving clarithromycin and 40% of patients receiving amoxicillin and clavulanate potassium therapy experienced adverse GI effects.

In studies in patients with acute exacerbation of chronic bronchitis or acute maxillary sinusitis, the incidence of GI overall adverse effects in patients receiving clarithromycin extended-release tablets was similar to the incidence in patients receiving clarithromycin conventional tablets; however, those receiving the extended-release tablets reported substantially less severe GI symptoms than those receiving the conventional tablets.

In these studies, discontinuance of therapy because of adverse GI effects or abnormal taste was required more frequently in those receiving the conventional tablets than in those receiving the extended-release tablets. In clinical trials in patients who received combined therapy with clarithromycin and omeprazole for the treatment of H. pylori infection and associated duodenal ulcer, taste perversion was reported in 15% of patients (versus 16 or 1% of those receiving clarithromycin or omeprazole alone, respectively). Nausea was reported in 5% of patients receiving clarithromycin-omeprazole therapy (versus 3 or 1% of those receiving clarithromycin or omeprazole alone, respectively), vomiting in 4% (versus 1% or less than 1% of those receiving clarithromycin or omeprazole alone, respectively), diarrhea in 4% (versus 7 or 3% of those receiving clarithromycin or omeprazole alone, respectively), and abdominal pain in 3% of patients (versus 1 or 2% of those receiving clarithromycin or omeprazole alone, respectively).

Tongue discoloration was reported in 2% of patients receiving combined clarithromycin-omeprazole therapy in controlled clinical trials.

In clinical trials in patients who received combined therapy with clarithromycin and ranitidine bismuth citrate for the treatment of H. pylori infection and associated duodenal ulcer, taste disturbance occurred in 10% (versus 11 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively).

Diarrhea was reported in 8% (versus 5 or 2% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), nausea and vomiting in 3% (versus 2 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), and constipation in 0% (versus 0 or 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively).

In clinical trials in which combined therapy with clarithromycin, amoxicillin, and lansoprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, adverse GI effects reported in less than 3% of patients included abdominal pain, dark stools, dry mouth/thirst, glossitis, rectal itching, nausea, oral candidiasis, stomatitis, tongue discoloration, tongue disorder, and vomiting.

Hepatic Effects

Elevation in serum ALT (SGPT), AST (SGOT), Gamma-glutamyltransferase (?- glutamyl transpeptidase, GGT, GGTP), alkaline phosphatase, LDH, and/or total bilirubin concentration has been reported infrequently (e.g., less than 1% of patients) in patients receiving clarithromycin alone or combined with omeprazole therapy. Hepatomegaly and hepatic dysfunction (including cholestasis, with or without jaundice) also have been reported in patients receiving the drug.

This hepatic dysfunction may be severe but usually is reversible. However, hepatic failure leading to death has been reported rarely, generally in patients with serious underlying diseases and/or receiving concomitant drug therapy. In animals, hepatotoxicity occurred in all species tested at clarithromycin dosages comparable to or twice the maximum recommended human dosage (on a mg/m2 basis).

Hematologic Effects

Increased prothrombin time has been reported in 1% of adult patients receiving clarithromycin. Decreased white blood cell (WBC) counts have been reported in less than 1% of patients receiving the drug. Thrombocytopenia has been reported in at least one patient receiving clarithromycin therapy. Lymphoid depletion has occurred in animals at dosages 2-3 times the maximum recommended human dosage (on a mg/m2 basis).

Renal Effects

Elevated BUN has been reported in 4% of patients receiving clarithromycin. Elevated serum creatinine concentration has been reported in less than 1% of patients receiving clarithromycin alone or combined with omeprazole therapy. Acute renal failure reportedly has occurred with clarithromycin therapy. In animals, renal tubular degeneration occurred at dosages 2-12 times (on a mg/m2 basis) the maximum recommended human dosage.

CNS Effects

Headache was reported in 2% of patients receiving clarithromycin in clinical studies. Transient adverse CNS effects, including acute psychosis, anxiety, behavioral changes, confusional states, depersonalization, disorientation, hallucinations, insomnia, nightmares, tinnitus, tremor, and vertigo, have been reported during postmarketing experience.

These adverse effects usually resolve following discontinuance of clarithromycin therapy. In clinical trials in patients who received combined therapy with clarithromycin and omeprazole for the treatment of H. pylori infection and associated duodenal ulcer, headache was reported in 5% of patients (versus 9 or 6% of those receiving clarithromycin or omeprazole alone, respectively), while infection was reported in 3% of patients receiving combined therapy (versus 2 or 4% of those receiving clarithromycin or omeprazole alone, respectively).

In clinical trials in patients who received combined therapy with clarithromycin and ranitidine bismuth citrate for the treatment of H. pylori infection and associated duodenal ulcer, headache occurred in 5% (versus less than 1 or 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), dizziness in 0% (versus 2 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively), and sleep disorder in 2% (versus less than 1% each of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively). In clinical trials in which combined therapy with clarithromycin, amoxicillin, and lansoprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, confusion or dizziness was reported in less than 3% of patients.

Other Adverse Effects

Allergic reactions ranging from mild urticaria and mild skin eruptions to rare cases of anaphylaxis, leukocytoclastic vasculitis, toxic epidermal necrolysis, and Stevens-Johnson syndrome have been reported in patients receiving clarithromycin; pruritus and rash (e.g., fixed drug eruption) also have been reported with the drug.

As with other macrolides, clarithromycin therapy has been associated with QT prolongation and ventricular arrhythmias, including ventricular tachycardia and atypical ventricular tachycardia (torsades de pointes).

Although a causal relationship to the drug has not been demonstrated, reversible hypoacusis (hearing loss) has been reported in a few patients receiving high (e.g., 2 g daily) dosages of clarithromycin for the treatment of M. avium complex infections. Hypoglycemia has been reported rarely with clarithromycin therapy; in some of these cases, patients were receiving concomitant therapy with insulin or oral antidiabetic agents. In clinical trials in patients who received combined therapy with clarithromycin and ranitidine bismuth citrate for the treatment of H. pylori infection and associated duodenal ulcer, gynecologic problems occurred in 3% (versus 6 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively).

Chest symptoms were reported in 2% (versus 0% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively) and pruritus in 3% (versus 0 or less than 1% of those receiving clarithromycin or ranitidine bismuth citrate alone, respectively). In clinical trials in which combined therapy with clarithromycin, amoxicillin, and lansoprazole was used for the treatment of H. pylori infection and associated duodenal ulcer, other adverse effects reported in less than 3% of patients include myalgia, respiratory disorders, skin reactions, vaginitis, and vaginal candidiasis.

Other adverse effects reported with combined clarithromycin-omeprazole therapy that differed from those reported with omeprazole alone included rhinitis (2% of patients), pharyngitis (1% of patients), and flu syndrome (1% of patients). Corneal opacities have occurred in animals at clarithromycin dosages 8- 12 times the maximum recommended human dosage (on a mg/m2 basis).

