Introduction ⬇
VA Class:AM200
AHFS Class:
Generic Name(s):
Chemical Name:
- [2R-(2 R ,3 S ,4 R ,5 R ,8 R ,10 R ,11 R ,12 S ,13 S ,14 R )]-13-[2,6,Dideoxy-3- C -methyl-3- O -methyl-α-L- ribo -hexopyranosyl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6,trideoxy-3-(dimethylamino)-β-D- xylo -hexopyranosyloxy]-1-oxa-6-azacyclopentadecan-15-one
- [2R-(2 R ,3 S ,4 R ,5 R ,8 R ,10 R ,11 R ,12 S ,13 S ,14 R )]-13-[2,6,Dideoxy-3- C -methyl-3- O -methyl-α-L- ribo -hexopyranosyl)oxy)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6,trideoxy-3-(dimethylamino)-β-D- xylo -hexopyranosyloxy]-dihydrate
Notification [Posted 08/03/2018] AUDIENCE: Patient, Health Professional, Oncology ISSUE: The antibiotic azithromycin (Zithromax, Zmax) should not be given long-term to prevent a certain inflammatory lung condition in patients with cancers of the blood or lymph nodes who undergo a donor stem cell transplant. Results of a clinical trial found an increased rate of relapse in cancers affecting the blood and lymph nodes, including death, in these patients. We are reviewing additional data and will communicate our conclusions and recommendations when our review is complete. BACKGROUND: The serious lung condition for which long-term azithromycin was being studied called bronchiolitis obliterans syndrome is caused by inflammation and scarring in the airways of the lungs, resulting in severe shortness of breath and dry cough. Cancer patients who undergo stem cell transplants from donors are at risk for bronchiolitis obliterans syndrome. The manufacturer of brand name azithromycin is providing a Dear Healthcare Provider letter on this safety issue to health care professionals who care for patients undergoing donor stem cell transplants. Azithromycin is not approved for preventing bronchiolitis obliterans syndrome. It is an FDA-approved antibiotic used to treat many types of infections affecting the lungs, sinuses, skin, and other parts of the body. The drug has been used for more than 26 years. It is sold under the brand names Zithromax and Zmax and as generics by many different drug companies. It works by stopping the growth of bacteria that can cause infections. RECOMMENDATION: Health care professionals should not prescribe long-term azithromycin for prophylaxis of bronchiolitis obliterans syndrome to patients who undergo donor stem cell transplants because of the increased potential for cancer relapse and death. Patients who have had a stem cell transplant should not stop taking azithromycin without first consulting with your health care professional. Doing so could be harmful without your health care professional's direct supervision. Talk with them if you have any questions or concerns about taking this medicine. For more information visit the FDA website at: [Web] and [Web]. |
Azithromycin is an azalide antibiotic, a subclass of macrolide antibiotics.1,3,10,163,196,210,211,302
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.1,3,202,210,211,302 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 .1,3,5,7,8,10,15,189,202,203,242 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.10,11,12,13,14,15,115,116,117,118,119,120,121,203,211
Azithromycin is used orally in children for the treatment of acute otitis media, community-acquired pneumonia, and pharyngitis or tonsillitis caused by susceptible organisms.1,93,94,106,155,173,174,175,176,210,211
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.196
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).3,163,179,210 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),91,179,210 a natural penicillin,93,102,179,210,224,225 amoxicillin (with or without clavulanic acid),96,98,103,179,210 or a cephalosporin (e.g., cefaclor).4,97,99,210 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.8,109,110,111,112,179,236,237,238 (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).10,66,145,162,211,250
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.179,250
Prior to initiation of azithromycin therapy, appropriate specimens should be obtained for identification of the causative organism(s) and in vitro susceptibility tests.1,10,196,302 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.1,10,196,302 (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 .1,94,106,139,174,175,176,177,179,203,211,294 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).1
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.180,203,269,270,271,272,273,274,275,276,277,278,279,280,281,282,294 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.203,269,275,280,281,282,283,284,285,294
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.203,294 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.282 For additional information regarding treatment of AOM and information regarding prophylaxis of recurrent AOM, treatment of persistent or recurrent AOM, and treatment of otitis media with effusion (OME), see Uses: Otitis Media in the Aminopenicillins General Statement 8:12.16.08.
In 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.1,177 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.1,174 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.1,174 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.1,175 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.1,155,174,175,176,177
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.1,15,29,139,159,179,202,203,210,211 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.1,159,202 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.1,202,203,309 (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.1
Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is effective, the CDC,6 AAP,203 American Academy of Family Physicians (AAFP),6 Infectious Diseases Society of America (IDSA),136 American Heart Association (AHA),137 American College of Physicians (ACP),6 and others15,29 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.136,203 Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternative agents.6,15,136,137,203 A 10-day regimen of oral erythromycin usually is considered the preferred alternative for the treatment of streptococcal pharyngitis in patients hypersensitive to penicillin.6,136,137,203 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.94,137,163 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.136 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.235,250,251
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.102 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).1,93 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.1,93 Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to the drug following therapy.1 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.224,225 However, bacteriologic eradication was reported in substantially fewer azithromycin-treated patients (65%) than penicillin-treated patients (82%).224,225
GI Infections
Campylobacter Infections
Azithromycin has been used as a first-line agent for the treatment of symptomatic enteric infections caused by Campylobacter jejuni †.15,203,308 The CDC,187,308 National Institutes of Health (NIH),308 IDSA,142,308 AAP,203 and other clinicians15 recommend oral erythromycin or azithromycin or fluoroquinolones (e.g., ciprofloxacin) for empiric treatment of these infections; 15,187,203,307,308 tetracyclines (doxycycline) also can be used.15,203 However, increasing emergence of fluoroquinolone-resistant strains of Campylobacter should be considered when selecting a first-line agent.308
When initiated early in the course of the Campylobacter infection, erythromycin or azithromycin shortens the duration of illness and prevents relapse.203 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.203
Cryptosporidiosis
Azithromycin has been used in the treatment of cryptosporidiosis† in HIV-infected adults, adolescents, or children.256,307,308 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†.256 In addition, azithromycin monotherapy may have contributed to resolution of symptoms in a few HIV-infected children with cryptosporidiosis.308 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.105,203,290,307,308
HIV-infected individuals at greatest risk for cryptosporidiosis are those with advanced immunosuppression (i.e., CD4+ T-cell counts less than 100/mm3)307,308 and fulminant infections usually have occurred in those with CD4+ T-cell counts less than 50/mm3.290 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.290,307,308 A highly potent antiretroviral regimen can result in immune restoration (CD4+ T-cell counts exceeding 100/mm3), which usually results in resolution of the infection.290,307,308 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;105,106,307,308 severe diarrhea may require intensive support.307 Adjunctive use of antimotility agents may be indicated, but these agents are not consistently effective and should be used with caution in young children.307,308
Escherichia coli Infections
Azithromycin has been recommended for use in the treatment of GI infections caused by Escherichia coli †.203,331
Diarrhea caused by enterotoxigenic E. coli † (ETEC) generally is of moderate severity and self-limited, but may be severe.187,203,356 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.187,203,356
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.203
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.331
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.142,187,203
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. 142,203,308,316,317,318
Fluoroquinolones (ciprofloxacin, levofloxacin, norfloxacin) usually are considered the drugs of choice for the treatment of shigellosis; alternatives are azithromycin, ampicillin, ceftriaxone, or co-trimoxazole.15,142,203,308 Because of increasing resistance, the choice of anti-infective should be based on susceptibility patterns of locally circulating Shigella .15,203,317 In the US, about 50% of S. flexneri and S. sonnei isolates are resistant to ampicillin and co-trimoxazole.203
Travelers' Diarrhea
Oral azithromycin is used as an alternative to fluoroquinolones for the treatment of travelers' diarrhea†.319,320,359,360,372
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 .319,320,336,372 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).319,320,372
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.320 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.320
Travelers' diarrhea usually is self-limited and may resolve within 3-4 days without anti-infective treatment.319,320,336 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.203,319,336,372 A fluoroquinolone (e.g., ciprofloxacin, levofloxacin, norfloxacin, ofloxacin) generally is recommended when treatment, including self-treatment, of travelers' diarrhea is indicated in adults.203,319,320,336,372 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.203,319,320,359,360,372 Rifaximin is another alternative for the treatment of travelers' diarrhea caused by noninvasive E. coli .203,319 Bismuth subsalicylate or an antimotility agent may be used as an adjunct to anti-infective treatment to provide symptomatic relief;203,319,320,336 oral rehydration therapy should be used if indicated, especially in young children or geriatric adults.203,319,320,336 Travelers should consult a physician if diarrhea persists despite treatment.336
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 .1,3,103,179,210,211,302
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.1
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.302 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).302 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.302 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 .302
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.1,3,96,97,98,179,202,210,211
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.1,3,4,96,97,98,163,179,202,210,211 In addition, eradication of H. influenzae in patients with chronic bronchitis has occurred more frequently in those receiving azithromycin than in those receiving cefaclor.3,97,210,211 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.3,163,179,210 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.15,159,179
Azithromycin is used in adults for the treatment of acute bacterial exacerbations of COPD caused by H. influenzae , M. catarrhalis , or S. pneumoniae .1 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.1 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.1
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.1,3,15,29,91,99,100,101,159,179,202,203,210,211,329 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.99,179 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 .302
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).1 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;163,179,210,250 parenteral therapy with IV azithromycin or another anti-infective agent may be preferred in such situations.179,250
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.196,197 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).196,197,251 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.196,197 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.196,197,251 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.196
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.329 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 ).329 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.329 Macrolides should not be used alone for empiric treatment of CAP in hospitalized patients.329
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.329 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.329
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.329 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).329
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.329
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).1,3,210,211 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).107,108,160,161,202,211 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.250 Skin structure infections resulting in abscess formation may require surgical or needle drainage in addition to antibacterial therapy.1,250
Babesiosis
A combination regimen of atovaquone and azithromycin is recommended as a regimen of choice for the treatment of babesiosis† caused by Babesia microti .125,203,288,337 The other regimen of choice for this infection is clindamycin and quinine.125,203,288,337 The clindamycin and quinine regimen may be preferred for severe babesiosis;288 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.125,337 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.125,203,288
Limited data in animals suggest that a regimen of azithromycin and quinine also may be effective in the management of babesiosis.126
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).15,203,261,310 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.203,261,310 Anti-infectives also are indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud's oculoglandular syndrome.203 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.15,203,261,310
