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azithromycin 250 mg tablet generic zithromax, zithromax z-pak

Out of Stock Manufacturer WOCKHARDT USA L 64679096105
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Uses

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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). Controlled and uncontrolled clinical studies in patients with community-acquired upper or lower respiratory tract infections suggest that 3-5 days of oral therapy with azithromycin generally is as effective as 7-10 days of oral therapy with other macrolides (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.(See Uses: Chlamydial Infections.) 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.)

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, and oral clarithromycin, have been used in the treatment of AOM. The American Academy of Pediatrics (AAP), Centers for Disease Control and Prevention (CDC), and other clinicians state that, despite the increasing prevalence of multidrug-resistant S. pneumoniae and presence of β-lactamase-producing H. influenzae or M. catarrhalis in many communities, amoxicillin remains the anti-infective of first choice when treatment of uncomplicated AOM is indicated since amoxicillin is highly effective, has a narrow spectrum of activity, is well distributed into middle ear fluid, and is well tolerated and inexpensive.

Azithromycin is not considered a first-line agent for treatment of AOM, but is recommended as an alternative, especially for individuals with type I penicillin hypersensitivity. 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 β-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; 14.3% 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.

Pharyngitis and Tonsillitis

Azithromycin is used orally for the treatment of pharyngitis and tonsillitis caused by Streptococcus pyogenes (group A β-hemolytic streptococci) in adults and children when first-line therapy (penicillins) cannot be used. 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 macrolides are common in some areas of the world (e.g., Italy, Japan, Korea, Finland, Spain, Taiwan) and azithromycin-resistant strains have been reported in the US.(See Resistance: Resistance in Gram-positive Bacteria.) Therefore, the manufacturer recommends that in vitro susceptibility tests be performed prior to use of azithromycin in patients with streptococcal pharyngitis.

Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is effective, the CDC, AAP, American Academy of Family Physicians (AAFP), Infectious Diseases Society of America (IDSA), American Heart Association (AHA), American College of Physicians (ACP), 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%).

GI Infections

Campylobacter Infections

Azithromycin has been used as a first-line agent for the treatment of symptomatic enteric infections caused by Campylobacter jejuni. The CDC, National Institutes of Health (NIH), IDSA, AAP, and other clinicians recommend oral erythromycin or azithromycin or fluoroquinolones (e.g., ciprofloxacin) for empiric treatment of these infections; tetracyclines (doxycycline) also can be used. However, increasing emergence of fluoroquinolone-resistant strains of Campylobacter should be considered when selecting a first-line agent.

When initiated early in the course of the Campylobacter infection, erythromycin or azithromycin shortens the duration of illness and prevents relapse. Either macrolide usually eradicates the organism from the stool within 2-3 days; however, a longer duration of treatment (5-7 days) is recommended for treatment of gastroenteritis.

Cryptosporidiosis

Azithromycin has been used in the treatment of cryptosporidiosis in HIV-infected adults, adolescents, or children. Oral azithromycin in conjunction with paromomycin was used with some success (i.e., reduction in oocyst excretion, improvement in diarrhea) in a limited number of patients with AIDS-related cryptosporidiosis. In addition, azithromycin monotherapy may have contributed to resolution of symptoms in a few HIV-infected children with cryptosporidiosis. However, no anti-infective has been found to reliably eradicate Cryptosporidium, although several drugs (e.g., paromomycin, azithromycin, nitazoxanide) may improve symptoms or suppress the infection.

HIV-infected individuals at greatest risk for cryptosporidiosis are those with advanced immunosuppression (i.e., CD4 T-cell counts less than 100/mm) and fulminant infections usually have occurred in those with CD4 T-cell counts less than 50/mm. The CDC, NIH, IDSA, and other clinicians state that the most appropriate treatment for cryptosporidiosis in HIV-infected individuals is the use of potent antiretroviral agents and symptomatic treatment of diarrhea. A highly potent antiretroviral regimen can result in immune restoration (CD4 T-cell counts exceeding 100/mm), which usually results in resolution of the infection. Symptomatic treatment of diarrhea in HIV-infected or immunocompetent individuals with cryptosporidiosis should include oral or IV fluids and electrolyte replacement to correct dehydration and nutritional supplementation when necessary; severe diarrhea may require intensive support. Adjunctive use of antimotility agents may be indicated, but these agents are not consistently effective and should be used with caution in young children.

Escherichia coli Infections

Azithromycin has been recommended for use in the treatment of GI infections caused by Escherichia coli.

Diarrhea caused by enterotoxigenic E. coli (ETEC) generally is of moderate severity and self-limited, but may be severe. Although anti-infectives are not usually indicated, the AAP, CDC, and others suggest that an anti-infective (e.g., azithromycin, co-trimoxazole, a fluoroquinolone, rifamycin) can be considered in addition to supportive care if diarrhea is severe or intractable and the causative organism is susceptible.

For the treatment of dysentery caused by enteroinvasive E. coli (EIEC), the AAP suggests than an oral anti-infective (e.g., azithromycin, ciprofloxacin, co-trimoxazole) can be used and, whenever possible, the anti-infective should be selected based on results of in vitro tests.

There is some evidence that azithromycin may shorten the course of diarrhea associated with enteroaggregative E. coli (EAEC) in adults and the drug has been recommended as a drug of choice for children with severe or persistent illness caused by this organism.

The role of anti-infectives in patients with hemorrhagic colitis caused by shiga toxin-producing E. coli (STEC; formerly known as enterohemorrhagic E. coli [EHEC] or verotoxin-producing E. coli) is unclear, and most experts do not recommend use of anti-infectives in the treatment of enteritis caused by E. coli 0157:H7 since there is no evidence of benefit from such therapy.

Shigella Infections

Azithromycin has been used in adults and children for the treatment of shigellosis caused by susceptible strains of Shigella dysenteriae, S. boydii, S. flexneri, or S. sonnei.

Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin) usually are considered the drugs of choice for the treatment of shigellosis; alternatives are azithromycin, ampicillin, ceftriaxone, or co-trimoxazole. Because of increasing resistance, the choice of anti-infective should be based on susceptibility patterns of locally circulating Shigella. In the US, about 50% of S. flexneri and S. sonnei isolates are resistant to ampicillin and co-trimoxazole.

Travelers' Diarrhea

Oral azithromycin is used as an alternative to fluoroquinolones for the treatment of travelers' diarrhea.

The most common cause of travelers' diarrhea worldwide is noninvasive enterotoxigenic strains of E. coli (ETEC), but travelers' diarrhea also can be caused by various other bacteria including enteroaggregative E. coli (EAEC), Campylobacter jejuni, Shigella, Salmonella, Aeromonas hydrophila, Plesiomonas shigelloides, Yersinia enterocolitica, Vibrio parahaemolyticus, or non-O-group 1 Vibrio cholerae. In some cases, travelers' diarrhea is caused by a parasitic enteric pathogen (e.g., Giardia duodenalis, Cryptosporidium parvum, Cyclospora cayetanensis, Entamoeba histolytica, Dientamoeba fragilis) or viral enteric pathogen (e.g., rotavirus, norovirus).

Countries where travelers are at low risk of travelers' diarrhea include the US, Canada, Australia, New Zealand, Japan, and countries in Northern and Western Europe. Travelers are at intermediate risk for travelers' diarrhea in Eastern Europe, South Africa, and some of the Caribbean islands, but are at high risk in Asia, the Middle East, Africa, and Central and South America.

Travelers' diarrhea usually is self-limited and may resolve within 3-4 days without anti-infective treatment. If diarrhea is moderate or severe, persists for longer than 3 days, or is associated with fever or bloody stools, short-term treatment (1-3 days) with an anti-infective may be indicated. A fluoroquinolone (e.g., ciprofloxacin, levofloxacin, norfloxacin, ofloxacin) generally is recommended when treatment, including self-treatment, of travelers' diarrhea is indicated in adults. Azithromycin can be used as a treatment alternative for individuals who should not receive fluoroquinolones (e.g., children, pregnant women) and may be a drug of choice for travelers in areas with a high prevalence of fluoroquinolone-resistant Campylobacter (e.g., Thailand, Nepal) or those who have not responded after 48 hours of fluoroquinolone treatment. Rifaximin is another alternative for the treatment of travelers' diarrhea caused by noninvasive E. coli. Bismuth subsalicylate or an antimotility agent may be used as an adjunct to anti-infective treatment to provide symptomatic relief; oral rehydration therapy should be used if indicated, especially in young children or geriatric adults. Travelers should consult a physician if diarrhea persists despite treatment.