Precautions and Contraindications

As with other anti-infective agents, use of clarithromycin may result in overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, appropriate therapy should be instituted. In clinical trials in patients who received anti-H. pylori regimens containing clarithromycin as the sole anti-infective agent, some H. pylori isolates demonstrated an increase in clarithromycin MICs over time, indicating decreased susceptibility and increasing resistance to the drug.

Patients in whom H. pylori was not eradicated following therapy with omeprazole/clarithromycin, ranitidine bismuth citrate/clarithromycin, omeprazole/clarithromycin/amoxicillin, or lansoprazole/clarithromycin/amoxicillin are likely to have clarithromycin-resistant H. pylori isolates. Susceptibility testing should be performed if possible in patients with H. pylori infection who fail therapy (i.e., as determined in clinical trials by a positive result for H. pylori on culture or histologic testing 4 weeks following completion of therapy). If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative anti-infective therapy (i.e., with a non-clarithromycin-containing regimen) should be instituted.

The American College of Gastroenterology (ACG) states that clarithromycin or metronidazole should not be used subsequently in patients with H. pylori infection who fail therapy that includes these drugs since resistance commonly emerges during such unsuccessful therapy. Because Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by overgrowth of toxin-producing clostridia has been reported with the use of many anti-infective agents, including macrolides, it should be considered in the differential diagnosis of patients who develop diarrhea during or following anti-infective therapy.

Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include sigmoidoscopy, appropriate bacteriologic studies, and treatment with fluid, electrolyte, and protein supplementation as indicated. If colitis is severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered. Isolation of the patient may be advisable. Other causes of colitis also should be considered.

Clarithromycin generally may be used without dosage adjustment in patients with hepatic impairment who have normal renal function. However, in patients who have severe renal impairment with or without hepatic impairment, dosage reduction or prolongation of dosing intervals for clarithromycin may be necessary. (See Dosage and Administration: Dosage.) Combined therapy with clarithromycin and ranitidine bismuth citrate is not recommended in patients with creatinine clearance less than 25 mL/minute, and should not be used in patients with a history of acute porphyria. (See Precautions and Contraindications, in Ranitidine 56:40.)

Concomitant administration of clarithromycin is contraindicated in patients receiving terfenadine (no longer commercially available in the US), astemizole (no longer commercially available in the US), cisapride, or pimozide since macrolide antibiotics may impair metabolism of these drugs, potentially resulting in serious cardiotoxicity. (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.) Clarithromycin is contraindicated in patients with known hypersensitivity to clarithromycin, erythromycin, or any other macrolide.

Pediatric Precautions

The manufacturer states that safety and efficacy of clarithromycin in children younger than 6 months of age have not been established, and safety of the drug in children younger than 20 months of age with M. avium complex infection has not been established.

However, children as young as 6 months of age have received the drug for the treatment of streptococcal pharyngitis or tonsillitis and for skin and skin structure infections without apparent unusual adverse effect. Safety and efficacy, including associated dosage recommendations, for extended-release tablets of clarithromycin in pediatric patients have not been established.

Geriatric Precautions

Limited data indicate that peak serum concentrations of clarithromycin and 14-hydroxyclarithromycin and values for area under the concentration-time curve may be increased in healthy geriatric individuals 65-84 years of age relative to those in healthy younger adults; this increase appears to result from age-related decreases in renal function.

However, an increased incidence of adverse effects in geriatric patients has not been reported to date in clinical studies. If clarithromycin is used in geriatric patients with severe renal impairment, use of a reduced dosage of the drug should be considered.

Mutagenicity and Carcinogenicity

Clarithromycin failed to exhibit mutagenic potential in several in vitro tests, including the Salmonella mammalian microsome test, bacterial induced mutation frequency test, rat hepatocyte DNA synthesis assay, mouse lymphoma assay, mouse dominant lethal test, and mouse micronucleus test. In the in vitro chromosome aberration test, clarithromycin produced weakly positive results in one test and negative results in another.

Results of a bacterial reverse-mutation test (Ames test) performed on several clarithromycin metabolites also were negative. Long-term studies have not been performed to date to evaluate the carcinogenic potential of clarithromycin.

Pregnancy, Fertitlity and Lactation

Although there are no adequate and controlled studies to date in humans, clarithromycin has been associated with adverse effects on pregnancy outcome and/or embryofetal development in animals at dosages that produced plasma drug concentrations 2-17 times those achieved with the maximum recommended human dosage.

While the potential risk to the fetus has not been clearly elucidated to date, the manufacturer states that clarithromycin should be used during pregnancy only in infections for which safer drugs cannot be used or are ineffective. If the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.

Teratogenicity studies in rats with oral or IV clarithromycin dosages up to 160 mg/kg daily administered during the period of major organogenesis and in rabbits at oral dosages up to 125 mg/kg daily (approximately twice the maximum recommended human dosage on a mg/m2 basis) or IV dosages of 30 mg/ kg daily administered during days 6-18 of gestation did not demonstrate evidence of teratogenicity.

However, other studies in a different rat strain demonstrated a low incidence of cardiovascular anomalies at a clarithromycin dosage of 150 mg/kg daily (resulting in plasma concentrations 2 times those in humans) administered during gestation days 6-15.

Studies in mice revealed a variable incidence of cleft palate with oral dosages of 1000 mg/kg daily (resulting in plasma concentrations 17 times those in humans) during gestation days 6-15; cleft palate also was observed at a dosage of 500 mg/kg daily. In monkeys, an oral dosage of 70 mg/kg daily (approximately equivalent to the maximum recommended human dosage on a mg/m2 basis) produced fetal growth retardation at plasma concentrations twice those attained in humans.

Fertility and reproduction studies in male and female rats using clarithromycin dosages up to 160 mg/kg daily (1. times the maximum recommended human dosage on a mg/m2 basis) have demonstrated no adverse effects of the drug on the estrous cycle, fertility, parturition, or number and viability of offspring.

Plasma concentrations in rats following clarithromycin dosages of 150 mg/kg daily were twice those observed in humans. Embryonic loss in monkeys has occurred at an oral clarithromycin dosage of 150 mg/kg daily (2.4 times the maximum recommended dosage in humans on a mg/m2 basis); this effect has been attributed to marked maternal toxicity at this high dosage. In addition, in utero fetal loss in rabbits has occurred at an IV dosage of 33 mg/m2, which is 17 times less than the proposed maximum human oral daily dosage of 618 mg/m2.

It is not known whether clarithromycin is distributed in human milk. However, the drug is distributed in the milk of lactating animals, and other macrolide antibiotics are distributed in human milk. Caution should be exercised when clarithromycin is administered to nursing women.

Pre-weaned rats, exposed indirectly via consumption of milk from dams treated with 150 mg/kg daily of clarithromycin for 3 weeks, did not demonstrate adverse effects despite evidence indicating higher drug concentrations in milk than in plasma.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Concomitant use of erythromycin or clarithromycin and drugs metabolized by hepatic microsomal enzymes (cytochrome P-450 (CYP) system) may be associated with increased serum concentrations of the latter drugs, and serum concentrations of such concomitantly administered drugs should be monitored closely.

Terfenadine and Astemizole

Current evidence indicates that certain macrolide antibiotics (e.g., erythromycin, clarithromycin) alter the metabolism of astemizole and terfenadine; however, these antihistamines are no longer commercially available in the US.

