Buy Azithromycin (Zithromax) Without Prescription 250/500mg

Azithromycin

Azithromycin is a semisynthetic azalide antibiotic, a subclass of macrolide antibiotics, with a broader spectrum than that of erythromycins or clarithromycin.

Uses

Azithromycin is used orally in adults for the treatment of mild to moderate upper and lower respiratory tract infections and uncomplicated skin and skin structure infections caused by susceptible organisms.

Oral azithromycin also is used for the treatment of urethritis or cervicitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae, and for the treatment of chancroid caused by Haemophilus ducreyi. Azithromycin is used orally for the treatment of disseminated infections caused by Mycobacterium avium complex (MAC) in patients with human immunodeficiency virus (HIV) infection and for prevention of disseminated MAC infection (both primary and secondary prophylaxis) in HIV-infected individuals.

Azithromycin is used orally in children for the treatment of acute otitis media, community-acquired pneumonia, and pharyngitis or tonsillitis caused by susceptible organisms. IV azithromycin is used for the treatment of community-acquired pneumonia and acute pelvic inflammatory disease (PID) caused by susceptible organisms when initial IV therapy is considered necessary.

Potential advantages of azithromycin compared with erythromycin include improved oral bioavailability and tissue penetration, increased activity against infections caused by gram-negative organisms (e.g., Haemophilus influenzae), fewer adverse GI effects, and less frequent and less prolonged dosing (promoting better compliance with therapy).

Current data from a limited number of controlled and uncontrolled clinical studies in patients with community-acquired upper or lower respiratory tract infections suggest that oral therapy for 3-5 days with azithromycin generally is as effective as oral therapy for 7-10 days with other macrolides (e.g., erythromycin, clarithromycin), a natural penicillin, amoxicillin (with or without clavulanic acid), or a cephalosporin (e.g., cefaclor). In addition, single-dose therapy with azithromycin for urethritis or cervicitis caused by Chlamydia trachomatis may be more cost-effective than longer courses of therapy with another anti-infective (e.g., doxycycline) in populations where noncompliance may be a problem.

The relative lack of clinically important drug interactions with azithromycin also may be advantageous when oral macrolide therapy is considered for patients in whom multiple-drug therapy is prescribed (e.g., HIV-infected patients, patients receiving theophylline or carbamazepine).

Considering the relative costs of drug therapy, erythromycin generally would be preferred for most infections in which oral macrolide therapy was indicated unless azithromycin would be expected to be more effective than erythromycin, the patient is intolerant of erythromycin (e.g., secondary to GI toxicity), or compliance with 3- or 4-times daily erythromycin dosing is considered a problem. Prior to initiation of azithromycin therapy, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests. Azithromycin may be started pending results of susceptibility tests, but should be discontinued and other appropriate anti-infective therapy substituted if the organism is found to be resistant to the drug. (See Spectrum: In Vitro Susceptibility Testing.)

Pharyngitis and Tonsillitis

Azithromycin is used orally for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A b-hemolytic streptococci) in adults and children who are intolerant of first-line therapy (a natural penicillin). Although azithromycin generally is effective in eradicating S. pyogenes from the nasopharynx, efficacy of the drug in the subsequent prevention of rheumatic fever has not been established. Strains of S. pyogenes resistant to azithromycin have been reported and appropriate in vitro susceptibility tests should be performed prior to use of the drug in patients with streptococcal pharyngitis.

Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is 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 alternative agents. A 10-day regimen of oral erythromycin usually is considered the preferred alternative for the treatment of streptococcal pharyngitis in patients hypersensitive to penicillin. It has been suggested that azithromycin offers an advantage over erythromycin in terms of ease of administration (i.e., fewer daily doses and a 5-day regimen) and better GI tolerance. However, because of limited data to date, the IDSA states that use of anti-infective regimens administered for 5 days or less for the treatment of S. pyogenes pharyngitis cannot be recommended at this time.

Because of lower relative rates of bacteriologic eradication reported in some studies, azithromycin should not be administered in a 3-day regimen for the treatment of streptococcal pharyngitis. In a controlled comparative study in patients 16 years of age or older with streptococcal pharyngitis, microbiologic and clinical response rates of approximately 91% or greater were achieved with either a 5-day, 5-dose course of azithromycin or a 10-day, 40-dose course of penicillin V. In several double-blind, controlled trials in children 2 years of age or older with streptococcal pharyngitis, clinical and microbiologic response with azithromycin (12 mg/kg once daily for 5 days) was superior to that with penicillin V (250 mg 3 times daily for 10 days). In these trials, bacteriologic eradication at day 14 or 30 occurred in a combined 95 or 77%, respectively, of azithromycin-treated children and 73 or 63%, respectively, of penicillin-treated children; clinical success (i.e., cure or improvement) at day 14 or 30 was achieved in a combined 98 or 94%, respectively, of children given azithromycin and 84 or 74%, respectively, of children given penicillin V. Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to the drug following therapy. In another study in children 1.5-14 years of age with streptococcal pharyngitis, oral therapy with azithromycin (10 mg/kg once daily for 3 days) or penicillin V (56 mg/kg daily in 3 divided doses for 10 days) produced clinical success (cure or improvement) in 93 or 89% of patients, respectively. However, bacteriologic eradication was reported in substantially fewer azithromycin-treated patients (65%) than penicillin-treated patients (82%).

Respiratory Tract Infections

Azithromycin is used orally for the treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella (Branhamella) catarrhalis when anti-infective therapy is considered appropriate.

Current data from a limited number of randomized, comparative studies suggest similar clinical and microbiologic efficacy for oral azithromycin and oral cefaclor, erythromycin, clarithromycin, or amoxicillin (with or without clavulanic acid) in these infections. In addition, eradication of H. influenzae in patients with chronic bronchitis has occurred more frequently in those receiving azithromycin than in those receiving cefaclor. In these studies, azithromycin generally was administered once daily for 3-5 days, while other anti-infective therapy was given 2 or more times daily for 5-10 days.

Although co-trimoxazole generally is considered the drug of choice for the treatment of upper respiratory tract infections and bronchitis caused by H. influenzae or M. catarrhalis, azithromycin is considered by many clinicians to be alternative therapy for the treatment of these infections. Azithromycin has been used in adults for the treatment of acute bacterial sinusitis caused by susceptible organisms. In a study in patients with acute maxillary sinusitis, oral therapy with a 5-dose course of azithromycin (500 mg as a single dose on day 1, followed by 250 mg daily for 4 days) and a 30-dose course of amoxicillin (500 mg 3 times daily for 10 days) produced comparable clinical and bacteriologic responses.

Community-Acquired Pneumonia

Azithromycin is used orally for the treatment of mild to moderate community-acquired pneumonia (CAP) caused by susceptible S. pneumoniae, H. influenzae, Mycoplasma pneumoniae, or Chlamydia pneumoniae in adults and children 6 months of age or older when outpatient oral therapy is indicated.

Limited data in patients with CAP caused by these pathogens suggest that oral azithromycin given for 3-5 days is as effective as a 10-days regimen of oral cefaclor or clarithromycin.

Oral azithromycin should not be used in patients who have moderate to severe pneumonia and/or who require hospitalization, those who are elderly or debilitated, or in those who have nosocomially acquired infection, known or suspected bacteremia, cystic fibrosis, or any clinically important underlying health problems (e.g., immunodeficiency or functional asplenia) that may compromise the patient’s ability to respond to his or her illness.

Although azithromycin is highly distributed into tissues and phagocytes, some clinicians suggest that oral azithromycin is unsuitable for the treatment of CAP possibly associated with bacteremia and/or potentially resistant organisms (e.g., penicillin-resistant Streptococcus pneumoniae) because of the relatively low serum concentrations achieved with oral administration of the drug; parenteral therapy with IV azithromycin or another anti-infective agent may be preferred in such infections. IV azithromycin is used for the treatment of CAP caused by susceptible C. pneumoniae, H. influenzae, Legionella pneumophila, M. catarrhalis, M. pneumoniae, S. aureus, or S. pneumoniae when initial IV drug therapy is considered necessary. In a comparative study in patients with CAP, clinical success (i.e., cure or improvement) 10-14 days after completion of therapy reportedly occurred in 78% of patients receiving azithromycin (500 mg IV once daily for 2-5 days followed by azithromycin 500 mg orally once daily to complete 7-10 days of therapy) and in 74% of patients receiving cefuroxime (750 mg IV every 8 hours for 2-5 days followed by cefuroxime 500 mg orally every 12 hours to complete 7-10 days of therapy) with or without erythromycin (up to 2 g daily IV or oral). In an uncontrolled study, clinical success (i.e., cure or improvement) was reported in 89% of patients receiving the same regimen of IV and oral azithromycin. In these studies, presumptive bacteriologic eradication (determined according to microbiologic data available at the patient’s last completed clinic visit) was evident in 96% of evaluable patients with S. pneumoniae infections (including 79% of those with positive blood cultures for S. pneumoniae), 95% of those with H. influenzae infection, 90% of those with M. catarrhalis or S. aureus infection.

At 10-14 days after azithromycin therapy, presumptive bacteriologic/clinical success was evident in 89% of patients with M. pneumoniae infection, 82% of those with C. pneumoniae infection, and 81% of those with L. pneumophila infection. 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 IDSA and American Thoracic Society (ATS) regarding use of azithromycin 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

Azithromycin is used orally in children for the treatment of acute otitis media (AOM) caused by H. influenzae, M. catarrhalis, or S. pneumoniae. Safety and efficacy of azithromycin for the treatment of AOM in children has been established when the drug is given in a single-dose regimen (a single 30-mg/kg dose), a 3-day regimen (10 mg/kg once daily for 3 days), or a 5-day regimen (10 mg/kg on day 1, then 5 mg/kg on days 2-5). 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). In a multicenter, randomized, comparative trial in children 1-15 years of age, oral azithromycin therapy (10 mg/kg as a single dose on day 1, followed by 5 mg/kg once daily for 4 days) produced a favorable clinical response (i.e., cure or improvement) in 88 or 73% of patients 11 or 30 days after initiation of therapy, respectively, while therapy with amoxicillin and clavulanate potassium produced a favorable clinical response in 88 or 71% of patients, respectively, at these time points. In another study in children 2-15 years of age with acute otitis media in areas of the US with a high incidence of b-lactamase-producing bacteria, azithromycin therapy produced a favorable clinical response (i.e., cure or improvement) in 84 or 70% of patients 11 or 30 days, respectively, after initiation of therapy.

At day 11 or 30, a presumptive bacteriologic/clinical cure was evident in 82 or 71%, respectively, of children with S. pneumoniae infections, 80 or 64% of those with H. influenzae infections, 80 or 73% of those with M. catarrhalis infections, and 100% of those with S. pyogenes infections; 14.% were considered treatment failures. In one open-label comparative study, the overall clinical success rate (i.e., presumed bacteriologic eradication/clinical cure outcomes) 11 or 30 days after initiation of therapy was 88 or 82%, respectively, in azithromycin-treated patients and 82 or 81%, respectively, in patients receiving amoxicillin and clavulanate potassium. In all studies, the adverse effects associated with any of the therapies were principally GI related (e.g., diarrhea), with a substantially lower incidence of adverse effects in the azithromycin-treated group compared with the group receiving amoxicillin and clavulanate potassium.

Skin and Skin Structure Infections

Azithromycin is used in adults for the treatment of uncomplicated skin and skin structure infections caused by susceptible Staphylococcus aureus, S. pyogenes, or S. agalactiae. Results of comparative studies indicate that oral azithromycin is as effective as oral cloxacillin, oral cephalexin, or oral erythromycin in the treatment of bacterial skin and skin structure infections (e.g., cellulitis, pyoderma, erysipelas, wound infections). However, some clinicians state that azithromycin or any macrolide should not be used for serious staphylococcal infections because of the propensity for development of resistance during therapy. Skin structure infections resulting in abscess formation may require surgical or needle drainage in addition to antibacterial therapy.

Chlamydial Infections

Urogenital Chlamydial Infections

Azithromycin is used orally for the treatment of urethritis and cervicitis caused by C. trachomatis. For the treatment of urogenital chlamydial infections in nonpregnant adults and adolescents, the CDC, AAP, and other clinicians recommend a single dose of oral azithromycin or a 7-day regimen of oral doxycycline. Alternatively, these adults and adolescents can receive a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or levofloxacin.

While tetracyclines are highly effective and experience with these drugs is more extensive than that with azithromycin, azithromycin may be particularly useful and cost-effective when compliance with a multiple-day (e.g., 7-day) anti-infective regimen cannot be ensured.

Results from controlled clinical studies in individuals 15 years of age or older indicate that a single 1-g oral dose of azithromycin is as effective as a 7-day course of doxycycline in the treatment of uncomplicated chlamydial genital infections. For the treatment of uncomplicated urogenital chlamydial infections in children 8 years of age and older, the CDC recommends a single-dose azithromycin regimen or a 7-day regimen of oral doxycycline. For children younger than 8 years of age who weigh at least 45 kg, the CDC recommends a single-dose azithromycin regimen.

For children weighing less than 45 kg, the CDC recommends a 14-day regimen of oral erythromcyin base or ethylsuccinate. The AAP recommends that infants younger than 6 months of age with urogenital chlamydial infections receive an erythromcyin regimen and that those 6 months to 12 years of age receive either azithromycin or erythromycin. The CDC and AAP recommend that urogenital chlamydial infections in pregnant women be treated with a 7-day regimen of oral erythromycin base or oral amoxicillin; alternative regimens recommended for these infections in pregnant women are a 14-day regimen of oral erythromycin base or ethylsuccinate, a 7-day regimen of erythromycin ethylsuccinate, or a single oral dose of azithromycin.

While preliminary data indicate that azithromycin may be safe and effective during pregnancy, there are insufficient data to recommend the routine use of azithromycin for the treatment of chlamydial infection in pregnant women.

When given in the usual dosage for the treatment of uncomplicated sexually transmitted chlamydial infections, azithromycin alone should not be relied on for effective therapy against possible concomitant syphilis and the possibility that the regimen may mask or delay development of the signs and symptoms of incubating syphilis should be considered. Appropriate serologic tests for syphilis and cultures for gonorrhea should be performed prior to initiating azithromycin therapy for chlamydial infection; appropriate anti-infective therapy and follow-up should be initiated if either infection is confirmed.

Presumptive Treatment of Chlamydial Infection in Patients with Gonorrhea

Because of the risks associated with untreated coexisting chlamydial infection, the CDC and most clinicians recommend that patients being treated for uncomplicated gonorrhea or disseminated gonococcal infection also receive an anti-infective regimen effective for presumptive treatment of uncomplicated urogenital chlamydial infection. For presumptive treatment of chlamydia in adults and adolescents being treated for uncomplicated or disseminated gonococcal infections, the CDC and many clinicians recommend use of a single dose of oral azithromycin or a 7-day regimen of oral doxycycline.