Azithromycin has been used in conjunction with IM or IV ceftriaxone for the treatment of bacteremia caused by Bartonella quintana † (formerly Rochalimaea quintana ).257 B. quintana , a gram-negative bacilli, can cause cutaneous bacillary angiomatosis, trench fever, bacteremia, endocarditis, and chronic lymphadenopathy.257,258,259,260 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.257,258,259 Optimum anti-infective regimens for the treatment of infections caused by B. quintana have not been identified,257,259,260,307,308,310 and various drugs have been used to treat these infections, including doxycycline, erythromycin, azithromycin, clarithromycin, or chloramphenicol.15,203,259,260,307,308 There is evidence that these infections tend to persist or recur and prolonged therapy (several months or longer) usually is necessary.257,259,308
Chancroid
Azithromycin is used orally in the treatment of chancroid (genital ulcers caused by Haemophilus ducreyi ).1,8,10,15,157,159,181,203,242
The CDC242 and others8,159,181,262 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.203 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.8,242,262 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.242
Chancroid occurs more frequently in men (90% of infections) than in women and experience with azithromycin treatment of this infection in women is limited.1,29,181 Consequently, efficacy of the drug in the treatment of chancroid in women has not been established to date,1,181,250 and the drug is labeled by the US Food and Drug Administration (FDA) for this use only in men.1 However, azithromycin has been used successfully for the treatment of chancroid in women†,8,157,159,181,203,262 and chancroid treatment guidelines from CDC, AAP, and other authorities do not provide gender-based recommendations.8,157,159,181,203,242,250
In the US, chancroid usually occurs in discrete outbreaks, but the disease is endemic in some areas.242 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.242 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.242 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.242 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.242 A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that is not widely available.242 The presence of a painful ulcer and tender suppurative inguinal adenopathy suggests a diagnosis of chancroid.242 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.242
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.203,242 Patients with chancroid should be examined 3-7 days after initiation of anti-infective therapy.242 If the regimen was effective, symptomatic improvement in the ulcers is evident within 3 days and objective improvement is evident within 7 days.242 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.242
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.242 Healing of ulcers may be slower in uncircumcised men who have ulcers under the foreskin.242 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.242 While needle aspiration of buboes is a simpler procedure, incision and drainage of buboes may be preferred.242
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.242
Chlamydial Infections
Urogenital Chlamydial Infections
Azithromycin is used orally for the treatment of urogenital infections caused by C. trachomatis .1,7,8,10,15,92,109,110,111,112,114,156,179,203,242
Urogenital Chlamydial Infection in Adults and Adolescents
Azithromycin is used orally for the treatment of urethritis and cervicitis caused by C. trachomatis .1,7,8,10,15,92,109,110,111,112,114,156,179,203,242
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.242 Urogenital C. trachomatis infection in women can result in serious sequelae, including pelvic inflammatory disease (PID), ectopic pregnancy, and infertility.242 Asymptomatic infection is common, and some women with uncomplicated cervical infection already have subclinical upper reproductive tract infection.242 There is evidence that routine screening for chlamydial infection in women can reduce the prevalence of infection and rates of PID.242 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).242 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).242
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.7,8,10,92,154,156,159,203,242 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.8,242 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.8,109,110,111,112,179,242 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.109,179,203
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.8,203,242 Alternative regimens recommended for these infections in pregnant women are a 7- or 14-day regimen of oral erythromycin base or ethylsuccinate.203,242 The CDC states that clinical experience and studies suggest that the single-dose azithromycin regimen is safe and effective,242 and some clinicians suggest that this is the regimen of choice for treatment of urogenital chlamydial infections in pregnant women.8
Individuals with HIV infection who also are infected with chlamydia should receive the same treatment regimens recommended for other individuals with chlamydial infections.242
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.1 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.1
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.242 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.242 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.203
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.8,203,230,242 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.8,203,242 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.242 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 .242 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.242 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.242
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.242 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.242 Although oral azithromycin also may be effective, the CDC states that clinical safety and efficacy data are lacking.242 Effective treatment cures the infection and prevents ongoing tissue damage, although tissue reaction can result in scarring.242 Aspiration of buboes through intact skin or incision and drainage may be necessary to prevent the formation of inguinal/femoral ulcerations.242
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).242
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.242
Chlamydial Pneumonia in Infants
Some clinicians recommend azithromycin for the treatment of chlamydial pneumonia in infants.8
Trachoma and Other Ocular Chlamydial Infections
Some clinicians recommend azithromycin for the treatment of chlamydial conjunctivitis in neonates.8,203,242
Azithromycin is used in the treatment of ocular trachoma caused by C. trachomatis † and is considered a drug of choice for this infection.15,29,112,114,189,203,217,301,354,370,373,374,375,376 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.354,370,375,376
Other Chlamydial Infections
Azithromycin is used for the treatment of C. pneumoniae respiratory tract infections.1,15,203 (See Uses: Respiratory Tract Infections.) IV azithromycin is used for the treatment of pelvic inflammatory disease (PID) caused by C. trachomatis .196,197 (See Uses: Pelvic Inflammatory Disease.)
Although tetracyclines are the drugs of choice for the treatment of psittacosis† caused by Chlamydophila psittaci (formerly Chlamydia psittaci ),15,203,329 macrolides (erythromycin, azithromycin, clarithromycin) are possible alternatives in children younger than 8 years of age who should not receive tetracyclines.203
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.114,231,247,248,249,297,298 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.231 However, these results were not confirmed in other studies.297,298 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.298 Because efficacy has not been proven to date, use of azithromycin for prevention of recurrent CAD is not recommended.298
Cholera
Azithromycin has been used in the treatment of cholera† caused by Vibrio cholerae O1 or O139.350,351,352
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.15,142,203 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.350,351,352
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 .1,179,182,183,190,191,242,303,305,306,371
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).8,242 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).303,306,371
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.182,183 However, the 2-g azithromycin regimen has been associated with a relatively high incidence of adverse GI effects179,182,183,242,306 and does not appear to offer any advantages over IM ceftriaxone for the treatment of uncomplicated gonorrhea.182,183,250
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,305 this lower single-dose regimen has been associated with a substantial incidence of therapeutic failure in some studies.182,183 Therefore, the CDC does not recommend use of a 1-g single-dose azithromycin regimen.303
The fact that N. gonorrhoeae with reduced susceptibility to azithromycin have been isolated in the US should be considered.286,304 (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.371
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 ).221,242
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.203,242 Anti-infective treatment of donovanosis should be continued until all lesions have healed completely; a minimum of 3 weeks of treatment usually is necessary.242 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.242 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.242 Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.242
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.242
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.242 The value of empiric therapy in the absence of clinical signs and symptoms has not been established.242
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†.254,255 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%).254,255 For more information on the treatment of H. pylori infection and peptic ulcer disease, see Uses: Helicobacter pylori Infection, in Clarithromycin 8:12.12.92.
Legionella Infections
Oral or IV azithromycin is used for the treatment of Legionnaires' disease† caused by Legionella pneumophila .15,130,168,203,232,250,311,312,314,329,330 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.15,203,232,311,312,329,330 An oral regimen (e.g., azithromycin, clarithromycin, doxycycline, erythromycin, a fluoroquinolone) may be effective for patients with mild to moderate Legionnaires' disease.311,329 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.203,232,312,329
Some clinicians suggest that azithromycin may be the preferred macrolide for the treatment of severe Legionnaires' disease203 and may also be preferred for empiric therapy in patients with severe community-acquired pneumonia that may be caused by Legionella .232 (See Community-acquired Pneumonia under Uses: Respiratory Tract Infections.)
Leptospirosis
Azithromycin is considered an alternative for the treatment of leptospirosis† caused by Leptospira .363,365 Penicillin G is the drug of choice for severe infections; tetracyclines (usually doxycycline) or ceftriaxone are recommended as alternatives for less severe infections.15,203 Azithromycin also has been effective.363,365
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.341,342,343 Azithromycin should not be used alone as monotherapy for the treatment of malaria.341,342
Although further study is needed, azithromycin has been used for the treatment or prevention of P. vivax malaria†.344,345 When used for treatment of such infections, the rate of resolution of parasitemia reported for azithromycin was considerably slower than that reported for chloroquine.345
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.10,12,203,234 Azithromycin and clarithromycin are the preferred drugs for primary prevention of disseminated MAC infections in adults, adolescents, and children.234
In controlled trials, azithromycin monotherapy was more effective than placebo or rifabutin monotherapy in preventing disseminated MAC infection in patients with advanced HIV infection (CD4+ T-cell counts less than 100/mm3) and infrequently resulted in the development of resistant organisms.10,11,12 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.10 In a randomized, comparative study in patients with advanced HIV infection (CD4+ T-cell counts less than 100/mm3), prophylaxis with rifabutin (300 mg daily), azithromycin (1.2 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.10,11,230 All patients also received fluconazole (200 mg daily or 400 mg once weekly) for prevention of fungal infections.11 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.11
The incidences of bacterial infections (e.g., pneumonia, sinusitis)11 and of manifestations of disseminated MAC infection (e.g., fever, night sweats, weight loss, anemia) in this study10 were lower with azithromycin or azithromycin-rifabutin prophylaxis than with rifabutin prophylaxis or placebo.10,11 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).268 Of patients in whom prophylaxis with azithromycin was unsuccessful, resistance to azithromycin (and clarithromycin) was found in 11%.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),11 although dose-limiting adverse effects (principally GI effects) occurred more frequently with combined azithromycin-rifabutin prophylaxis (23% of patients)11 than with rifabutin (16%)11 or azithromycin (13%)11 prophylaxis.10,11
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/mm3.234 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/mm3; children 2-6 years of age, less than 75 cells/mm3; children 1-2 years of age, less than 500 cells/mm3; and children less than 1 year of age, less than 750 cells/mm3.234
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.234
Current evidence indicates that primary MAC prophylaxis can be discontinued with minimal risk of developing disseminated MAC disease in HIV-infected adults and adolescents who have responded to highly active antiretroviral therapy (HAART) with an increase in CD4+ T-cell counts to greater than 100/mm3 that has been sustained for at least 3 months.205,222,230,234 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.234 However, primary MAC prophylaxis should be restarted in adults and adolescents if CD4+ T-cell counts decrease to less than 50-100/mm3.234 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.234
HIV-infected pregnant women are at risk for MAC disease, and chemoprophylaxis should be given to such women who have T-cell counts less than 50/mm3.234,250 However, some clinicians may choose to withhold prophylaxis during the first trimester of pregnancy because of general concerns regarding drug administration during this period.234 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.234
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.12,14,117,123,203
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.15,117,203,233,234,307,308