Respiratory Tract Infections

Acute Sinusitis

Azithromycin is used in adults and children 6 months of age or older for the treatment of acute bacterial sinusitis caused by H. influenzae, M. catarrhalis, or S. pneumoniae.

In a randomized, controlled study in patients with acute bacterial sinusitis who received azithromycin (500 mg once daily for 3 days) or amoxicillin and clavulanate (500 mg of amoxicillin and 125 mg of clavulanate 3 times daily for 10 days), the clinical cure rate (modified intent-to-treat analysis) at day 10 was 88% in those who received azithromycin and 85% in those who received amoxicillin and clavulanate; the clinical cure rate at day 28 was 71.5% in both groups.

Safety and efficacy of a single-dose azithromycin regimen for the treatment of acute bacterial maxillary sinusitis were evaluated in a randomized, double-blind study in 270 adults. Patients were randomized to receive a single 2-g dose of azithromycin as an extended-release oral suspension (Zmax) or a 10-day regimen of oral levofloxacin (500 mg once daily). The clinical cure rate was 94.5% in those who received the single-dose azithromycin regimen and 92.9% in those who received the multiple-dose levofloxacin regimen. When patients were stratified according to causative organism, the single-dose azithromycin regimen cured 97.3% of infections caused by S. pneumoniae, 96.3% of those caused by H. influenzae, and 100% of those caused by M. catarrhalis.

Acute Bacterial Exacerbations of Chronic Obstructive Pulmonary Disease

Azithromycin is used orally for the treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) caused by Haemophilus influenzae, Streptococcus pneumoniae, or Moraxella 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) for treatment of acute bacterial exacerbations of COPD. 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 is used in adults for the treatment of acute bacterial exacerbations of COPD caused by H. influenzae, M. catarrhalis, or S. pneumoniae. In a randomized, double-blind, controlled study in patients with acute exacerbation of chronic bronchitis who received azithromycin (500 mg once daily for 3 days) or clarithromycin (500 mg twice daily for 10 days), the clinical cure rate (modified intent-to-treat analysis) at day 21-24 was 85% in those who received azithromycin and 82% in those who received clarithromycin. When results from patients who received azithromycin were stratified according to causative organism, the cure rate was 86% for those with H. influenzae infections and 91-92% for those with S. pneumoniae or M. catarrhalis infections.

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 Chlamydophila pneumoniae (formerly Chlamydia pneumoniae) in adults and children 6 months of age or older when 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-day regimen of oral cefaclor or clarithromycin. When an oral regimen is appropriate, a single-dose regimen of azithromycin given as an extended-release oral suspension (Zmax) can be used for the treatment of mild to moderate CAP caused by susceptible C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae.

Oral azithromycin should not be used in patients who have moderate to severe pneumonia or when there are risk factors that make oral therapy inappropriate (e.g., cystic fibrosis, nosocomial infection, known or suspected bacteremia, illness requiring hospitalization, geriatric or debilitated status, immunodeficiency or functional asplenia or other underlying conditions that may compromise ability to respond to treatment). Although azithromycin is highly distributed into tissues and phagocytes, some clinicians suggest that oral azithromycin is unsuitable for the treatment of CAP bacteremia or potentially resistant organisms (e.g., penicillin-resistant S. pneumoniae) may be involved 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 situations.

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 and local susceptibility patterns, but should be modified to provide more specific therapy (pathogen-directed therapy) 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. Macrolides should not be used alone for empiric treatment of CAP in hospitalized patients.

For empiric outpatient treatment of CAP in previously healthy adults without risk factors for drug-resistant S. pneumoniae (DRSP), IDSA and ATS recommend monotherapy with a macrolide (azithromycin, clarithromycin, erythromycin) or, alternatively, doxycycline. If risk factors for DRSP are present (e.g., chronic heart, lung, liver, or renal disease, diabetes mellitus, alcoholism, malignancy, asplenia, immunosuppression, history of anti-infective treatment within the last 3 months), IDSA and ATS recommend monotherapy with a fluoroquinolone with enhanced activity against S. pneumoniae (gemifloxacin, levofloxacin, moxifloxacin) or, alternatively, a combination regimen that includes a β-lactam active against S. pneumoniae (high-dose amoxicillin or fixed combination of amoxicillin and clavulanic acid or, alternatively, ceftriaxone, cefpodoxime, or cefuroxime) given in conjunction with a macrolide (azithromycin, clarithromycin, erythromycin) or doxycycline.

For empiric inpatient treatment of CAP when treatment in an intensive care unit (ICU) is not necessary, IDSA and ATS recommend adults receive monotherapy with a fluoroquinolone with enhanced activity against S. pneumoniae (gemifloxacin, levofloxacin, or moxifloxacin) or, alternatively, a combination regimen that includes a β-lactam (usually cefotaxime, ceftriaxone, or ampicillin) given in conjunction with a macrolide (azithromycin, clarithromycin, erythromycin) or doxycycline. For empiric inpatient treatment of CAP in ICU patients when Pseudomonas and oxacillin-resistant (methicillin-resistant) Staphylococcus aureus are not suspected, IDSA and ATS recommend a combination regimen that includes a β-lactam (cefotaxime, ceftriaxone, fixed combination of ampicillin and sulbactam) given in conjunction with either azithromycin or a fluoroquinolone (gemifloxacin, levofloxacin, moxifloxacin).

For empiric treatment of CAP in adults with risk factors for Ps. aeruginosa, IDSA and ATS recommend a combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (cefepime, imipenem, meropenem, fixed combination of piperacillin and tazobactam) and ciprofloxacin or levofloxacin; one of these β-lactams, an aminoglycoside, and azithromycin; or one of these β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.

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 (group B streptococci). 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.

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 clindamycin and quinine regimen may be preferred for severe babesiosis; in those with mild or moderate illness, the atovaquone and azithromycin regimen may be as effective and better tolerated than the quinine and clindamycin regimen. Use of exchange transfusions also should be considered in severely ill patients with high levels of parasitemia (at least 10%), substantial hemolysis, or compromised renal, hepatic, or pulmonary function.

Limited data in animals suggest that a regimen of azithromycin and quinine also may be effective in the management of babesiosis.

Bartonella Infections

Azithromycin has been used for the treatment of infections caused by Bartonella henselae (formerly Rochalimaea henselae) (e.g., cat scratch disease, bacillary angiomatosis, peliosis hepatitis). 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 azithromycin, ciprofloxacin, erythromycin, doxycycline, rifampin, co-trimoxazole, gentamicin, or third generation cephalosporins.

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, clarithromycin, or chloramphenicol. There is evidence that these infections tend to persist or recur and prolonged therapy (several months or longer) usually is necessary.

Chancroid

Azithromycin is used orally in the treatment of chancroid (genital ulcers caused by Haemophilus ducreyi).

The CDC and others state that a single oral dose of a conventional formulation 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 a conventional formulation 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 single-dose 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 ensured; some experts recommend that HIV-infected individuals with chancroid receive the 7-day erythromycin regimen.

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.

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. 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. Ideally, diagnostic evaluation of patients with genital ulcers should include a serologic test for syphilis and darkfield examination or direct immunofluorescence test for T. pallidum, culture for H. ducreyi, and culture or antigen test for HSV. A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that is not widely available. The presence of a painful ulcer and tender suppurative inguinal adenopathy suggests a diagnosis of chancroid. 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 based on a 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, and regional lymphadenopathy (if present) are typical for chancroid.

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 needle aspiration or incisional drainage may be necessary even during otherwise 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.

Chlamydial Infections

Urogenital Chlamydial Infections

Azithromycin is used orally for the treatment of urogenital infections caused by C. trachomatis.

Urogenital Chlamydial Infection in Adults and Adolescents

Azithromycin is used orally for the treatment of urethritis and cervicitis caused by C. trachomatis.