The strategy of routine administration of a regimen effective against chlamydia in patients being treated for gonococcal infection has been recommended by the CDC for more than 10 years and appears to have resulted in substantial decreases in the prevalence of genital chlamydial infection in some populations. In addition, since most N. gonorrhoeae isolated in the US are susceptible to doxycycline and azithromycin, dual therapy may delay the development of resistance in N. gonorrhoeae. Since the cost of presumptive treatment of chlamydia is less than the cost of testing for presence of chlamydia, routine dual therapy without chlamydial testing can be cost-effective for populations in which coinfection with chlamydia has been reported in 10-30% of patients with N. gonorrhoeae infection. In areas where the rate of coinfection with chlamydia is low and chlamydial testing is widely available, some clinicians may prefer to test for chlamydia rather than treat presumptively; however, presumptive treatment is indicated for patients who may not return for test results.

Other Chlamydial Infections

A single oral dose (20 mg/kg) of azithromycin has been used for the treatment of ocular trachoma caused by C. trachomatis; some clinicians consider azithromycin the drug of choice for this infection. Azithromycin is used for the treatment of C. pneumoniae respiratory tract infections. (See Uses: Respiratory Tract Infections.) IV azithromycin is used for the treatment of pelvic inflammatory disease (PID) caused by C. trachomatis.(See Uses: Pelvic Inflammatory Disease.) In a randomized, placebo-controlled study in men who had survived a myocardial infarction and who had elevated anti-C. pneumoniae antibody titers (a possible risk factor for myocardial infarction or chronic coronary heart disease), the risk of subsequent adverse cardiovascular events (i.e., MI, unstable angina requiring IV therapy, coronary angioplasty, or coronary artery bypass, cardiovascular death) during a follow-up period averaging 18 months was reduced in individuals who received azithromycin therapy (500 mg daily for 3-6 days) compared with C. pneumoniae-seropositive individuals who received placebo and was similar to that in men who were C. pneumoniae seronegative. Because these preliminary findings may have important implications for secondary prevention of coronary heart disease, additional studies are in progress to verify these results.

Chancroid

Azithromycin is used orally in the treatment of chancroid (genital ulcers caused by Haemophilus ducreyi). Chancroid occurs more frequently in men (90% of infections) than in women and experience with azithromycin treatment of this infection in women is limited. Consequently, efficacy of the drug in the treatment of chancroid in women has not been established to date, and the drug is labeled by the US Food and Drug Administration (FDA) for this use only in men.

However, azithromycin has been used successfully for the treatment of chancroid in women, and chancroid treatment guidelines from CDC, AAP, and other authorities do not provide gender-based recommendations. The CDC242 and others state that a single oral dose of azithromycin, a single IM dose of ceftriaxone, a 3-day regimen of oral ciprofloxacin (contraindicated in pregnant or lactating women), or a 7-day regimen of oral erythromycin are the regimens of choice for the treatment of chancroid. The AAP states that a single oral dose of azithromycin or a single IM dose of ceftriaxone is the preferred regimen in infants, children, and adolescents. All 4 regimens generally are effective for the treatment of chancroid; however, patients with human immunodeficiency virus (HIV) infection and patients who are uncircumcised may not respond to therapy as well as those who are HIV-negative or circumcised.

Because data on the efficacy of the single-dose azithromycin and ceftriaxone regimens for treatment of chancroid in patients with HIV infection are limited, the CDC recommends that these regimens be used in HIV-infected patients only if follow-up can be assured; some experts recommend that HIV-infected individuals with chancroid receive the 7-day erythromycin regimen. In the US, chancroid usually occurs in discrete outbreaks, but the disease is endemic in some areas.

Approximately 10% of patients with chancroid acquired in the US also are coinfected with Treponema pallidum or herpes simplex virus (HSV); this percentage is higher in individuals who acquired the infection outside the US. In addition, high rates of HIV infection have been reported in patients with chancroid, and the disease appears to be a cofactor for HIV transmission. Ideally, diagnostic evaluation of patients with genital ulcers should include a serologic test for syphilis and either darkfield examination or direct immunofluorescence test for T. pallidum, culture for H. ducreyi, and culture or antigen test for HSV.

Evaluation of the physical features of genital ulcers (without laboratory evaluation and testing) usually is inadequate to provide a differential diagnosis between chancroid, primary syphilis, and genital HSV infection. A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that is not widely available. However, a probable diagnosis of chancroid can be made if the patient has one or more painful genital ulcers, there is no evidence of T. pallidum infection because of negative darkfield examination of ulcer exudate or a negative serologic test for syphilis (performed at least 7 days after onset of ulcers), culture or antigen test for HSV is negative, and the clinical presentation (appearance of genital ulcers, regional lymphadenopathy) are typical for chancroid. While the presence of a painful ulcer and tender inguinal adenopathy suggests a diagnosis of chancroid, the additional presence of suppurative inguinal adenopathy is a clearer indication of the disease.

When the diagnosis is uncertain, many clinicians recommend that all patients with nonherpetic genital ulcers be treated presumptively for both chancroid and syphilis if they reside in communities where the prevalence of chancroid is high. In communities where the prevalence of chancroid is high, the CDC recommends that all patients with nonherpetic genital ulcers be treated presumptively for both chancroid and syphilis.

Patient Follow-up and Management of Sexual Partners

The CDC recommends that all patients diagnosed with chancroid be tested for HIV and, if the test is negative, retested for HIV and for syphilis 3 months later. Patients with chancroid should be examined 3-7 days after initiation of anti-infective therapy. If the regimen was effective, symptomatic improvement in the ulcers is evident within 3 days and objective improvement is evident within 7 days. If clinical improvement is not evident within 3-7 days, consideration should be given to the possibility that the diagnosis was incorrect, there is coinfection with another sexually transmitted disease, the patient was noncompliant with the anti-infective regimen, the strain of H. ducreyi is resistant to the anti-infective agent used, or the patient is HIV seropositive.

The time required for complete ulcer healing is related to the size of the ulcer; large ulcers may require more than 2 weeks to heal. Healing of ulcers may be slower in uncircumcised men who have ulcers under the foreskin. Resolution of fluctuant lymphadenopathy is slower than that of ulcers, and drainage may be necessary despite effective anti-infective therapy. While needle aspiration of buboes is a simpler procedure, incision and drainage of buboes may be preferred.

The CDC recommends that any individual who had sexual contact with a patient with chancroid (within 10 days before the onset of the patient’s symptoms) should be examined and treated for the disease, even if no symptoms are present.

Gonorrhea and Associated Infections

Azithromycin is used orally for the treatment of uncomplicated gonorrhea (i.e., urethritis and/or crevices) caused by penicillinase-producing strains of N. gonorrhoeae (PPNG) or nonpenicillinase-producing strains of the organism. Limited data suggest that a single 2-g oral dose of azithromycin is as effective as a single 250-mg IM dose of ceftriaxone in the treatment of uncomplicated gonorrhea. However, the CDC and many clinicians currently recommend that uncomplicated gonorrhea in adults and adolescents be treated with a single IM dose of ceftriaxone, a single oral dose of cefixime, or a single oral dose of certain fluoroquinolones (ciprofloxacin, ofloxacin, levofloxacin) given in conjunction with an anti-infective regimen effective for presumptive treatment of chlamydia (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline).

Azithromycin currently is not listed in CDC treatment guidelines as a recommended or alternative treatment for uncomplicated gonorrhea in adults, and the single 2-g oral dose of azithromycin recommended by the manufacturer is associated with a relatively high incidence of adverse GI effects. Studies in which a single 1-g oral dose of azithromycin was used for the treatment of uncomplicated gonorrhea indicate that the 1-g dose is associated with a substantial incidence of therapeutic failure. Clinical experience with azithromycin in the treatment of gonorrhea is limited, and the drug does not appear to offer any clear advantages over IM ceftriaxone for the treatment of uncomplicated gonorrhea. N. gonorrhoeae with reduced susceptibility to azithromycin have been isolated in the US. (See Resistance.)

Nongonococcal Urethritis

Azithromycin is used orally for the treatment of nongonococcal urethritis (NGU). CDC currently considers oral azithromycin (a single 1-g dose) or oral doxycycline (100 mg twice daily for 7 days) to be the regimens of choice for the treatment of NGU. In a randomized, double-blind, comparative study in men with nongonococcal urethritis, a single 1-g oral dose of azithromycin was as effective as a 7-day course of doxycycline; in addition, clinical cure rates were comparable with either regimen regardless of the presence or absence of Chlamydia or Ureaplasma infection.

Pelvic Inflammatory Disease

IV azithromycin is used for the treatment of acute pelvic inflammatory disease (PID) caused by C. trachomatis, Mycoplasma hominis, or N. gonorrhoeae when initial IV therapy is considered necessary. While azithromycin has been evaluated for the treatment of upper reproductive tract infections, neither IV nor oral azithromycin is an agent of choice for the treatment of PID, and azithromycin is not included in the current CDC guidelines for the treatment of PID. Acute PID generally is a polymicrobial infection that may be caused by various pathogens, including N. gonorrhoeae, C. trachomatis, anaerobic bacteria, facultative gram-negative bacteria, streptococci, and Mycoplasma spp.

The optimum regimen for the treatment of PID has not been identified. Because it may be difficult to identify the various causative organisms and because no single anti-infective agent is effective against all possible pathogens, PID should be treated with a regimen that includes several anti-infective agents active against a broad range of organisms. Individuals with PID who are in areas endemic or hyperendemic for resistant gonorrhea (e.g., penicillin-resistant) should be treated with a regimen that includes an anti-infective agent effective against antibiotic-resistant N. gonorrhoeae.

While azithromycin has activity against several causative organisms in PID, an anti-infective with activity against anaerobic organisms should be administered concomitantly with azithromycin whenever such organisms may contribute to the infection. Although many clinicians have recommended that all patients with acute PID be hospitalized so that bed rest and supervised treatment with parenteral anti-infectives could be initiated, the CDC currently states that decisions regarding the necessity for hospitalization and whether an oral or parenteral regimen is most appropriate should be made on an individual basis since data are not available to date comparing efficacy of parenteral or oral therapy or inpatient or outpatient therapy. Based on observational data and theoretical concerns, the CDC states that hospitalization is indicated if surgical emergencies such as appendicitis cannot be excluded; the patient is pregnant; the patient is unable to follow or tolerate an outpatient oral regimen; the patient has severe illness, nausea and vomiting, or high fever; the patient has a tubo-ovarian abscess; or a clinical response was not obtained with an oral anti-infective regimen.

Mycobacterium avium Complex (MAC) Infections

Primary Prevention of Disseminated MAC Infection

Oral azithromycin is used alone or combined with rifabutin 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) states that azithromycin or clarithromycin is the preferred agent for primary prevention of disseminated MAC infections in adults and pediatric patients. In controlled trials, azithromycin monotherapy was more effective than placebo or rifabutin monotherapy in preventing disseminated MAC infection in patients with advanced HIV infection (CD4+ T-cell counts less than 100/mm3) and infrequently resulted in the development of resistant organisms.

In a placebo-controlled trial, the cumulative incidence rate of MAC infection at 1 year in patients receiving azithromycin 1.2 g once weekly was 10.% less than that in patients receiving placebo (19.1 versus 8.2% incidence, respectively), while both groups had a comparable incidence of adverse effects. In a randomized, comparative study in patients with advanced HIV infection (CD4+ T-cell counts less than 100/mm3), prophylaxis with rifabutin (300 mg daily), azithromycin (1. g once weekly), or both drugs concomitantly was associated with a cumulative incidence of MAC infection at 1 year of 15..6, or 2.8%, respectively. All patients also received fluconazole (200 mg daily or 400 mg once weekly) for prevention of fungal infections.

The risk of MAC infection (after adjustment for baseline CD4+ T-cell counts) in patients receiving azithromycin prophylaxis was 47% lower than that with rifabutin prophylaxis, while prophylaxis with both drugs reduced the risk by 72% compared with rifabutin alone.

The incidences of bacterial infections (e.g., pneumonia, sinusitis) and of manifestations of disseminated MAC infection (e.g., fever, night sweats, weight loss, anemia) in this study were lower with azithromycin or azithromycin-rifabutin prophylaxis than with rifabutin prophylaxis or placebo. Analyses of the occurrence of Pneumocystis carinii pneumonia in these patients indicated that prophylaxis with azithromycin (alone or combined with rifabutin) provided additional protection against this opportunistic infection (45% risk reduction) compared with that provided by rifabutin alone in patients without previous P. carinii episodes; no additional benefit from azithromycin was observed to enhance when azithromycin was used as secondary prophylaxis (i.e., in patients with priorP. carinii episodes). Of patients in whom prophylaxis with azithromycin was unsuccessful, resistance to azithromycin (and clarithromycin) was found in 11%.

The overall incidence of adverse effects was similar among the 3 groups (i.e., 76, 88, or 90% of patients receiving rifabutin, azithromycin, or combined rifabutin-azithromycin prophylaxis, respectively), although dose-limiting adverse effects (principally GI effects) occurred more frequently with combined azithromycin-rifabutin prophylaxis (23% of patients) than with rifabutin (16%) or azithromycin (13%) prophylaxis. The USPHS/IDSA recommends primary prophylaxis against MAC disease for HIV-infected adults and adolescents (13 years of age or older) who have CD4+ T-cell counts less than 50/mm3. Severely immunocompromised HIV-infected children should also receive primary prophylaxis against MAC 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 children less than 1 year of age, less than 750 cells/mm3.

The USPHS/IDSDA states that either azithromycin or clarithromycin is the preferred agent for primary prophylaxis; alternatively, if these drugs cannot be tolerated, rifabutin should be used. Although the combination of azithromycin and rifabutin is more effective than azithromycin alone for primary MAC prophylaxis, the USPHS/IDSA currently does not recommend routine prophylaxis with the combination because of additional cost, increased incidence of adverse effects, and absence of a difference in survival in patients receiving the combination compared with azithromycin 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 chemoprophylaxis 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 disease prophylaxis in HIV-infected pregnant women because of the drug’s safety profile in animal studies and anecdotal information on safety in humans.

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

Azithromycin is recommended as part of a multiple-drug regimen for the treatment of disseminated MAC infections or for prevention of recurrence (secondary prophylaxis) in patients with HIV infection. The ATS currently recommends therapy that includes either clarithromycin or azithromycin combined with at least one other drug (i.e., ethambutol or rifabutin) for the treatment or secondary prevention of disseminated MAC infections in HIV-infected patients; the ATS states that consideration should be given to adding a third drug (preferably rifabutin) to a regimen consisting of either clarithromycin or azithromycin and ethambutol.

The choice of the drug regimen should be made in consultation with an expert, and treatment 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.

