Azithromycin (Systemic)

• Zithromax
• Zithromax Tri-Pak
• Zithromax Z-Pak
• Zmax

Acne vulgaris

Data from controlled trials support the use of azithromycin in the treatment of acne vulgaris in adults with moderate to severe acne.

Based on the American Academy of Dermatology guidelines of care for the management of acne vulgaris, azithromycin, in combination with topical therapy, may be considered as a treatment option for moderate and severe acne and forms of inflammatory acne that are resistant to topical treatments. However, its use should be limited to patients who cannot receive a tetracycline (ie, pregnant women or children <8 years). Concomitant topical therapy with benzoyl peroxide or a retinoid should be administered with systemic antibiotic therapy (eg, azithromycin) and continued for maintenance after the antibiotic course is completed.

Babesiosis

Data from a prospective, nonblinded, randomized trial in patients with non-life-threatening babesiosis, support the use of azithromycin (in combination with atovaquone) for the treatment of this condition [Krause 2000]. Clinical experience also suggests the utility of azithromycin (in combination with atovaquone) for the treatment of immunocompetent patients with mild-to-moderate babesiosis [Vannier 2012]. Additional trials may be necessary to further define the role of azithromycin in the treatment of this condition.

Based on the Infectious Diseases Society of America (IDSA) guidelines for the clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis, azithromycin (in combination with atovaquone) is effective and recommended for the treatment of babesiosis.

Bronchiolitis obliterans syndrome

Data from two retrospective observational studies, a prospective observational study, and several case series found that 30% to 83% of lung transplant patients with bronchiolitis obliterans syndrome (BOS) had improved lung function (increase in FEV1 of ≥10%) after receiving azithromycin treatment; however, in some studies, nonresponders experienced lung function decline [Gottlieb 2008], [Jain 2010], [Meyer 2014], [Vos 2010]. Two of the observational studies found that lower mortality was seen in select patients (ie, early post-transplant or BOS stage 1) who received azithromycin treatment [Jain 2010], [Vos 2010]. Additional data may be necessary to further define the role of azithromycin for the treatment of BOS.

The International Society for Heart and Lung Transplantation, American Thoracic Society, and European Respiratory Society (ISHLT/ATS/ERS) clinical practice guidelines for the diagnosis and management of BOS suggest a trial of azithromycin (continuous treatment for a minimum of 3 months) for lung transplant patients who experience a decline in forced expiratory volume in 1 second (FEV1) consistent with the onset of BOS

Cat scratch disease

Data from a prospective, randomized, double-blind, placebo controlled trial in patients (children and adults) with cat scratch disease caused by Bartonella henselae supports the use of azithromycin for the treatment of this condition [Bass 1998].

Based on the Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of skin and soft tissue infections (SSTI), azithromycin is an effective and recommended treatment for cat scratch disease.

Cesarean section (nonelective), prophylaxis (preoperative)

Data from a prospective, randomized, double-blind, placebo-controlled trial in patients undergoing nonelective cesarean section support the use of a single preoperative dose of azithromycin IV, in conjunction with standard preoperative antibiotics, to reduce postpartum maternal infection rate [Tita 2016]. Additional data may be necessary to further define the role of azithromycin in this condition.

Cholera

Data from a prospective, double-blind, randomized trial supports the use of azithromycin for the treatment of severe cholera in adults [Saha 2006].

Gonococcal conjunctivitis

Based on the Centers for Disease Control and Prevention (CDC) sexually transmitted diseases treatment guidelines, azithromycin in combination with ceftriaxone is an effective and recommended treatment for patients with conjunctivitis due to gonorrhea.

Gonococcal, disseminated infections (arthritis, arthritis-dermatitis syndrome, meningitis, and endocarditis)

Based on the CDC sexually transmitted diseases treatment guidelines, azithromycin in combination with ceftriaxone is an effective and recommended treatment for patients with disseminated gonococcal infections including arthritis, arthritis-dermatitis syndrome, meningitis, and endocarditis.

Gonococcal infection, expedited partner therapy

Based on the CDC sexually transmitted diseases treatment guidelines, azithromycin in combination with cefixime is an effective and recommended treatment of gonorrhea only in the following circumstances: Heterosexual partners with gonorrhea if health department partner-management strategies are impractical/unavailable and there is concern by the provider for the prompt evaluation and treatment of the partner; medication may be delivered to partner by patient, collaborating pharmacy, or disease investigation specialist as permitted by law; written materials to educate partners about their exposure to gonorrhea, importance of therapy, and when to seek clinical evaluation for adverse reactions/complications must also be provided with the medication.