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).233,307,308 Some clinicians state that clarithromycin is the preferred macrolide for the initial treatment regimen because of more extensive experience and because it appears to be associated with more rapid clearance of MAC from blood; however, azithromycin can be substituted if clarithromycin cannot be used because of drug interactions or intolerance and is preferred in pregnant women.307,308 Rifabutin should be included in the treatment regimen if the patient has advanced immunosuppression (CD4+ T-cell count less than 50/mm3) or high mycobacterial load (exceeding 2 log10 colony forming units/mL of blood) or is not receiving effective antiretroviral therapy because there is an increased risk of mortality and emergence of drug resistance.308 If a third drug is indicated in the treatment regimen and rifabutin cannot be used (e.g., because of drug interactions or intolerance), use of a fluoroquinolone (ciprofloxacin or levofloxacin) or amikacin may be considered.307,308
To prevent recurrence of MAC disease in HIV-infected adults, adolescents, or children who have previously been treated for an acute episode of MAC infection and in whom macrolide resistance has not been documented, CDC, NIH, and IDSA recommend a regimen consisting of a macrolide (clarithromycin or azithromycin) given with ethambutol (with or without rifabutin).234,307,308 Azithromycin usually is the preferred macrolide for use in conjunction with ethambutol for secondary prophylaxis of disseminated MAC infection in pregnant women.234,307,308 Secondary MAC prophylaxis generally is administered for life in adults and adolescents unless immune recovery has occurred as a result of potent antiretroviral therapy.234 Limited data indicate that secondary MAC prophylaxis can be discontinued in adults and adolescents who have immune recovery in response to potent antiretroviral therapy.240,241,234,308 Based on these data and more extensive cumulative data on safety of discontinuing secondary prophylaxis for other opportunistic infections, CDC, NIH, and IDSA state that it may be reasonable to consider discontinuance of secondary MAC prophylaxis in adults and adolescents who have successfully completed at least 12 months of MAC therapy, have remained asymptomatic with respect to MAC, and have CD4+ T-cell counts exceeding 100/mm3 as the result of potent antiretroviral therapy and this increase has been sustained (e.g., for 6 months or longer).234,308 Some experts would obtain a blood culture for MAC (even in asymptomatic patients) prior to discontinuing secondary MAC prophylaxis to substantiate that the disease is no longer active.234,308 Secondary MAC prophylaxis should be restarted in adults or adolescents if CD4+ T-cell counts decrease to less than 100/mm3.234,308 The safety of discontinuing secondary MAC prophylaxis in HIV-infected children receiving potent antiretroviral therapy has not been studied and children with a history of disseminated MAC should receive lifelong secondary prophylaxis.234,307
Treatment of Pulmonary MAC Infections in HIV-negative Adults
Azithromycin has been used in multiple-drug regimens for the treatment of pulmonary MAC† infections in patients not infected with HIV.233,308,313,315
The ATS recommends that pulmonary MAC infections in HIV-negative adults be treated with a regimen that includes at least 3 drugs, including clarithromycin (500 mg twice daily) or azithromycin (250 mg daily or 500 mg 3 times weekly), rifabutin (300 mg daily) or rifampin (600 mg daily), and ethambutol (25 mg/kg daily for 2 months, then 15 mg/kg daily).233 For patients with a small body mass and/or who are older than 70 years of age, clarithromycin 250 mg twice daily or azithromycin 250 mg 3 times weekly may be better tolerated.233 The ATS states that the addition of streptomycin given intermittently (2 or 3 times weekly) for the first 2-3 months may be considered for patients with extensive disease.233
A 3-drug regimen of azithromycin (250 mg daily on weekdays) or clarithromycin (500 mg twice daily) with ethambutol (15 mg/kg daily) and clofazimine (100 mg daily) also has been used with some success for the treatment of pulmonary MAC infections in HIV-negative adults.315
Mycobacterium abscessus, M. kansasii, and M. marinum Infections
Azithromycin has been recommended for use in combination with other antimycobacterial anti-infectives for the treatment of infections caused by M. abscessus †, M. kansasii †, and M. marinum †.233
For serious skin, soft tissue, and bone infections caused by M. abscessus , the ATS and IDSA recommend a multiple-drug regimen of clarithromycin (or azithromycin) used in conjunction with a parenteral anti-infective (e.g., amikacin, cefoxitin, imipenem);233 surgery usually is indicated for extensive disease, abscess formation, and when drug therapy is difficult.233 This multiple-drug regimen also has been used in the treatment of M. abscessus lung disease; anti-infectives may control symptoms and disease progression, but generally cannot produce long-term sputum conversion.233 Curative therapy may be possible in those with focal infections and limited lung disease if surgical resection is used in conjunction with a multiple-drug treatment regimen.233
For the treatment of rifampin-resistant M. kansasii † infections, the ATS and IDSA recommend a 3-drug regimen based on results of in vitro susceptibility testing, including clarithromycin (or azithromycin), moxifloxacin, ethambutol, sulfamethoxazole, or streptomycin.233
For the treatment of M. marinum † infections, a regimen of clarithromycin and ethambutol has been used.233 Based on experience in other mycobacterial infections, the ATS and IDSA state that a regimen of azithromycin and ethambutol may be an alternative regimen.233
Neisseria meningitidis Infections
Azithromycin has been recommended as an alternative for elimination of nasopharyngeal carriage of N. meningitidis †.346,347,349
The CDC and AAP consider rifampin, ceftriaxone, or ciprofloxacin the drugs of choice to eliminate nasopharyngeal carriage of N. meningitidis and for postexposure prophylaxis in household or other close contacts of patients with invasive meningococcal disease.203,349 Although further study is needed,349 the CDC suggests that azithromycin can be used as an alternative in areas where ciprofloxacin-resistant N. meningitidis have been reported (e.g., Minnesota, North Dakota).347
Nongonococcal Urethritis
Azithromycin is used orally for the treatment of nongonococcal urethritis (NGU).8,184,185,242 CDC currently considers oral azithromycin (a single 1-g dose as a conventional formulation) or oral doxycycline (100 mg twice daily for 7 days) to be the regimens of choice for the treatment of NGU.242 In a randomized, double-blind, comparative study in men with nongonococcal urethritis, a single 1-g oral dose of azithromycin as a conventional formulation was as effective as a 7-day course of doxycycline; in addition, clinical cure rates were comparable with either regimen regardless of the presence or absence of Chlamydia or Ureaplasma infection.184,185,203
Pelvic Inflammatory Disease
IV azithromycin is used for the treatment of acute pelvic inflammatory disease (PID) caused by C. trachomatis , Mycoplasma hominis , or N. gonorrhoeae when initial IV therapy is considered necessary.196,197
Although azithromycin is not included in CDC's recommended or alternative regimens for the treatment of PID,242,371 the CDC states that a regimen of azithromycin and metronidazole has demonstrated short-term clinical cure when used in outpatients with PID.371
Pertussis
Azithromycin is used for the treatment of pertussis† caused by Bordetella pertussis and for postexposure prophylaxis of pertussis in household and other close contacts of an individual with pertussis.15,28,138,203,324,325,326,329,333,334
Macrolides (azithromycin, clarithromycin, erythromycin) are the drugs of choice for treatment of pertussis.15,138,203,326,333,334 Although erythromycin traditionally has been considered the drug of choice for treatment and postexposure prophylaxis of pertussis,15,138,203,326,333,334 azithromycin and clarithromycin appear to be as effective and may be associated with better compliance because shorter regimens are required and the drugs are better tolerated than erythromycin.203,324,333,334
Treatment
For the treatment of pertussis in adults and children 1 month of age or older, the CDC recommends a macrolide (5 days of azithromycin, 7 days of clarithromycin, 14 days of erythromycin).203,334 Co-trimoxazole is recommended as an alternative in adults and children 2 months of age or older when a macrolide cannot be used.203,334 AAP and CDC state that azithromycin is the preferred macrolide for treatment of pertussis in infants younger than 1 month of a however, safety and efficacy have not been established in this age group and only limited data are available.203,334
If given during the catarrhal stage of pertussis (approximately 1-2 weeks of nasal congestion, runny nose, mild sore throat, nonproductive cough, minimal or no fever), anti-infectives may reduce the duration and severity of symptoms and lessen the period of communicability.203,334 After paroxysmal cough is established, anti-infectives may not affect the course of the illness but are recommended to limit spread of the disease to others.203
In a randomized study in children 6 months to 16 years of age with culture-proven B. pertussis infection or a cough illness suspected of being pertussis, a 5-day regimen of oral azithromycin (10 mg/kg on day 1 and 5 mg/kg once daily on days 2-5) was as effective and better tolerated than a 10-day regimen of oral erythromycin (40 mg/kg daily).324
Prevention
All household and other close contacts of an individual with suspected pertussis should receive anti-infective postexposure prophylaxis, regardless of age or vaccination status.203 Prophylaxis should be initiated within 21 days of exposure; if more than 21 days have elapsed since onset of cough in the index patient, prophylaxis has limited value but should be considered for those in households with high-risk contacts (e.g., young infants, pregnant women, individuals with contact with infants).203 In addition, all close contacts who are unvaccinated or incompletely vaccinated against pertussis should receive age-appropriate vaccination with a preparation containing pertussis antigens.203
Scrub Typhus
Azithromycin is recommended as an alternative for the treatment of scrub typhus caused by Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi ).362,363,364 The usual drug of choice for these infections is doxycycline;15,362,363,364 alternatives are chloramphenicol or a fluoroquinolone.15,362,364 Some clinicians suggest that azithromycin may be a preferred alternative for treatment of scrub typhus in children or pregnant women or when scrub typhus was acquired in areas where doxycycline-resistant O. tsutsugamushi have been reported (e.g., South Korea, Thailand).362,363,364
Spirochetal Infections
Lyme Disease
Azithromycin has been used in the treatment of early Lyme disease†, a spirochetal infection caused by tick-borne Borrelia burgdorferi .15,124,179,211,226,227,288 However, some evidence in patients with early Lyme disease suggests that azithromycin or erythromycin may be less effective than penicillins or tetracyclines,203,226,289 and the IDSA, AAP, and other clinicians recommend that macrolide antibiotics not be used as first-line therapy for early Lyme disease.15,203,226,288,289,291 Results of a randomized, controlled study in patients with erythema migrans (localized skin lesion associated with early Lyme disease) suggest that a 20-day regimen of oral amoxicillin is more effective than a 7-day regimen of oral azithromycin (500 mg daily).226,227
Oral doxycycline or oral amoxicillin is recommended as first-line therapy for the treatment of early localized or early disseminated Lyme disease associated with erythema migrans, in the absence of neurologic involvement or third-degree atrioventricular (AV) heart block; alternatively, oral cefuroxime axetil has been used.15,203,289,226,288 The IDSA and other clinicians state that macrolide antibiotics should be reserved for patients who are intolerant of doxycycline, amoxicillin, and cefuroxime axetil15,226,288,289 and that patients treated with macrolides should be monitored closely.288 For more detailed information on the manifestations of Lyme disease and the efficacy of various anti-infective regimens in early or late Lyme disease, see Lyme Disease in Uses: Spirochetal Infections, in the Tetracyclines General Statement 8:12.24.
Syphilis
Although penicillin G is the drug of choice for the treatment of all stages of syphilis,8,203,242 the CDC, NIH, and IDSA state that oral azithromycin can be considered as a possible alternative for the treatment of primary, secondary, or early latent syphilis† in nonpregnant adults and adolescents who are hypersensitive to penicillin if close follow-up can be ensured.203,242,293,308,358
There is evidence that a single 2-g dose of a conventional formulation of azithromycin can be effective for the treatment of early syphilis in some patients.292,293 Single-dose azithromycin regimens are being investigated for treatment of syphilis in disease-control programs, including mass treatment programs.293,328 However, efficacy is not well documented (especially in HIV-infected individuals) and resistance and treatment failures have been reported.8,242,293,308,327,328 In addition, a mutation that is associated with in vivo resistance to azithromycin has been identified in some T. pallidum isolates.327 (See Resistance: Resistance in Neisseria and Treponema.) Therefore, azithromycin should be used for the treatment of syphilis with caution and only if close follow-up can be ensured.8,203,242,293,308 If compliance and follow-up cannot be ensured, patients with penicillin hypersensitivity should be desensitized and treated with penicillin G.203,242
Azithromycin is not included in CDC recommendations for the treatment of any other form of syphilis, including late latent syphilis, latent syphilis of unknown duration, tertiary syphilis, or neurosyphilis.242 In addition, azithromycin is not recommended by the CDC or others for the treatment of syphilis in pregnant women242,307 or for the treatment of congenital syphilis in neonates, infants, or older children.242
Toxoplasmosis
Azithromycin has been used alone and in conjunction with pyrimethamine and leucovorin for the treatment of infections caused by Toxoplasma gondii †, including toxoplasmic encephalitis in HIV-infected patients.127,128,129,296,307,308 Azithromycin also has been used in conjunction with pyrimethamine for the treatment of ocular toxoplasmosis†.295
The CDC, NIH, IDSA, and other clinicians usually recommend a regimen of pyrimethamine in conjunction with sulfadiazine and leucovorin for the treatment of toxoplasmosis in adults and children, especially in immunocompromised patients (e.g., HIV-infected individuals).125,307,308 These clinicians state that azithromycin in conjunction with pyrimethamine and leucovorin is one of several alternative regimens that can be considered in adults when the regimen of choice cannot be used;308 however, the azithromycin regimen has not been evaluated for the treatment of toxoplasmosis in children.307
For information on recommendations regarding treatment and prophylaxis of toxoplasmosis, see Toxoplasmosis under Uses: Pyrimethamine, in Pyrimethamine and Sulfadoxine and Pyrimethamine 8:30.08.