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 and in whom macrolide resistance has not been documented, the USPHS/IDSA recommends a regimen consisting of a macrolide (i.e., azithromycin or clarithromycin) given with ethambutol (with or without rifabutin). 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.

Treatment of Pulmonary MAC Infection

Azithromycin has been included in multiple-drug regimens for the treatment of MAC pulmonary infections. The ATS recommends that therapy for MAC pulmonary infections in HIV-negative adults 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). 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 Infections, under Management of Other Mycobacterial Diseases: Mycobacterium avium complex [MAC] Infections, in the Antituberculosis Agents General Statement 8:16.04.)

Prevention of Bacterial Endocarditis

Azithromycin is recommended for prevention of a-hemolytic (viridans group) streptococcal bacterial 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 certain dental or upper respiratory tract procedures likely to cause transient bacteremia and increase the risk of endocarditis.

These procedures include dental and oral procedures 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; and routine professional cleaning) and minor upper respiratory tract surgery or instrumentation (e.g., tonsillectomy, adenoidectomy, bronchoscopy with a rigid bronchoscope).

While erythromycin previously was recommended by the American Heart Association (AHA) as an alternative to penicillins in penicillin-allergic patients, erythromycin is not included in the current recommendations because of adverse GI effects and the complicated pharmacokinetics of the various erythromycin formulations. (See Streptococcal Infections: Prophylaxis of Bacterial Endocarditis, in the Erythromycins General Statement 8:12.12.04.) AHA recognizes that its current recommendations for prophylaxis against 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 American Dental Association (ADA), and most clinicians generally recommend routine use of prophylactic anti-infectives in patients with the cardiac conditions previously described since these are associated with a high or moderate risk for bacterial endocarditis. The AHA, ADA, and others state that prophylaxis against bacterial endocarditis is not considered necessary for adults or children with cardiac conditions deemed to be associated with a negligible risk for endocarditis since these individuals are at no greater risk than the general population.

Cardiac conditions considered to be associated with a negligible risk include a history of isolated secundum atrial septal defect; surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 months); previous coronary artery bypass graft (CABG) surgery; mitral valve prolapse without valvar regurgitation; physiologic, functional, or innocent heart murmurs; previous Kawasaki disease without valvar dysfunction; previous rheumatic fever without valvar dysfunction; or cardiac pacemaker (intravascular and epicardial) and implanted defibrillators.

Azithromycin is not suitable for prophylaxis against bacterial endocarditis in patients undergoing GI, biliary, or genitourinary tract surgery or instrumentation because causative organisms (enterococci) are likely to be resistant to the drug. When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations published by the AHA should be consulted.

Prophylaxis in Sexual Assault Victims

Azithromycin is used in conjunction with IM ceftriaxone and oral metronidazole for empiric anti-infective prophylaxis in adult or adolescent victims of sexual assault. The CDC states that trichomoniasis, genital chlamydial infection, gonorrhea, and bacterial vaginosis are the sexually transmitted diseases (STDs) most commonly diagnosed in women following sexual assault; however, the prevalence of these infections is substantial among sexually active women, and their presence after assault does not necessarily indicate that the infections were acquired during the assault.

Chlamydial and gonococcal infections among females are of special concern because of the possibility of ascending infection. Many experts recommend routine empiric prophylactic therapy after a sexual assault, and use of such prophylaxis probably benefits most patients since follow-up of assault victims can be difficult and such prophylaxis allays the patient’s concerns about possible infections.

When empiric anti-infective prophylaxis is indicated in adult or adolescent sexual assault victims, the CDC recommends administration of a single 125-mg IM dose of ceftriaxone given in conjunction with a single 2-g oral dose of metronidazole and a single 1-g oral dose of azithromycin or a 7-day regimen of oral doxycycline (100 mg twice daily). This 3-drug regimen provides coverage against gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, but efficacy in preventing these infections after sexual assault has not been specifically evaluated.

Because of possible adverse GI effects with the 3-drug regimen, the CDC suggests that the patient be counseled regarding the possible benefits, as well as the possibility of toxicity, of such prophylaxis. Alternative regimens may be required for some patients because of the likelihood of transmission of other STDs from the assailant. Postexposure hepatitis B vaccination also is recommended for sexual assault victims who have not previously received the vaccine; hepatitis B vaccine (without hepatitis B immune globulin) should be given to susceptible victims at the time of the initial examination.

The CDC states that although a definitive recommendation concerning the appropriateness of antiretroviral prophylaxis against HIV cannot be made based on currently available information, such prophylaxis should be considered in cases in which the risk for HIV exposure during the assault is considered high. The decision to offer such prophylaxis should be individualized taking into account the probability of HIV transmission from a single act of intercourse and the nature of the assault (e.g., extent and site of physical trauma and exposure to ejaculate), the potential benefits and risks of prophylaxis, and the time interval between the exposure and initiation of therapy. (See Guidelines for Use of Antiretroviral Agents: Postexposure Prophylaxis following Sexual Assault or Nonoccupational Exposures to HIV, in the Antiretroviral Agents General Statement 8:18.08.) There are few data available to establish the risk of a child acquiring a sexually transmitted disease as a result of sexual assault or abuse.

The risk is believed to be low in most circumstances, although documentation to support this position is inadequate. The CDC currently states that presumptive treatment for children who have been sexually assaulted or abused is not widely recommended because girls appear to be at lower risk for ascending infection than adolescent or adult women and regular follow-up usually can be ensured. Even if the risk is perceived by the health-care provider to be low, some children or their parents or guardians may have concerns about the possibility of the child contracting a sexually transmitted disease as a result of the assault, and these concerns may be an appropriate indication for presumptive treatment in some settings, but only after appropriate specimens for STD testing have been obtained.

Helicobacter pylori Infection

Azithromycin has been used in multiple-drug regimens for the treatment of Helicobacter pylori infection and peptic ulcer disease. However, data from a limited number of clinical studies indicate that such combination regimens generally are associated with a high incidence of adverse effects (principally GI effects) or low H. pylori eradication rates (i.e., 50-70%). For more information on the treatment of H. pylori infection and peptic ulcer disease, see Uses: Helicobacter pylori Infection, in Clarithromycin 8:12.12.92.

Bartonella Infections

Azithromycin has been used in conjunction with IM or IV ceftriaxone for the treatment of bacteremia caused by Bartonella quintana (formerly Rochalimaea quintana). B. quintana, a gram-negative bacilli, can cause cutaneous bacillary angiomatosis, trench fever, bacteremia, endocarditis, and chronic lymphadenopathy. B. quintana infections have been reported most frequently in immunocompromised patients (e.g., individuals with HIV infection), homeless individuals in urban areas, and chronic alcohol abusers. Optimum anti-infective regimens for the treatment of infections caused by B. quintana have not been identified, and various drugs have been used to treat these infections, including doxycycline, erythromycin, azithromycin, chloramphenicol, or cephalosporins. There is evidence that these infections tend to persist or recur and prolonged therapy (several months or longer) usually is necessary.

The role of azithromycin in the treatment of infections caused by Bartonella henselae (formerly Rochalimaea henselae) (e.g., cat scratch disease, bacillary angiomatosis, peliosis hepatitis) has not been determined. Cat scratch disease generally is a self-limited illness in immunocompetent individuals and may resolve spontaneously in 2-4 months; however, some clinicians suggest that anti-infective therapy be considered for acutely or severely ill patients with systemic symptoms, particularly those with hepatosplenomegaly or painful lymphadenopathy, and such therapy probably is indicated in immunocompromised patients. Anti-infectives also are indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud’s oculoglandular syndrome. While the optimum anti-infective regimen for the treatment of cat scratch disease or other B. henselae infections has not been identified, some clinicians recommend use of erythromycin, doxycycline, ciprofloxacin, rifampin, co-trimoxazole, gentamicin, azithromycin, or third generation cephalosporins.

Campylobacter Infections

Azithromycin has been used as a first-line agent for the treatment of symptomatic enteric infections caused by Campylobacter jejuni. The CDC, IDSA, and AAP203 consider oral erythromycin the drug of choice for these infections. Azithromycin or a fluoroquinolone (e.g., ciprofloxacin) also is recommended; tetracycline can be used for patients 8 years of age or older. When initiated early in the course of the Campylobacter infection, erythromycin or azithromycin shortens the duration of illness and prevents relapse. Both of these macrolides usually eradicate the organism from the stool within 2-3 days; in patients with gastroenteritis, the recommended duration of therapy is 5-7 days.

Pertussis

Azithromycin (10-12 mg/kg once daily for 5-7 days) has been suggested as an alternative to erythromycin for the treatment of pertussis caused by Bordetella pertussis. However, a 14-day regimen of oral erythromycin currently is considered the drug of choice for the treatment of pertussis and for prevention in contacts of patients with pertussis. The AAP states that additional study is needed to evaluate efficacy of the azithromycin regimen in the treatment of pertussis.

Legionnaires’ Disease

Oral or IV azithromycin is used for the treatment of Legionnaires’ disease caused by Legionella pneumophila. Macrolides or fluoroquinolones generally are considered the drugs of choice for the treatment of pneumonia caused by L. pneumophila and doxycycline and co-trimoxazole are alternatives. A parenteral regimen usually is necessary for the initial treatment of severe Legionnaires’ disease and the addition of oral rifampin is recommended during the first 3-5 days of macrolide or doxycycline therapy in severely ill and/or immunocompromised patients; after a response is obtained, rifampin can be discontinued and therapy changed to an oral regimen. Some clinicians suggest that azithromycin may be the preferred macrolide for the treatment of severe Legionnaires’ disease and may also be preferred for empiric therapy in patients with severe community-acquired pneumonia that may be caused by Legionella. (See Community-acquired Pneumonia under Uses: Respiratory Tract Infections.)

Spirochetal Infections

Lyme Disease

Azithromycin has been used in the treatment of early Lyme disease, a spirochetal infection caused by tick-borne Borrelia burgdorferi. 288 However, some evidence in patients with early Lyme disease suggests that azithromycin or 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. Results of a randomized, controlled study in patients with erythema migrans (localized skin lesion associated with early Lyme disease) suggest that a 20-day regimen of oral amoxicillin is more effective than a 7-day regimen of oral azithromycin (500 mg daily).

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.

Syphilis

Although penicillin G is the drug of choice for the treatment of all stages of syphilis, the CDC states that oral azithromycin can be considered for the treatment of primary, secondary, or early latent syphilis in nonpregnant adults and adolescents who are hypersensitive to penicillin if close follow-up can be ensured. Data to support the use of penicillin alternatives in the treatment of primary, secondary, or early latent syphilis in penicillin-hypersensitive individuals are limited, but oral tetracyclines (doxycycline, tetracycline) usually have been used in these patients. However, preliminary data suggest that a single 2-g dose of azithromycin may be effective.

The CDC states that use of azithromycin in HIV-infected individuals has not been studied and such therapy should be undertaken with caution. If compliance with penicillin alternatives and follow-up cannot be ensured, adults and adolescents with penicillin hypersensitivity should be desensitized and treated with penicillin G. Azithromycin is not included in CDC recommendations for the treatment of any other form of syphilis, including late latent syphilis, latent syphilis of unknown duration, tertiary syphilis, or neurosyphilis. In addition, azithromycin is not included in CDC recommendations for the treatment of syphilis in pregnant women or for the treatment of congenital syphilis in neonates, infants, or older children.

Toxoplasmosis

Azithromycin has been used alone and in combination with pyrimethamine for the treatment of Toxoplasma gondii encephalitis in a few HIV-infected patients. Further controlled studies are needed and are ongoing to determine the potential role of azithromycin in the treatment of this infection.

Babesiosis

A combination regimen of atovaquone and azithromycin is recommended as a regimen of choice for the treatment of babesiosis caused by Babesia microti. The other regimen of choice for this infection is clindamycin and quinine. The atovaquone and azithromycin regimen appears to be as effective as the clindamycin and quinine regimen and may be better tolerated. Limited data in animals suggest that azithromycin in combination with quinine also may be effective in the management of babesiosis. Exchange transfusions have been used in asplenic individuals with life-threatening babesiosis and should be considered in severely ill patients with high levels of parasitemia (more than 10%).

Granuloma Inguinale (Donovanosis)

Oral azithromycin (1 g once weekly) reportedly has been effective in the treatment of granuloma inguinale (donovanosis), a chronic, progressively destructive sexually transmitted disease caused by Calymmatobacterium granulomatis. The CDC recommends that donovanosis be treated with a regimen of oral co-trimoxazole or oral doxycycline or, alternatively, a regimen of oral ciprofloxacin or oral erythromycin.

Cryptosporidiosis

Oral azithromycin (600 mg once daily for 4 weeks) in conjunction with paromomycin (1 g twice daily for 12 weeks) has been used with some success (i.e., reduction in oocyst excretion, improvement in diarrhea) in a limited number of patients with AIDS-related cryptosporidiosis. 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 the use of an appropriate anti-infective agent in conjunction with an antidiarrheal agent.

Dosage and Administration

Reconstitution and Administration

Azithromycin is administered orally or by IV infusion. Azithromycin injection should not be given by direct IV injection or IM.

Oral Administration

Reconstituted multiple-dose oral suspension containing 100 or 200 mg of azithromycin per 5 mL1 and reconstituted single-dose packets for oral suspension containing 1 g of azithromycin can be taken with or without food. Azithromycin tablets can be taken with or without food; tolerability may be increased when tablets are taken with food. Two 250-mg tablets of azithromycin are bioequivalent to one 500-mg tablet.

Azithromycin should not be taken simultaneously with aluminum- or magnesium-containing antacids. Azithromycin for multiple-dose oral suspension should be reconstituted at the time of dispensing by adding 9 mL of water to a bottle labeled as containing 300 mg of azithromycin to obtain a suspension containing 100 mg of azithromycin per 5 mL or by adding 9, 12, or 15 mL of water to a bottle labeled as containing 600 mg, 900 mg, or 1.2 g of azithromycin, respectively, to obtain a suspension containing 200 mg/5 mL. Following reconstitution, the bottle adapter supplied by the manufacturer should be inserted into the neck of the bottle and sealed with the original closure. The bottle should be kept tightly closed and should be shaken well before each use.

The dosing device supplied by the manufacturer should be used to measure the indicated dosage of the oral suspension; the dosing device may need to be filled multiple times to provide the full indicated dose.

The dosing device should be rinsed with water after the complete dose has been administered. For reconstitution of azithromycin for oral suspension in single-dose packets, the contents of a 1-g packet should be mixed thoroughly with 60 mL of water and the entire contents ingested immediately; an additional 60 mL of water should be added, mixed, and the entire contents ingested to ensure complete consumption of the dose. Single-dose packets of azithromycin for oral suspension are not for pediatric use and should not be used for administration of azithromycin doses other than 1 g.