Prolongation of the QT interval, ST-U abnormalities, and ventricular tachycardia, including torsades de pointes, have been reported in some patients receiving terfenadine concomitantly with erythromycin or the structurally related macrolides troleandomycin or josamycin.

Therefore, terfenadine was contraindicated in patients receiving clarithromycin, erythromycin, or troleandomycin, especially patients who had preexisting cardiac abnormalities (e.g., arrhythmia, bradycardia, QT interval prolongation, ischemic heart disease, congestive heart failure) or electrolyte disturbances. In addition, QT prolongation and torsades de pointes have been reported in patients receiving concomitant erythromycin and astemizole, and coadministration of these drugs was contraindicated. Because clarithromycin also is metabolized by the cytochrome P-450 system, coadministration of clarithromycin and astemizole also was contraindicated.

Pimozide

Macrolide antibiotics, including azithromycin, clarithromycin, erythromycin, and dirithromycin, inhibit the metabolism of pimozide, resulting in increased plasma pimozide concentrations. Since pimozide prolongs the QT interval, such increased plasma concentrations of the drug may increase the risk of serious cardiovascular effects, including fatal ventricular arrhythmias; at least 2 deaths have been reported in patients following addition of clarithromycin to pimozide therapy. Concomitant administration of pimozide and macrolide antibiotics, including clarithromycin, is contraindicated. (See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes, in Pimozide 28:16.08.)

Cisapride

Coadministration of clarithromycin and/or erythromycin with cisapride has been associated with QT prolongation and serious cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, torsades de pointes); fatalities have been reported. In 2 patients with chronic renal failure who were receiving cisapride (10 mg 3-4 times daily), QT prolongation and/or torsades de pointes occurred within several days after initiating therapy with clarithromycin (500 mg twice daily). Elevated serum cisapride concentrations observed in one patient decreased following discontinuance of clarithromycin. Concomitant administration of clarithromycin and cisapride is contraindicated.

Carbamazepine

Limited data in healthy men indicate that clarithromycin may increase area under the serum concentration-time curve (AUC) for carbamazepine and decrease peak serum concentration and AUC for carbamazepine 10,-epoxide (CBZ-E). In addition, increased plasma concentrations of carbamazepine (but not CBZ-E) and, in some patients, manifestations of carbamazepine toxicity (i.e., drowsiness, dizziness, ataxia) occurred within 3-5 days after initiation of clarithromycin therapy (200 mg twice daily) in several patients receiving carbamazepine (600 mg/day) with or without other drugs; plasma carbamazepine concentrations decreased and toxic manifestations subsided within several days following carbamazepine discontinuation.

Clarithromycin should be used with caution in patients receiving carbamazepine; if such concomitant therapy is used, a reduction in carbamazepine dosage and/or monitoring of plasma carbamazepine concentrations is advised.

Hydroxymethylglutaryl-CoA (HMG-CoA)

Reductase Inhibitors As with other macrolides, clarithromycin has been reported to increase serum concentrations of concomitantly administered HMG-CoA reductase inhibitor (statin) antilipemic agents (e.g., lovastatin, simvastatin) via inhibition of metabolism by cytochrome P-450 isoenzymes.

Rhabdomyolysis, sometimes accompanied by acute renal failure secondary to myoglobinuria, has been reported rarely with HMG-CoA reductase inhibitor therapy given alone or concomitantly with macrolide antibiotics (e.g., erythromycin, clarithromycin), immunosuppressive agents (including cyclosporine) in transplant patients, gemfibrozil, niacin (in dosages of at least 1 g daily), or nefazodone. (See Cautions: Musculoskeletal Effects, in Lovastatin 24:06.)

Rifabutin and Rifampin

Concomitant administration of clarithromycin and rifabutin or rifampin has been reported to increase the metabolism of clarithromycin. In addition, in a randomized study in patients with advanced HIV infection (CD4+ T-cell counts less than 200/mm3), a drug interaction consistent with inhibition of rifabutin metabolism by clarithromycin and induction of clarithromycin metabolism by rifabutin was demonstrated.

Four weeks after initiation of therapy with rifabutin (300 mg daily) in HIV-infected patients who had been receiving clarithromycin (500 mg every 12 hours) alone for 2 weeks, clarithromycin AUC had decreased by an average of 44%, AUC for 14-hydroxyclarithromycin had increased by 57%, and peak plasma clarithromycin concentration had decreased by 41%. In the same study, patients who received clarithromycin for 4 weeks after 2 weeks of rifabutin monotherapy had average increases of 99 and 375% in the AUCs of rifabutin and 25-desacetyl rifabutin, respectively, and an increase of 69% in peak plasma rifabutin concentration.

It has been suggested that the increased plasma concentrations of rifabutin and/or its 25-desacetyl metabolite associated with concomitant administration of clarithromycin may explain the increased frequency of uveitis observed with such concomitant therapy.

Other Drugs

Affecting Hepatic Microsomal Enzymes Ventricular fibrillation, prolongation of the QT interval, and a marked increase in disopyramide elimination half-life (40 hours) were reported in a patient maintained on disopyramide (200 mg twice daily) who received clarithromycin (250 mg twice daily), omeprazole (20 mg twice daily), and metronidazole (400 mg twice daily) for the treatment of H. pylori-associated chronic duodenal ulceration.

QT prolongation, which had not been documented previously during a 7-year period of disopyramide therapy, resolved with a decline in disopyramide plasma concentrations. In postmarketing studies, interactions with erythromycin and/or clarithromycin have been reported with a number of other drugs metabolized by the cytochrome P-450 system, including cyclosporine, tacrolimus, hexobarbital, phenytoin, alfentanil, lovastatin, bromocriptine, and valproate. Serum concentrations of drugs metabolized by the cytochrome P-450 system should be monitored closely in patients receiving concomitant therapy with erythromycin or clarithromycin.

Anticoagulants

Postmarketing data suggest that the concomitant administration of clarithromycin and oral anticoagulants may potentiate the effects of the oral anticoagulant. The manufacturer recommends that in patients receiving concomitant clarithromycin and oral anticoagulant therapy, the prothrombin time be monitored carefully.

Antiretroviral Agents

Atazanavir

Concomitant use of clarithromycin (500 mg once daily) and atazanavir (400 mg once daily) increased the peak plasma concentration and AUC of clarithromycin, decreased the peak plasma concentration and AUC of 14-hydroclarithromycin, and increased the peak plasma concentration and AUC of atazanavir.

Because increased concentrations of clarithromycin may result in prolongation of the QTc interval, the manufacturer of atazanavir recommends that the clarithromycin dosage be reduced by 50% in patients receiving atazanavir. In addition, alternative anti-infective therapy should be considered for indications other than Mycobacterium avium complex infections since the decreased plasma concentrations of 14-hydroclarithromycin could adversely affect clarithromycin’s efficacy in the treatment of certain infections.

Delavirdine

Concomitant use of clarithromycin (500 mg twice daily for 15 days) and delavirdine (300 mg 3 times daily for 30 days) resulted in a 100% increase in the AUC of clarithromycin but had no appreciable effect on the pharmacokinetics of delavirdine.