In the US, urogenital chlamydial infection is the most frequently reported infectious disease and these infections occur most frequently in individuals 25 years of age or younger. Urogenital C. trachomatis infection in women can result in serious sequelae, including pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. Asymptomatic infection is common, and some women with uncomplicated cervical infection already have subclinical upper reproductive tract infection. There is evidence that routine screening for chlamydial infection in women can reduce the prevalence of infection and rates of PID. Therefore, the CDC recommends annual screening of all sexually active women 25 years of age or younger and also recommends screening of older women who have risk factors for chlamydial infection (e.g., new or multiple sex partners). Although data are insufficient to date to recommend routine screening for C. trachomatis in sexually active young men, the CDC states that screening of such men should be considered in clinical settings with a high prevalence of chlamydial infection (e.g., adolescent clinics, correctional facilities, sexually transmitted disease clinics).

For the treatment of urogenital chlamydial infections in nonpregnant adults and adolescents, the CDC, AAP, and other clinicians recommend a single oral dose of a conventional formulation of 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 doxycycline is highly effective and experience with the drug 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 a conventional formulation of azithromycin is as effective as a 7-day course of doxycycline in the treatment of uncomplicated chlamydial genital infections.

The CDC, AAP, and others recommend that urogenital chlamydial infections in pregnant women be treated with a single-dose regimen of a conventional formulation of azithromycin or a 7-day regimen of oral amoxicillin. Alternative regimens recommended for these infections in pregnant women are a 7- or 14-day regimen of oral erythromycin base or ethylsuccinate. The CDC states that clinical experience and studies suggest that the single-dose azithromycin regimen is safe and effective, and some clinicians suggest that this is the regimen of choice for treatment of urogenital chlamydial infections in pregnant women.

Individuals with HIV infection who also are infected with chlamydia should receive the same treatment regimens recommended for other individuals with chlamydial infections.

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.

Urogenital Chlamydial Infection in Infants and Children

For the treatment of uncomplicated urogenital chlamydial infections in children 8 years of age and older, the CDC recommends a single-dose of a conventional formulation of azithromycin or a 7-day regimen of oral doxycycline. For children younger than 8 years of age, the CDC recommends that those weighing at least 45 kg receive a single-dose azithromycin regimen and that those weighing less than 45 kg receive a 14-day regimen of oral erythromycin base or ethylsuccinate. The AAP recommends that infants younger than 6 months of age with urogenital chlamydial infections receive an erythromycin regimen and that those 6 months to 12 years of age receive either azithromycin or erythromycin.

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 oral dose of 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. Nucleic acid amplification tests (NAAT) for C. trachomatis are highly sensitive and patients with a negative chlamydial NAAT result at the time of treatment for gonorrhea do not need to be treated for chlamydia. However, if test results are not available or if a test other than a NAAT was performed and was negative for chlamydia, patients should receive treatment for both gonorrhea and chlamydia.

Lymphogranuloma Venereum

Although some clinicians suggest that azithromycin may be effective for the treatment of lymphogranuloma venereum caused by invasive serotypes of C. trachomatis (serovars L1, L2, L3), safety and efficacy of the drug for this use have not been established. The CDC recommends a 21-day regimen of doxycycline as the treatment of choice and a 21-day regimen of erythromycin base as an alternative for the treatment of lymphogranuloma venereum. Although oral azithromycin also may be effective, the CDC states that clinical safety and efficacy data are lacking. Effective treatment cures the infection and prevents ongoing tissue damage, although tissue reaction can result in scarring. Aspiration of buboes through intact skin or incision and drainage may be necessary to prevent the formation of inguinal/femoral ulcerations.

The CDC recommends that individuals who had sexual contact with a lymphogranuloma venereum patient within 60 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated with a regimen usually recommended for the treatment of urogenital chlamydial infections (a single 1-g dose of azithromycin or 100 mg of doxycycline twice daily for 7 days).

While HIV-infected individuals with lymphogranuloma venereum should receive the same treatment regimens recommended for other patients, there is some evidence that HIV-infected patients may require more prolonged therapy and resolution may be delayed.

Chlamydial Pneumonia in Infants

Some clinicians recommend azithromycin for the treatment of chlamydial pneumonia in infants.

Trachoma and Other Ocular Chlamydial Infections

Some clinicians recommend azithromycin for the treatment of chlamydial conjunctivitis in neonates.

Azithromycin is used in the treatment of ocular trachoma caused by C. trachomatis and is considered a drug of choice for this infection. Azithromycin is recommended for use in mass treatment programs, usually as a single-dose regimen; however, the optimal number of doses required to minimize reservoirs of infection when mass treatment programs are undertaken in high-prevalence areas is unclear.

Other Chlamydial Infections

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.)

Although tetracyclines are the drugs of choice for the treatment of psittacosis caused by Chlamydophila psittaci (formerly Chlamydia psittaci), macrolides (erythromycin, azithromycin, clarithromycin) are possible alternatives in children younger than 8 years of age who should not receive tetracyclines.

Azithromycin has been used to treat adults with coronary artery disease (CAD) who have elevated anti-C. pneumoniae antibody titers (a possible risk factor for myocardial infarction [MI] or CAD) in an attempt to reduce recurrent ischemic events. In a randomized, placebo-controlled study in men who had survived an MI and who had elevated anti-C. pneumoniae antibody titers, 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 (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. However, these results were not confirmed in other studies. In a large study in stable patients with documented MI (at least 6 weeks previously) and serologic evidence of exposure to C. pneumoniae, those who received azithromycin (600 mg daily for 3 days then once weekly for 11 weeks) had a 7% (nonsignificant) reduction in the risk of the primary endpoint (death, MI, coronary revascularization procedure, hospitalization for angina) compared with placebo. Because efficacy has not been proven to date, use of azithromycin for prevention of recurrent CAD is not recommended.

Cholera

Azithromycin has been used in the treatment of cholera caused by Vibrio cholerae O1 or O139.

A tetracycline or, alternatively, a fluoroquinolone or co-trimoxazole generally is used for the treatment of cholera in conjunction with fluid and electrolyte replacement therapy. Although further study is needed, azithromycin may be an alternative, especially for treatment of cholera in children or infections caused by V. cholerae resistant to tetracyclines and fluoroquinolones.

Gonorrhea and Associated Infections

Azithromycin is used orally for the treatment of uncomplicated gonorrhea (i.e., urethritis and/or crevices) caused by susceptible N. gonorrhoeae.

The CDC and many clinicians currently recommend that uncomplicated gonorrhea in adults and adolescents be treated with a single IM dose of ceftriaxone or a single oral dose of cefixime 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). Although not recommended for routine use, the CDC and other clinicians state that the single 2-g azithromycin regimen of a conventional preparation can be used as an alternative for the treatment of uncomplicated gonorrhea when preferred drugs cannot be used (e.g., in patients hypersensitive to cephalosporins when spectinomycin is unavailable and desensitization to cephalosporins is not an option).

Limited data suggest that a single 2-g oral dose of a conventional formulation of azithromycin is as effective as a single 250-mg IM dose of ceftriaxone in the treatment of uncomplicated gonorrhea. However, the 2-g azithromycin regimen has been associated with a relatively high incidence of adverse GI effects and does not appear to offer any advantages over IM ceftriaxone for the treatment of uncomplicated gonorrhea.

Although a single 1-g oral dose of a conventional formulation of azithromycin also has been effective in some patients for the treatment of uncomplicated gonorrhea, this lower single-dose regimen has been associated with a substantial incidence of therapeutic failure in some studies. Therefore, the CDC does not recommend use of a 1-g single-dose azithromycin regimen.

The fact that N. gonorrhoeae with reduced susceptibility to azithromycin have been isolated in the US should be considered.(See Resistance: Resistance in Neisseria and Treponema.) Because of concerns related to emerging resistance to macrolides, the CDC recommends that azithromycin be used for the treatment of gonorrhea only when considered necessary.

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 Klebsiella granulomatis (formerly Calymmatobacterium granulomatis).

The CDC and AAP recommend that donovanosis be treated with a regimen of oral doxycycline or, alternatively, an oral regimen of azithromycin, ciprofloxacin, erythromycin, or co-trimoxazole. Anti-infective treatment of donovanosis should be continued until all lesions have healed completely; a minimum of 3 weeks of treatment usually is necessary. If lesions do not respond within the first few days of therapy, the CDC recommends that a parenteral aminoglycoside (e.g., 1 mg/kg of gentamicin IV every 8 hours) be added to the regimen. Anti-infective therapy appears to halt progressive destruction of tissue, although prolonged duration of therapy often is required to enable granulation and re-epithelization of ulcers. Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.