IV Infusion

Azithromycin for injection is reconstituted by adding 4.8 mL of sterile water for injection to a vial labeled as containing 500 mg of the drug to provide a solution containing azithromycin 100 mg/mL. Since azithromycin for injection is supplied under vacuum, the manufacturer recommends that a standard 5 mL (non-automated) syringe be used to ensure that exactly 4.8 mL of sterile water for injection is added during reconstitution.

Reconstituted solutions should be further diluted prior to administration with 250 or 500 mL of a compatible IV solution to a concentration of 2 or 1 mg/mL. IV solutions containing azithromycin in a concentration of 1 mg/mL generally are infused over 3 hours, and solutions containing azithromycin 2 mg/mL generally are infused over 1 hour. The manufacturer states that solutions containing a 500-mg dose of azithromycin should be infused over a period of not less than 1 hour. Prior to administration, azithromycin solution should be inspected visually for particulate matter; if particulate matter is evident in reconstituted fluids, the solution should be discarded. Azithromycin should not be admixed with other drugs or infused simultaneously through the same tubing with other drugs.

Dosage

Dosage of azithromycin, which is commercially available for oral and IV use as the dihydrate, is expressed in terms of anhydrous azithromycin.

Adult Dosage

Pharyngitis and Tonsillitis

The usual oral dosage of azithromycin in adults for the treatment of pharyngitis or tonsillitis (as second-line therapy) is 500 mg given as a single dose on the first day of therapy, followed by 250 mg once daily for 4 additional days of therapy (total cumulative dose: 1.5 g administered over 5 days).

Respiratory Tract Infections

The usual oral dosage of azithromycin in adults for the treatment of mild to moderate acute bacterial exacerbations of chronic bronchitis is 500 mg daily for 3 days or, alternatively, 500 mg given as a single dose on the first day of therapy followed by 250 mg once daily for 4 additional days of therapy (total cumulative dose: 1.5 g administered over 5 days). For the treatment of mild community-acquired pneumonia (CAP) in adults, the usual dosage is 500 mg given as a single dose on the first day of therapy, followed by 250 mg once daily for 4 additional days of therapy (total cumulative dose: 1.5 g administered over 5 days).

For the treatment of CAP in adults or adolescents 16 years of age or older who require initial IV therapy, 500 mg of azithromycin is given IV as a single daily dose for 2 days. IV therapy generally is followed by oral azithromycin given as a single, daily 500-mg dose to complete a 7- to 10-day course of therapy. The timing of the change from IV to oral therapy should be individualized by the clinician, taking into account the clinical response of the patient.

Skin and Skin Structure Infections

The usual oral dosage of azithromycin in adults for the treatment of uncomplicated skin and skin structure infections is 500 mg given as a single dose on the first day of therapy, followed by 250 mg once daily for 4 additional days of therapy (total cumulative dose 1.5 g administered over 5 days).

Chlamydial Infections

For the treatment of uncomplicated chlamydial infections, including nongonococcal urethritis or cervicitis, the usual adult oral dosage of azithromycin is 1 g administered as a single dose. The 1-g dose may be administered using one single-dose packet of azithromycin for oral suspension or four 250-mg tablets. Limited evidence indicates that lower doses (e.g., a single 500-mg dose) of azithromycin may be associated with a high failure rate in, and therefore are not recommended for, the treatment of uncomplicated chlamydial infections.

Chancroid

For the treatment of chancroid, the usual oral dosage of azithromycin in adults or adolescents is 1 g administered as a single dose. Most authorities recommend that chancroid be examined 3-10 days after initiation of anti-infective therapy to assess treatment response. (See Uses: Chancroid.)

Gonorrhea and Associated Infections

For the treatment of urethritis and cervicitis caused by Neisseria gonorrhoeae, the usual oral dosage of azithromycin is 2 g administered as a single dose. Limited evidence suggests that lower doses (e.g., 1 g) of azithromycin may be associated with a high failure rate and should not be used for the treatment of gonorrhea.

Nongonococcal Urethritis

For the treatment of nongonococcal urethritis, the usual oral dosage of azithromycin in men is 1 g administered as a single dose.

Pelvic

Inflammatory Disease

For the treatment of acute pelvic inflammatory disease (PID) in patients requiring initial IV therapy, 500 mg of azithromycin is given IV as a single daily dose for 1-2 days. IV therapy generally is followed by oral azithromycin 250 mg once daily to complete a 7-day course of therapy. The timing of the change from IV to oral therapy should be individualized by the clinician, taking into account clinical response of the patient.

Primary Prevention of Disseminated MAC Infection

For primary prevention of disseminated Mycobacterium avium complex (MAC) infection (primary prophylaxis) in adults and adolescents with advanced HIV infection, the usual oral dosage of azithromycin is 1.2 g once weekly. Azithromycin can be given alone or in conjunction with rifabutin (300 mg once daily) for primary prophylaxis against MAC. (See Dosage and Administration: Dosage, in Rifabutin 8:16.04.) 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/mm3. 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/mm3 that has been sustained for at least 3 months (see Primary Prevention of Disseminated MAC Infection under Uses: Mycobacterium avium Complex [MAC] Infections), the USPHS/IDSA states that primary MAC prophylaxis should be restarted if the CD4+ T-cell count decreases to less than 50-100/mm3.

Treatment and Prevention of Recurrence of Disseminated MAC Infection

For the treatment of disseminated MAC infection in adults, the manufacturer recommends an azithromycin dosage of 600 mg once daily in conjunction with ethambutol (15 mg/kg daily); additional antimycobacterial drugs may be added to the regimen at the discretion of the clinician. The American Thoracic Society (ATS) has recommended a regimen of 250-500 mg of azithromycin once daily with ethambutol (15 mg/kg once daily) and rifabutin (300 mg once daily) for the treatment of disseminated MAC. For long-term suppressive or chronic maintenance therapy (secondary prophylaxis) to prevent recurrence of disseminated MAC in HIV-infected adults or adolescents who responded to treatment, the USPHS/IDSA recommends that adults and adolescents receive azithromycin in a dosage of 500 mg once daily in conjunction with ethambutol (15 mg/kg once daily) with or without rifabutin (300 mg once daily). Secondary MAC prophylaxis in HIV-infected individuals usually is continued for life.

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 Uses: Mycobacterium avium Complex [MAC] Infections), but states that such prophylaxis should be restarted if CD4+ T-cell counts decrease to less than 100/mm3.

Treatment of Pulmonary MAC Infection

As an alternative to clarithromycin in multiple-drug regimens (containing at least 3 drugs) for the treatment of mild to moderately advanced MAC pulmonary infections in HIV-negative adults, the ATS and some clinicians currently recommend therapy with azithromycin 250 mg daily or 500 mg 3 times weekly in combination with rifabutin (300 mg daily) or rifampin (600 mg daily) and ethambutol (25 mg/kg daily for 2 months, then 15 mg/kg daily). A lower dosage of azithromycin (250 mg 3 times weekly) in this regimen may be better tolerated in patients with a small body mass and/or those who are older than 70 years of age.

The ATS states that the addition of streptomycin therapy given intermittently (2 or 3 times weekly) for at least 2 months may be considered in patients with extensive disease. The optimal duration of therapy for pulmonary MAC disease has not been established.

Prevention of Bacterial Endocarditis

When an oral regimen is indicated for the prevention of bacterial endocarditis in penicillin-allergic adults at high or moderate risk undergoing certain dental or upper respiratory tract procedures likely to cause transient bacteremia, a single 500-mg dose of azithromycin should be administered 1 hour prior to the procedure.

Prophylaxis in Sexual Assault Victims

For empiric anti-infective prophylaxis in adult and adolescent victims of sexual assault, the usual oral dosage of azithromycin is 1 g administered as a single dose. 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 adults who are intolerant of amoxicillin, doxycycline, and cefuroxime axetil, the IDSA suggests an oral azithromycin dosage of 500 mg once daily for 7-10 days. Syphilis If azithromycin is used as an alternative agent for the treatment of primary, secondary, or early latent syphilis in nonpregnant adults or adolescents hypersensitive to penicillins, the CDC recommends a single 2-g oral dose.

Babesiosis

For the treatment of babesiosis caused by Babesia microti, some clinicians recommend that adults receive oral azithromycin in a dosage of 600 mg once daily given in conjunction with atovaquone (750 mg twice daily) for 7-10 days.

Pediatric Dosage

Pharyngitis and Tonsillitis

The usual oral dosage of azithromycin for the treatment of Streptococcus pyogenes (group A b-hemolytic streptococci) pharyngitis or tonsillitis in children 2 years of age or older is 12 mg/kg daily (maximum daily dosage 500 mg) for 5 days.

Respiratory Tract Infections

The usual oral dosage of azithromycin for the treatment of community-acquired pneumonia (CAP) in children 6 months of age or older is a single 10-mg/kg dose (maximum daily dosage 500 mg) given on day 1 followed by 5 mg/kg once daily (maximum daily dosage 250 mg) on days 2-5. Efficacy of shorter regimens (e.g., 1- or 3-day regimens) for the treatment of CAP in children has not been established.

Acute Otitis Media

For the treatment of acute otitis media in children 6 months of age or older, oral azithromycin can be given as a single 30-mg/kg dose. Alternatively, azithromycin can be given in a 3-day regimen consisting of 10 mg/kg once daily for 3 days or a 5-days regimen consisting of a single 10-mg/kg dose given on day 1 followed by 5 mg/kg once daily on days 2-5. The manufacturer states that the safety of redosing children who vomit after receiving the single 30-mg/kg azithromycin dose has not been established; in clinical studies involving 487 acute otitis media patients, a second 30-mg/kg dose was administered to 8 patients who vomited within 30 minutes of receiving the initial 30-mg/kg dose.

Chlamydial Infections

When azithromycin is used for the treatment of uncomplicated chlamydial genital tract infection (e.g., nongonococcal urethritis or cervicitis), the usual oral dosage for children 8 years of age or older or who weigh at least 45 kg is 1 g given as a single dose. Some clinicians suggest that ophthalmia neonatorum caused by C. trachomatis can be treated with oral azithromycin given in a dosage of 20 mg/kg once daily for 3 days. Chancroid For the treatment of chancroid, infants and children may receive a single 20-mg/kg (maximum 1 g) oral dose.

Primary Prevention of Disseminated MAC Infection

For primary prevention (primary prophylaxis) of disseminated MAC infections in infants and children with advanced HIV infection, the usual oral dosage of azithromycin is 20 mg/kg (maximum 1.2 g) once weekly. Alternatively, azithromycin 5 mg/kg (maximum 250 mg) can be given once daily. In children 6 years of age or older, azithromycin can be given in conjunction with rifabutin (300 mg once daily) for primary prophylaxis against MAC. The USPHS/IDSA recommends long-term primary prophylaxis against disseminated MAC infection in severely immunocompromised HIV-infected infants and children (see Primary Prevention of Disseminated MAC Infection under Uses: Mycobacterium avium Complex [MAC] Infections). 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.

Prevention of Recurrence of Disseminated MAC Infection

As an alternative to clarithromycin in a multiple-drug regimen for the prevention of recurrence (secondary prophylaxis) of disseminated MAC infections in infants and children, the USPHS/IDSA recommends an oral azithromycin dosage of 5 mg/kg (maximum 250 mg) once daily in combination with ethambutol (15 mg/kg [maximum 900 mg] once daily, with or without rifabutin (5 mg/kg [maximum 300 mg] once daily). 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.

Prevention of Bacterial Endocarditis

When an oral regimen is indicated for prevention of bacterial endocarditis in penicillin-allergic children at high or moderate risk undergoing certain dental or upper respiratory tract procedures likely to cause transient bacteremia, a single 15-mg/kg dose of azithromycin should be administered 1 hour prior to the procedure; pediatric dosage should not exceed the adult dosage.

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 children who are intolerant of amoxicillin, doxycycline, and cefuroxime axetil, the IDSA suggests an oral azithromycin dosage of 10 mg/kg (maximum dose: 500 mg) once daily for 7-10 days.

Babesiosis

For the treatment of babesiosis caused by Babesia microti, some clinicians recommend that pediatric patients receive oral azithromycin in a dosage of 12 mg/kg once daily given in conjunction with atovaquone (20 mg/kg twice daily) for 7-10 days.

Dosage in Renal and Hepatic Impairment

The manufacturer states that dosage adjustment is not necessary in patients with renal impairment (glomerular filtration rate of 80 mL/minute or less). However, data are limited regarding use of the drug in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute) and caution should be exercised when the drug is used in these patients. Because the pharmacokinetics of azithromycin in patients with hepatic impairment have not been established, the manufacturer states that recommendations for dosage adjustment in these patient cannot be made. However, caution should be exercised in patients with hepatic impairment since the drug is eliminated principally via the liver.

Cautions

Azithromycin generally is well tolerated. In clinical studies, most adverse effects were mild to moderate in severity and were reversible upon discontinuance of the drug. Limited data from comparative studies suggest that the overall incidence of adverse effects with oral azithromycin therapy is similar to or lower than that with oral erythromycin. As with oral erythromycin, the most common adverse effects of oral azithromycin involve the GI tract. In addition to effects reported in clinical trials, adverse effects reported in the Cautions section include those reported during postmarketing studies with azithromycin and from case reports for which a causal relationship to the drug may not have been established. Adverse GI effects (e.g., nausea, vomiting, diarrhea, abdominal pain) and rash are the most frequent adverse effects requiring discontinuance of the drug.

The manufacturer states that rate of discontinuance of azithromycin was approximately 0.7% in adults or children receiving a 5-day oral regimen; 0.4% in adults receiving a 3-day oral regimen (500 mg daily); or 1% in children receiving a single 30-mg/kg oral dose or a 3-day oral regimen (10 mg/kg daily). In adults with human immunodeficiency virus (HIV) infection receiving long-term therapy with oral azithromycin (600 mg daily) combined with oral ethambutol for the treatment of Mycobacterium avium complex infection, the discontinuance rate was 9.1%. The rate of discontinuance of azithromycin therapy In addition, 1.2-2.% of adults receiving a regimen that included both IV and oral azithromycin discontinued therapy because of adverse effects.

GI Effects

The most frequent adverse effects of azithromycin involve the GI tract (i.e., diarrhea/loose stools, nausea, abdominal pain). While these adverse effects generally are mild to moderate in severity and occur less frequently than with oral erythromycin therapy, adverse GI effects are the most frequent reason for discontinuing azithromycin therapy. The manufacturer states that administration of azithromycin tablets with food may improve GI tolerability.