Didanosine

Simultaneous administration of clarithromycin tablets and didanosine in a limited number of HIV-infected adults did not alter the pharmacokinetics of didanosine.

Ritonavir

In a study in healthy individuals, concomitant administration of ritonavir (200 mg every 8 hours) with clarithromycin (500 mg every 12 hours) for 4 days increased the peak plasma concentration and area under the AUC of clarithromycin by 31 and 77%, respectively, and decreased the peak plasma concentration and AUC of 14-hydroxyclarithromycin by 99 and 100%, respectively. The peak plasma concentration and AUC of ritonavir also were increased by 12-15%.

Because 14-hydroxyclarithromycin appears to enhance the antimicrobial activity of the parent drug against some pathogens (e.g., Haemophilus influenzae), it has been suggested that the decreased plasma concentrations of the metabolite reported with concomitant ritonavir theoretically could adversely affect clarithromycin’s efficacy in the treatment of certain infections.

The manufacturer of clarithromycin and ritonavir states that when clarithromycin is used in patients receiving ritonavir, modification of the usual clarithromycin dosage generally is not necessary in those with normal renal function; however, the clarithromycin dosage should be reduced by 50% in patients with creatinine clearances of 30-60 mL/minute and reduced by 75% in patients with creatinine clearances less than 30 mL/minute.

Zidovudine

In one study, simultaneous administration of clarithromycin and zidovudine in HIV-infected adults decreased peak plasma concentrations of zidovudine by about 41% but had no appreciable effect on the pharmacokinetics of clarithromycin. In a limited number of HIV-infected adults, clarithromycin (500 mg twice daily) decreased the steady-state AUC of zidovudine by a mean of 12% (range: from a decrease of 34% to an increase of 14%). When clarithromycin tablets were administered 2-4 hours prior to zidovudine doses, steady-state peak zidovudine serum concentrations were increased twofold but the AUC was unaffected.

Digoxin

Elevated serum concentrations of digoxin have been reported during postmarketing surveillance in patients receiving concomitant digoxin and clarithromycin therapy. Some of these patients exhibited clinical manifestations consistent with digoxin toxicity, including arrhythmias. The manufacturer recommends that serum digoxin levels be monitored carefully in patients receiving concomitant clarithromycin and digoxin therapy.

Fluconazole

In healthy individuals receiving clarithromycin 500 mg twice daily concomitantly with fluconazole 200 mg daily, steady-state trough serum concentrations and area under the serum concentration-time curve (AUC) for clarithromycin reportedly increased by an average of 33 and 18%, respectively; steady-state concentrations of 14-hydroxyclarithromycin were not substantially affected.

Omeprazole

Concomitant administration of clarithromycin and omeprazole alters the pharmacokinetics (e.g., increased concentrations in gastric tissue and/or serum) of clarithromycin, 14-hydroxyclarithromycin, and omeprazole. (See Pharmacokinetics: Absorption.)

Theophylline

Concomitant use of clarithromycin in patients who are receiving theophylline may be associated with an increase in serum theophylline concentrations, probably as a result of reduced hepatic metabolism and/or clearance of theophylline.

Clarithromycin reportedly causes less alteration in serum theophylline concentration than erythromycin or oleandomycin, but changes in theophylline dosage have been required in some patients treated concurrently with clarithromycin and theophylline. In 2 studies in healthy individuals who were given an extended-release theophylline preparation (6.5 or 12 mg/kg per dose) concomitantly with clarithromycin (250-500 mg every 12 hours), the peak and trough serum concentrations at steady state and the area under the serum concentration-time curve (AUC) for theophylline reportedly were increased by approximately 20%.

However, in at least one of these studies in healthy men, serum theophylline concentrations remained within the therapeutic range, and no clinical toxicity was observed. The manufacturer states that monitoring of serum theophylline concentrations should be considered for patients receiving clarithromycin concomitantly with high doses of theophylline or in those who have baseline serum theophylline concentrations in the upper therapeutic range. Theophylline dosage should be adjusted if necessary when clarithromycin is added or withdrawn in a patient receiving theophylline.

Other Drugs

Limited data in healthy adults suggest that the pharmacokinetics of clarithromycin are not altered by concurrent administration of ranitidine or an antacid. Concurrent use of erythromycin or clarithromycin and ergotamine or dihydroergotamine reportedly has been associated with acute ergot toxicity, characterized by severe peripheral vasospasm and dysesthesia, in some patients.

Erythromycin reportedly may decrease the clearance of triazolam and therefore may increase the pharmacologic effects of triazolam; CNS effects (e.g., somnolence, confusion) have been reported in postmarketing experience with concomitant administration of clarithromycin and triazolam.

Although other drug interactions reported with erythromycin may not have been reported to date with clarithromycin, it should be kept in mind that clarithromycin and erythromycin have similar pharmacologic effects and may have similar drug interactions. (See Drug Interactions in the Erythromycins General Statement 8:12..04.)

Mechanism of Action

Clarithromycin usually is bacteriostatic, although it may be bactericidal in high concentrations or against highly susceptible organisms. Bactericidal activity has been observed against Streptococcus pyogenes, S. pneumoniae, Haemophilus influenzae, and Chlamydia trachomatis. Clarithromycin inhibits protein synthesis in susceptible organisms by penetrating the cell wall and binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis.

The site of action of clarithromycin appears to be the same as that of erythromycin, clindamycin, lincomycin, and chloramphenicol. Spectrum Clarithromycin generally displays in vitro activity similar to or greater than that of erythromycin against erythromycin-sensitive organisms and also exhibits activity against some organisms (e.g., atypical mycobacteria, Toxoplasma) for which therapy currently is limited.The drug’s principal metabolite, 14- hydroxyclarithromycin, is as active or only slightly less active in vitro than clarithromycin against most organisms and appears to enhance the antimicrobial activity of the parent drug against selected pathogens (e.g., Haemophilus influenzae).

However, the activity of 14-hydroxyclarithromycin against Mycobacterium avium complex (MAC) isolates was 4-7 times less than that of the parent compound; the clinical importance of this difference in activity is unknown.

In Vitro Susceptibility Testing

The National Committee for Clinical Laboratory Standards (NCCLS) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to clarithromycin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated. If results indicate that a clinical isolate has intermediate susceptibility to clarithromycin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.

Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used.

This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins. If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to clarithromycin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.

For testing the susceptibility of M. avium complex (MAC) isolates to clarithromycin, the usual disk-diffusion procedures or dilution tests used for determining in vitro susceptibility of bacterial isolates should not be used. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values of clarithromycin against MAC organisms have neither been standardized nor validated.

MICs reported for clarithromycin will vary depending on the susceptibility testing method employed, the composition and pH of the media, and use of nutritional supplements. Values representing susceptibility or resistance of MAC isolates to clarithromycin have not been established.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to clarithromycin, a disk containing 15 mcg of clarithromycin should be used. When the disk-diffusion procedure is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus with growth inhibition zones of 18 mm or greater are susceptible to clarithromycin, those with zones of 14-17 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.