Typhoid Fever and Other Salmonella Infections
Azithromycin has been used in adults or children for the treatment of uncomplicated typhoid fever† caused by susceptible Salmonella .321,322,323,332 Fluoroquinolones (e.g., ciprofloxacin, ofloxacin) usually are considered the drugs of choice for the treatment of typhoid fever or other severe Salmonella infections, especially in areas where multidrug-resistant strains (strains resistant to ampicillin, co-trimoxazole, chloramphenicol) are reported; third generation cephalosporins (cefotaxime, ceftriaxone, cefixime) and azithromycin are considered alternatives (e.g., for fluoroquinolone-resistant strains).15,203,332
When oral azithromycin was used in children 3-17 years of age with uncomplicated typhoid fever, the mean time to defervescence was 4.1-4.5 days and the microbiologic cure rate was 97%.321,322
Prevention of Bacterial Endocarditis
Azithromycin is recommended for prevention of α-hemolytic (viridans group) streptococcal bacterial endocarditis† in penicillin-allergic adults and children with certain cardiac conditions who are undergoing certain dental procedures (i.e., procedures that involve manipulation of gingival tissue, the periapical region of teeth, or perforation of oral mucosa) or certain invasive respiratory tract procedures (i.e., procedures involving incision or biopsy of respiratory mucosa).201
The American Heart Association (AHA) generally recommends routine use of prophylactic anti-infectives prior to certain procedures only in patients with cardiac conditions that are associated with the highest risk of adverse outcome from endocarditis, including congenital heart disease, prosthetic heart valves, cardiac valvulopathy after cardiac transplant, and previous bacterial endocarditis.201 The AHA no longer recommends prophylaxis against bacterial endocarditis based solely on an increased lifetime risk of acquisition of infective endocarditis.201 When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations published by the AHA should be consulted.201
Prophylaxis in Sexual Assault Victims
Azithromycin is used in conjunction with IM ceftriaxone and oral metronidazole for empiric anti-infective prophylaxis in adult or adolescent victims of sexual assault†.8,242 The CDC states that trichomoniasis, genital chlamydial infection, gonorrhea, and bacterial vaginosis are the sexually transmitted diseases (STDs) most commonly diagnosed in women following sexual assault; however, the prevalence of these infections is substantial among sexually active women, and their presence after assault does not necessarily indicate that the infections were acquired during the assault.242 Chlamydial and gonococcal infections among females are of special concern because of the possibility of ascending infection.242
Many experts recommend routine empiric prophylactic therapy after a sexual assault, and use of such prophylaxis probably benefits most patients since follow-up of assault victims can be difficult and such prophylaxis allays the patient's concerns about possible infections.242 When empiric anti-infective prophylaxis is indicated in adult or adolescent sexual assault victims, the CDC recommends administration of a single 125-mg IM dose of ceftriaxone given in conjunction with a single 2-g oral dose of metronidazole and a single 1-g oral dose of a conventional formulation of azithromycin or a 7-day regimen of oral doxycycline (100 mg twice daily).242 This 3-drug regimen provides coverage against gonorrhea, chlamydia, trichomoniasis, and bacterial vaginosis, but efficacy in preventing these infections after sexual assault has not been specifically evaluated.242 Because of possible adverse GI effects with the 3-drug regimen, the CDC suggests that the patient be counseled regarding the possible benefits, as well as the possibility of toxicity, of such prophylaxis.242 Alternative regimens may be required for some patients because of the likelihood of transmission of other STDs from the assailant.242
Postexposure hepatitis B vaccination also is recommended for sexual assault victims who have not previously received the vaccine; hepatitis B vaccine (without hepatitis B immune globulin) should be given to susceptible victims at the time of the initial examination.242 The CDC states that although a definitive recommendation concerning the appropriateness of antiretroviral prophylaxis against HIV cannot be made based on currently available information, such prophylaxis should be considered in cases in which the risk for HIV exposure during the assault is considered high.242 The decision to offer such prophylaxis should be individualized taking into account the probability of HIV transmission from a single act of intercourse and the nature of the assault (e.g., extent and site of physical trauma and exposure to ejaculate), the potential benefits and risks of prophylaxis, and the time interval between the exposure and initiation of therapy.242 (See Guidelines for Use of Antiretroviral Agents: Postexposure Prophylaxis following Sexual Assault or Nonoccupational Exposures to HIV, in the Antiretroviral Agents General Statement 8:18.08.)
There are few data available to establish the risk of a child acquiring a sexually transmitted disease as a result of sexual assault or abuse.242 The risk is believed to be low in most circumstances, although documentation to support this position is inadequate.242 The CDC currently states that presumptive treatment for children who have been sexually assaulted or abused is not widely recommended because girls appear to be at lower risk for ascending infection than adolescent or adult women and regular follow-up usually can be ensured.242 Even if the risk is perceived by the health-care provider to be low, some children or their parents or guardians may have concerns about the possibility of the child contracting a sexually transmitted disease as a result of the assault, and these concerns may be an appropriate indication for presumptive treatment in some settings, but only after appropriate specimens for STD testing have been obtained.242
Dosage and Administration ⬆ ⬇
Reconstitution and Administration
Azithromycin is administered orally.1,10,302 or by IV infusion.196 Azithromycin should not be given by direct IV injection or IM.196
Oral Administration
For oral administration, azithromycin is commercially available as conventional film-coated tablets,1 conventional powder for oral suspension,1 and extended-release microspheres for oral suspension.302
The extended-release oral suspension is not bioequivalent to and is not interchangeable with conventional oral suspension or tablets.302
Reconstituted conventional oral suspension containing 100 or 200 mg of azithromycin per 5 mL1 and reconstituted single-dose packets of conventional oral suspension containing 1 g of azithromycin10 can be taken with or without food.
Azithromycin conventional tablets can be taken with or without food;1,10 tolerability may be increased when tablets are taken with food.10
Reconstituted conventional oral suspension containing 100 or 200 mg of azithromycin per 5 mL may be taken without regard to food.1,10 The safety of repeating a dose in children who vomit after receiving 30 mg/kg as a single dose has not been established.1 The single-dose 1-g packets should not be used to administer doses other than 1 g and are not for pediatric use.10
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).302 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.302 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.302 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.302
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,302 conventional oral azithromycin preparations (film-coated tablets, oral suspension) should not be taken simultaneously with aluminum- or magnesium-containing antacids.1,10
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.10 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.10
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.1 The bottle should be kept tightly closed and should be shaken well before each use.1
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.302 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.302 The single-dose extended-release oral suspension is not for pediatric use.302
IV Infusion
Azithromycin for IV infusion must be reconstituted and then further diluted prior to administration.196
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.196
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.196 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.196 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.196
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.196 Azithromycin should not be admixed with other drugs or infused simultaneously through the same tubing with other drugs.196
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.196 The manufacturer states that solutions containing a 500-mg dose of azithromycin should be infused over a period of at least 1 hour.196
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.1,10,196,302
Two 250-mg tablets of azithromycin are bioequivalent to one 500-mg tablet.1 The extended-release oral suspension is not bioequivalent to and is not interchangeable with the conventional oral suspension or tablets.302
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).1
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.1
If the extended-release oral suspension (Zmax®) is used for the treatment of acute sinusitis, adults should receive a single 2-g dose.302
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).1,96,97,98
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).1,96,97,98,99,330
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.302
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.196,197 IV therapy generally is followed by oral azithromycin given as a single, daily 500-mg dose to complete a 7-10 days of therapy.196,251 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.196
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).1,107,108
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).288 Higher azithromycin dosage (0.6-1 g daily) may be used in immunocompromised patients.288
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).125
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 2-5.310
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.308 If relapse occurs, lifelong secondary prophylaxis (chronic maintenance therapy) with erythromycin or doxycycline should be considered.308
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.308 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.308
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.1,8,203,242
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.242 (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.1,7,8,10,109,112,114,203,242 The 1-g dose may be administered using one single-dose packet of azithromycin for oral suspension or four 250-mg tablets.10 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.250
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.242
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.112,114,189,353,354,370 Alternatively, a dosage of 1 g once weekly for 3 weeks has been used.301 The single-dose regimen has been used in mass treatment programs;370,373,375 however, multiple doses (e.g., once yearly for 3 years) may be necessary to minimize reservoirs of infection in high-prevalence areas.354,370,374,375
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.350
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).256
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.1,182,183,191,242,303,306,371 Because this single-dose regimen has been associated with a relatively high incidence of adverse GI effects,179,182,183,242,306 the patient should be observed for at least 30 minutes after ingesting the dose.303 Taking the dose with food may minimize adverse effects; an antiemetic may be needed.306
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.242,371
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.221,242 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.242 Despite effective anti-infective therapy, relapse may occur 6-18 months later.242
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.311,312,314 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.311,312
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.363 Alternatively, a dosage of 15 mg/kg daily in 2 divided doses for 7 days has been used.365
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.288 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.288
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.242
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.10,233,234 Azithromycin usually is given alone for primary prophylaxis against MAC, but has been given in conjunction with rifabutin.10,233,234 (See Dosage and Administration: Dosage, in Rifabutin 8:16.04.)