Adverse GI effects have occurred more frequently in patients receiving azithromycin as a single oral dose of 1, 1.2, or 2 g than in those receiving a 5-day oral regimen. Diarrhea/loose stools or nausea was reported in 7 or 5%, respectively, of adults receiving a single 1-g oral dose of azithromycin, in 14 or 18%, respectively, of adults receiving a single 2-g oral dose, and in 5 or 3%, respectively, of those receiving a 5-day oral regimen. In adults receiving initial therapy with IV azithromycin followed by oral therapy, diarrhea/loose stools or nausea occurred in 4.3 or 3.9% of those with community-acquired pneumonia, and in 8.5 or 6.6% of those with pelvic inflammatory disease (PID). Diarrhea/loose stools or nausea has been reported in up to 53 or 33%, respectively, of HIV-infected patients receiving the drug for prevention of disseminated M. avium complex (MAC) infections. Vomiting was reported in 7, 2, or 1% or less of adults on the single 2-g dose, single 1-g dose, or 5-day oral regimens, respectively.

Vomiting occurred in 1.4% of adults with community-acquired pneumonia who received both IV and oral azithromycin therapy and in 6.7-9% of patients receiving oral azithromycin for prevention of disseminated M. avium complex infections.

Abdominal pain occurred in 3% of adults receiving the 5-day oral regimen, 1.9-2.% of those receiving a regimen that included both IV and oral azithromycin, 5% of those receiving a single 1-g oral dose, 7% of those receiving a single 2-g oral dose, and 27-32.% of patients receiving azithromycin for prevention of disseminated MAC infections.

Dyspepsia or flatulence occurred in 9 or up to 10.7% of patients receiving azithromycin for prevention of disseminated MAC infections; anorexia was reported in 2.1% of these patients. Anorexia occurred in 1.9% of patients with pelvic inflammatory disease (PID) receiving initial therapy with IV azithromycin followed by oral therapy.

Dyspepsia, flatulence, melena, constipation, anorexia,mucositis, gastritis, oral candidiasis, pseudomembranous colitis, or vomiting/diarrhea rarely resulting in dehydration has been reported in 1% or less of patients receiving azithromycin for other infections and/or during postmarketing studies. Tongue discoloration has been reported rarely. Taste disturbance has occurred in about 1% of patients receiving azithromycin therapy.

The incidence rates, but not the types, of adverse effects in children receiving azithromycin multiple-dose regimens in clinical trials differed from those reported in adults. In children with otitis media, community-acquired pneumonia, or pharyngitis/tonsillitis receiving oral azithromycin in the recommended regimen, diarrhea/loose stools or nausea was reported in 2-6 or 1-2%, respectively.

While less than 2% of children receiving azithromycin for otitis media or community acquired pneumonia experienced vomiting, about 5% of those receiving the drug for pharyngitis/tonsillitis experienced this adverse effect. Abdominal pain has been reported in approximately 2-3% of azithromycin-treated children.

Dermatologic and Sensitivity Reactions

Serious allergic (i.e., angioedema, anaphylaxis, bronchospasm) and dermatologic (i.e., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis) reactions, sometimes resulting in death, have been reported rarely in patients receiving azithromycin. If allergic reactions occur, azithromycin should be discontinued and appropriate therapy initiated. (See Cautions: Precautions and Contraindications.) Allergic symptoms generally resolve following discontinuance of the drug and symptomatic treatment; however, allergic manifestations have reappeared following discontinuance of initial symptomatic therapy in some patients.

The manufacturer states that patients experiencing serious allergic reactions (i.e., anaphylaxis, angioedema, severe dermatologic reactions) require prolonged periods of observation and symptomatic therapy. The relationship between these prolonged allergic episodes and the long tissue half-life of azithromycin with subsequent prolonged exposure to antigen has not been determined. Rash, urticaria, pruritus, and photosensitivity have been reported in 1% or less of patients receiving a 5-day regimen of oral azithromycin. Rash or pruritus occurred in 1.9%, and urticaria in 1% or less of adults receiving a regimen that included both IV and oral azithromycin.

Pruritus or rash has been reported in up to 4 or 8%, respectively, of patients receiving azithromycin 1.2 g weekly for prevention of disseminated MAC infections.

Eczema has been reported rarely during azithromycin therapy.

Local Reactions

Approximately 12% of patients experienced an adverse effect related to IV infusion of azithromycin. Pain at the injection site or local inflammation occurred in 6.5 or 3.1%, respectively, of patients receiving IV azithromycin. The incidence and severity of these local reactions in patients receiving IV azithromycin in 250 mL of fluid (2 mg/mL) infused over 1 hour were essentially the same as those in patients receiving azithromycin in 500 mL of fluid (1 mg/mL) infused over 3 hours.

Hepatic Effects

Elevations in ALT (SGPT), AST (SGOT), or Gamma-glutamyltransferase (GGT, GGTP) have been reported in 1-2% of adults receiving oral azithromycin; elevations in serum alkaline phosphatase, lactic dehydrogenase (LDH), and/or total bilirubin concentration have been reported in less than 1% of such patients. In patients receiving a regimen that included both IV and oral azithromycin, elevations in ALT or AST were reported in 4-6%, elevations in serum alkaline phosphatase in less than 1%, and elevations in serum bilirubin or LDH concentration in 1-3% of patients.

Available follow-up data have revealed that liver function test abnormalities in patients receiving azithromycin therapy generally are reversible. However, azithromycin therapy was discontinued in clinical trials because of treatment-related liver enzyme abnormalities in at least 3 patients receiving a 5-day regimen of oral azithromycin and in less than 2% of patients receiving a regimen that included both IV and oral azithromycin. Elevations in ALT, AST, or serum alkaline phosphatase have been reported in 2-5% of patients receiving azithromycin (1. g weekly) for prevention of disseminated MAC infections.

Abnormal liver function, including cholestatic jaundice and hepatitis, and pancreatitis has been reported infrequently in clinical trials or during postmarketing studies with azithromycin. Hepatic necrosis and hepatic failure, sometimes resulting in death, have occurred rarely.

Renal and Genitourinary Effects

Elevation in serum potassium concentration has been reported in 1-2% of adults receiving azithromycin in clinical trials. Elevation in BUN, serum creatinine, or serum phosphate concentration has been reported in less than 1% of adults receiving oral azithromycin, while elevated serum creatinine concentration has been reported in 4-6% of patients receiving IV azithromycin.

Available follow-up data revealed that these elevations generally were reversible. Nephritis has been reported in 1% or less of adults receiving azithromycin in clinical studies. Interstitial nephritis and acute renal failure have been reported during postmarketing studies with the drug. Azithromycin was discontinued because of an unspecified renal function abnormality in at least one patient receiving the drug in clinical trials. Vaginitis has been reported in about 1-2.8% of women receiving azithromycin; candidiasis has been reported in 1% or less of adults receiving the drug.

Cardiovascular Effects

Palpitations, chest pain, edema hypotension, or syncope has been reported in 1% or less of patients receiving oral azithromycin. While not directly attributed to azithromycin therapy, arrhythmia (including ventricular tachycardia) has been reported in at least one patient receiving the drug. In one patient with a history of arrhythmia, torsades de pointes with subsequent myocardial infarction occurred following completion of azithromycin therapy.

Nervous System Effects

Adverse CNS effects reported in 1% or less of adults receiving azithromycin include dizziness, headache, vertigo, or somnolence, and those reported in 1% or less of children include headache, hyperkinesia, dizziness, agitation, nervousness, fatigue, malaise, and insomnia. Fatigue or malaise has been reported and has occurred in 2-4 or about 1%, respectively, of patients receiving azithromycin 1.2 g weekly. Seizures also have been reported during azithromycin therapy. Dizziness or headache has occurred in about 1-4% of patients receiving azithromycin (1. g weekly) for the prevention of disseminated MAC infections. Asthenia, aggressive reaction, anxiety, or paresthesia has been reported during postmarketing studies with azithromycin.

Hematologic Effects

Leukopenia, neutropenia, neutrophilia, or thrombocytopenia has been reported in less than 1% of adults receiving azithromycin, although a causal relationship to the drug has not been established. In studies in patients receiving azithromycin for prevention of disseminated MAC infections, a hemoglobin concentration less than 8 g/dL was reported in 2% of patients, platelet count less than 50,000/mm3 in 2%, leukocyte count less than 1000/mm3 in 3%, or neutrophil count less than 500/mm3 in 4%.

Otic Effects

While audiometric testing revealed no drug-related hearing abnormalities in a limited number of individuals receiving short-term therapy with oral azithromycin (1. g over 5 days or 1 g as a single dose), hearing loss has been reported in some patients receiving long-term high-dose azithromycin therapy (i.e., 500-600 mg daily for up to 9 months). In one study in HIV-infected adults evaluating azithromycin (600 mg daily) in conjunction with ethambutol for the treatment of disseminated MAC infections, reversible hearing loss was reported in 5% of patients. Hearing loss generally develops within 1.5-20 weeks and generally resolves within 5 weeks following discontinuance of azithromycin. Hearing loss, deafness, or tinnitus also has been reported during postmarketing studies.

Other Adverse Effects

Fever or conjunctivitis has been reported in 1% or less of children receiving azithromycin. In patients receiving azithromycin for the prevention of disseminated MAC infections, fever or arthralgia occurred in about 1-3% of patients; fever has been reported in 1% or less of patients receiving the drug for other indications. Arthralgia also has been reported during postmarketing studies with azithromycin. Hypothermia has occurred in a few patients receiving azithromycin. Increases in serum creatine kinase (CK, creatine phosphokinase, CPK) have occurred in 1-2% of patients receiving oral azithromycin, and increases in blood glucose concentration have been reported in less than 1% of patients. Hyponatremia and/or the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, has been reported rarely with azithromycin therapy; a causal relationship to the drug has not been established.

Effects on Phospholipids

Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. Such phospholipid accumulation has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, pancreas) in dogs at azithromycin doses approximately equivalent to twice the recommended adult human dose (on a mg/kg basis) and in rats at doses comparable to the recommended adult human dose.

Phospholipidosis also has been observed in the tissues of neonatal rats and dogs given azithromycin daily for 10-30 days; the extent of phospholipidosis observed in these neonates was similar to that observed in adult animals.

In neonatal rats or dogs given 30 or 10 mg/kg, respectively, of azithromycin, phospholipidosis was observed at a peak plasma azithromycin concentration of 1.3 mcg/mL (6 times greater than the peak plasma concentration of 0.216 mcg/mL observed in children receiving azithromycin 10 mg/kg) or 1.5 mcg/mL (7 times greater than the peak plasma concentration observed in children receiving azithromycin 10 mg/kg), respectively. On a mg/m2 basis, azithromycin 30 mg/kg in the rat (135 mg/m2) or 10 mg/kg in the dog (79 mg/m2) are approximately 0.4 or 0.6 times, respectively, the recommended pediatric dose for a child who weighs 25 kg.

Phospholipidosis in animals has been reversible upon discontinuance of azithromycin treatment, and the clinical importance, if any, of these findings in humans is not known. Ultramicroscopy revealed no azithromycin-related myelin figures (a sensitive indicator of phospholipidosis) in peripheral blood lymphocytes in a limited number of individuals treated for 5 days with oral azithromycin.

Precautions and Contraindications

Serious hypersensitivity reactions, including angioedema and anaphylaxis, have occurred rarely in patients receiving azithromycin. Patients should be advised to discontinue azithromycin therapy immediately and to contact their clinician if any signs of an allergic reaction occur.

Severe acute hypersensitivity reactions should be treated with appropriate therapy (e.g., epinephrine, maintenance of an adequate airway, oxygen, IV fluids, maintenance of blood pressure as indicated). In addition, clinicians should be aware that allergic symptoms associated with azithromycin therapy may reappear following discontinuance of initial symptomatic therapy and that patients may require prolonged observation and therapy.

The manufacturer warns that oral azithromycin should not be used for the treatment of pneumonia that is considered unsuitable for outpatient oral therapy because of the severity of the infection (e.g., moderate to severe) or when risk factors such as nosocomially acquired infection, known or suspected bacteremia, cystic fibrosis, or any clinically important underlying health problem that might compromise the patient’s ability to respond adequately (e.g., immunodeficiency, functional asplenia) are present. In addition, the manufacturer warns that the drug should not be used for the treatment of pneumonia in patients requiring hospitalization or in geriatric or debilitated patients. Because azithromycin is eliminated principally via the liver, the drug should be used with caution in patients with impaired hepatic function.

Azithromycin has not been systematically evaluated in patients with renal impairment; therefore, the drug should be used with caution in such patients.

Although not reported in patients receiving azithromycin in clinical trials, ventricular arrhythmias, including ventricular tachycardia and atypical ventricular tachycardia (torsade de pointes), have been reported rarely with erythromycin therapy in patients with prolonged QT intervals.

During postmarketing studies, torsades de pointes with subsequent myocardial infarction occurred following a course of azithromycin therapy in a patient with a history of arrhythmias. As with other anti-infective agents, use of azithromycin may result in overgrowth of nonsusceptible bacteria or fungi. If superinfection occurs, appropriate therapy should be instituted.

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 appropriate bacteriologic and toxin studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary. 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. Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any other macrolide antibiotic (e.g., clarithromycin, dirithromycin).

Pediatric Precautions

The manufacturer states that safety and efficacy of oral azithromycin in infants younger than 6 months of age with acute otitis media or community-acquired pneumonia (CAP) have not been established. While safety and efficacy of oral azithromycin in infants and children with CAP caused by Chlamydia pneumoniae or Mycoplasma pneumoniae were documented bacteriologically in pediatric studies, similar documentation of safety and efficacy is not available for infections caused by Haemophilus influenzae or Streptococcus pneumoniae because of difficulty in obtaining specimens.

However, the manufacturer states that use of oral azithromycin in pediatric patients with CAP caused by H. influenzae or S. pneumoniae is supported by evidence from adequate, controlled studies in adults.

The manufacturer states that safety and efficacy of azithromycin in children younger than 2 years of age with pharyngitis/tonsillitis have not been established. Safety and efficacy of oral azithromycin for the treatment or prevention of Mycobacterium avium complex (MAC) infection in children with human immunodeficiency virus (HIV) infection have not been established. Safety data are available for 72 children 5 months to 18 years of age (mean: 7 years) who received azithromycin for the treatment of opportunistic infections; the mean duration of therapy was 242 days (range: 3-2004 days) and the mean dosage was 12 mg/kg daily (range: from less than 1 to 52 mg/kg daily). Adverse effects were similar to those reported in adults and most involved the GI tract.

Treatment-related reversible hearing impairment was reported in 4 children. Azithromycin was discontinued prematurely in 2 children because of adverse effects (back pain or abdominal pain, hot and cold flushes, dizziness, headache, and numbness) and in one child because of eosinophilia. Safety and efficacy of IV azithromycin in children or adolescents younger than 16 years of age have not been established.

Geriatric Precautions

When a 5-day oral azithromycin regimen is used, clinically important differences in the pharmacokinetic profile the drug have not been observed in studies in healthy geriatric individuals (65-85 years of age) compared with younger adults (18-40 years of age). Although azithromycin peak plasma concentrations appear to be higher in geriatric women (but not geriatric men) compared with younger adults, accumulation of the drug has not been reported in these women. Therefore, dosage adjustment on the basis of age in geriatric patients receiving oral azithromycin therapy generally is not required.