Gonococcal, uncomplicated infections of the pharynx or rectum

Based on the CDC sexually transmitted diseases treatment guidelines, azithromycin in combination with ceftriaxone is an effective and recommended treatment for patients with uncomplicated gonococcal infections of the pharynx or rectum.

Granuloma inguinale (donovanosis)

Based on the CDC sexually transmitted diseases treatment guidelines, azithromycin is an effective and recommended agent in the treatment of granuloma inguinale.

Group A streptococcal pharyngitis (children); 3-day regimen

Guidelines recommend a 5-day azithromycin regimen (FDA approved) as a possible alternative in pediatric patients with group A streptococcal (GAS) pharyngitis who are sensitive to beta-lactams. Azithromycin 3-day regimens have produced variable results, which may be dose dependent. Larger controlled trials are needed to establish the optimal dose of a 3-day regimen.

Helicobacter pylori infection

Several trials have evaluated the use of azithromycin in combination with other agents for the treatment of H. pylori infection and noted conflicting results. Current guidelines do not address its use. Considering the large body of evidence supporting the efficacy of other available agents, azithromycin cannot be recommended for routine inclusion in Helicobacter eradication regimens until controlled studies can unequivocally demonstrate its place in therapy.

Infection prophylaxis in neutropenia (adults)

Infectious Diseases Society of America (IDSA) and American Society for Blood and Marrow Transplantation (ASBMT) guidelines recommend the use of fluoroquinolone prophylaxis in high-risk adult cancer patients (anticipated duration of neutropenia of at least 7 days) to reduce the risk for febrile episodes and infectious complications. The ASBMT lists azithromycin as an alternative to fluoroquinolones as bacterial prophylaxis for adult hematopoietic stem cell transplant (HSCT) patients; this recommendation appears to be based on expert opinion. The IDSA does not recommend combining agents (eg, macrolides, penicillins, rifampin) with fluoroquinolones to enhance gram-positive coverage for prophylaxis.

Infective endocarditis (prophylaxis)

Based on the American Heart Association (AHA) guidelines for the prevention of infective endocarditis, azithromycin is an effective and recommended alternative for administration to patients with certain cardiac conditions who are allergic to penicillins or ampicillin to provide prophylaxis against infective endocarditis associated with dental procedures.

Lyme disease

Based on the IDSA guidelines for the Clinical Assessment, Treatment and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis, azithromycin is an effective and recommended alternative agent for the treatment of early localized or disseminated lyme disease (erythema migrans or borrelial lymphocytoma) in patients who are unable to take or who are intolerant of tetracyclines, penicillins, or cephalosporins.

Mycobacterium avium complex, pulmonary disease, in non-HIV-infected patients:

Based on the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) Guideline for the Diagnosis, Treatment, and Prevention of Nontuberculosis Mycobacterial Disease, azithromycin (in combination with other antimicrobials) is effective and recommended for the treatment of Mycobacterium avium complex (MAC) pulmonary disease in non-HIV-infected patients.

Mycoplasma genitalium

A meta-analysis of controlled trials and observational studies supports the use of azithromycin in the management of Mycoplasma genitalium but notes that overall susceptibility to the drug appears to be decreasing, with cure rates of less than 70% reported since 2009.

Centers for Disease Control and Prevention (CDC) guidelines for treatment of sexually transmitted diseases (STDs) state that azithromycin is more effective and preferred over doxycycline for the treatment of M. genitalium. The extended 5-day regimen may be slightly more effective than single-dose therapy and be less likely to select for macrolide resistance of M. genitalium.

Nontuberculous mycobacterial disease

Based on the American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) Guideline for the Diagnosis, Treatment, and Prevention of Nontuberculosis Mycobacterial Disease and the US Cystic Fibrosis (CF) Foundation and European CF Society Consensus Recommendations for the Management of Nontuberculous Mycobacteria in Individuals with Cystic Fibrosis, azithromycin (in combination with other antimicrobials) is effective and recommended for the treatment of Mycobacterium abscessus pulmonary disease in patients with CF and M. abscessus skin, soft tissue, and bone infection.