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/mm3.233,234 Although consideration can be given to discontinuing such prophylaxis in adults and adolescents when there is immune recovery in response to potent antiretroviral therapy and an increase in CD4+ T-cell count to greater than 100/mm3 that has been sustained for at least 3 months (see Primary Prevention of Disseminated MAC Infection under Uses: Mycobacterium avium Complex [MAC] Infections), primary MAC prophylaxis should be restarted if the CD4+ T-cell count decreases to less than 50-100/mm3.233,234
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.10 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.233,308
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).233,308 Secondary MAC prophylaxis in HIV-infected individuals usually is continued for life.233,234,308 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/mm3.233,234,308
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).233 The regimen should be continued until the patient has been culture negative on treatment for 1 year.233 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.233
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).233 The regimen should be continued until the patient has been culture negative on treatment for 1 year.233 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.233
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.233 The duration of therapy should be at least 4 months for serious infections; a duration of 6 months is recommended for bone infections.233
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.346,349
Nongonococcal Urethritis
For the treatment of nongonococcal urethritis, the usual oral dosage of azithromycin in men is 1 g administered as a single dose.8,184,185,242
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.196 If anaerobic bacteria are suspected, an anti-infective active against anaerobes should also be used.196 IV therapy generally is followed by oral azithromycin 250 mg once daily to complete a 7-day course of therapy.196 The timing of the change from IV to oral therapy should be individualized by the clinician, taking into account clinical response of the patient.196
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 2-5.203,334
When postexposure prophylaxis of pertussis is indicated, it should be initiated within 3 weeks of exposure or onset of cough in the index patient.203,334
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.362,364 Alternatively, 1 g has been given as a single dose on day 1 followed by 500 mg once daily for 2 days.363
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.242,293,308 Close follow-up is essential since efficacy is not well documented.8,242,293,308
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 2-5.308,316 If bacteremia is present, the drug should be continued for 14 days depending on the severity of infection.308
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.308 A longer duration of treatment may be appropriate if the disease is extensive or the response is incomplete at 6 weeks.308
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.319,359,360,372
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.323 A dosage of 8-10 mg/kg (up to 500 mg) once daily for 7 days also has been recommended.332,361
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.201
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).242
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.1 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 2-5.1,294
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.1
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.1,93
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.1
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 2-5.1,203,330 Efficacy of shorter regimens (e.g., 1-3 days) for the treatment of CAP in children has not been established.1
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).288 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).125
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 2-5.310
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.203 Adolescents and children weighing 45 kg or more should receive 1 g administered as a single dose of a conventional formulation.8,203,242
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.242 (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.203,242
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.217,353,354,370,373,375 Alternatively, a dosage of 20 mg/kg once weekly for 3 weeks203,217,301 or 20 mg/kg once every 4 weeks for a total of 6 doses has been used.217 The single-dose regimen has been used in mass treatment programs;370,373,375 however, multiple doses (e.g., once yearly for 3 years) may be necessary to minimize reservoirs of infection in high-prevalence areas.354,370,374,375
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.8,203
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 2-10.307 The optimum duration of treatment is unknown;307 no anti-infective reliably eradicates Cryptosporidium .203,290,307,308
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.356
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.203 If the patient is improving, parenteral therapy may be switched to oral therapy.203
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.365
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.288 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.288
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.234 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.234
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).234 Primary prophylaxis should be initiated if CD4+ T-cell count is less than 750/mm3 in those younger than 1 year, less than 500/mm3 in those 1-2 years, less than 75/mm3 in those 2-6 years, or less than 50/mm3 in those 6 years of age or older.234
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.234
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]).307
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.234
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.234
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 2-5.203,324,325,334
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.203,334 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.334
When postexposure prophylaxis of pertussis is indicated, it should be initiated within 3 weeks of exposure or onset of cough in the index patient.203,334
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 2-5.318
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.319,372
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.321,322 An azithromycin dosage of 10 mg/kg (up to 500 mg) once daily for 7 days also has been used.361
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.201
Dosage in Renal and Hepatic Impairment
Dosage adjustment is not necessary in patients with renal impairment (glomerular filtration rate 80 mL/minute or less).1,10,188,196,302 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.1,10,196,302
The pharmacokinetics of azithromycin in patients with hepatic impairment have not been established.1,10,196,302 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.1,10,196 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.173
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.1,3,10,132,143,196,210,211 In clinical studies, most adverse effects were mild to moderate in severity and were reversible upon discontinuance of the drug.1,3,10,132,143,196,202,210,211 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.3,132,143,155,163,179,211 As with oral erythromycin, the most common adverse effects of oral azithromycin involve the GI tract.1,3,10,132,143,155,202,210,211
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.1,10,196
Adverse GI effects (e.g., nausea, vomiting, diarrhea, abdominal pain) and rash are the most frequent adverse effects requiring discontinuance of the drug.1,10,196 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).1 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%.10 The rate of discontinuance of IV azithromycin therapy in adults was 1.2%.196
GI Effects
The most frequent adverse effects of azithromycin involve the GI tract (i.e., diarrhea/loose stools, nausea, abdominal pain).1,3,10,11,108,110,132,155,196,202,210,211 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.1,2,10,11,132,196,211 Administration of conventional azithromycin tablets or oral suspension with food may improve GI tolerability.10,306
In adults receiving multiple-dose azithromycin regimens, diarrhea/loose stools, nausea, and abdominal pain generally occur in 2-5% of patients.1,10 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.1,10 Diarrhea/loose stools1,2,3,10,70,96,97,99,102,107,109,111,115,124,132,211 or nausea1,2,3,10,11,70,97,99,102,103,107,109,111,132 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.1,10,132,302 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).196 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.10,11
Vomiting1,2,3,10,11,70,97,99,107,109,111,115,132,199 was reported in 7 or 2% of adults on the single 2-g dose or single 1-g dose oral regimen, respectively.1,10 Vomiting occurred in 1.4% of adults with community-acquired pneumonia who received both IV and oral azithromycin therapy196 and in 6.7-9% of patients receiving oral azithromycin for prevention of disseminated M. avium complex infections.10,11 Abdominal pain1,3,10,11,102,107,109,111,115,124,132,196,198,199,202,210,211 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.1,10,196
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.10 Anorexia occurred in 1.9% of patients with pelvic inflammatory disease (PID) receiving initial therapy with IV azithromycin followed by oral therapy.196 Dyspepsia,1,10,70,196 flatulence,1,10,196 melena,10 constipation,1,196 anorexia,1,196 mucositis,196 enteritis,1 gastritis,1,196 oral candidiasis,196 pseudomembranous colitis,196 or vomiting/diarrhea rarely resulting in dehydration1,196 has been reported in 1% or less of patients receiving azithromycin for other infections and/or during postmarketing studies.1,10,196 Tongue discoloration has been reported rarely.196 Taste/smell perversion and/or loss have occurred rarely in patients receiving azithromycin .1,196,199
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.1
Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,10,196,263,264,265,266,267,302 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.1,10,196,263,264,265,266,267,302 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.1,10,196,202,302 (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.1,10,196,302 If allergic reactions occur, azithromycin should be discontinued and appropriate therapy initiated.1,10,196,302 (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.1,10,196,302 Patients experiencing serious allergic reactions (i.e., anaphylaxis, angioedema, severe dermatologic reactions) require prolonged periods of observation and symptomatic treatment.1,10,196,302 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.1,10,196,302
Rash,1,11,109,132,199 urticaria,1,107,196 pruritus,1 and photosensitivity1,10 have been reported in 1% or less of patients receiving a 5-day regimen of oral azithromycin.1 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.196 Pruritus10 or rash10 has been reported in up to 4 or 8%, respectively, of patients receiving azithromycin 1.2 g weekly for prevention of disseminated MAC infections.10 Eczema has been reported rarely during azithromycin therapy.96
Local Reactions
Approximately 12% of patients experienced an adverse effect related to IV infusion of azithromycin.196 Pain at the injection site or local inflammation occurred in 6.5 or 3.1%, respectively, of patients receiving IV azithromycin.196 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.196
Hepatic Effects
Elevations in ALT (SGPT), AST (SGOT), or γ-glutamyltransferase (GGT, GGTP) have been reported in 1-2% of adults receiving oral azithromycin;1,3,10,11,97,98,102,103,109,111,132,199,210,211 elevations in serum alkaline phosphatase,1,10,132 lactic dehydrogenase (LDH),1,10 and/or total bilirubin concentration1,10,108,132,199 have been reported in less than 1% of such patients.97,98,102,103,109,111 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.196 Available follow-up data have revealed that liver function test abnormalities in patients receiving azithromycin therapy generally are reversible.1,10,196 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.1,115,132,196 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.10,11
Abnormal liver function, including cholestatic jaundice1,196,218 and hepatitis,1,196 and pancreatitis196 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.196
Renal and Genitourinary Effects
Elevation in serum potassium concentration has been reported in 1-2% of adults receiving azithromycin in clinical trials.1,10,132 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.1,10,132,196 Available follow-up data revealed that these elevations generally were reversible.1,10,196 Nephritis1,10,133 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.1,196 Azithromycin was discontinued because of an unspecified renal function abnormality in at least one patient receiving the drug in clinical trials.1,10
Vaginitis1,10,196 has been reported in about 1-2.8% of women receiving azithromycin; candidiasis,1,10,96,196 including oral moniliasis, has been reported in 1% or less of adults receiving the drug.1,10,196
Cardiovascular Effects
Palpitations,1,10 chest pain,1,10 edema1,196 hypotension,196 or syncope196 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.1 In one patient with a history of arrhythmia, torsades de pointes with subsequent myocardial infarction occurred following completion of azithromycin therapy.1 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 effects70,90,109 reported in 1% or less of adults receiving azithromycin include dizziness,1,10,108,132,199,210 headache,1,10,70,103,132,210,196,199 vertigo,1,10,199 or somnolence,1,10,70,96,196,210 and those reported in 1% or less of children include headache,1 hyperkinesia,1 dizziness,1 agitation,1 nervousness,1 fatigue,1,196 malaise,1,196 and insomnia.1 Fatigue10,196 or malaise196 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.1,196 Dizziness or headache has occurred in about 1-4% of patients receiving azithromycin (1.2 g weekly) for the prevention of disseminated MAC infections.10 Asthenia,1 aggressive reaction, 196 anxiety,196 or paresthesia1 has been reported during postmarketing studies with azithromycin.
Hematologic Effects
Anemia,1 leukopenia,1,10,132,196 neutropenia,1,10,97,99,102,196,198,210 neutrophilia,97,99,102,132,210 or thrombocytopenia1,196 has been reported in less than 1% of adults receiving azithromycin, although a causal relationship to the drug has not been established.1,10,196 In studies in patients receiving azithromycin for prevention of disseminated MAC infections, a hemoglobin concentration less than 8 g/dL was reported in 2% of patients, platelet count less than 50,000/mm3 in 2%, leukocyte count less than 1000/mm3 in 3%, or neutrophil count less than 500/mm3 in 4%.10
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),132 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).1,10,134,135,199,220 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.10 Hearing loss generally develops within 1.5-20 weeks and generally resolves within 5 weeks following discontinuance of azithromycin.134,220 Hearing loss,1,10 deafness,1,10 or tinnitus1,10 also has been reported during postmarketing studies.1
Other Adverse Effects