When the disk-diffusion procedure is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 13 mm or greater are susceptible to clarithromycin, those with zones of 11-12 mm have intermediate susceptibility, and those with zones of 10 mm or less are resistant to the drug.

When susceptibility of Streptococcus pneumoniae or other Streptococcus spp. is determined according to NCCLS standardized procedures using Mueller-Hinton agar (supplemented with 5% sheep blood), those with growth inhibition zones of 21 mm or greater are susceptible to clarithromycin, those with zones of 17-20 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.

Dilution Susceptibility Tests

In dilution susceptibility testing procedures (agar or broth dilution), Staphylococcus with MICs of 2 mcg/mL or less are susceptible to clarithromycin, those with MICs of 4 mcg/mL have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater are resistant to the drug.

When dilution susceptibility testing is performed according to NCCLS standardized procedures using HTM, Haemophilus with MICs of 8 mcg/mL or less are susceptible to clarithromycin, those with MICs of 16 mcg/mL have intermediate susceptibility, and those with MICs of 32 mcg/mL or greater are resistant to the drug.

When dilution susceptibility testing of Helicobacter pylori is performed according to NCCLS standardized procedures using Mueller-Hinton agar with 5% aged sheep blood, H. pylori with MICs of 0.25 mcg/mL or less are susceptible to clarithromycin, those with MICs of 0.5 mcg/mL have intermediate susceptibility, and those with MICs of 1 mcg/mL or greater are resistant to the drug.

These breakpoints presume that clarithromycin will be used in a regimen that includes a proton-pump inhibitor or an H2-receptor antagonist.

When dilution susceptibility testing is performed according to NCCLS standardized procedures using cation-adjusted Mueller-Hinton broth (supplemented with 2-5% lysed horse blood), S. pneumoniae or other streptococci with MICs of 0.25 mcg/mL or less are susceptible to clarithromycin, those with MICs of 0.5 mcg/mL have intermediate susceptibility, and those with MICs of 1 mcg/mL or greater are resistant to the drug.

Gram-positive Aerobic Bacteria

Clarithromycin is active in vitro against gram-positive cocci (streptococci and staphylococci). Minimum inhibitory concentrations (MICs) of clarithromycin for oxacillin-susceptible Staphylococcus aureus (previously known as methicillin-susceptible S. aureus) and most streptococci generally are twofold to fourfold lower than those of erythromycin, while oxacillin-resistant staphylococci (previously known as methicillin-resistant staphylococci) and coagulase-negative staphylococci (e.g., Staphylococcus epidermidis) generally are resistant to clarithromycin or erythromycin.

Most enterococci (e.g., Enterococcus faecalis [formerly Streptococcus faecalis]) are resistant both to clarithromycin and erythromycin, although the drugs appear to have similar activity against erythromycin-sensitive strains. The in vitro antimicrobial activity (MICs) of clarithromycin against S. aureus and S. epidermidis, but not E. faecalis, appears to decrease when the size of the inoculum is increased.

Clarithromycin is active in vitro against some gram-positive aerobic bacilli such as Listeria monocytogenes and some strains of Corynebacterium. Results of in vitro susceptibility testing of 11 Bacillus anthracis isolates that were associated with cases of inhalational or cutaneous anthrax that occurred in the US (Florida, New York, District of Columbia) during September and October 2001 in the context of an intentional release of anthrax spores (biologic warfare, bioterrorism) indicate that these strains had clarithromycin MICs of 0.25 mcg/mL.

Based on interpretive criteria established for staphylococci, these strains are considered susceptible to clarithromycin. Limited or no data are available to date regarding in vivo activity of clarithromycin against B. anthracis or use of the drug in the treatment of anthrax.

Gram-negative Aerobic Bacteria

Clarithromycin is active in vitro against some gram-negative organisms, including Neisseria gonorrhoeae and Moraxella (Branhamella) catarrhalis.

Clarithromycin’s activity against M. catarrhalis generally exceeds that of erythromycin and reportedly is enhanced by 14-hydroxyclarithromycin. Clarithromycin and erythromycin appear to have similar activity against Neisseria gonorrhoeae. Clarithromycin also is active in vitro against Haemophilus influenzae, H. parainfluenzae, and Pasteurella multocida. Although the in vitro activity of clarithromycin alone against H. influenzae generally is similar to or less than that of erythromycin, the 14-hydroxy metabolite of clarithromycin has greater activity against this organism. In in vitro studies, the combination of clarithromycin and 14-hydroxyclarithromycin generally has demonstrated either additive or synergistic activity against H. influenzae; however, MICs for this organism vary depending on the method used to determine susceptibility.

Limited data from a few studies in which in vitro susceptibilities of b-lactamase- producing strains of H. influenzae have been reported separately from those of non-b-lactamase-producing strains suggest no substantial effect of the enzyme on inhibitory or bactericidal activity of clarithromycin.

Limited data suggest that high concentrations of and/or prolonged exposure to clarithromycin and its active metabolite may be required for bactericidal activity against some strains of H. influenzae. Clarithromycin has greater activity than erythromycin against Legionella pneumophila in vitro and in animals; clarithromycin’s activity against Legionella spp. also may be enhanced by its 14-hydroxy metabolite.

Clarithromycin also has in vitro activity against Campylobacter spp. (e.g., C. jejuni.) and Bordetella pertussis. Clarithromycin is active against most strains of Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis) in vitro and in clinical infections when used in multiple-drug regimens including omeprazole, omeprazole or lansoprazole and amoxicillin, or ranitidine bismuth citrate. Clarithromycin exhibits greater activity than most other macrolides against H. pylori.

Mycobacteria

Although macrolide antibiotics generally have little activity against Mycobacterium tuberculosis, clarithromycin has been shown to inhibit several types of atypical mycobacteria in vitro, including M. kansasii, M. fortuitum, M. marinum,M. chelonae, M. abscessus, and M. avium complex (MAC). MAC represents 2 closely related organisms, M. avium and M. intracellulare.

Although gene probe techniques may be used to distinguish M. avium species from M. intracellulare, most studies do not distinguish between the organisms and report results on MAC isolates.

Clarithromycin has exhibited both in vitro and in vivo activity against M. leprae, and reportedly is 8-32 times as active as erythromycin in vitro against MAC. Some in vitro data indicate that clarithromycin is bactericidal against MAC and that this activity is enhanced by ethambutol and/or rifampin.

However, resistant strains of MAC have developed during therapy with clarithromycin, both when the drug was used as monotherapy or when used as a component of multiple-drug therapy. Although the activity of 14-hydroxyclarithromycin against MAC isolates was 4-7 times less than that of clarithromycin, the clinical importance of this difference in activity is unknown.

Other Aerobic Bacteria

The activity of clarithromycin versus erythromycin against Mycoplasma pneumoniae generally is comparable, but clarithromycin has greater activity against Ureaplasma urealyticum. Clarithromycin has up to tenfold greater activity in vitro than erythromycin against Chlamydia trachomatis and some strains of C. pneumoniae.