Safety data are available regarding use of azithromycin for the treatment of a variety of opportunistic infections, including MAC, in 30 geriatric patients (65-94 years of age) who received the drug in dosages exceeding 300 mg daily for a mean of 207 days. Adverse effects reported in these geriatric patients generally were similar to those reported in younger adults, although these older patients had a higher incidence of adverse GI effects and reversible hearing impairment. The pharmacokinetic profile of IV azithromycin in geriatric patients has not been determined to date.

Mutagenicity and Carcinogenicity

Azithromycin was not mutagenic in several in vitro tests, including the mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. Long-term studies have not been performed to date to evaluate the carcinogenic potential of azithromycin.

Pregnancy, Fertitlity and Lactation

Reproduction studies in rats and mice using azithromycin dosages up to 200 mg/kg daily (approximately equivalent on a mg/m2 basis to 4 and 2 times, respectively, the human daily oral azithromycin dosage of 500 mg; to 2 or 1 times, respectively, the 1.2-g weekly dosage used for prevention of M. avium complex infection; or 3.3 or 1.7 times, respectively, the 600-mg daily oral dosage used for the treatment of M. avium complex) have not revealed evidence of harm to the fetus.

Preliminary data indicate that azithromycin may be safe and effective in the treatment of chlamydial infections in pregnant women; however, there are insufficient data to recommend routine use of the drug during pregnancy.(See Chlamydial Infections: Urogenital Chlamydial Infections, in Uses.) The US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) currently consider azithromycin to be the drug of choice for Mycobacterium avium complex (MAC) prophylaxis in HIV-infected pregnant women. (See Mycobacterium Avium Complex (MAC) infections: Prevention of Disseminated MAC Infection, in Uses.)

However, there are no adequate and controlled studies to date using azithromycin in pregnant women, and the drug should be used during pregnancy only when clearly needed. Reproductive studies with azithromycin have not revealed evidence of impaired fertility.

Azithromycin has been detected in human milk. The drug should be used with caution in nursing women.

Drug Interactions

Drugs Affecting Hepatic Microsomal Enzymes

Many drug interactions reported in clinical trials with macrolides (e.g., erythromycin, clarithromycin) have not been reported to date with azithromycin. While azithromycin appears to have no effect on the cytochrome P-450 (CYP) enzyme system and interactions mediated by this enzyme system would not be expected to occur, it should be kept in mind that azithromycin and other macrolides have similar pharmacologic effects and the possibility that similar drug interactions may occur cannot be ruled out.

The manufacturer recommends careful monitoring in patients receiving digoxin (for elevated serum digoxin concentrations), ergotamine or dihydroergotamine (for ergot toxicity characterized by severe peripheral vasospasm and dysesthesia), or drugs metabolized by CYP isoenzymes, including cyclosporine, hexobarbital, terfenadine (no longer commercially available in the US), or phenytoin (for elevated serum drug concentrations). While interactions with the above agents have not been reported with azithromycin, interactions have occurred with other macrolides.

Prolongation of QT interval and, rarely, serious cardiovascular effects, including ventricular arrhythmias and death, have been reported in patients receiving drugs that inhibit the cytochrome P-450 isoenzyme (e.g., clarithromycin) concomitantly with pimozide.

Macrolide antibiotics may inhibit metabolism of pimozide, resulting in increased plasma concentrations of unchanged drug. Because such alterations in pharmacokinetics of pimozide may be associated with prolongation of the QT and QTc interval, the manufacturer of pimozide states that concomitant administration of pimozide and azithromycin, clarithromycin, erythromycin, or dirithromycin is contraindicated. Unlike some macrolides (i.e., erythromycin, clarithromycin), azithromycin does not appear to alter the metabolism of terfenadine.

Concomitant administration of terfenadine (60 mg twice daily) and oral azithromycin (500 mg on day 1, then 250 mg daily for 4 days or 250 mg daily for 5 days) had no effect on the AUC of terfenadine carboxylate; unmetabolized terfenadine was not detected in patients receiving terfenadine and azithromycin.

Antacids

Administration of azithromycin 500 mg orally with an aluminum- and magnesium hydroxide-containing antacid resulted in a decreased rate of absorption of azithromycin as evidenced by 24% reduction in peak serum azithromycin concentrations; however, the extent of azithromycin absorption (AUC) was unaffected. Oral azithromycin should not be administered simultaneously with aluminum- or magnesium-containing antacids.

Antilipemic Agents

The manufacturer of azithromycin states that concomitant use of atorvastatin and azithromycin results in only a modest effect on the pharmacokinetics of the antilipemic agent and that dosage adjustments are not necessary when azithromycin and atorvastatin are used concomitantly. However, in a patient receiving long-term therapy with lovastatin, administration of oral azithromycin (250 mg daily for 5 days) appeared to precipitate rhabdomyolysis. Rhabdomyolysis has occurred rarely in patients receiving lovastatin, and some evidence suggests that concomitant administration of erythromycin may increase the risk of this adverse effect. While the mechanism of this interaction remains to be determined, the risk of drug-induced rhabdomyolysis should be considered in patients receiving azithromycin, erythromycin, or clarithromycin concomitantly with lovastatin or another hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitor.

Antiretroviral Agents

HIV Protease Inhibitors

Concomitant use of indinavir (800 mg 3 times daily for 5 days) and azithromycin (a single 1.2-g dose on day 5) in healthy adults had only a modest effect on the pharmacokinetics of the HIV protease inhibitor. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and indinavir are used concomitantly. In healthy adults receiving nelfinavir (750 mg 3 times daily), administration of a single 1.2-g oral dose of azithromycin at steady state resulted in a 15% decrease in the mean AUC0-8 of nelfinavir and its M8 metabolite, but peak plasma concentrations of nelfinavir and its M8 metabolite were not affected. However, concomitant use of these drugs increases the peak plasma concentration and area under the concentration-time curve (AUC) of azithromycin by about twofold. The manufacturer of azithromycin states that, although dosage adjustments are not necessary when azithromycin and nelfinavir are used concomitantly, patients should be closely monitored for azithromycin adverse effects (e.g., hepatic enzyme abnormalities, hearing impairment).

Nonnucleoside Reverse Transcriptase Inhibitors

Concomitant use of efavirenz (400 mg daily for 7 days) and azithromycin (a single 600-mg oral dose on day 7) in healthy adults had no effect on the pharmacokinetics of the antiretroviral agent; peak plasma concentrations of azithromycin were increased about 22% but the AUC was not affected. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin is used concomitantly with efavirenz.

Nucleoside Reverse Transcriptase Inhibitors

Concomitant use of zidovudine and azithromycin results in a modest effect on the pharmacokinetics of zidovudine, and the manufacturer of azithromycin states that dosage adjustments are not necessary when the drugs are used concomitantly. Concomitant use of oral azithromycin (600 or 1200 mg daily) and oral zidovudine (100 mg every 3 hours, 5 times daily) increased the mean peak plasma concentration, area under the plasma concentration-time curve (AUC), and clearance of zidovudine by 26, 10, and 38%, respectively; increased the mean AUC of phosphorylated zidovudine by 75%, and increased the peak plasma concentration and AUC for zidovudine glucuronide by less than 10%.

Limited data in HIV-infected individuals indicate that administration of azithromycin 1 g as a single weekly dose did not produce clinically important changes in plasma concentrations of zidovudine, its glucuronide metabolite, or azithromycin. In HIV-infected patients maintained on zidovudine (10 mg/kg daily), addition of azithromycin 1 g as a single weekly dose increased peak plasma zidovudine concentration and AUC by 25 and 13%, respectively, and increased the peak plasma concentration and AUC of zidovudine glucuronide by 16 and 8%, respectively. Concomitant administration of azithromycin (1. g daily for 14 days) and didanosine (200 mg every 12 hours) increased the peak plasma concentration and AUC of didanosine by 44 and 14%, respectively. However, these changes were not considered clinically important since similar variability in didanosine pharmacokinetic values occurred in control patients (i.e., patients receiving didanosine and placebo). The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and didanosine are used concomitantly.

Benzodiazepines

Concomitant use of azithromycin (500 mg on day 1, then 250 mg on day 2) and triazolam (0. mg on day 2) or concomitant use of azithromycin (500 mg daily for 3 days) and midazolam (15 mg on day 3) does not appreciably affect the pharmacokinetics of these benzodiazepines. Azithromycin does not appear to alter the effects of oral midazolam on psychomotor performance or subjective feelings of sedation. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and midazolam or triazolam are used concomitantly.

Carbamazepine

Limited data in healthy adults receiving carbamazepine (200 mg once daily for 2 days, then 200 mg twice daily) suggest that concomitant use of azithromycin (500 mg daily for 3 days) does not alter plasma carbamazepine or carbamazepine 10,-epoxide concentrations. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and carbamazepine are used concomitantly.

Cetirizine

Concomitant use of azithromycin and cetirizine has no appreciable effect on the pharmacokinetics of cetirizine and the manufacturer of azithromycin states that dosage adjustments are not necessary when the drugs are used concomitantly.

Cimetidine

Administration of cimetidine 800 mg 2 hours prior to azithromycin 500 mg had no effect on plasma azithromycin concentrations.

Co-trimoxazole

Concomitant use of co-trimoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole for 7 days) and azithromycin (a single 1.2-g dose on day 7) in healthy adults had only a modest effect on the pharmacokinetics of azithromycin or either component of co-trimoxazole. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and co-trimoxazole are used concomitantly.

Fluconazole

Concomitant use of a single 1.2-g oral dose of azithromycin and a single 800-mg oral dose of fluconazole in healthy adults did not affect the pharmacokinetics of the antifungal agent; although peak plasma concentrations of azithromycin were decreased by about 18%, the AUC and half-life were not affected. In addition, concomitant use of a single 1.2-g oral dose of azithromycin and a single 200-mg oral dose of fluconazole had only a modest effect on the pharmacokinetics of either drug. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and fluconazole are used concomitantly.

Rifabutin

Concomitant administration of azithromycin and rifabutin does not appear to affect the average serum concentrations of either drug. In one study, peak plasma concentrations on day 1 in individuals receiving azithromycin (500 mg on day 1, 250 mg daily on days 2-9) with rifabutin (300 mg daily for 10 days) were essentially the same as those in individuals receiving azithromycin alone; mean plasma concentrations for rifabutin one-half day after the last dose were the same as those obtained in individuals receiving rifabutin alone. In addition, plasma concentrations for both drugs obtained 5 days after the last dose were the same as those obtained in individuals receiving either drug alone. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and rifabutin are used concomitantly.

Sildenafil

Concomitant use of azithromycin and sildenafil has only a modest effect on the pharmacokinetics of sildenafil and the manufacturer of azithromycin states that dosage adjustments are not necessary when the drugs are used concomitantly.

Theophylline

While concurrent use of macrolides (e.g., erythromycin, clarithromycin) and theophylline has been associated with increases in serum theophylline concentrations, current evidence indicates that azithromycin does not induce or activate hepatic cytochrome P-450 (CYP) isoenzymes. The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and theophylline are used concomitantly. Administration of oral azithromycin for 5 days (500 mg on day 1, 250 mg daily on days 2-5) did not affect the plasma concentrations or pharmacokinetics of theophylline administered as a single IV dose. In addition, administration of this 5-day regimen of oral azithromycin reportedly did not affect theophylline plasma concentrations in patients receiving an extended-release theophylline formulation (300 mg twice daily for 15 days).

Warfarin

Limited data suggest that oral azithromycin (500 mg on day 1, then 250 mg daily for 4 days) does not affect prothrombin time response in individuals receiving concurrent oral warfarin sodium, although an increased international normalized ratio (INR) has been reported in one patient maintained on long-term warfarin therapy following completion of a 5-day course of oral azithromycin. The manufacturer states that prudent medical practice dictates careful monitoring of prothrombin time in all patients treated concurrently with azithromycin and warfarin. Concomitant use of warfarin and macrolides has been associated with increased anticoagulant effect in clinical practice.

Acute Toxcicity

Limited information is available on the acute toxicity of azithromycin. The acute lethal dose of the drug in humans is not known. The oral LD50 of azithromycin in mice or rats is 3000-4000 mg/kg. Mechanism of Action Azithromycin usually is bacteriostatic, although the drug may be bactericidal in high concentrations against selected organisms. Bactericidal activity has been observed in vitro against Streptococcus pyogenes, S. pneumoniae, and Haemophilus influenzae.

Azithromycin 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 azithromycin appears to be the same as that of the macrolides (i.e., erythromycin, clarithromycin, dirithromycin, troleandomycin), clindamycin, lincomycin, and chloramphenicol. The antimicrobial activity of azithromycin is reduced at low pH. Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts. (See Pharmacokinetics: Distribution.) Penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus, Legionella pneumophila, Chlamydia trachomatis, Salmonella typhi). Spectrum Azithromycin has an expanded spectrum of activity compared with erythromycin, clarithromycin, or dirithromycin.

Azithromycin is active in vitro against many gram-positive and gram-negative aerobic and anaerobic bacteria as well as Borrelia burgdorferi, Chlamydia pneumoniae, C. trachomatis, Mycoplasma pneumoniae, and Mycobacterium avium complex (MAC). Azithromycin generally is more active in vitro against gram-negative organisms than erythromycin or clarithromycin and has activity comparable to erythromycin against most gram-positive organisms. Azithromycin has in vitro microbiologic activity similar to clarithromycin or erythromycin against C. pneumoniae and M. pneumoniae, but clarithromycin is fourfold more active against MAC in vitro than azithromycin. Streptococci and staphylococci that are resistant to erythromycin usually are resistant to azithromycin and clarithromycin.

Azithromycin is not inactivated by b-lactamases produced by H. influenzae or M. catarrhalis. Azithromycin appears to have a postantibiotic inhibitory effect against susceptible gram-positive and gram-negative aerobic organisms. In in vitro studies, exposure of S. pyogenes, S. pneumoniae, or H. influenzae for 1-2 hours to azithromycin concentrations several times higher than the MIC for the organism resulted in a recovery period of about 3-4, 2.2-5, or 2.5-8 hours, respectively, after the drug was removed before the organism resumed growth.

In Vitro Susceptibility Testing

The in vitro activity of azithromycin is markedly affected by the pH of the microbiologic growth medium during incubation. Incubation in a carbon dioxide atmosphere will result in lowering of media pH (7. to 6.6 after 18 hours in 10% carbon dioxide) and an apparent reduction in in vitro susceptibility of gram-positive and gram-negative bacterial isolates to azithromycin. Thus, the initial pH of the growth medium should be 7.2-7.4, and the carbon dioxide content of the incubation atmosphere should be as low as practical.