Individuals with HIV infection should receive the same treatment regimens recommended for other individuals with donovanosis; however, the CDC suggests that addition of a parenteral aminoglycoside to the regimen should be strongly considered in HIV-infected patients.

Any individual who had sexual contact with a patient with donovanosis should be examined and treated if they had sexual contact with the patient during the 60 days preceding the onset of symptoms in the patient and they have clinical signs and symptoms of the disease. The value of empiric therapy in the absence of clinical signs and symptoms has not been established.

Helicobacter pylori Infection and Duodenal Ulcer Disease

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, .

Legionella Infections

Oral or IV azithromycin is used for the treatment of Legionnaires' disease caused by Legionella pneumophila. Macrolides (usually azithromycin) or fluoroquinolones are considered the drugs of choice for the treatment of pneumonia caused by L. pneumophila; alternatives are doxycycline or co-trimoxazole. An oral regimen (e.g., azithromycin, clarithromycin, doxycycline, erythromycin, a fluoroquinolone) may be effective for patients with mild to moderate Legionnaires' disease. However, a parenteral regimen (e.g., azithromycin, a fluoroquinolone) 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 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.)

Leptospirosis

Azithromycin is considered an alternative for the treatment of leptospirosis caused by Leptospira. Penicillin G is the drug of choice for severe infections; tetracyclines (usually doxycycline) or ceftriaxone are recommended as alternatives for less severe infections. Azithromycin also has been effective.

Malaria

Although further study is needed, azithromycin has been used in conjunction with an antimalarial agent (e.g., chloroquine, quinine, artesunate [not commercially available in the US]) for the treatment of uncomplicated malaria caused by Plasmodium falciparum, including multidrug-resistant strains. Azithromycin should not be used alone as monotherapy for the treatment of malaria.

Although further study is needed, azithromycin has been used for the treatment or prevention of P. vivax malaria. When used for treatment of such infections, the rate of resolution of parasitemia reported for azithromycin was considerably slower than that reported for chloroquine.

Mycobacterium avium Complex (MAC) Infections

Primary Prevention of Disseminated MAC Infection

Oral azithromycin is used to prevent Mycobacterium avium complex (MAC) bacteremia and disseminated infections (primary prophylaxis) in adults, adolescents, and children with advanced HIV infection. Azithromycin and clarithromycin are the preferred drugs for primary prevention of disseminated MAC infections in adults, adolescents, and children.

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/mm) 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 as a conventional formulation was 10.9% 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/mm), prophylaxis with rifabutin (300 mg daily), azithromycin (1.2 g once weekly as a conventional formulation), or both drugs concomitantly was associated with a cumulative incidence of MAC infection at 1 year of 15.2, 7.6, 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 prior P. 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.

Primary prophylaxis against MAC disease is recommended for HIV-infected adults and adolescents (13 years of age or older) who have CD4 T-cell counts less than 50/mm. Severely immunocompromised HIV-infected children younger than 13 years of age also should 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/mm; children 2-6 years of age, less than 75 cells/mm; children 1-2 years of age, less than 500 cells/mm; and children less than 1 year of age, less than 750 cells/mm.

There is evidence that the combination of azithromycin and rifabutin is more effective than azithromycin alone for primary MAC prophylaxis; however, routine prophylaxis with the combination is not recommended 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/mm that has been sustained for at least 3 months. 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, primary MAC prophylaxis should be restarted in adults and adolescents if CD4 T-cell counts decrease to less than 50-100/mm. 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/mm. 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, azithromycin usually is considered 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 a multiple-drug regimen since monotherapy results in drug resistance and clinical failure.

Treatment and Prevention of Recurrence of Disseminated MAC Infection

Azithromycin is used as part of a multiple-drug regimen for the treatment of disseminated MAC infections and for prevention of recurrence (secondary prophylaxis or chronic maintenance therapy) of MAC infections in HIV-infected patients.

For the treatment of disseminated MAC infections in HIV-infected adults, adolescents, and children, the ATS, CDC, NIH, IDSA, and other clinicians recommend a regimen of clarithromycin (or azithromycin) and ethambutol and state that consideration may be given to adding a third drug (preferably rifabutin). Some clinicians state that clarithromycin is the preferred macrolide for the initial treatment regimen because of mo

Dosage and Administration

Reconstitution and Administration

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

Oral Administration

For oral administration, azithromycin is commercially available as conventional film-coated tablets, conventional powder for oral suspension, and extended-release microspheres for oral suspension.

The extended-release oral suspension is not bioequivalent to and is not interchangeable with conventional oral suspension or tablets.

Reconstituted conventional oral suspension containing 100 or 200 mg of azithromycin per 5 mL and reconstituted single-dose packets of conventional oral suspension containing 1 g of azithromycin can be taken with or without food.

Azithromycin conventional tablets can be taken with or without food; tolerability may be increased when tablets are taken with food.

Reconstituted conventional oral suspension containing 100 or 200 mg of azithromycin per 5 mL may be taken without regard to food. The safety of repeating a dose in children who vomit after receiving 30 mg/kg as a single dose has not been established. The single-dose 1-g packets should not be used to administer doses other than 1 g and are not for pediatric use.

Reconstituted extended-release oral suspension containing 2 g of azithromycin (Zmax) should be taken as a single dose on an empty stomach (at least 1 hour before or 2 hours after a meal). Patients should be advised to contact a clinician if they vomit within 1 hour of taking a dose of the extended-release oral suspension. If the patient vomits within 5 minutes of taking the 2-g dose of the extended-release oral suspension, additional anti-infective treatment should be considered because only minimal absorption of the drug would have occurred. If the patient vomits within 5-60 minutes after taking the dose, alternative treatment should be considered because data are insufficient regarding absorption of the drug under these circumstances. If a patient with normal gastric emptying vomits at least 60 minutes after taking the 2-g dose, additional azithromycin doses or alternative treatments are not required.

Although the single-dose extended-release oral suspension of azithromycin (Zmax) may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide, conventional oral azithromycin preparations (film-coated tablets, oral suspension) should not be taken simultaneously with aluminum- or magnesium-containing antacids.

Reconstitution

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.

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. The bottle should be kept tightly closed and should be shaken well before each use.

Azithromycin single-dose extended-release oral suspension (Zmax) should be reconstituted at the time of dispensing by adding 60 mL of water to the bottle labeled as containing 2 g of azithromycin. The reconstituted suspension should be shaken well at the time of dispensing and immediately prior to consumption; the entire contents of the bottle should be consumed as a single dose. The single-dose extended-release oral suspension is not for pediatric use.

IV Infusion

Azithromycin for IV infusion must be reconstituted and then further diluted prior to administration.

Other IV substances, additives, or other drugs should not be added to azithromycin IV infusions and should not be infused simultaneously through the same IV line.

Reconstitution and Dilution

For IV infusion, azithromycin for injection should be 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.

Prior to administration, azithromycin solutions 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.

Rate of Administration

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 at least 1 hour.

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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

Two 250-mg tablets of azithromycin are bioequivalent to one 500-mg tablet. The extended-release oral suspension is not bioequivalent to and is not interchangeable with the conventional oral suspension or tablets.

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 on days 2-5 (total cumulative dose: 1.5 g administered over 5 days).

Acute Sinusitis

For the treatment of acute sinusitis, the usual adult oral dosage of azithromycin tablets or conventional oral suspension is 500 mg once daily for 3 days.

If the extended-release oral suspension (Zmax) is used for the treatment of acute sinusitis, adults should receive a single 2-g dose.

Acute Exacerbations of Chronic Bronchitis

For the treatment of mild to moderate acute bacterial exacerbations of chronic bronchitis, the usual adult dosage of azithromycin is 500 mg once 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 on days 2-5 (total cumulative dose: 1.5 g administered over 5 days).

Community-acquired Pneumonia

For the treatment of mild to moderate community-acquired pneumonia (CAP) in adults, the usual dosage of azithromycin is 500 mg given as a single dose on the first day of therapy, followed by 250 mg once daily on days 2-5 (total cumulative dose: 1.5 g administered over 5 days).