Anaerobic Bacteria

Clarithromycin is active in vitro against most strains of Peptococcus, Peptostreptococcus, Clostridium perfringens, and Propionibacterium acnes. The activity of clarithromycin against anaerobic gram-positive cocci generally is similar to that of erythromycin, but may be slightly better against C. perfringens. Clarithromycin is active in vitro against most strains of Prevotella melaninogenica (formerly Bacteroides melaninogenicus); the drug’s activity against Prevotella spp. and Bacteroides fragilis generally is similar to or greater than that of erythromycin but less than that of clindamycin.

Other Organisms

Clarithromycin reportedly has exhibited in vitro activity against Toxoplasma gondii, Gardnerella vaginalis, and Borrelia burgdorferi, the causative agent of Lyme disease. Limited data in animals also indicate activity of clarithromycin against Cryptosporidium parvum and synergism (as determined by reduction in cyst burden in lung tissue) with sulfamethoxazole against Pneumocystis carinii. Clarithromycin generally is inactive against Enterobacteriaceae (e.g., Salmonella enteriditis, Yersinia enterocolitica, Shigella and Vibrio spp.).

Resistance Resistance to macrolide antibiotics usually involves an alteration at the antibiotic target site, but resistance caused by modification and/or active efflux of the antibiotic also have been reported. Such resistance may be chromosomally or plasmid mediated and be either constitutive or induced.

Bacteria resistant to macrolides produce an enzyme that leads to methylation of adenine residues in ribosomal RNA and subsequent inhibition of binding of the antibiotic to the ribosome. Organisms resistant to erythromycin generally are resistant to all 14- and 15-membered macrolides because all of these drugs induce the methylase enzyme.

Resistance in Mycobacteria

Strains of Mycobacterium avium complex (MAC) with decreased susceptibility or resistance to clarithromycin have been reported in patients who received the drug for treatment or prevention of MAC infection and have developed when the drug was used as monotherapy or as a component of multiple-drug therapy. MAC isolates resistant to clarithromycin are cross-resistant to azithromycin.

Resistance in Helicobacter pylori

In clinical studies in patients who received clarithromycin as the sole anti- infective agent in combination regimens for Helicobacter pylori infection, some H. pylori isolates demonstrated an increase in clarithromycin MICs over time, indicating decreased susceptibility and increasing resistance to the drug. In 2 US clinical studies in which clarithromycin and omeprazole were administered concomitantly for the treatment of H. pylori infection, 3.5% of patients had H. pylori strains resistant to clarithromycin before treatment.

In 3 clinical studies in which therapy with clarithromycin, amoxicillin, and omeprazole (triple therapy) was compared with clarithromycin and amoxicillin (dual therapy) for the treatment of H. pylori infection, 9.3% of patients (41/439) receiving triple therapy and 3.5% of patients (4/113) receiving dual therapy had clarithromycin-resistant strains of H. pylori before treatment. In these studies, 99.% of patients had pretreatment H. pylori isolates that were susceptible to amoxicillin (MIC of 0.25 mcg/mL or less) and 0.7% of patients, all of whom were in the clarithromycin/amoxicillin group, had pretreatment amoxicillin MICs greater than 0.25 mcg/mL.

Of the patients who received triple therapy (clarithromycin, amoxicillin, omeprazole) in these studies, H. pylori was eradicated in 84.9% (157/185) who had pretreatment amoxicillin-susceptible H. pylori isolates (MIC of 0.25 mcg/mL or less). Of the 28 patients who failed therapy, 11 had no posttreatment susceptibility test results and 17 had H. pylori isolates that were susceptible to amoxicillin.

Clarithromycin-resistant H. pylori isolates also were found posttreatment in 11 of the patients who failed triple therapy. In 5 clinical studies in which therapy with lansoprazole and amoxicillin (dual therapy) or clarithromycin, amoxicillin, and lansoprazole (triple therapy) was given for the treatment of H. pylori infection, pretreatment clarithromycin- resistant strains of H. pylori were identified in 9.5% of patients using Etest and in 11.% using agar dilution. In these studies, pretreatment H. pylori isolates were susceptible (MIC of 0.25 mcg/mL or less) to amoxicillin in 97. or 98% of patients using Etest or agar dilution, respectively.

Two patients had an unconfirmed pretreatment amoxicillin MIC exceeding 256 mcg/mL according to Etest. In these studies, H. pylori was eradicated in 82.% who had pretreatment amoxicillin-susceptible H. pylori isolates. Of 6 patients who had pretreatment amoxicillin MICs exceeding 0.25 mcg/mL, H. pylori was eradicated in 3 patients.

Eradication of H. pylori was not achieved in 30% of patients (21/70) receiving lansoprazole-amoxicillin and 12.% of patients (22/172) receiving clarithromycin-amoxicillin-lansoprazole for 10 or 14 days.

Clarithromycin-resistant H. pylori isolates were found posttreatment in 9 of 11 patients who had amoxicillin posttreatment MICs and who failed triple therapy; 11 patients who failed triple therapy had no posttreatment susceptibility test results. In a study in which clarithromycin and ranitidine bismuth citrate were given for the treatment of H. pylori infection, pretreatment clarithromycin-resistant strains of H. pylori were found in 12.6% of patients (44/348).

Pharmacokinetics

Absorption

Clarithromycin is absorbed rapidly from the GI tract after oral administration; GI absorption of the drug exceeds that of erythromycin. The absolute bioavailability of clarithromycin following oral administration of the drug as 250-mg conventional tablets has been reported to be approximately 50-55%, which probably is an underestimate of systemic activity because of the drug’s rapid first-pass metabolism to its active metabolite 14-hydroxyclarithromycin. In a study in adults, the bioavailability of 10 mL of 125 mg/5 mL or 250 mg/ 5 mL clarithromycin suspension was similar to that of the 250- or 500-mg conventional tablet, respectively.

While the 24-hour area under the plasma concentration-time curves (AUCs) for clarithromycin and 14-hydroxyclarithromycin following administration of clarithromycin extended-release tablets are equivalent to the 24-hour AUCs following administration of the same total daily dose as conventional tablets, the extended-release tablets result in lower and later steady-state plasma concentrations of clarithromycin and 14-hydroxyclarithromycin compared with conventional tablets.

Food causes a slight delay in the onset of clarithromycin absorption and increases the peak plasma concentration of clarithromycin by 24% when the drug is administered as conventional oral tablets; however, the extent of clarithromycin absorption is unaffected by concomitant ingestion of food.

Food does not affect the onset of formation or the peak plasma concentration of 14- hydroxyclarithromycin when the drug is administered as conventional oral tablets; however, the AUC of the metabolite is decreased by about 11% when the conventional tablets are administered with food.

Administration of clarithromycin extended-release tablets under fasting conditions results in a 30% decrease in the AUC of clarithromycin compared with administration with food; the extent of formation of 14-hydroxyclarithromycin is not affected by food when the drug is administered as extended- release tablets. In a limited number of adults, administration of 250 mg of clarithromycin as the oral suspension with food appeared to decrease the mean peak serum concentration by about 17% and the mean AUC by about 10%, while in a limited number of children, administration of a single 7.5-mg/kg dose of clarithromycin oral suspension with food appeared to increase the mean peak serum concentration of the drug by about 27% and the mean AUC by about 42%. In fasting healthy adults receiving clarithromycin conventional tablets or oral suspension, peak serum clarithromycin concentrations averaged 0.6 mcg/ mL and were attained within 1-4 hours after administration of a single 250- mg dose.