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 azithromycin, 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 azithromycin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue drug 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 (e.g., urine) 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 azithromycin, 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 reliably demonstrated in clinical trials.

The disk diffusion and dilution techniques used to determine susceptibility of gram-positive and gram-negative bacterial isolates should not be used to test susceptibility of MAC isolates to azithromycin. Interpretive criteria for MAC isolates that would represent susceptibility or resistance to azithromycin have not been established. In addition, the clinical relevance of azithromycin in vitro susceptibility tests results for other mycobacteria, including M. tuberculosis, using any susceptibility testing method has not been determined.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to azithromycin, a disk containing 15 mcg of the drug should be used. When disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using NCCLS interpretive criteria, Staphylococcus with growth inhibition zones of 18 mm or greater are susceptible to azithromycin, 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 disk-diffusion susceptibility testing is performed according to NCCLS standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 12 mm or greater are considered susceptible to azithromycin. Because of limited data on resistant strains, NCCLS recommends that any Haemophilus isolate that appears to be nonsusceptible to azithromycin should be submitted to a reference laboratory for further testing. When the NCCLS standardized procedure for disk susceptibility testing of streptococci is performed using Mueller-Hinton agar (supplemented with 5% sheep blood), S. pneumoniae or other streptococci (b-hemolytic streptococci, viridans streptococci) with growth inhibition zones of 18 mm or greater are susceptible to azithromycin, those with zones of 14-17 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures, Staphylococcus with MICs of 2 mcg/mL or less are susceptible to azithromycin, and 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 NCCLS standardized procedure for broth dilution is performed using HTM, Haemophilus with MICs of 4 mcg/mL or less are considered susceptible to azithromycin. Because of limited data on resistant strains, any Haemophilus isolate that appears to be nonsusceptible to azithromycin should be submitted to a reference laboratory for further testing. When broth dilution susceptibility testing for streptococci 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 (b-hemolytic streptococci, viridans streptococci) with MICs of 0.5 mcg/mL or less are susceptible to azithromycin, those with MICs of 1 mcg/mL have intermediate susceptibility, and those with MICs of 2 mcg/mL or greater are resistant to the drug.

Gram-positive Aerobic Bacteria

Azithromycin is active in vitro and in vivo against Staphylococcus aureus, Streptococcus agalactiae, S. pneumoniae, and S. pyogenes. The MIC90 (minimum inhibitory concentration of the drug at which 90% of tested strains are inhibited) of azithromycin for erythromycin-susceptible S. aureus is 1 mcg/mL; the MIC90 for S. agalactiae is 0.12 to greater than 12 mcg/mL. The MIC90 of azithromycin for S. pneumoniae or S. pyogenes is 0.12-2 or 0.12-4, respectively. The MIC90 of azithromycin for groups C, F, or G streptococci and viridans streptococci is 0.12-0.25 mcg/mL. The MIC of azithromycin for most staphylococci and streptococci generally are similar to or twofold higher than those for erythromycin; azithromycin does not inhibit erythromycin-resistant isolates of these species. Methicillin-resistant staphylococci and coagulase-negative staphylococci (e.g., Staphylococcus epidermidis) generally are resistant both to azithromycin and erythromycin. Azithromycin is not active against enterococci (e.g., Enterococcus faecalis[formerly S. faecalis]). The MIC90 of azithromycin for Listeria monocytogenes is 2-4 mcg/mL.

Gram-negative Aerobic Bacteria

Azithromycin is twofold to eightfold more active than erythromycin against erythromycin-susceptible gram-negative organisms. Azithromycin is active in vitro and in vivo against Haemophilus influenzae, H. ducreyi, Moraxella (Branhamella) catarrhalis, Legionella pneumophila, and Neisseria gonorrhoeae. Azithromycin is not inactivated by b-lactamases produced by H. influenzae or M. catarrhalis. The MIC90 of azithromycin for H. influenzae or M. catarrhalis is 1 or 0.03-0.5 mcg/mL, respectively. The MIC90 of azithromycin for H. ducreyi is less than 0.125 mcg/mL. The MIC90 of azithromycin for L. pneumophila, N. gonorrhoeae, Bordetella pertussis, or Campylobacter jejuni ranges from 0.03-2 mcg/mL. Although azithromycin has demonstrated greater in vitro activity than erythromycin against Escherichia coli and species of Salmonella and Shigella, the importance of this activity in clinical infections caused by these organisms has not been established. Azithromycin and erythromycin are less active than clarithromycin against Helicobacter pylori (formerly C. pylori); the MIC90 of clarithromycin for H. pylori is 0.03 mcg/mL versus 0.25 mcg/mL for azithromycin or erythromycin.

Mycobacteria

Azithromycin has in vitro and in vivo activity against Mycobacterium avium complex (MAC) organisms. 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. Azithromycin has activity against phagocytized MAC organisms in mouse and human macrophage cell cultures and in the beige mouse infection model. MAC organisms resistant to clarithromycin also are resistant to azithromycin. M. tuberculosis, M. kansasii, M. scrofulaceum, M. chelonae, M. fortuitum and M. leprae are resistant to azithromycin.

Anaerobic Bacteria

Azithromycin has in vitro activity (i.e., MIC 90 of 2 mcg/mL or less) against Clostridium perfringens and Peptostreptococcus spp. Like erythromycin and clarithromycin, azithromycin is active in vitro against Propionibacterium acnes, with an MIC90 for this organism of 0.03 mcg/mL.

Azithromycin is active in vitro against most Prevotella (formerly Bacteroides) spp. associated with bacterial vaginosis. The MIC90 of azithromycin for P. bivia, P. disiens, P. melaninogenica, or Bacteroides ureolyticus is 2 mcg/mL or less. B. fragilis spp. generally are resistant to azithromycin.

Chlamydiae

Azithromycin is active in vitro and in vivo against Chlamydia pneumoniae and C. trachomatis. The MIC90 of azithromycin for C. pneumoniae is 0.25 mcg/mL and for C. trachomatis is 0.06-1 mcg/mL. The reported MIC of azithromycin for C. psittaci is 0.125 mcg/mL.

Mycoplasma

The MIC90 of azithromycin for Mycoplasma pneumoniae is 0.25 mcg/mL, and the MIC90 reported for Ureaplasma urealyticum is 0.5-4 mcg/mL. The activity of azithromycin against M. pneumoniae generally is comparable to that of erythromycin or clarithromycin, but azithromycin has less activity than clarithromycin against U. urealyticum. The MIC90 of azithromycin for M. hominisreportedly ranges from 4-32 mcg/mL.

Spirochetes

Azithromycin has exhibited in vitro and in vivo activity against Borrelia burgdorferi (the causative agent of Lyme disease). The MIC90 of azithromycin for B. burgdorferi is 0.015-0.03 mcg/mL. Azithromycin is active in vitro against Treponema pallidum; however, the safety and efficacy of azithromycin in treating infections caused by this organism have not been established.

Protozoa

Azithromycin has exhibited in vitro and in vivo activity against T. gondii. In addition, synergistic activity against Toxoplasma gondii has been reported in in vitro studies employing azithromycin with pyrimethamine. Limited data in animals indicate that azithromycin with either pyrimethamine or sulfadiazine produces enhanced anti-Toxoplasma activity (i.e., greater reduction in blood and organ parasite burden, lower incidence of relapse following discontinuation of therapy, reduced mortality rate) compared with administration of azithromycin, pyrimethamine, or sulfadiazine alone.

Azithromycin is active in vitro against Entamoeba histolytica. Resistance Resistance to macrolide antibiotics may be natural or acquired. Resistance to macrolide antibiotics may be related to decreased permeability of the cell envelope (e.g., Enterobacteriaceae, Pseudomonas spp., Acinetobacter spp.), plasmid-mediated active efflux of the antibiotic (e.g., Staphylococcus epidermidis), enzymatic inactivation of antibiotic by plasmid-mediated esterases or phosphotransferase (e.g., Enterobacteriaceae), chromosomal-mediated alteration of a single 50S ribosomal protein at the receptor site resulting in decreased macrolide binding affinity (e.g., Streptococcus pyogenes, some Campylobacter spp., Escherichia coli), or alteration of the 23S ribosomal RNA of the 50S ribosomal subunit by methylation of adenine resulting in decreased macrolide binding to the receptor site (e.g., Staphylococcus aureus, streptococci, enterococci, Campylobacter spp., Bacteroides fragilis, Clostridium perfringens, Listeria spp., Mycoplasma pneumoniae, Legionella spp.).

Resistance as a result of alteration of the 23S ribosomal RNA is referred to as MLSB phenotype, is usually mediated by plasmids or transposons, may be constitutive or induced, and generally results in resistance to other 14- and 15-membered macrolides. Azithromycin MIC values for S. pyogenes, Haemophilus influenzae, or Enterobacteriaceae associated with exposure to sublethal concentrations of the drug in vitro increased by less than one dilution. In addition, emergence of resistance (i.e., increase in MIC values by greater than one dilution) to azithromycin was not observed in in vivo studies in animals employing S. aureus and E. coli. In 1999, Neisseria gonorrhoeae with reduced susceptibility to azithromycin were isolated from a cluster of 12 men with gonorrhea in Kansas City, MO.

These isolates had a median MIC of azithromycin of 2mcg/mL (range: 1-4 mcg/mL) and also were resistant to tetracycline (MIC 1-2 mcg/mL); however, they were susceptible to ceftriaxone, cefixime, spectinomycin, ciprofloxacin, and penicillin.

Resistance in Mycobacteria Macrolide-resistant

Mycobacterium avium complex (MAC) isolates have been detected in patients with disseminated MAC infections receiving macrolide (i.e., azithromycin, clarithromycin) therapy. In studies evaluating prevention of disseminated MAC disease, drug-resistant isolates were detected in 29-58% of individuals in whom disease developed while receiving clarithromycin and 11% of those receiving azithromycin. Although the mechanism(s) of resistance or reduced susceptibility of MAC to clarithromycin or azithromycin has not been fully determined to date, base substitution within domain V (the peptidyl transferase region) of the 23S ribosomal RNA gene, resulting in a residue change from adenine to cytosine, guanine, or thymine at position 2274, appears to be the principal mechanism in individuals receiving such therapy. Limited evidence indicates that these changes in the peptidyl transferase loop result in a conformational change in the ribosome at the macrolide binding site.

Cross-resistance

Streptococci and staphylococci that are resistant to erythromycin also are resistant to azithromycin and clarithromycin. MAC isolates resistant to azithromycin also are resistant to clarithromycin and complete cross-resistance occurs between these anti-infectives for this organism. Cross-resistance in these isolates appears to be the result of a single point mutation at the position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene.

MAC isolates exhibiting cross-resistance generally have an increase in azithromycin MICs to 128 mcg/mL or greater or clarithromycin MICs to 32 mcg/mL or greater (determined using a radiometric broth dilution susceptibility test with Middlebrook 7H12 medium). Although the clinical importance of cross-resistance between azithromycin and clarithromycin is not fully understood, preclinical data suggest that reduced activity to both drugs will occur after MAC isolates produce the 23S rRNA mutation.

Pharmacokinetics

The pharmacokinetic profile of azithromycin is characterized by low plasma drug concentrations but high and persistent tissue concentrations. Although plasma drug concentrations are the traditional predictors of antibiotic activity, the pharmacokinetic characteristics of azithromycin suggest that tissue concentrations may be a more relevant parameter for this drug.

Absorption

Azithromycin is rapidly absorbed from the GI tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. The absolute oral bioavailability of azithromycin is reported to be approximately 34-52% with single doses of 500 mg to 1.2 g administered as various oral dosage forms (e.g., capsules [no longer commercially available in the US], tablets, oral suspension).

Limited evidence indicates that the low bioavailability of azithromycin results from incomplete GI absorption rather than acid degradation of the drug or extensive first-pass metabolism. Studies evaluating the bioequivalence of oral preparations of azithromycin indicate that peak plasma concentrations and times to peak concentration are similar following administration of 1 g of the drug as a suspension or as four 250-mg capsules (no longer commercially available in the US). Limited data also indicate similar pharmacokinetic parameters for azithromycin capsules and tablets.

Following oral administration of azithromycin 500 mg as two 250-mg capsules or tablets in fasting healthy men, peak plasma azithromycin concentrations averaged 0.5 mcg/mL at about 2 hours; extent of absorption (AUC0-72) also was similar. Presence of food in the GI tract may affect the extent of absorption of oral azithromycin; however, the effect of food on absorption depends on the dosage form administered.

When azithromycin was administered as capsules with food to healthy men, peak plasma drug concentration and area under the plasma concentration-time curve (AUC) were reduced by 52 and 43%, respectively. Food does not have a substantial effect on the extent of absorption (AUC) of azithromycin tablets or suspension in adults, although the rate of absorption (as indicated by peak plasma concentrations of the drug) may be increased. In healthy men receiving a single 500-mg dose of azithromycin as the oral suspension with food, peak plasma drug concentration increased by 46% and AUC increased by 14% compared with administration in the fasting state. In another study in healthy men receiving azithromycin oral suspension, peak plasma drug concentration increased by 56% when the suspension was administered with food compared with fasting administration, but food did not affect extent of absorption (AUC).

Compared with fasting administration, single-dose administration of azithromycin as two 250-mg tablets with a high-fat meal or as two 600-mg tablets with food was associated with a 23 or 31% increase in peak plasma drug concentrations, respectively, but no change in AUC. Food-associated increases in azithromycin plasma concentration reportedly are short-lived, persisting for less than 4 hours.

After oral administration of a single 500-mg dose of azithromycin (as two 250-mg capsules on day 1 followed by 250 mg daily for the next 4 days in fasting healthy adults 18-40 years of age, peak plasma azithromycin concentrations on days 1 and 5 averaged 0.41 and 0.24 mcg/mL, respectively, at 2.5-3. hours. With this dosage regimen, peak and trough plasma azithromycin concentrations remained essentially unchanged from day 2 through day 5; trough concentrations averaged 0.05 mcg/mL. In this study, the disposition of azithromycin in these men and women was similar.

In healthy and asymptomatic HIV-infected adults receiving 1.2 g of azithromycin as two 600-mg tablets, peak plasma drug concentrations averaged 0.66 mcg/mL at 2.5 hours; plasma concentrations averaged 0.074 mcg/mL 24 hours after administration. In asymptomatic HIV-infected adults receiving a single 600-mg tablet of azithromycin once daily for 22 days, steady-state serum azithromycin concentrations were achieved on day 15. In fasting children 6-15 years of age, administration of azithromycin oral suspension 10 mg/kg as a single dose on day 1 followed by 5 mg/kg daily for the next 4 days produced peak plasma drug concentrations on day 5 averaging 0.383 mcg/mL at 2.4 hours.