Prevention of exacerbations of chronic obstructive pulmonary disease (COPD)

Data from randomized, placebo-controlled trials support the use of azithromycin in prevention of exacerbations of COPD [Albert 2011], [Uzun 2014].

Prevention of pulmonary exacerbations with noncystic fibrosis bronchiectasis

Data from a randomized, double-blind, placebo-controlled trial in patients with at least one pulmonary exacerbation requiring antibiotic treatment in the prior year with a diagnosis of bronchiectasis defined by high-resolution CT supports the use of azithromycin for the prevention of exacerbations in patients with noncystic fibrosis bronchiectasis [Wong 2012].

Prophylaxis against sexually transmitted diseases following sexual assault

Based on the CDC sexually transmitted diseases treatment guidelines, azithromycin in combination with ceftriaxone (plus metronidazole or tinidazole), is a recommended regimen for prophylaxis against sexually transmitted diseases following sexual assault in adolescents and adults.

Shigella dysenteriae type 1

Based on the World Health Organization (WHO) guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1, azithromycin, as an alternative to ciprofloxacin, may be used to treat this condition although there is limited data on efficacy.

Syphilis, primary and secondary

Based on the CDC sexually transmitted diseases treatment guidelines, azithromycin is a recommended alternative treatment for primary and secondary syphilis in patients who are unable to receive penicillin or doxycycline. Note: Azithromycin should be used with caution and should not be used to treat syphilis in patients with HIV, pregnant women, or in the MSM population.

Traveler’s diarrhea

Data from two prospective, randomized, double-blind trials in a limited number of patients support the use of azithromycin, with or without loperamide, as an effective treatment alternative for patients with traveler’s diarrhea. The use of azithromycin may even be superior to fluoroquinolones especially in areas in which fluoroquinolone resistance rates are increasing [Ericsson 2007], [Tribble 2007]. Additional trials may be necessary to further define the role of azithromycin in the treatment of this condition.

Based on the CDC, azithromycin given for traveler’s diarrhea is effective and is suggested as an acceptable alternative to fluoroquinolones in the management of this condition, especially when fluoroquinolone resistance has been reported.

Toxoplasma gondii encephalitis (treatment) in HIV-infected patients (adults and adolescents)

Based on the US Department of Health and Human Services (HHS) Guidelines for Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents, azithromycin, in combination with pyrimethamine and leucovorin, is an effective and recommended alternative regimen in the treatment of Toxoplasma gondii encephalitis in adolescent and adult HIV-infected patients.

Additional Off-Label Uses

Pertussis

Note: Extended-release suspension (Zmax) is not interchangeable with immediate-release formulations. Use should be limited to approved indications. All doses are expressed as immediate release azithromycin unless otherwise specified.

Acne vulgaris (off-label use): Oral: Dosing regimens used in clinical trials have varied greatly. All trials used pulse-dosing regimens; regimens included: 500 mg once daily for 4 consecutive days per month for 3 consecutive months (Babaeinejad 2011; Parsad 2001) or 500 mg once daily for 3 days in the first week, followed by 500 mg once weekly until week 10 (Maleszka 2011) or 500 mg once daily for 3 consecutive days each week in month 1, followed by 500 mg once daily for 2 consecutive days each week in month 2, then 500 mg once daily for 1 day each week in month 3 (Kus 2005). The shortest possible duration should be used to minimize development of bacterial resistance; re-evaluate at 3 to 4 months (AAD [Zaenglein 2016]).

Babesiosis (off-label use): Oral: 500 to 1,000 mg on day 1, followed by 250 mg once daily for 7 to 10 days with atovaquone; higher doses may be required in immunocompromised patients (600 to 1,000 mg daily). Note: Relapsing infection may require at least 6 weeks of therapy (Krause 2000; Vannier 2012; IDSA [Wormser 2006]).

Bacterial sinusitis, acute: Oral: 500 mg daily for a total of 3 days

Extended-release suspension (Zmax): 2 g as a single dose

Bronchiolitis obliterans syndrome (off-label use): Oral: 250 mg daily for 5 days, followed by 250 mg 3 times per week for a minimum of 3 months (Meyer 2014). Note: It is unclear whether azithromycin should be continued long-term if a benefit is observed or if it should be discontinued if lung function does not improve (Meyer 2014).