Following oral administration of the drug as conventional oral tablets, steady-state peak clarithromycin concentrations were achieved within 3 days and averaged approximately 1-2 or 3-4 mcg/mL following a 250-mg dose of the drug every 12 hours or a 500-mg dose every 8-12 hours, respectively.

Following oral administration of clarithromycin as conventional oral tablets, steady-state peak 14-hydroxyclarithromycin concentrations were achieved after 3-4 days and were about 0.6 or up to 1 mcg/mL following a 250-mg dose of the drug every 12 hours or a 500-mg dose every 8-12 hours, respectively.

Following oral administration of clarithromycin as extended-release tablets, steady-state peak clarithromycin concentrations of 2-3 mcg/mL were obtained 5-8 hours following a 1-g dose of the drug (two 500-mg extended-release tablets); steady-state peak concentrations were 1-2 mcg/mL and were obtained 5-6 hours following a 500-mg dose. Steady-state peak plasma concentrations of 14-hydroxyclarithromycin of 0.8 or 0.6 mcg/mL were achieved 6-9 hours following a 1- or 500-mg daily dose of clarithromycin extended-release tablets, respectively.

Following oral administration of clarithromycin oral suspension in fasting healthy adults, steady-state peak clarithromycin concentrations were achieved after 2-3 days and averaged approximately 2 mcg/mL following a 250- mg dose of the drug every 12 hours.

Peak serum concentrations of the principal metabolite, 14-hydroxyclarithromycin, reportedly average about 0.7 mcg/mL and are achieved approximately 2 hours after a 250-mg dose of clarithromycin.

Preliminary data from a study in healthy men suggest that the ratio of the AUCs of clarithromycin to 14-hydroxyclarithromycin at steady state is approximately 3:1. In children receiving therapy with clarithromycin as the oral suspension, administration of 7.5 mg/kg of the drug every 12 hours generally resulted in peak steady-state serum clarithromycin concentrations of 3-7 mcg/mL and peak steady-state serum 14-hydroxyclarithromycin concentrations of 1-2 mcg/mL.

In pharmacokinetic studies of HIV-infected adults receiving 500 mg of clarithromycin orally every 12 hours, steady-state concentrations of the drug and its 14-hydroxy metabolite were similar to those observed in healthy individuals receiving the same dose. Peak plasma concentrations of clarithromycin in HIV-infected adults receiving 0.5- or 1-g doses of the drug orally every 12 hours ranged from 2-4 or 5-10 mcg/mL, respectively.

Following oral administration of the drug as the suspension every 12 hours in HIV-infected children, peak steady-state concentrations generally ranged from 6-15 mcg/mL following a dose of 15 mg/kg.

Following IV administration of a 250-mg dose of clarithromycin, peak serum concentrations of the parent drug and 14-hydroxyclarithromycin were 2.8 and 0.5 mcg/mL, respectively.

Plasma concentrations and areas under the concentration-time curve (AUCs) of clarithromycin and 14-hydroxyclarithromycin are increased by concomitant administration of omeprazole. In healthy men receiving clarithromycin 500 mg every 8 hours and omeprazole 40 mg daily, peak and trough plasma concentrations of clarithromycin averaged approximately 10 and 27% higher, respectively, than those following administration of clarithromycin alone, while AUC averaged 15% greater than that with administration of clarithromycin alone.

Peak and trough plasma concentrations of 14-hydroxyclarithromycin averaged approximately 45 and 57% higher, respectively, and AUC averaged 45% greater, than those values with clarithromycin alone. In a limited number of healthy men, clarithromycin concentrations 2 hours after administration of clarithromycin alone or with omeprazole averaged 10. or 20 mcg/g, respectively, in the gastric antrum; 20. or 24. mcg/g, respectively, in the gastric fundus; and 4.2 or 39. mcg/g, respectively, in gastric mucus. Concomitant administration of clarithromycin and omeprazole also results in increased steady-state peak plasma concentrations, area under the concentration-time curve (AUC), and elimination half-life of omeprazole compared with omeprazole administration alone.

Coadministration of clarithromycin and ranitidine bismuth citrate results in increased plasma ranitidine concentrations, increased plasma bismuth trough concentrations, and increased plasma concentrations of 14- hydroxyclarithromycin.

Clarithromycin undergoes extensive first-pass metabolism and exhibits nonlinear, dose-dependent pharmacokinetics, apparently as a result of capacity- limited saturation of metabolic pathways; however, such nonlinearity is slight at the usual dosages of 250-500 mg every 8-12 hours.

Disproportionate increases in peak serum concentrations and areas under the concentration-time curve (AUC) of clarithromycin and 14-hydroxyclarithromycin have been reported in patients receiving single high (e.g., 1.2 g) or multiple doses of clarithromycin, although some data indicate that peak serum concentrations of clarithromycin and 14-hydroxyclarithromycin are proportional to dose. In a single-dose study in healthy men, a fivefold increase in clarithromycin dosage (250 mg to 1.2g) resulted in a 13-fold increase in AUC of the parent drug.

The AUC of 14-hydroxyclarithromycin following 250- mg oral or IV doses of clarithromycin was higher after oral administration, suggesting that the parent drug undergoes substantial first-pass metabolism in the liver to the 14-hydroxy metabolite. In healthy geriatric individuals 65-84 years of age who received 500 mg of clarithromycin every 12 hours, peak and trough serum concentrations of clarithromycin and 14-hydroxyclarithromycin at steady state and area under the concentration-time curve (AUC) were increased relative to those in healthy younger adults (18-30 years of age); these increases were attributed to age- related reductions in renal function.

Limited data indicate that serum concentrations of clarithromycin at steady state in patients with impaired hepatic function do not differ from those in healthy individuals; however, 14-hydroxyclarithromycin concentrations are lower in patients with hepatic dysfunction.

Distribution

Limited data are available on the distribution of clarithromycin in humans. Clarithromycin and 14-hydroxyclarithromycin appear to be distributed into most body tissues and fluids.

Because of high intracellular concentrations of the drug, tissue concentrations are higher than serum concentrations.

High concentrations of clarithromycin were present in tissue samples obtained from patients undergoing surgery. In patients who received 250-500 mg of clarithromycin orally every 12 hours for 3 days prior to surgery, peak clarithromycin concentrations in lung, tonsils, and nasal mucosa reportedly were attained 4 hours after administration and averaged 13.5-17.5, 5.3-6.5, and 5.9-8.3 mg/ kg, respectively; however, it has been suggested that these data may represent an overestimate of clarithromycin tissue concentrations because of the microbiologic assay’s inability to distinguish between parent drug and its active metabolite.

In children receiving clarithromycin suspension for otitis media at a dosage of 7.5 mg/kg every 12 hours for 5 doses, peak clarithromycin and 14- hydroxyclarithromycin concentrations in middle ear fluid were 2.5 and 1.3 mcg/ mL, respectively; concomitant serum concentrations were 1.7 and 0.8 mcg/mL, respectively.