Administration of this dosage regimen in fasting children 7.5 months to 5 years of age produced peak plasma azithromycin concentrations on day 5 averaging 0.216-0. mcg/mL at 1.8-1. hours. In fasting children 4 months to 15 years of age, administration of azithromycin 12 mg/kg as a single dose or in multiple daily doses for up to 5 days produced peak plasma drug concentrations averaging 0.318 mcg/mL at 2.4 hours after the dose. In healthy geriatric men 65-85 years of age who received azithromycin 500 mg as a single oral dose on day 1 followed by 250 mg daily for the next 4 days, pharmacokinetic parameters for azithromycin were similar to those in young adults; peak plasma drug concentrations in geriatric women 60-85 years of age reportedly were 30-50% higher than those in younger adults, although substantial accumulation of azithromycin was not reported.

Pharmacokinetic values for azithromycin following IV administration in patients with community-acquired pneumonia are similar to those in healthy individuals. Following IV infusion of azithromycin 500 mg over 1 hour daily for 2-5 days in patients with community-acquired pneumonia, peak and trough plasma concentrations of azithromycin averaged 3.63 and 0.2 mcg/mL, respectively. In healthy individuals receiving azithromycin 500 mg by IV infusion over 3 hours daily for 5 days, peak and trough plasma concentrations of azithromycin averaged 1.14 and 0.18 mcg/mL, respectively.

Compared with values following a single 500-mg IV dose, accumulation of azithromycin occurs when the same dose is given IV daily for 5 days as evidenced by an 8% increase in peak plasma concentration, and a 61% increase in AUC0-24. Azithromycin plasma concentrations following IV administration of a single 500-mg dose of the drug are substantially higher than those following oral administration of the same dose. In healthy individuals receiving a single 500-mg oral dose of azithromycin, peak plasma concentration, trough concentration, and AUC were 38, 83, and 52% of the values in individuals receiving azithromycin 500 mg IV over 3 hours.

Distribution

Azithromycin appears to be distributed into most body tissues and fluids after oral or IV administration. The extensive tissue uptake of azithromycin has been attributed to cellular uptake of this basic antibiotic into relatively acidic lysosomes as a result of ion trapping and to an energy-dependent pathway associated with the nucleoside transport system. Results from in vitro studies demonstrate that azithromycin is rapidly concentrated within cells; intracellular to extracellular drug concentration ratios exceed 30 after 1 hour, and ratios of up to 200 have been reported after 24 hours.

Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts, as demonstrated by in vitro incubation techniques. Because azithromycin is released more slowly from phagocytes than is erythromycin, substantial azithromycin concentrations are maintained for prolonged periods within these cells. In asymptomatic HIV-infected adults receiving a single 600-mg tablet of azithromycin once daily, mean peak azithromycin concentrations in peripheral leukocytes was 252 mcg/mL and steady-state trough concentrations in peripheral leukocytes averaged 146 mcg/mL; the mean ratio of peak leukocyte to peak serum concentrations was 456 and the mean AUC ratio was 816.

Following oral administration of azithromycin 1.2 g (as two 600-mg tablets), drug concentrations in peripheral leukocytes averaged 140 mcg/mL; azithromycin concentrations in these leukocytes exceeded 32 mcg/mL for about 60 hours following administration. While the clinical importance has not been determined, leukocyte to peak plasma concentrations ratio averaged 258 or 175 in men or women, respectively, and the AUC ratios averaged 804 or 541, respectively. The concentration of azithromycin achieved within phagocytes substantially exceeds that of other antimicrobial agents, including erythromycin.

In human polymorphonuclear leukocytes exposed in vitro to azithromycin or erythromycin for 24 hours, intracellular azithromycin concentrations were tenfold higher than those of erythromycin. In addition to direct tissue uptake, it has been suggested that uptake and release of azithromycin by phagocytic cells contribute to distribution of the drug into inflamed and infected tissues.

Spontaneous release of azithromycin from fibroblasts and phagocytes occurs gradually; however, release of the drug from phagocytes may be enhanced by exposure of the cell membrane to bacteria. Although release of azithromycin from fibroblasts is not enhanced by cell membrane exposure to pathogens, fibroblasts may act as drug reservoirs, releasing the drug to phagocytes for subsequent transport to the site of inflammation or infection.

The presence of azithromycin within phagocytes does not appear to have clinically important effects on phagocytic function. Because of rapid distribution into tissues and high intracellular concentrations of azithromycin, tissue concentrations of the drug generally exceed plasma concentrations by 10- to 100-fold following single-dose administration; with multiple dosing, the tissue-to-plasma ratio increases. While extensive distribution of the drug to tissues may be relevant to clinical activity, a quantitative relationship between high tissue concentration and clinical efficacy has not been established. The antimicrobial activity of azithromycin is pH related (i.e., only un-ionized azithromycin has antimicrobial activity).

Because lysosomes have a low intraorganelle pH, a substantial portion of azithromycin within the lysosome is ionized (and therefore inactive) drug. Administration of a single 500-mg oral dose of azithromycin generally produces drug concentrations of 1-9 mcg/g in various tissues, including lung, gastric, prostatic, and gynecologic tissue. Following administration of azithromycin as a single oral 500-mg dose, azithromycin concentrations in sputum averaged 1 or 2.9 mcg/g at 2-4 or 10-12 hours, respectively, and concentrations in lung tissue averaged 4 mcg/g at 73 hours.

Following administration of azithromycin 500 mg as a single oral dose in patients with pulmonary infections, peak drug concentrations in sputum, bronchial mucosa, and alveolar macrophages averaged 1.56, 3.48, and 23 mcg/mL, respectively, at 48 hours. Following oral administration of azithromycin 250 mg every 12 hours for 2 doses, drug concentration in tonsillar tissue 9-18 or 180 hours after the second dose averaged 4.5 or 0.9 mcg/g, respectively.

While azithromycin concentrations in sinus fluid averaged 1.34 mcg/mL on day 2 and 2.33 mcg/mL on day 6 in patients with acute sinusitis receiving oral azithromycin therapy (i.e., 500 mg on day 1 followed by 250 mg daily for 4 days), drug concentrations in patients with chronic sinusitis receiving this regimen averaged 0.25 and 0.38 mcg/mL on days 2 and 6, respectively, suggesting greater drug delivery to acutely inflamed tissue. Following administration of azithromycin 500 mg as a single oral dose in patients undergoing gastric resection, drug concentrations in gastric tissue averaged approximately 4 mcg/g within 24 hours and persisted for 96 hours.

Azithromycin concentrations in gastric mucosa averaged 0.5 mcg/mL within 24 hours and persisted for 120 hours, while peak drug concentrations of 0.2 mcg/mL in gastric juice were achieved within 73-93 hours. In patients undergoing prostatectomy who received oral azithromycin 250 mg every 12 hours for 2 doses, drug concentrations in prostatic tissue averaged 2.54, 0.74, or 0.62 mcg/g at 14, 104-122, or 137 hours, respectively, following the second dose. In addition, azithromycin concentrations greater than 1 mcg/g were detected in liver, kidney, bladder wall, adrenal gland, bone, testicle, epididymis, and vas deferens.

Distribution of azithromycin into ejaculate also has been reported. Following administration of azithromycin 500 mg as a single oral dose, drug concentration in the uterine cervix averaged 2.8 mcg/g at 19 hours. In surgical patients receiving a single oral dose of azithromycin 500 mg, drug concentration in ovarian tissue, uterine tissue, and salpinx (fallopian tube) averaged 2.7, 3.5, and 3.3 mcg/g, respectively, at 17 hours.

In another study in surgical patients receiving a single 500-mg oral dose of azithromycin, drug concentrations in gynecologic tissue (i.e., uterus, uterine cervix, fallopian tube) averaged 1.44 or 0.78 mcg/g at 24 or 96 hours, respectively.

Following administration of azithromycin as a single 500-mg oral dose, azithromycin concentrations in skin averaged 0.4 mcg/g at 73 hours. Only very low concentrations of azithromycin (less than 0.01 mcg/mL) have been detected in CSF in the presence of noninflamed meninges. While tissue levels have not been evaluated following IV administration of azithromycin, extensive tissue uptake would be expected to occur following IV administration of the drug. The serum protein binding of azithromycin decreases with increasing drug concentration over a concentration range of 0.02-2 mcg/mL.

Azithromycin is 51% bound to plasma proteins at drug concentrations of 0.02 mcg/mL and 7% bound at drug concentrations of 2 mcg/mL. In children 1.6-7.5 years of age receiving oral azithromycin 10 mg/kg daily for 3 days, drug concentrations in tonsillar tissue averaged 10..21, 9.3, or 1.49 mg/kg at 1, 2, 4, or 8 days, respectively, after the third dose. In children 1-6 years of age with secretory otitis media who were undergoing insertion of tympanotomy tubes, azithromycin concentrations in ear effusion averaged 1.02, 3.97, or 1.42 mcg/mL at 12, 24, or 48 hours, respectively, following administration of a single oral dose of 10 mg/kg. In children 1-8 years of age with acute otitis media, administration of azithromycin 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5 resulted in azithromycin concentrations in middle ear effusion averaging 8.61 or 9.43 mcg/mL on day 2 or 3, respectively.

Elimination

Plasma azithromycin concentrations following a single 500-mg oral or IV dose decline in a polyphasic manner with a terminal elimination half-life averaging 68 hours. The high values for apparent steady-state volume of distribution (31.-33. L/kg) and plasma clearance (630 mL/minute, 10. mL/minute per kg) of azithromycin suggest that the prolonged half-life is related to extensive uptake and subsequent release of the drug from tissues.

The average tissue half-life of azithromycin is estimated to be 1-4 days. The half-life of the drug in peripheral leukocytes ranges from 34-57 hours. The recommended azithromycin oral dosing regimen (1. g over 5 days) produces drug concentrations in excess of the MIC90 for many pathogens at tissue sites of infection for 5 days or longer following completion of therapy. An elimination half-life of 54. hours has been reported in children 4 months to 15 years of age receiving single or multiple oral doses of azithromycin. Azithromycin is excreted in feces principally as unchanged drug.

The principal route of biotransformation involves N-demethylation of the desosamine sugar or at the 9a position on the macrolide ring. Other metabolic pathways include O-demethylation and hydrolysis and/or hydroxylation of the cladinose and desosamine sugar moieties and the macrolide ring. Up to 10 metabolites of azithromycin have been identified, and all are microbiologically inactive.

While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex formation does not occur. In contrast to erythromycin, azithromycin does not inhibit its own metabolism via this pathway.

Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination following oral administration. Although the high biliary concentrations of azithromycin relative to serum concentrations suggest biliary excretion as an important route of elimination, transintestinal excretion may be the principal route of excretion for unchanged azithromycin.

Only a small portion of each azithromycin dose is excreted in urine.

While approximately 6% of a 500-mg oral dose of azithromycin appears in urine as unchanged drug over a 1-week period, 11% of a 500-mg IV dose was recovered over 24 hours on day 1, and 14% was recovered on day 5. The manufacturer states that azithromycin has not been systematically evaluated in patients with hepatic or renal impairment. In one study, the mean residence time of azithromycin was prolonged in patients with moderate hepatic dysfunction; however, AUC, volume of distribution, and total and renal clearance in patients with moderate hepatic disease were similar to those in healthy individuals. Limited data indicate that azithromycin pharmacokinetic values (i.e., peak plasma concentration, AUC, volume of distribution) following a single 1-g oral dose in patients with renal impairment are similar to those in individuals with normal renal function.

Chemistry and Stability

Chemistry

Azithromycin is a semisynthetic azalide antibiotic, a subclass of macrolide antibiotics. Azalides are distinguished from other macrolides by the addition of nitrogen at position 9a of the lactone ring. Azithromycin differs structurally from erythromycin by the addition of a methyl-substituted nitrogen atom at the 9a position of the macrolide ring. This structural modification in azithromycin results in resistance to acid degradation, improved tissue-penetration characteristics, improved activity against gram-negative organisms, and a prolonged elimination half-life compared with erythromycin.

Azithromycin is commercially available as the dihydrate; potency is calculated on the anhydrous basis. Azithromycin dihydrate occurs as a white crystalline powder and has solubilities of 39 mg/mL in water (pH 7.4) at 37°C. Azithromycin for injection is a sterile, lyophilized, white to off-white powder; each 500-mg vial of azithromycin for injection contains approximately 413. mg of citric acid and 198. mg of sodium hydroxide. Intact vials of azithromycin for injection contain a vacuum. Following reconstitution of azithromycin for injection with sterile water for injection, solutions containing 100 mg of azithromycin per mL are clear and colorless and have an a pH of 6.4-6.6.

Stability

Commercially available azithromycin 250-mg tablets should be stored at 15-30°C. Azithromycin 600-mg tablets and powder for multiple-dose oral suspension should be stored at temperatures below 30°C. Azithromycin powder in single-dose packets for oral suspension should be stored at 5-30°C. Following reconstitution as directed, the multiple-dose oral suspension of azithromycin should be stored in tight containers at 5-30°C; any unused suspension should be discarded after 10 days. Following reconstitution of azithromycin for oral suspension in single-dose packets, the entire contents should be ingested immediately.

Commercially available azithromycin for injection should be stored at or below 30°C. Following reconstitution with sterile water for injection, solutions containing 100 mg of azithromycin per mL are stable for 24 hours when stored below 30°C. Azithromycin is physically and chemically compatible with the following IV solutions: 0.45% or 0.9% sodium chloride, 5% dextrose, 5% dextrose and 0.3% or 0.45% sodium chloride, 5% dextrose and 0.45% sodium chloride with 20 mEq potassium chloride, 5% dextrose in lactated Ringer’s, lactated Ringer’s, Normosol®-M in 5% dextrose, and Normosol®-R in 5% dextrose.

Reconstituted solutions of azithromycin that have been further diluted with 250-500 mL of one of these IV solutions are physically and chemically stable for 24 hours when stored at or below room temperature (30°C) or for at least 7 days when refrigerated at 5°C.

Preparations

Azithromycin Oral For suspension 100 mg (of anhydrous Zithromax®, azithromycin) per 5 mL Pfizer 200 mg (of anhydrous Zithromax®, azithromycin) per 5 mL Pfizer 1 g (of anhydrous Zithromax® Single Dose Packets azithromycin) per packet , Pfizer Tablets, film- 250 mg (of anhydrous Zithromax®, (scored) coated azithromycin) Pfizer Zithromax® Z-Pak®, (scored; available as a 5-day mnemonic pack of 6 tablets) Pfizer 500 mg (of anhydrous Zithromax®, (scored) azithromycin) Pfizer Zithromax® Tri-Paks®, (scored; available as a 3-day mnemonic pack of 3 tablets) Pfizer 600 mg (of anhydrous Zithromax®, (scored) azithromycin) Pfizer Parenteral For injection, for 500 mg (of anhydrous Zithromax®, IV infusion only azithromycin) Pfizer