Fever1 or conjunctivitis1 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;10 fever has been reported in 1% or less of patients receiving the drug for other indications.1,10 Arthralgia1 also has been reported during postmarketing studies with azithromycin. Hypothermia has occurred in a few patients receiving azithromycin.219
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.1,10
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.246,251
Effects on Phospholipids
Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin.1,10,196 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.1,10,196 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.1,196 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.1,196,251 On a mg/m2 basis, azithromycin 30 mg/kg in the rat (135 mg/m2) or 10 mg/kg in the dog (79 mg/m2) are approximately 0.4 or 0.6 times, respectively, the recommended pediatric dose for a child who weighs 25 kg.1,196
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.1,10,132,196 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.132
Precautions and Contraindications
Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide or ketolide antibiotic.1,10,196,302
Serious hypersensitivity reactions, including angioedema, anaphylaxis, and dermatologic reactions, have occurred rarely in patients receiving azithromycin.1,10,196,302 Fatalities have been reported.1,10,196,302 Patients should be advised to discontinue azithromycin therapy immediately and to contact their clinician if any signs of an allergic reaction occur.1,10,196,302 Severe acute hypersensitivity reactions should be treated with appropriate therapy1,10,196 (e.g., epinephrine, maintenance of an adequate airway, oxygen, IV fluids, maintenance of blood pressure as indicated).251 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.1,10,196,302
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.1,10,202 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.1,10,202
Because azithromycin is eliminated principally via the liver, the drug should be used with caution in patients with impaired hepatic function.1,10,196,202,302 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.1,10,196,302
Prolonged cardiac repolarization and QT interval with risk of cardiac arrhythmia and torsades de pointes has been reported with macrolides, including azithromycin.1,10,196,202,302 There have been reports of arrhythmias, ventricular tachycardia, hypotension, QT prolongation, and torsades de pointes in patients receiving azithromycin during postmarketing surveillance.1 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.1,196,302 When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1,196,302 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1,196,302 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).1,196,302 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.1,196,302
As with other anti-infective agents, use of azithromycin may result in overgrowth of nonsusceptible bacteria or fungi.1,10,196,202,302 If superinfection occurs, appropriate therapy should be instituted.1,10,196,202,302
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.1,10,196,263,264,265,266,267,302 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.1,10,196,302 If CDAD is suspected or confirmed, azithromycin may need to be discontinued.1,10,196,263,264,265,266,267,302 Some mild cases may respond to discontinuance of the drug alone.1,10,196,263,264,265,266,267,302 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.1,10,196,263,264,265,266,267,302 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.1,10,196,302
Pediatric Precautions
Safety and efficacy of azithromycin extended-release oral suspension (Zmax®) have not been established in pediatric patients.302
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.1
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.1 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.1
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.1,10 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.1 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.1
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.10 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).10 Adverse effects were similar to those reported in adults and most involved the GI tract.10 Treatment-related reversible hearing impairment was reported in 4 children.10 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.10
Safety and efficacy of IV azithromycin in children or adolescents younger than 16 years of age have not been established.196
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.1
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).1,10,70,196,202 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.1 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.1,10,70,202,302
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,1,10,302 but the possibility of increased sensitivity in some geriatric individuals cannot be ruled out.1,10 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.196
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.10 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.10
The pharmacokinetic profile of IV azithromycin in geriatric patients has not been determined to date.196
Azithromycin preparations contain sodium.1,10,196,302 A 2-g dose of azithromycin as the extended-release oral suspension (Zmax®) contains 148 mg (6.43 mEq) of sodium.302 Patients receiving the usual IV dosage will receive 114 mg (4.96 mEq) of sodium per dose.196 Geriatric patients may respond to salt loading with blunted natriuresis,196 and the total sodium content from dietary and nondietary sources may be clinically important with regard to such diseases as congestive heart failure.196
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.1,10,196,202,302
Long-term studies have not been performed to date to evaluate the carcinogenic potential of azithromycin.1,10,196,202,302
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/m2 basis to 4 and 2 times, respectively, the human daily oral azithromycin dosage of 500 mg; to 2 or 1 times, respectively, the 1.2-g weekly dosage used for prevention of M. avium complex infection; or 3.3 or 1.7 times, respectively, the 600-mg daily oral dosage used for the treatment of M. avium complex) have not revealed evidence of harm to the fetus.1,10,196,202,302 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.1,10,196,202,302
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.242 (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.234 (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.1,10,302
Lactation
Azithromycin has been detected in human milk.144 The drug should be used with caution in nursing women.1,10,196,202,302
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.1,10,132,162,196,211 While azithromycin appears to have no effect on the cytochrome P-450 (CYP) enzyme system65,67,162,211 and interactions mediated by this enzyme system would not be expected to occur,162,211 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.1,10,196,211 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).1,10,196,302 While interactions with the above agents have not been reported with azithromycin, interactions have occurred with other macrolides.1,10,196
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.243,244,245 Macrolide antibiotics may inhibit metabolism of pimozide, resulting in increased plasma concentrations of unchanged drug.243,244 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.245
Unlike some macrolides (i.e., erythromycin, clarithromycin), azithromycin does not appear to alter the metabolism of terfenadine (no longer commercially available in the US).152,153,194,251
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.355 This effect is not considered clinically important.355 (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,302 conventional oral azithromycin preparations (tablets or oral suspension) should not be administered simultaneously with aluminum- or magnesium-containing antacids.1,10 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.1,10,146,211
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.1,196,302 However, in a patient receiving long-term therapy with lovastatin, administration of oral azithromycin (250 mg daily for 5 days) appeared to precipitate rhabdomyolysis.229 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.229 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.229
Antimalarial Agents
Chloroquine
Clinically important pharmacokinetic interactions did not occur when chloroquine and azithromycin were used concomitantly.338
There is in vitro evidence of additive to synergistic effects between azithromycin and chloroquine against P. falciparum , including multidrug-resistant strains.339,357
Quinine
There is in vitro evidence of additive to synergistic effects between azithromycin and quinine against P. falciparum , including multidrug-resistant strains.339,340,357
Antiretroviral Agents
HIV Protease Inhibitors
Atazanavir
Clinically important pharmacokinetic interactions between azithromycin and atazanavir are not expected.299
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.1,10 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and indinavir are used concomitantly.1,196,302
Lopinavir
Clinically important pharmacokinetic interactions between azithromycin and lopinavir are not expected.300
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.10 However, concomitant use of these drugs increases the peak plasma concentration and area under the concentration-time curve (AUC) of azithromycin by about twofold.1,10 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).1,10,196,302
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.10 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin is used concomitantly with efavirenz.1,196,302
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.10,196 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).10 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and didanosine are used concomitantly.1,196,302
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.1,10,196,302 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%.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.150,151,211 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.10
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.1 Azithromycin does not appear to alter the effects of oral midazolam on psychomotor performance or subjective feelings of sedation.149 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and midazolam or triazolam are used concomitantly.1,196,302
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.1,147,148 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and carbamazepine are used concomitantly.1,196,302
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.1,196,302
Cimetidine
Administration of cimetidine 800 mg 2 hours prior to azithromycin 500 mg had no effect on absorption or pharmacokinetics of azithromycin.1,10,146,193,196,202
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.1,10 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and co-trimoxazole are used concomitantly.1,196,302
Cyclosporine
Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased cyclosporine concentrations.1,10,196 Therefore, the patient should be carefully monitored if azithromycin and cyclosporine are used concomitantly.1,10,196
Digoxin
Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased digoxin concentrations.1,10,196 Therefore, the patient should be carefully monitored if azithromycin and digoxin are used concomitantly.1,10,196
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).1,10,196 Therefore, the patient should be carefully monitored if azithromycin and ergot alkaloids are used concomitantly.1,10,196
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.10 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.1 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and fluconazole are used concomitantly.1,196,302
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.355 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.355
Phenytoin
Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased phenytoin concentrations.1,10,196 Therefore, the patient should be carefully monitored if azithromycin and phenytoin are used concomitantly.1,10,196
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,243,244,245 the manufacturer of pimozide states that concomitant use of pimozide and macrolides (including azithromycin) is contraindicated.245
Rifabutin
Concomitant administration of azithromycin and rifabutin does not have a clinically important effect on the pharmacokinetics of rifabutin.1,10,196,302 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.10 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.10 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and rifabutin are used concomitantly.1,196,302
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.1,196,302
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.65,162,211 The manufacturer of azithromycin states that dosage adjustments are not necessary when azithromycin and IV or oral theophylline are used concomitantly.1,196,302
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.1,10,196,211,251 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).145,251
Warfarin
Azithromycin does not appear to affect the prothrombin time (PT) response to a single dose of warfarin1,10,196 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.10,192,195 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 azithromycin192 and concomitant use of warfarin and macrolides has been associated with increased anticoagulant effect in clinical practice.1,10,196,202,302 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.1,10,196,302
Other Information ⬆ ⬇
Acute Toxicity
Limited information is available on the acute toxicity of azithromycin.1,10,196,250,251 The acute lethal dose of the drug in humans is not known.250,251 The oral LD50 of azithromycin in mice or rats is 3000-4000 mg/kg.251
Mechanism of Action
Azithromycin usually is bacteriostatic,3,29,163,211,212,216 although the drug may be bactericidal in high concentrations against selected organisms.3,18,29,163,211,212,216 Bactericidal activity has been observed in vitro against Streptococcus pyogenes , S. pneumoniae , and Haemophilus influenzae .3,18,29,163,204,211,212,213
Azithromycin inhibits protein synthesis in susceptible organisms by penetrating the cell wall and binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis.1,3,10,29,163,164,167,196,202,211,216 The site of action of azithromycin appears to be the same as that of the macrolides (i.e., erythromycin, clarithromycin), clindamycin, lincomycin, and chloramphenicol.29,250 The antimicrobial activity of azithromycin is reduced at low pH.1,10,74,196 Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts.1,10,65,66,67,68,71,72,73,74,75,76,85,105,164,202 (See Pharmacokinetics: Distribution.) Penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus , Legionella pneumophila , Chlamydia trachomatis , Salmonella typhi ).65,66,67,68,71,72,73,74,75,76,104,105
Spectrum
Azithromycin has an expanded spectrum of activity compared with erythromycin and clarithromycin.3,29,163,164,204,207,210 Azithromycin is active in vitro against many gram-positive and gram-negative aerobic and anaerobic bacteria as well as Borrelia burgdorferi , Chlamydophila pneumoniae ( Chlamydia pneumoniae ), C. trachomatis , Mycoplasma pneumoniae , and Mycobacterium avium complex (MAC).1,3,5,10,11,29,33,34,39,40,41,89,111,163,164,166,167,168,169,196,206,210,211,214 Azithromycin generally is more active in vitro against gram-negative organisms than erythromycin or clarithromycin and has activity comparable to erythromycin against most gram-positive organisms.3,29,163,164,204,207,210,250 Azithromycin has in vitro microbiologic activity similar to clarithromycin or erythromycin against C. pneumoniae and M. pneumoniae , but clarithromycin is fourfold more active against MAC in vitro than azithromycin.29 Streptococci and staphylococci that are resistant to erythromycin usually are resistant to azithromycin and clarithromycin.1,10,29,163,196,202,207,210,212,213 Azithromycin is not inactivated by β-lactamases produced by H. influenzae or M. catarrhalis .1,10,17,18,196,202,210,211