Results of studies in animals given radiolabeled clarithromycin or erythromycin indicate higher and more prolonged activity of clarithromycin in various body tissues, particularly the lung. No data currently are available on CSF penetration of clarithromycin. Protein binding of clarithromycin in vitro has been reported to range from approximately 42-72% at usual therapeutic concentrations. In one study, protein binding of radiolabeled drug in human serum ranged from approximately 42-50% at clarithromycin concentrations of 0.25-5 mcg/mL.

Protein binding of clarithromycin and 14-hydroxyclarithromycin decreases with increasing serum drug concentration.

Elimination

Elimination of clarithromycin appears to follow nonlinear, dose-dependent pharmacokinetics, possibly as a result of capacity-limited metabolism. Following oral administration of single 250-mg or 1.2-g doses of clarithromycin conventional tablets in healthy men, the elimination half-life averaged 4 or 11 hours, respectively.

During multiple dosing every 12 hours, the elimination half-life of clarithromycin reportedly increased from 3-4 hours following a 250-mg dose (conventional tablets) every 12 hours to 5-7 hours following a 500-mg dose every 8-12 hours; the half-life of 14-hydroxyclarithromycin increased from 5-6 hours with a 250-mg dose to 7-9 hours with a 500-mg dose.

When clarithromycin is administered as the oral suspension, the elimination half-life of the drug and of its 14-hydroxy metabolite appear to be similar to those observed at steady-state following administration of equivalent doses of clarithromycin as tablets. In a single-dose study in healthy men, average total body clearance of clarithromycin decreased from 1116 mL/minute following a 250-mg dose to 403 mL/minute following a 1.2-g dose.

This reduction in total body clearance was attributed principally to a reduction in metabolic (nonrenal) clearance, which declined from 913 mL/minute with the 250-mg dose to 289 mL/minute with the 1.2-g dose. The renal clearance of clarithromycin is relatively independent of dose and approximates the normal glomerular filtration rate. Total body clearance and renal clearance of clarithromycin in healthy geriatric individuals are decreased compared with those in younger adults, apparently as a result of age-related reductions in renal function.

However, since differences in pharmacokinetic values appear to be small and an increase in adverse effects has not been reported in geriatric versus younger adults, dosage adjustment solely on the basis of age generally is not required. Clarithromycin is eliminated by both renal and nonrenal mechanisms. Clarithromycin is extensively metabolized in the liver, principally by oxidative N- demethylation and hydroxylation at the 14 position; hydrolytic cleavage of the cladinose sugar moiety also occurs in the stomach to a minor extent.

Although at least 7 metabolites of clarithromycin have been identified, 14-hydroxyclarithromycin is the principal metabolite in serum and the only one with substantial antibacterial activity. (See Spectrum.) While both the R- and S-epimers of 14-hydroxyclarithromycin are formed in vivo, the R-epimer is present in greater amounts and has the greatest antimicrobial activity. Metabolism of clarithromycin appears to be saturable since the amount of 14-hydroxyclarithromycin after an 800-mg dose of the parent drug is only marginally greater than that after a 250-mg dose. Following oral administration of a single 250-mg dose of radiolabeled clarithromycin in healthy men, approximately 38% of the dose (18% as clarithromycin) was excreted in urine, and 40% in feces (4% as clarithromycin), over 5 days.

With oral administration of 250 or 500 mg of clarithromycin as tablets every 12 hours, approximately 20 or 30% of the respective dose is excreted unchanged in urine within 12 hours. After an oral clarithromycin dosage of 250 mg every 12 hours as the suspension, approximately 40% of the administered dose is excreted unchanged in urine. The principal metabolite found in urine is 14-hydroxyclarithromycin, which accounts for approximately 10-15% of the dose following administration of 250 or 500 mg of clarithromycin as tablets.

The serum half-life of clarithromycin is prolonged in patients with impaired renal function. Marked increases in peak serum concentration, AUC, and half- life of clarithromycin and 14-hydroxyclarithromycin have been reported in patients with creatinine clearances less than 30 mL/minute, and reduction of clarithromycin dosage may be required in such patients. (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Moderate to severe hepatic impairment reportedly reduces the formation of 14-hydroxyclarithromycin but is accompanied by an increase in the renal clearance of the parent drug; therefore, a decrease in dosage would not be needed in patients with hepatic dysfunction unless renal function also is impaired. In fact, the total concentration of biologically active drug (clarithromycin plus 14-hydroxyclarithromycin) in circulation reportedly is decreased in patients with severe hepatic impairment.

Chemistry and Stability

Chemistry

Clarithromycin is a semisynthetic macrolide antibiotic. The drug differs structurally from erythromycin only by the methylation of a hydroxyl group at position 6 of the lactone ring.

The presence of a methyl group at this position minimizes acid-catalyzed degradation of clarithromycin to the inactive 8,- anhydro-6,-hemiketal and subsequently the 6,9,9,12-spiroketal products; some erythromycin degradation products (e.g., the anhydrohemiketal form) have been shown to increase GI motility and may contribute to the adverse GI effects of that drug. Clarithromycin occurs as a white to off-white crystalline powder.

The drug is practically insoluble in water and slightly soluble in alcohol, having solubilities of approximately 0.07 mg/mL in water and 5.2 mg/mL in alcohol at room temperature. The solubility of clarithromycin reportedly is pH dependent, increasing with decreasing pH.

Stability

Commercially available clarithromycin 250-mg conventional tablets should be stored in well-closed containers at 15-30°C and should be protected from light. Clarithromycin 500-mg conventional tablets should be stored in well- closed containers at controlled room temperature between 20-25°C.

Clarithromycin extended-release tablets should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.

When stored as directed, the commercially available conventional tablets have an expiration date of 2 years following the date of manufacture.

Clarithromycin granules for oral suspension should be stored in well-closed containers at 15-30°C. Following reconstitution as directed, oral suspensions of clarithromycin should be stored at 15-30°C in well-closed containers; the reconstituted suspension should not be refrigerated. Any unused suspension should be discarded after 14 days.

Preparations

Clarithromycin Oral For suspension 125 mg/5 mL Biaxin® Granules, (with povidone) Abbott 250 mg/5 mL Biaxin® Granules, (with povidone) Abbott Tablets, film- 250 mg Biaxin® Filmtab®, (with coated povidone and propylene glycol) Abbott 500 mg Biaxin® Filmtab®, (with povidone and propylene glycol) Abbott Tablets, extended- 500 mg Biaxin® XL Filmtab, (with release, film- propylene glycol) Abbott coated Biaxin® XL Pac, (with propylene glycol; available as a 7-day mnemonic pack of 14 tablets) Abbott Clarithromycin Combinations Oral Kit 4 Capsules, Amoxicillin (trihydrate) 500 mg (of amoxicillin) (Trimox®) 2 Capsules, delayed-release (containing enteric-coated granules), Lansoprazole, 500 mg (Prevacid®) 2 Tablets, film-coated, Clarithromycin, 500 mg (Biaxin® Filmtab®(with povidone and propylene glycol) Prevpac®, TAP Pharmaceuticals