If the extended-release oral suspension (Zmax) is used for the treatment of mild to moderate CAP, adults should receive a single 2-g dose.

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 7-10 days 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 on days 2-5 (total cumulative dose 1.5 g administered over 5 days).

Babesiosis

For the treatment of babesiosis caused by Babesia microti, the Infectious Diseases Society of America (IDSA) recommends an azithromycin dosage of 0.5-1 g once on day 1, then 250 mg once daily for a total of 7-10 days in conjunction with atovaquone (750 mg twice daily for 7-10 days). Higher azithromycin dosage (0.6-1 g daily) may be used in immunocompromised patients.

Other clinicians recommend that adults receive oral azithromycin in a dosage of 600 mg once daily for 7-10 days given in conjunction with atovaquone (750 mg twice daily for 7-10 days).

Bartonella Infections

If oral azithromycin is used for the treatment of cat scratch disease caused by Bartonella henselae in patients with extensive lymphadenopathy, some clinicians recommend an initial dose of 500 mg on day 1 followed by 250 mg once daily on days 2-5.

If oral azithromycin is used for the treatment of infections caused by Bartonella in HIV-infected adults and adolescents, the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and IDSA recommend a dosage of 600 mg once daily for at least 3 months. If relapse occurs, lifelong secondary prophylaxis (chronic maintenance therapy) with erythromycin or doxycycline should be considered.

Campylobacter Infections

If oral azithromycin is used for the treatment of mild to moderate infections caused by Campylobacter jejuni in adults and adolescents, the CDC, NIH, and IDSA recommend a dosage of 500 mg once daily for 7 days. If bacteremia is present, treatment should be continued for at least 2 weeks and use of a second anti-infective (e.g., an aminoglycoside) should be considered.

Chancroid

For the treatment of chancroid, the usual oral dosage of azithromycin in adults or adolescents is 1 g administered as a single dose of a conventional formulation.

Because data on the efficacy of the single-dose azithromycin regimen for treatment of chancroid in patients with HIV infection are limited, the CDC recommends that the single-dose regimen be used in HIV-infected patients only if follow-up can be ensured.(See Uses: Chancroid.)

Chlamydial Infections

For the treatment of uncomplicated chlamydial infections, including nongonococcal urethritis or cervicitis, the usual oral dosage of azithromycin for adults or adolescents is 1 g administered as a single dose of a conventional formulation. 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.

For the treatment of recurrent or persistent urethritis, the CDC recommends a single 1-g dose of azithromycin in conjunction with a single 2-g dose of oral metronidazole or tinidazole.

For the treatment of ocular trachoma, the usual dosage of azithromycin for adults is 20 mg/kg (up to 1 g) given as a single dose. Alternatively, a dosage of 1 g once weekly for 3 weeks has been used. The single-dose regimen has been used in mass treatment programs; however, multiple doses (e.g., once yearly for 3 years) may be necessary to minimize reservoirs of infection in high-prevalence areas.

Cholera

For the treatment of cholera caused by Vibrio cholerae O1 or O139, adults have received oral azithromycin in a dosage of 1 g given as a single dose.

Cryptosporidiosis

For the symptomatic treatment of cryptosporidiosis in HIV-infected adults and adolescents, oral azithromycin has been given in a dosage of 600 mg once daily for 4 weeks in conjunction with oral paromomycin (1 g twice daily for 12 weeks).

Gonorrhea and Associated Infections

For the treatment of uncomplicated gonorrhea (urethritis or cervicitis) caused by Neisseria gonorrhoeae when the drugs of choice cannot be used, adults may receive a single 2-g dose of azithromycin as a conventional formulation. Because this single-dose regimen has been associated with a relatively high incidence of adverse GI effects, the patient should be observed for at least 30 minutes after ingesting the dose. Taking the dose with food may minimize adverse effects; an antiemetic may be needed.

Because of concerns regarding rapid emergence of macrolide resistance, azithromycin should not be given in a lower dosage and should be used for the treatment of gonorrhea only when considered necessary.

Granuloma Inguinale (Donovanosis)

For the treatment of granuloma inguinale (donovanosis), CDC recommends an oral azithromycin dosage of 1 g once weekly for at least 3 weeks or until all lesions have healed completely. Some experts recommend that patients receive an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) concomitantly if they are HIV-infected or if improvement is not evident within the first few days of treatment. Despite effective anti-infective therapy, relapse may occur 6-18 months later.

Legionella Infections

For the treatment of Legionnaires' disease, some clinicians recommend that oral or IV azithromycin be given in a dosage of 500 mg once daily. The usual duration of azithromycin therapy is 3-5 days for the treatment of mild to moderate infections in immunocompetent patients; however, a longer duration of treatment (at least 7-10 days or 3 weeks) may be necessary to prevent relapse in those with more severe infections or with underlying comorbidity or immunodeficiency.

Leptospirosis

For the treatment of leptospirosis caused by Leptospira, adults have received oral azithromycin in a dosage of 1 g as a single dose on day 1 followed by 500 mg once daily for 2 days. Alternatively, a dosage of 15 mg/kg daily in 2 divided doses for 7 days has been used.

Lyme Disease

For the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree AV heart block, when first-line agents (oral doxycycline, amoxicillin, or cefuroxime) cannot be used, the IDSA suggests that adults receive an oral azithromycin dosage of 500 mg once daily for 7-10 days. The patient should be monitored closely to ensure resolution of clinical manifestations since macrolides generally are less effective for treatment of Lyme disease than first-line agents.

Lymphogranuloma Venereum

For the treatment of lymphogranuloma venereum caused by invasive serotypes of C. trachomatis (serovars L1, L2, L3), 1 g of azithromycin orally once weekly for 3 weeks may be effective.

Mycobacterium avium Complex (MAC) Infections (Primary Prophylaxis of Disseminated 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 usually is given alone for primary prophylaxis against MAC, but has been given in conjunction with rifabutin.

The ATS, IDSA, and others recommend primary prophylaxis against disseminated MAC infection in HIV-infected adults and adolescents with CD4 T-cell counts less than 50/mm. Although consideration can be given to discontinuing such prophylaxis in adults and adolescents when there is immune recovery in response to potent antiretroviral therapy and an increase in CD4 T-cell count to greater than 100/mm that has been sustained for at least 3 months (see Primary Prevention of Disseminated MAC Infection under Uses: Mycobacterium avium Complex [MAC] Infections), primary MAC prophylaxis should be restarted if the CD4 T-cell count decreases to less than 50-100/mm.

Mycobacterium avium Complex (MAC) Infections (Treatment and Prevention of Recurrence of Disseminated 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 ATS, CDC, NIH, and IDSA recommend a regimen of 500-600 mg of oral azithromycin once daily in conjunction with ethambutol (15 mg/kg once daily) with or without rifabutin (300 mg once daily) in HIV-infected adults and adolescents.

For prevention of recurrence (secondary prophylaxis or chronic maintenance therapy) of disseminated MAC in HIV-infected adults or adolescents who responded to treatment, the ATS, CDC, NIH, and IDSA recommend that adults and adolescents receive azithromycin in a dosage of 500-600 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, consideration may 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 such prophylaxis should be restarted if CD4 T-cell counts decrease to less than 100/mm.

Mycobacterium avium Complex (MAC) Infections (Treatment of Pulmonary Infections)

For initial treatment of pulmonary MAC infections (nodular/bronchiectatic disease) caused by macrolide-susceptible strains, ATS and IDSA recommend an azithromycin dosage of 500-600 mg 3 times weekly in conjunction with ethambutol (25 mg/kg 3 times weekly) and rifampin (600 mg 3 times weekly). The regimen should be continued until the patient has been culture negative on treatment for 1 year. An intermittent (3-times weekly) regimen is not recommended for those with cavitary or moderate or severe disease or those who have been previously treated.

For initial treatment of pulmonary MAC infections (fibrocavitary or severe nodular/bronchiectatic disease) caused by macrolide-susceptible strains, ATS and IDSA recommend an azithromycin regimen of 250-300 mg once daily in conjunction with ethambutol (15 mg/kg once daily) and either rifampin (450-600 mg once daily) or rifabutin (150-300 mg once daily). The regimen should be continued until the patient has been culture negative on treatment for 1 year. Consideration can be given to including amikacin or streptomycin 3-times weekly during the first 2-3 months of treatment for extensive disease, especially fibrocavitary disease, or when previous therapy has failed.