Azithromycin appears to have a postantibiotic inhibitory effect against susceptible gram-positive and gram-negative aerobic organisms.63,64,163,251 In in vitro studies, exposure of S. pyogenes , S. pneumoniae , or H. influenzae for 1-2 hours to azithromycin concentrations several times higher than the MIC for the organism resulted in a recovery period of about 3-4, 2.2-5, or 2.5-8 hours, respectively, after the drug was removed before the organism resumed growth.63,64,163
In Vitro Susceptibility Testing
The in vitro activity of azithromycin is markedly affected by the pH of the microbiologic growth medium during incubation.3,10 Incubation in a carbon dioxide atmosphere will result in lowering of media pH (7.2 to 6.6 after 18 hours in 10% carbon dioxide) and an apparent reduction in in vitro susceptibility of gram-positive and gram-negative bacterial isolates to azithromycin.3,10 Thus, the initial pH of the growth medium should be 7.2-7.4, and the carbon dioxide content of the incubation atmosphere should be as low as practical.10
When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), clinical isolates identified as susceptible to azithromycin are inhibited by drug concentrations usually achievable when the recommended dosage is used for the site of infection.186 Clinical isolates classified as intermediate have minimum inhibitory concentrations (MICs) that approach usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.186 Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a higher than usual dosage can be used.186 This intermediate category also includes a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation, especially for drugs with narrow pharmacotoxicity margins.186 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to azithromycin, the strain is not inhibited by drug concentrations generally achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and clinical efficacy of the drug against the isolate has not been reliably demonstrated in clinical studies.186
The disk diffusion and dilution techniques used to determine susceptibility of gram-positive and gram-negative bacterial isolates should not be used to test susceptibility of MAC isolates to azithromycin.10 Interpretive criteria for MAC isolates that would represent susceptibility or resistance to azithromycin have not been established.10 In addition, the clinical relevance of azithromycin in vitro susceptibility tests results for other mycobacteria, including M. tuberculosis , using any susceptibility testing method has not been determined.10
Disk Susceptibility Tests
When the disk-diffusion procedure is used to test susceptibility to azithromycin, a disk containing 15 mcg of the drug should be used.186
When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus with growth inhibition zones of 18 mm or greater are susceptible to azithromycin, those with zones of 14-17 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.186
When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using Haemophilus test medium (HTM), Haemophilus with growth inhibition zones of 12 mm or greater are considered susceptible to azithromycin.186 Because of limited data on resistant strains, CLSI recommends that any Haemophilus isolate that appears to be nonsusceptible to azithromycin should be retested to confirm results and then submitted to a reference laboratory for further testing.186
When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures, S. pneumoniae or other streptococci (β-hemolytic streptococci, viridans streptococci) with growth inhibition zones of 18 mm or greater are susceptible to azithromycin, those with zones of 14-17 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.186
When testing susceptibility of Neisseria meningitidis using CLSI standardized procedures, strains with growth inhibition zones of 20 mm or greater are susceptible to azithromycin.186 However, these results only pertain to use of the drug for postexposure prophylaxis of meningococcal disease and do not apply to use of the drug for the treatment of invasive meningococcal disease.186 Because of limited data on resistant strains, CLSI recommends that N. meningitidis isolates that appear to be nonsusceptible to azithromycin should be retested to confirm results and then submitted to a reference laboratory for further testing.186
Dilution Susceptibility Tests
When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures, Staphylococcus with MICs of 2 mcg/mL or less are susceptible to azithromycin, those with MICs of 4 mcg/mL have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater are resistant to the drug.186
When CLSI standardized procedure for broth dilution is performed using HTM, Haemophilus with MICs of 4 mcg/mL or less are considered susceptible to azithromycin.186 Because of limited data on resistant strains, any Haemophilus isolate that appears to be nonsusceptible to azithromycin should be retested to confirm results and then submitted to a reference laboratory for further testing.186
When broth dilution susceptibility testing for streptococci is performed according to CLSI standardized procedures, S. pneumoniae or other streptococci (β-hemolytic streptococci, viridans streptococci) with MICs of 0.5 mcg/mL or less are susceptible to azithromycin, those with MICs of 1 mcg/mL have intermediate susceptibility, and those with MICs of 2 mcg/mL or greater are resistant to the drug.186
When testing susceptibility of Neisseria meningitidis using CLSI standardized procedures, strains with MICs of 2 mcg/mL or less are susceptible to azithromycin.186 However, these results only pertain to use of the drug for postexposure prophylaxis of meningococcal disease and do not apply to use of the drug for the treatment of invasive meningococcal disease.186 Because of limited data on resistant strains, CLSI recommends that N. meningitidis isolates that appear to be nonsusceptible to azithromycin should be retested to confirm results and then submitted to a reference laboratory for further testing.186
Gram-positive Aerobic Bacteria
Azithromycin is active in vitro and in vivo against Staphylococcus aureus , Streptococcus agalactiae , S. pneumoniae , and S. pyogenes .1,3,10,17,29,163,164,196,202,204,207,210,211,212,213,215 The MIC90 (minimum inhibitory concentration of the drug at which 90% of tested strains are inhibited) of azithromycin for erythromycin-susceptible S. aureus is 1 mcg/mL;163,212 the MIC90 for S. agalactiae is 0.12 to greater than 12 mcg/mL.3,163,212 The MIC90 of azithromycin for S. pneumoniae or S. pyogenes is 0.12-2 or 0.12-4, respectively.3,163,201,207,211,212 The MIC90 of azithromycin for groups C, F, or G streptococci and viridans streptococci is 0.12-0.25 mcg/mL.1,10,17,196,202,207,211,212,213 The MIC of azithromycin for most staphylococci and streptococci generally are similar to or twofold higher than those for erythromycin; azithromycin does not inhibit erythromycin-resistant isolates of these species.1,10,17,29,163,164,196,204,212,213 Methicillin-resistant staphylococci1,10,29,163,196,202,207,210,212,213 and coagulase-negative staphylococci (e.g., Staphylococcus epidermidis )1,10,16,17,29,196,207,211,212 generally are resistant both to azithromycin and erythromycin. Azithromycin is not active against enterococci (e.g., Enterococcus faecalis [formerly S. faecalis ]).1,3,10,29,164,196,211,212
The MIC90 of azithromycin for Listeria monocytogenes is 2-4 mcg/mL.3,207,211,212
Gram-negative Aerobic Bacteria
Azithromycin is twofold to eightfold more active than erythromycin against erythromycin-susceptible gram-negative organisms.3,212 Azithromycin is active in vitro and in vivo against Haemophilus influenzae , H. ducreyi , Moraxella catarrhalis , Legionella pneumophila , and Neisseria gonorrhoeae .1,3,10,17,18,19,20,26,29,59,163,164,196,202,204,207,208,211,212,213,232 Azithromycin also is active in vitro against N. meningitidis 346,348 and some strains of Bordetella pertussis 1 and Legionella pneumophila .1,196
Azithromycin is not inactivated by β-lactamases produced by H. influenzae or M. catarrhalis .1,10,17,18,196,202,210,211 The MIC90 of azithromycin for H. influenzae or M. catarrhalis is 1 or 0.03-0.5 mcg/mL, respectively.3,163,207,212 The MIC90 of azithromycin for H. ducreyi is less than 0.125 mcg/mL.228 The MIC90 of azithromycin for L. pneumophila , N. gonorrhoeae , Bordetella pertussis , or Campylobacter jejuni ranges from 0.03-2 mcg/mL.1,3,10,25,26,29,37,163,164,196,202,204,207,211,212,213
Azithromycin may be more active in vitro than erythromycin against Escherichia coli , Salmonella , and Shigella .23,24,25,27,29,30,203,211,212
Azithromycin concentrations of 0.006-0.03 inhibit some strains of Bartonella henselae B. quintana , B. bacilliformis , B. vinsonii , and B. elizabethae in vitro.310
Azithromycin and erythromycin are less active than clarithromycin against Helicobacter pylori (formerly C. pylori ); the MIC90 of clarithromycin for H. pylori is 0.03 mcg/mL versus 0.25 mcg/mL for azithromycin or erythromycin.21,22,29,164,211,212
Mycobacteria
Azithromycin has in vitro and in vivo activity against Mycobacterium avium complex (MAC) organisms.3,5,10,11,39,40,41,89,111,165,166,167,168,169 MAC represents 2 closely related organisms, M. avium and M. intracellulare .3,5,10,11,39,40,41,111 Although gene probe techniques may be used to distinguish M. avium species from M. intracellulare , most studies do not distinguish between the organisms and report results on MAC isolates.3,5,10,11,39,40,41,111 Azithromycin has activity against phagocytized MAC organisms in mouse and human macrophage cell cultures and in the beige mouse infection model.3,5,10,11,39,40,41,111 MAC organisms resistant to clarithromycin also are resistant to azithromycin.11,44,45,166,167,168,169
M. tuberculosis ,40M. kansasii ,40,56M. scrofulaceum ,40M. chelonae ,40,42M. fortuitum 40,42 and M. leprae 43 are resistant to azithromycin.
Anaerobic Bacteria
Azithromycin has in vitro activity (i.e., MIC90 of 2 mcg/mL or less) against Clostridium perfringens and Peptostreptococcus spp.1,3,10,196,207,211,212 Like erythromycin and clarithromycin, azithromycin is active in vitro against Propionibacterium acnes ,3,211,212 with an MIC90 for this organism of 0.03 mcg/mL.3,211,212
Azithromycin is active in vitro against most Prevotella (formerly Bacteroides ) spp. associated with bacterial vaginosis.29,38,211 The MIC90 of azithromycin for P. bivia , P. disiens , P. melaninogenica , or Bacteroides ureolyticus is 2 mcg/mL or less.1,10,38,196,202,211 B. fragilis spp. generally are resistant to azithromycin.3,38,164,211,212,213
Chlamydiae
Azithromycin is active in vitro and in vivo against Chlamydophila pneumoniae ( Chlamydia pneumoniae ) and C. trachomatis .1,3,10,29,31,32,33,34,35,163,196,202,204,206,210,211,212,214 The MIC90 of azithromycin for C. pneumoniae is 0.25 mcg/mL and for C. trachomatis is 0.06-1 mcg/mL.32,163,211,212 The reported MIC of azithromycin for C. psittaci is 0.125 mcg/mL.214
Mycoplasma
The MIC90 of azithromycin for Mycoplasma pneumoniae is 0.25 mcg/mL, and the MIC90 reported for Ureaplasma urealyticum is 0.5-4 mcg/mL.16,36,90,212 The activity of azithromycin against M. pneumoniae generally is comparable to that of erythromycin or clarithromycin, but azithromycin has less activity than clarithromycin against U. urealyticum .1,3,10,16,29,36 The MIC90 of azithromycin for M. hominis reportedly ranges from 4-32 mcg/mL.16,36,90,196
Spirochetes
Azithromycin has exhibited in vitro and in vivo activity against Borrelia burgdorferi (the causative agent of Lyme disease).3,10,26,46,47,88,202,210,211 The MIC90 of azithromycin for B. burgdorferi is 0.015-0.03 mcg/mL.46,47,211
Azithromycin is active in vitro against Treponema pallidum ; however, the safety and efficacy of azithromycin in treating infections caused by this organism has not been clearly established.1,3,10,87,158,202,211,212
Other Organisms
Azithromycin has exhibited in vitro and in vivo activity against T. gondii .3,48,49,50,51,52,212 In addition, synergistic activity against Toxoplasma gondii has been reported in in vitro studies employing azithromycin with pyrimethamine.53 Limited data in animals indicate that azithromycin with either pyrimethamine or sulfadiazine produces enhanced anti- Toxoplasma activity (i.e., greater reduction in blood and organ parasite burden, lower incidence of relapse following discontinuation of therapy, reduced mortality rate) compared with administration of azithromycin, pyrimethamine, or sulfadiazine alone.54
Azithromycin is active in vitro against Entamoeba histolytica .55
Azithromycin is active against Plasmodium falciparum ,340,357 Orientia tsutsugamushi (formerly Rickettsia tsutsugamushi ),366 Rickettsia conorii ,367 R. typhi ,367 and Coxiella burnettii .367
Resistance
Resistance to macrolide antibiotics may be natural or acquired.3,29,58,60,61,62,166,167,168,169,210,216 Resistance to macrolide antibiotics may be related to decreased permeability of the cell envelope (e.g., Enterobacteriaceae, Pseudomonas spp., Acinetobacter spp.), plasmid-mediated active efflux of the antibiotic (e.g., Staphylococcus epidermidis ), enzymatic inactivation of antibiotic by plasmid-mediated esterases or phosphotransferase (e.g., Enterobacteriaceae), chromosomal-mediated alteration of a single 50S ribosomal protein at the receptor site resulting in decreased macrolide binding affinity (e.g., Streptococcus pyogenes , some Campylobacter spp., Escherichia coli ), or alteration of the 23S ribosomal RNA of the 50S ribosomal subunit by methylation of adenine resulting in decreased macrolide binding to the receptor site (e.g., Staphylococcus aureus , streptococci, enterococci, Campylobacter spp., Bacteroides fragilis , Clostridium perfringens , Listeria spp., Mycoplasma pneumoniae , Legionella spp.).3,29,58,60,61,62,166,210,216 Resistance as a result of alteration of the 23S ribosomal RNA is referred to as MLSB phenotype, is usually mediated by plasmids or transposons, may be constitutive or induced, and generally results in resistance to other 14- and 15-membered macrolides.3,29,58,60,61,62
Resistance in Gram-positive Bacteria
The overall incidence of macrolide-resistant Streptococcus pyogenes (group A β-hemolyte streptococci) in the US is reported to be 3-9%.309 In one US study, about 7% of S. pyogenes isolates (principally pharyngeal isolates) were resistant to azithromycin.309
Resistance in Neisseria and Treponema
In 1999, Neisseria gonorrhoeae with reduced susceptibility to azithromycin were isolated from a cluster of 12 men with gonorrhea in Kansas City, MO.286,304 These isolates had a median azithromycin MIC of 2 mcg/mL (range: 1-4 mcg/mL) and also were resistant to tetracycline (MIC 1-2 mcg/mL); however, they were susceptible to ceftriaxone, cefixime, spectinomycin, ciprofloxacin, and penicillin.286
A mutation in Treponema pallidum that confers resistance to macrolides (including azithromycin) has been identified.327 T. pallidum containing this mutation has been isolated from several syphilis patients in San Francisco who failed to respond to azithromycin treatment.327 The overall prevalence of this mutation in T. pallidum has not been determined, but it has been found in specimens obtained in the US (Baltimore, San Francisco, Seattle) and Ireland (Dublin).327
Resistance in Mycobacteria
Macrolide-resistant Mycobacterium avium complex (MAC) isolates have been detected in patients with disseminated MAC infections receiving macrolide (i.e., azithromycin, clarithromycin) therapy.10,12,122,166,168,169 In studies evaluating prevention of disseminated MAC disease, drug-resistant isolates were detected in 29-58% of individuals in whom disease developed while receiving clarithromycin and 11% of those receiving azithromycin.11,12,13
Although the mechanism(s) of resistance or reduced susceptibility of MAC to clarithromycin or azithromycin has not been fully determined to date, base substitution within domain V (the peptidyl transferase region) of the 23S ribosomal RNA gene, resulting in a residue change from adenine to cytosine, guanine, or thymine at position 2274, appears to be the principal mechanism in individuals receiving such therapy.12,166,167 Limited evidence indicates that these changes in the peptidyl transferase loop result in a conformational change in the ribosome at the macrolide binding site.166,167
Cross-resistance
Streptococci and staphylococci that are resistant to erythromycin also are resistant to azithromycin and clarithromycin.1,10,29,163,196,202,207,210,212,213
MAC isolates resistant to azithromycin also are resistant to clarithromycin and complete cross-resistance occurs between these anti-infectives for this organism.10,11,44,45,166,167,168,169 Cross-resistance in these isolates appears to be the result of a single point mutation at the position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene.10 MAC isolates exhibiting cross-resistance generally have an increase in azithromycin MICs to 128 mcg/mL or greater or clarithromycin MICs to 32 mcg/mL or greater (determined using a radiometric broth dilution susceptibility test with Middlebrook 7H12 medium).10 Although the clinical importance of cross-resistance between azithromycin and clarithromycin is not fully understood, preclinical data suggest that reduced activity to both drugs will occur after MAC isolates produce the 23S rRNA mutation.10
Pharmacokinetics
The pharmacokinetic profile of azithromycin is characterized by low plasma drug concentrations but high and persistent tissue concentrations.1,3,10,65,70,202 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.3,65,66,67,68,104,163,202
Absorption
Azithromycin is rapidly absorbed from the GI tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin.1,3,65,66,67,68,202,211 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).3,10,11,66,67,68,131,163,170,196,200 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.200
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).10,170 Limited data also indicate similar pharmacokinetic parameters for azithromycin capsules and tablets.1,251 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.1
The commercially available extended-release oral suspension of azithromycin (Zmax®) is not bioequivalent with the conventional oral suspension or tablets (Zithromax®).302 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.302 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.302 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.1,3,65,70,196,211 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.1,65,70 In this study, the disposition of azithromycin in these men and women was similar.1
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.10 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 15.10
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.1,69 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.1,86,251 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.252
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;70 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.1
Pharmacokinetic values for azithromycin following IV administration in patients with community-acquired pneumonia are similar to those in healthy individuals.196 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.196,223 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.196 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 AUC0-24.196
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.196 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.196
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.1,10,170,202
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.1,10,170 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.10,170,251 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).1 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.1,10 Food-associated increases in azithromycin plasma concentration reportedly are short-lived, persisting for less than 4 hours.170,251
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.302 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.302
Distribution
Azithromycin appears to be distributed into most body tissues and fluids after oral or IV administration.1,3,10,65,66,67,68,71,131,163,164,196,202 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.1,10,29,65,66,67,68,72,104,105,164,210
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.1,65,67,71,164 Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts, as demonstrated by in vitro incubation techniques.1,10,65,66,67,68,71,72,73,74,75,76,85,105,164,202 Because azithromycin is released more slowly from phagocytes than is erythromycin, substantial azithromycin concentrations are maintained for prolonged periods within these cells.65,67,71 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 816.10 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.10 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.10 The concentration of azithromycin achieved within phagocytes substantially exceeds that of other antimicrobial agents, including erythromycin.65,66,67,68,71,72,73,74,75,76 In human polymorphonuclear leukocytes exposed in vitro to azithromycin or erythromycin for 24 hours, intracellular azithromycin concentrations were tenfold higher than those of erythromycin.65,67,71
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.1,10,65,66,67,71,85,164 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.65,66,67,68,164 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.65,164 The presence of azithromycin within phagocytes does not appear to have clinically important effects on phagocytic function.65,67,71,72,164
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.1,3,10,65,66,67,84,163,164,202 While extensive distribution of the drug to tissues may be relevant to clinical activity,1,3,10,65,66,67,68,202,210 a quantitative relationship between high tissue concentration and clinical efficacy has not been established.1,10,74,104 The antimicrobial activity of azithromycin is pH related (i.e., only un-ionized azithromycin has antimicrobial activity).1,10,74 Because lysosomes have a low intraorganelle pH, a substantial portion of azithromycin within the lysosome is ionized (and therefore inactive) drug.1,10,74,104,105
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.1,10,65,196,202,210 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.1,10,11,65,77,196,202,210 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.80,210,211 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.1,10,78,196,202 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.79,163
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.81 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.81
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.82 In addition, azithromycin concentrations greater than 1 mcg/g were detected in liver, kidney, bladder wall, adrenal gland, bone, testicle, epididymis, and vas deferens.82 Distribution of azithromycin into ejaculate also has been reported.1,10,202
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.1,10,196,202 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.196 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.83
Following administration of azithromycin as a single 500-mg oral dose, azithromycin concentrations in skin averaged 0.4 mcg/g at 73 hours.1,10,196,202
Only very low concentrations of azithromycin (less than 0.01 mcg/mL) have been detected in CSF in the presence of noninflamed meninges.1,10,196,202
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.196
The serum protein binding of azithromycin decreases with increasing drug concentration over a concentration range of 0.02-2 mcg/mL.1,3,10,65,66,67,131,163,196,202,210,211 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.1,3,10,65,66,67,131,163,196,202,210,211,302
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.172 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.171 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.171
Azithromycin crosses the placenta and is distributed into cord blood and amniotic fluid.368,369
Azithromycin is distributed into milk.144
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.1,10,131,163,196,198 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.1,3,10,65,70,196,198,202 The average tissue half-life of azithromycin is estimated to be 1-4 days.65,66,67,131 The half-life of the drug in peripheral leukocytes ranges from 34-57 hours.10 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.65,66,67,131,198,211
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.252
Azithromycin is excreted in feces principally as unchanged drug.65,66,67,68,163,210,211 The principal route of biotransformation involves N -demethylation of the desosamine sugar or at the 9a position on the macrolide ring.65,66,67,68,210,211 Other metabolic pathways include O -demethylation and hydrolysis and/or hydroxylation of the cladinose and desosamine sugar moieties and the macrolide ring.211 Up to 10 metabolites of azithromycin have been identified, and all are microbiologically inactive.65,66,67,210,211 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.65,67 In contrast to erythromycin, azithromycin does not inhibit its own metabolism via this pathway.65
Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination following oral administration.1,2,10,65,66,67,68,163,196,210,211,302 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.65,163,210,211 Only a small portion of each azithromycin dose is excreted in urine.1,2,10,65,66,67,68,131,163,196,210,211 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 5.1,2,10,66,67,131,163,196,211,251
The manufacturer states that azithromycin has not been systematically evaluated in patients with hepatic impairment.1,10,196,202 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.163,173,211
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.1,10,196
Chemistry and Stability
Chemistry
Azithromycin is a semisynthetic10 azalide antibiotic, a subclass of macrolide antibiotics.1,3,10,65,163,196,198,202,204,207,209,210,211,212 Azalides are distinguished from other macrolides by the addition of nitrogen at position 9a of the lactone ring.1,3,10,65,163,196,198,202,204,207,209,210,211,212,251 Azithromycin differs structurally from erythromycin by the addition of a methyl-substituted nitrogen atom at the 9a position of the macrolide ring.1,3,10,65,163,196,198,202,204,207,209,210,211,212 This structural modification in azithromycin results in resistance to acid degradation, improved tissue-penetration characteristics, improved activity against gram-negative organisms, and a prolonged elimination half-life compared with erythromycin.3,26,65,163,198,207,210
Azithromycin is commercially available as the dihydrate; potency is calculated on the anhydrous basis.1,10,196,202 Azithromycin dihydrate occurs as a white crystalline powder1,10,196,202 and has solubilities of 39 mg/mL in water (pH 7.4) at 37°C.251
For oral administration, azithromycin is commercially available as film-coated tablets,1 conventional powder for oral suspension,1 and extended-release microspheres for oral suspension. The extended-release oral suspension contains 148 mg (6.43 mEq) of sodium per 2-g dose.302
Azithromycin for injection is a sterile, lyophilized, white to off-white powder; each 500-mg vial of azithromycin for injection contains approximately 413.6 mg of citric acid and 198.3 mg of sodium hydroxide.196,251 Intact vials of azithromycin for injection contain a vacuum.196 Following reconstitution of azithromycin for injection with sterile water for injection, solutions containing 100 mg of azithromycin per mL are clear and colorless and have an a pH of 6.4-6.6.251
Stability
Commercially available azithromycin 250- or 500-mg tablets should be stored at 15-30°C.1
Azithromycin 600-mg tablets or powder for multiple-dose oral suspension should be stored at temperatures below 30°C.10,202,302 Following reconstitution as directed, the multiple-dose oral suspension of azithromycin should be stored in tight containers at 5-30°C; any unused suspension should be discarded after 10 days.1
Azithromycin powder in single-dose packets for oral suspension should be stored at 5-30°C.10 Following reconstitution, the entire contents of the single-dose packet should be ingested immediately.10
Azithromycin powder for extended-release oral suspension (Zmax®) should be stored at 30°C or lower.302 Following reconstitution, azithromycin single-dose extended-release oral suspension should be stored in the original bottle at 25°C but may be exposed to 15-30°C. The reconstituted suspension should be consumed within 12 hours.302
Commercially available azithromycin for injection should be stored at or below 30°C.251 Following reconstitution with sterile water for injection, solutions containing 100 mg of azithromycin per mL are stable for 24 hours when stored below 30°C.196 Azithromycin is physically and chemically compatible with the following IV solutions: 0.45% or 0.9% sodium chloride, 5% dextrose, 5% dextrose and 0.3% or 0.45% sodium chloride, 5% dextrose and 0.45% sodium chloride with 20 mEq potassium chloride, 5% dextrose in lactated Ringer's, lactated Ringer's, Normosol®-M in 5% dextrose, and Normosol®-R in 5% dextrose.196 Reconstituted solutions of azithromycin that have been further diluted with 250-500 mL of one of these IV solutions to provide a solution containing 1-2 mg/mL are physically and chemically stable for 24 hours when stored at or below room temperature (30°C) or 7 days when refrigerated at 5°C.196
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Azithromycin Dihydrate
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Oral | For suspension | 100 mg (of anhydrous azithromycin) per 5 mL* | Azithromycin for Suspension | |
| | | Zithromax® | Pfizer |
| | 200 mg (of anhydrous azithromycin) per 5 mL* | Azithromycin for Suspension | |
| | | Zithromax® | Pfizer |
| | 1 g (of anhydrous azithromycin) per packet* | Azithromycin for Suspension | |
| | | Zithromax® Single Dose Packets | Pfizer |
| For suspension, extended-release | 2 g (of anhydrous azithromycin) | Zmax® | Pfizer |
| Tablets, film-coated | 250 mg (of anhydrous azithromycin)* | Azithromycin Tablets | |
| | | Azithromycin Tablets (available as a 5-day mnemonic pack of 6 tablets) | |
| | | Zithromax® | Pfizer |
| | | Zithromax® Z-Paks® (available as a 5-day mnemonic pack of 6 tablets) | Pfizer |
| | 500 mg (of anhydrous azithromycin)* | Azithromycin Tablets | |
| | | Azithromycin Tablets (available as a 3-day mnemonic pack of 3 tablets) | |
| | | Zithromax® | Pfizer |
| | | Zithromax® Tri-Paks® (available as a 3-day mnemonic pack of 3 tablets) | Pfizer |
| | 600 mg (of anhydrous azithromycin)* | Azithromycin Tablets | |
| | | Zithromax® | Pfizer |
Parenteral | For injection, for IV infusion only | 500 mg (of anhydrous azithromycin)* | Azithromycin for Injection | |
| | | Zithromax® | Pfizer |
| | 2.5 g (of anhydrous azithromycin)* | Azithromycin for Injection | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions August 7, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
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