Mycobacterium abscessus Infections

For the treatment of infections caused by M. abscessus, azithromycin may be given in a dosage of 250 mg daily in conjunction with parenteral amikacin, cefoxitin, or imipenem. The duration of therapy should be at least 4 months for serious infections; a duration of 6 months is recommended for bone infections.

Neisseria meningitidis Infections

For elimination of nasopharyngeal carriage of Neisseria meningitidis, azithromycin may be given in a dosage of 500 mg as a single dose.

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. If anaerobic bacteria are suspected, an anti-infective active against anaerobes should also be used. 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.

Pertussis

For the treatment of pertussis or for postexposure prophylaxis of pertussis, the CDC and AAP recommend that adults and adolescents receive an initial azithromycin dose of 500 mg once on day 1 followed by 250 mg once daily on days 2-5.

When postexposure prophylaxis of pertussis is indicated, it should be initiated within 3 weeks of exposure or onset of cough in the index patient.

Scrub Typhus

For the treatment of scrub typhus caused by Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi), azithromycin has been given in a dosage of 500 mg as a single dose. Alternatively, 1 g has been given as a single dose on day 1 followed by 500 mg once daily for 2 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 and others recommend a single 2-g oral dose as a conventional formulation. Close follow-up is essential since efficacy is not well documented.

Shigella Infections

If oral azithromycin is used for the treatment of shigellosis in adults, an initial dose of 500 mg should be given on day 1 followed by 250 mg once daily on days 2-5. If bacteremia is present, the drug should be continued for 14 days depending on the severity of infection.

Toxoplasmosis

For the treatment of toxoplasmosis caused by Toxoplasma gondii, the CDC, NIH, IDSA, and other clinicians state that adults and adolescents can receive azithromycin in a dosage of 900-1200 mg once daily in conjunction with pyrimethamine and leucovorin given for at least 6 weeks. A longer duration of treatment may be appropriate if the disease is extensive or the response is incomplete at 6 weeks.

Travelers' Diarrhea

If oral azithromycin is used in the empiric treatment of travelers' diarrhea, some clinicians suggest that adults receive a single 1-g dose as a conventional formulation or, alternatively, 500 mg once daily for 3 days.

Typhoid Fever and Other Salmonella Infections

For the treatment of uncomplicated typhoid fever caused by susceptible Salmonella, adults have received oral azithromycin in a dosage of 1 g once daily for 5 days. A dosage of 8-10 mg/kg (up to 500 mg) once daily for 7 days also has been recommended.

Prevention of Bacterial Endocarditis

When an oral regimen is indicated for the prevention of bacterial endocarditis in penicillin-allergic adults at risk undergoing certain dental or respiratory tract procedures likely to cause transient bacteremia, the American Heart Association (AHA) states that adults can receive a single azithromycin dose of 500 mg given 30-60 minutes 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 as a conventional formulation given in conjunction with other anti-infectives (e.g., IM ceftriaxone and oral metronidazole).

Pediatric Dosage

Acute Otitis Media

For the treatment of acute otitis media, children 6 months of age or older can receive a single azithromycin dose of 30 mg/kg or a 3-day regimen of 10 mg/kg once daily. Alternatively, 5-day regimen can be used consisting of 10 mg/kg given once 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.

Pharyngitis and Tonsillitis

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

Acute Sinusitis

The usual oral dosage of azithromycin for the treatment of acute sinusitis in children 6 months of age or older is 10 mg/kg once daily for 3 days.

Community-acquired Pneumonia

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

Babesiosis

For the treatment of babesiosis caused by Babesia microti, IDSA recommends that children receive oral azithromycin 10 mg/kg (up to 500 mg) once on day 1, then 5 mg/kg (up to 250 mg) once daily for a total of 7-10 days in conjunction with atovaquone (20 mg/kg [up to 750 mg] twice daily for 7-10 days). Alternatively, some clinicians recommend that pediatric patients receive oral azithromycin in a dosage of 12 mg/kg once daily for 7-10 days given in conjunction with atovaquone (20 mg/kg daily in 2 divided doses for 7-10 days).

Bartonella Infections

If oral azithromycin is used for the treatment of cat scratch disease caused by B. henselae in children with extensive lymphadenopathy, some clinicians recommend an initial dose of 10 mg/kg on day 1 followed by 5 mg/kg once daily on days 2-5.

Chancroid

For the treatment of chancroid in infants and children weighing less than 45 kg, the AAP recommends azithromycin 20 mg/kg (maximum 1 g) given as a single oral dose of a conventional formulation. Adolescents and children weighing 45 kg or more should receive 1 g administered as a single dose of a conventional formulation.

Because data on the efficacy of the single-dose azithromycin regimen for treatment of chancroid in patients with HIV infection are limited, the CDC recommends that the single-dose regimen be used in HIV-infected patients only if follow-up can be ensured.(See Uses: Chancroid.)

Chlamydial Infections

When azithromycin is used for the treatment of uncomplicated chlamydial genital tract infection (urethritis and/or cervicitis), the usual oral dosage for children 8 years of age or older or children younger than 8 years of age who weigh at least 45 kg is a single 1-g dose given as a conventional formulation.

For the treatment of ocular trachoma in children, oral azithromycin has been given in a dosage of 20 mg/kg (up to 1 g) as a single dose. Alternatively, a dosage of 20 mg/kg once weekly for 3 weeks or 20 mg/kg once every 4 weeks for a total of 6 doses has been used. The single-dose regimen has been used in mass treatment programs; however, multiple doses (e.g., once yearly for 3 years) may be necessary to minimize reservoirs of infection in high-prevalence areas.

Some clinicians suggest that chlamydial pneumonia or 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.

Cryptosporidiosis

For the symptomatic treatment of cryptosporidiosis, children have received oral azithromycin in a dosage of 10 mg/kg on day 1 followed by 5 mg/kg orally once daily (up to 600 mg daily) on days 2-10. The optimum duration of treatment is unknown; no anti-infective reliably eradicates Cryptosporidium.

Escherichia coli Infections

If azithromycin is used for the treatment of severe diarrhea caused by enterotoxigenic Escherichia coli (ETEC) when an anti-infective is considered necessary, some clinicians recommend that children receive oral azithromycin in a dosage of 10 mg/kg once daily for 2 days.

Legionella Infections

For the treatment of legionella infections caused by Legionella pneumophila, AAP recommends that children receive IV azithromycin in a dosage of 10 mg/kg (up to 500 mg) once daily for 5-10 days. If the patient is improving, parenteral therapy may be switched to oral therapy.

Leptospirosis

For the treatment of leptospirosis caused by Leptospira, children 5-18 years of age have received oral azithromycin in a dosage of 15 mg/kg daily in 2 divided doses for 7 days.

Lyme Disease

For the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree AV heart block, when first-line agents (oral doxycycline, amoxicillin, or cefuroxime) cannot be used, the IDSA suggests an oral azithromycin dosage of 10 mg/kg (maximum: 500 mg) once daily for 7-10 days. The patient should be monitored closely to ensure resolution of clinical manifestations since macrolides generally are less effective for treatment of Lyme disease than first-line agents.

Mycobacterium avium Complex (MAC) Infections (Primary Prophylaxis of Disseminated 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 or 5 mg/kg (maximum 250 mg) 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.

Long-term primary prophylaxis against disseminated MAC infection is recommended in severely immunocompromised HIV-infected infants and children (see Primary Prevention of Disseminated MAC Infection under Uses: Mycobacterium avium Complex [MAC] Infections). Primary prophylaxis should be initiated if CD4 T-cell count is less than 750/mm in those younger than 1 year, less than 500/mm in those 1-2 years, less than 75/mm in those 2-6 years, or less than 50/mm in those 6 years of age or older.

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.

Mycobacterium avium Complex (MAC) Infections (Treatment and Prevention of Recurrence of Disseminated Infection)

For treatment of disseminated MAC infections in HIV-infected children, the CDC, NIH, and IDSA recommend that oral azithromycin be given in a dosage of 10-12 mg/kg once daily (up to 500 mg daily) in conjunction with ethambutol (15-25 mg/kg once daily [up to 1 g daily]) with or without rifabutin (10-20 mg/kg once daily [up to 300 mg daily]).

For prevention of recurrence (secondary prophylaxis or chronic maintenance therapy), an oral azithromycin dosage of 5 mg/kg (maximum 250 mg) once daily in conjunction with ethambutol (15 mg/kg [maximum 900 mg] once daily) with or without rifabutin (5 mg/kg [maximum 300 mg] once daily) is recommended.

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.

Pertussis

For the treatment of pertussis or for postexposure prophylaxis of pertussis in children and infants 6 months of age or older, the AAP, CDC, and others recommend an initial azithromycin dose of 10 mg/kg (up to 500 mg) on day 1 followed by 5 mg/kg (up to 250 mg) once daily on days 2-5.

AAP and CDC state that infants 1-5 months of age may receive oral azithromycin in a dosage of 10 mg/kg once daily for 5 days for treatment or postexposure prophylaxis of pertussis. Although only limited data are available in infants younger than 1 month of age, the CDC states that a dosage of 10 mg/kg once daily for 5 days can be used when necessary for treatment or prophylaxis of pertussis in this age group.

When postexposure prophylaxis of pertussis is indicated, it should be initiated within 3 weeks of exposure or onset of cough in the index patient.

Shigella Infections

For the treatment of shigellosis, children have received oral azithromycin in a dosage of 12 mg/kg (up to 500 mg) on day 1 followed by 6 mg/kg orally once daily (up to 250 mg daily) on days 2-5.

Travelers' Diarrhea

If oral azithromycin is used for empiric treatment of travelers' diarrhea, some clinicians suggest that children receive 10 mg/kg once daily for 3 days.

Typhoid Fever and Other Salmonella Infections

For the treatment of uncomplicated typhoid fever caused by susceptible Salmonella, children 3-17 years of age have received oral azithromycin in a dosage of 20 mg/kg (up to 1 g) once daily for 5-7 days. An azithromycin dosage of 10 mg/kg (up to 500 mg) once daily for 7 days also has been used.

Prevention of Bacterial Endocarditis

When an oral regimen is indicated for prevention of bacterial endocarditis in penicillin-allergic children at risk undergoing certain dental or respiratory tract procedures likely to cause transient bacteremia, the AHA states that children can receive a single azithromycin dose of 15 mg/kg (up to 500 mg) given 30-60 minutes prior to the procedure.

Dosage in Renal and Hepatic Impairment

Dosage adjustment is not necessary in patients with renal impairment (glomerular filtration rate 80 mL/minute or less). However, data are limited regarding use of azithromycin in patients with severe renal impairment (glomerular filtration rate less than 10 mL/minute) and the manufacturer states that the drug should be used with caution in these patients.

The pharmacokinetics of azithromycin in patients with hepatic impairment have not been established. The manufacturer states that data are insufficient to make dosage recommendations for patients with hepatic impairment and azithromycin should be used with caution in such patients since the drug is eliminated principally via the liver. Based on results of a limited study in patients with impaired hepatic function, some clinicians state that dosage adjustments are not necessary in patients with class A or B liver cirrhosis.

Cautions

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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; 0.6% 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 (MAC) infection, the discontinuance rate was 9.1%. The rate of discontinuance of IV azithromycin therapy in adults was 1.2%.

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, adverse GI effects are the most frequent reason for discontinuing azithromycin therapy. Administration of conventional azithromycin tablets or oral suspension with food may improve GI tolerability.

In adults receiving multiple-dose azithromycin regimens, diarrhea/loose stools, nausea, and abdominal pain generally occur in 2-5% of patients. Adverse GI effects have occurred more frequently in patients receiving azithromycin as a single oral dose (1, 1.2, or 2 g) than in those receiving multiple-dose oral regimens. Diarrhea/loose stools or nausea was reported in 7 or 5%, respectively, of adults receiving a single 1-g oral dose of azithromycin and in 12-14 or 4-18%, respectively, of adults receiving a single 2-g oral dose. 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 MAC infections.

Vomiting was reported in 7 or 2% of adults on the single 2-g dose or single 1-g dose oral regimen, 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 1.9-2.7% 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 27-32.3% 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, enteritis, 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/smell perversion and/or loss have occurred rarely in patients receiving azithromycin .

In children with otitis media, community-acquired pneumonia, or pharyngitis/tonsillitis receiving oral azithromycin in the recommended regimen, diarrhea/loose stools, vomiting, abdominal pain, or nausea was reported in 2-6, 1-6, 1-3, or 1-2%, respectively.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile.C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including azithromycin, and may range in severity from mild diarrhea to fatal colitis. Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.(See Cautions: Precautions and Contraindications.)

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 treatment in some patients. Patients experiencing serious allergic reactions (i.e., anaphylaxis, angioedema, severe dermatologic reactions) require prolonged periods of observation and symptomatic treatment. 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 γ-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 (1.2 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, including oral moniliasis, 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. FDA states that azithromycin can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm. Patients at particular risk for developing this condition include those with known risk factors such as existing QT interval prolongation, low blood concentrations of potassium or magnesium, a slower than normal heart rate, or use of certain drugs used to treat abnormal heart rhythms, or arrhythmias. (See Cautions: Precautions and Contraindications.)

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 (1.2 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

Anemia, 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/mm in 2%, leukocyte count less than 1000/mm in 3%, or neutrophil count less than 500/mm 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 (1.5 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/m basis, azithromycin 30 mg/kg in the rat (135 mg/m) or 10 mg/kg in the dog (79 mg/m) 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

Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide or ketolide antibiotic.

Serious hypersensitivity reactions, including angioedema, anaphylaxis, and dermatologic reactions, have occurred rarely in patients receiving azithromycin. Fatalities have been reported. 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 treatment and that patients may require prolonged observation and symptomatic treatment.

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. In addition, because of limited data regarding use of azithromycin in patients with renal impairment, the drug should be used with caution in patients with glomerular filtration rates less than 10 mL/minute.

Prolonged cardiac repolarization and QT interval with risk of cardiac arrhythmia and torsades de pointes has been reported with macrolides, including azithromycin. There have been reports of arrhythmias, ventricular tachycardia, hypotension, QT prolongation, and torsades de pointes in patients receiving azithromycin during postmarketing surveillance. FDA states that health care professionals should consider the risk of torsades de pointes and fatal heart rhythms with azithromycin when considering treatment options for patients who are already at risk for cardiovascular events. FDA notes that the potential risk of QT prolongation with azithromycin should be placed in appropriate context when choosing an antibacterial drug: Alternative drugs in the macrolide class, or non-macrolides such as the fluoroquinolones, also have the potential for QT prolongation or other clinically significant adverse effects that should be considered when choosing an antibacterial drug.

To reduce development of drug-resistant bacteria and maintain effectiveness of azithromycin and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria. When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy. Patients should be advised that antibacterials (including azithromycin) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold). Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with azithromycin or other antibacterials in the future.

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 C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infective agents, including macrolides, it should be considered in the differential diagnosis of patients who develop diarrhea during or following azithromycin therapy and managed accordingly. Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued. If CDAD is suspected or confirmed, azithromycin may need to be discontinued. Some mild cases may respond to discontinuance of the drug alone. Moderate to severe cases should be managed with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated. Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.

Pediatric Precautions

Safety and efficacy of azithromycin extended-release oral suspension (Zmax) have not been established in pediatric patients.

Safety and efficacy of oral azithromycin for the treatment of acute otitis media (AOM) in children younger than 6 months of age or for the treatment of pharyngitis and tonsillitis in children younger than 2 years of age have not been established.

Safety and efficacy of oral azithromycin for the treatment of acute bacterial sinusitis in children younger than 6 months of age have not been established. Use of the drug for the treatment of acute bacterial sinusitis in children 6 months of age or older is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adult and pediatric patients, and studies of AOM in pediatric patients.

Safety and efficacy of oral azithromycin for the treatment of community-acquired pneumonia (CAP) in infants younger than 6 months of age have not been established. Safety and efficacy of oral azithromycin for treatment of CAP caused by Chlamydophila pneumoniae (Chlamydia pneumoniae) or Mycoplasma pneumoniae in children 6 months of age or older were documented bacteriologically in pediatric studies, but 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.

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.

Adverse effects reported in children receiving single- or multiple-doses of azithromycin are similar to those reported in adults, although the incidence rates may differ from those in adults.

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 with conventional or extended-release formulations (Zmax) generally is not required.

No overall differences in safety and efficacy have been reported with use of conventional or extended-release oral azithromycin formulations in those 65 years of age and older compared with younger adults, but the possibility of increased sensitivity in some geriatric individuals cannot be ruled out. In studies evaluating IV azithromycin in patients with CAP, there were no overall differences in safety in those 65 years of age and older compared with younger adults; similar decreases in clinical response were noted with increasing age in both azithromycin- and comparator-treated patients.

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.

Azithromycin preparations contain sodium. A 2-g dose of azithromycin as the extended-release oral suspension (Zmax) contains 148 mg (6.43 mEq) of sodium. Patients receiving the usual IV dosage will receive 114 mg (4.96 mEq) of sodium per dose. Geriatric patients may respond to salt loading with blunted natriuresis, and the total sodium content from dietary and nondietary sources may be clinically important with regard to such diseases as congestive heart failure.

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, Fertility, and Lactation

Pregnancy

Reproduction studies in rats and mice using azithromycin dosages up to 200 mg/kg daily (approximately equivalent on a mg/m 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. 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.

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.) Azithromycin is considered 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.)

Fertility

Reproductive studies with azithromycin have not revealed evidence of impaired fertility.

Lactation

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

Drug Interactions

Drugs Affecting or Metabolized by 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, or erythromycin is contraindicated.

Unlike some macrolides (i.e., erythromycin, clarithromycin), azithromycin does not appear to alter the metabolism of terfenadine (no longer commercially available in the US).

Albendazole

Increased peak plasma concentration and area under the concentration-time curve (AUC) of azithromycin have been reported when azithromycin was used concomitantly with albendazole and ivermectin. This effect is not considered clinically important.(See Drug Interactions: Ivermectin.)

Antacids

Although the single-dose extended-release oral suspension of azithromycin (Zmax) may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide, conventional oral azithromycin preparations (tablets or oral suspension) should not be administered simultaneously with aluminum- or magnesium-containing antacids. A study using azithromycin capsules (no longer commercially available) indicate that administration of oral azithromycin 500 mg 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.

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.

Antimalarial Agents

Chloroquine

Clinically important pharmacokinetic interactions did not occur when chloroquine and azithromycin were used concomitantly.

There is in vitro evidence of additive to synergistic effects between azithromycin and chloroquine against P. falciparum, including multidrug-resistant strains.

Quinine

There is in vitro evidence of additive to synergistic effects between azithromycin and quinine against P. falciparum, including multidrug-resistant strains.

Antiretroviral Agents

HIV Protease Inhibitors

Atazanavir

Clinically important pharmacokinetic interactions between azithromycin and atazanavir are not expected.

Indinavir

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.

Lopinavir

Clinically important pharmacokinetic interactions between azithromycin and lopinavir are not expected.

Nelfinavir

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

Efavirenz

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

Didanosine

Concomitant administration of oral didanosine (200 mg every 12 hours for 21 days) and oral azithromycin (1.2 g daily on days 8-21) 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.

Zidovudine

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.

Benzodiazepines

Concomitant use of azithromycin (500 mg on day 1, then 250 mg on day 2) and triazolam (0.125 mg on day 2) or concomitant use of azithromycin (500 mg daily for 3 days) and midazolam (15 mg on day 3) has only a modest effect on 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 10,11-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 only a modest 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 absorption or pharmacokinetics of azithromycin.

Co-trimoxazole

Concomitant use of oral co-trimoxazole (160 mg of trimethoprim and 800 mg of sulfamethoxazole for 7 days) and oral 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.

Cyclosporine

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased cyclosporine concentrations. Therefore, the patient should be carefully monitored if azithromycin and cyclosporine are used concomitantly.

Digoxin

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased digoxin concentrations. Therefore, the patient should be carefully monitored if azithromycin and digoxin are used concomitantly.

Ergot Alkaloids

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased concentrations of ergot alkaloids (ergotamine, dihydroergotamine). Therefore, the patient should be carefully monitored if azithromycin and ergot alkaloids 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.

Ivermectin

Increased peak plasma concentration and AUC of azithromycin and increased peak plasma concentrations and AUC of ivermectin have been reported when azithromycin, ivermectin, and albendazole were used concomitantly. The effect on azithromycin pharmacokinetics is not considered clinically important; additional study is needed to determine the clinical importance of the effect on ivermectin pharmacokinetics.

Phenytoin

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased phenytoin concentrations. Therefore, the patient should be carefully monitored if azithromycin and phenytoin are used concomitantly.

Pimozide

Because concomitant use of pimozide and other macrolides (e.g., clarithromycin) has increased pimozide concentrations and is associated with a risk of prolonged QT interval and serious cardiovascular effects, the manufacturer of pimozide states that concomitant use of pimozide and macrolides (including azithromycin) is contraindicated.

Rifabutin

Concomitant administration of azithromycin and rifabutin does not have a clinically important effect on the pharmacokinetics of rifabutin. 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 IV or oral 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

Azithromycin does not appear to affect the prothrombin time (PT) response to a single dose of warfarin and limited data suggest that oral azithromycin (500 mg on day 1, then 250 mg daily for 4 days) does not affect the PT response in individuals receiving concurrent oral warfarin sodium. However, 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 and concomitant use of warfarin and macrolides has been associated with increased anticoagulant effect in clinical practice. Therefore, the manufacturer of azithromycin states that prudent medical practice dictates careful monitoring of PT or other appropriate test in all patients treated concurrently with azithromycin and warfarin.

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 conventional 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 conventional oral 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.

The commercially available extended-release oral suspension of azithromycin (Zmax) is not bioequivalent with the conventional oral suspension or tablets (Zithromax). Results of a 2-way crossover study in healthy adults who received a single 2-g dose of azithromycin as the extended-release oral suspension or the conventional oral suspension indicate that mean peak serum concentration and AUC of azithromycin are 57 and 17 % lower, respectively, with the extended-release formulation. Bioavailability of the azithromycin extended-release oral solution is approximately 83% of that reported with the conventional oral suspension and, in general, peak serum concentrations are attained approximately 2.5 hours later compared with the conventional oral suspension. However, higher peak serum concentrations and greater systemic exposure (AUC) are achieved with a single 2-g dose as the extended-release suspension relative to that of a 1.5-g dose as conventional tablets given over 3 days (500 mg daily) or 5 days (500 mg on day 1 and 250 mg daily on days 2-5).

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 2.5-3.2 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 0.216-0.224 mcg/mL at 1.8-1.9 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.

Food

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.

Food does not have a substantial effect on the extent of absorption (AUC) of azithromycin tablets or conventional oral 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 conventional 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 conventional 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.

When a single 2-g dose of azithromycin was given to adults as the extended-release oral suspension (Zmax), administration with a high-fat meal (150 kcal proteins, 250 kcal carbohydrates, 500-600 kcal fats) increased the mean peak plasma concentration and mean AUC of the drug by 115 and 23%, respectively, compared with administration in the fasted state. When the same dose was given following a standard meal (56 kcal proteins, 316 kcal carbohydrates, 207 kcal fats), mean peak azithromycin concentrations and mean AUC0-72 increased by 119 and 12%, respectively, compared with administration in the fasted state.

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 10.33, 7.21, 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.

Azithromycin crosses the placenta and is distributed into cord blood and amniotic fluid.

Azithromycin is distributed into milk.

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 (31.3-33.3 L/kg) and plasma clearance (630 mL/minute, 10.18 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 (1.5 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 54.5 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 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 these patients were similar to those in healthy individuals.

In a study in adults 21-85 years of age with varying degrees of renal impairment who received a single 1-g oral dose (four 250-mg capsules [no longer commercially available]), peak plasma concentrations and AUC were increased only slightly in patients with mild to moderate renal impairment (glomerular filtration rate 10-80 mL/minute) compared with those with normal renal function; however, peak plasma concentrations were increased 61% and AUC was increased 35% in those with severe renal impairment (glomerular filtration rate less than 10 mL/minute) compared with those with normal renal function.

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