Cat scratch disease (off-label use): Oral: ≥45.5 kg: 500 mg as a single dose, then 250 mg once daily for 4 additional days (Bass 1998; Stevens 2014)

Cesarean section (nonelective), prophylaxis (preoperative) (off-label use): IV: 500 mg as a single dose 1 hour prior to surgical incision; used in conjunction with standard preoperative antibiotics (Tita 2016)

Chancroid due to H. ducreyi: Oral: 1 g as a single dose. Note: Data are limited concerning the efficacy in HIV infected patients (CDC [Workowski 2015]).

Chlamydia trachomatis infection: Oral: 1 g as a single dose (CDC [Workowski 2015])

Cholera (off-label use): Oral: 1 g as a single dose (Saha 2006)

Community-acquired pneumonia:

Oral: 500 mg on day 1 followed by 250 mg once daily on days 2 to 5

Extended-release suspension (Zmax): 2 g as a single dose

IV: 500 mg as a single dose for at least 2 days, follow IV therapy by the oral route with a single daily dose of 500 mg to complete a 7- to 10-day course of therapy. Note: Guidelines recommend a duration of ≥5 days dosing (IDSA/ATS [Mandell 2007])

Gonococcal infection, conjunctivitis (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (CDC [Workowski 2015])

Gonococcal infection, disseminated (arthritis, arthritis-dermatitis, meningitis, endocarditis) (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (CDC [Workowski 2015])

Gonococcal infection, expedited partner therapy (off-label use): Oral: 1 g as a single dose in combination with cefixime (CDC [Workowski 2015]). Note: To be used only for heterosexual partners with gonorrhea if health department partner-management strategies are impractical/unavailable and there is concern by the provider for the prompt evaluation and treatment of the partner; medication may be delivered to partner by patient, collaborating pharmacy, or disease investigation specialist as permitted by law; written materials to educate partners about their exposure to gonorrhea, importance of therapy, and when to seek clinical evaluation for adverse reactions/complications must also be provided with the medication (CDC [Workowski 2015]).

Gonococcal infection, uncomplicated (cervix, rectum [off-label use], urethra) (off-label regimen): Oral: 1 g as a single dose in combination with ceftriaxone (preferred) or cefixime (only if ceftriaxone unavailable) (CDC [Workowski 2015])

Patients with severe cephalosporin allergy (off-label regimen): 2 g as a single dose in combination with gemifloxacin or gentamicin IM (CDC [Workowski 2015])

Gonococcal infection, uncomplicated (pharynx) (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (CDC [Workowski 2015])

Granuloma inguinale (donovanosis) (off-label use): Oral: 1 g once weekly or 500 mg once daily for at least 3 weeks and until lesions have healed. Note: If symptoms do not improve within the first few days of therapy, the addition of gentamicin may be considered (CDC [Workowski 2015]).

Helicobacter pylori infection (off-label use): Oral: 500 mg once daily for 3 to 7 days in combination with an acid-reducing drug and other antibiotics (Laine 1999; Trevisani 1998)

Infection prophylaxis in neutropenia (off-label use): Oral: 250 mg once daily; initiate at the time of stem cell infusion and continue until recovery from neutropenia or initiation of empiric antibiotics for neutropenic fever (IDSA [Freifeld 2011]; Tomblyn 2009)

Lyme disease (erythema migrans or borrelial lymphocytoma) (off-label use): Oral: 500 mg once daily for 7 to 10 days (IDSA [Wormser 2009])

Mild to moderate respiratory tract, skin, and soft tissue infections: Oral: 500 mg in a single loading dose on day 1 followed by 250 mg daily as a single dose on days 2 to 5

Alternative regimen: Bacterial exacerbation of COPD: 500 mg daily for a total of 3 days

Mycobacterium avium complex (MAC) infection: Oral:

Disseminated disease in HIV-infected patients (HHS [OI adult 2017]):

Treatment: 500 to 600 mg daily in combination with ethambutol

Primary prophylaxis (patients with CD4 count <50 cells/mm3): 1,200 mg once weekly (preferred) or 600 mg twice weekly; may discontinue prophylaxis when CD4 count >100 cells/mm3 for ≥3 months in response to antiretroviral therapy (ART). Note: If effective ART is initiated immediately and viral suppression is achieved, some experts do not recommend routine initiation of MAC primary prophylaxis, regardless of initial CD4 count (IAS-USA [Günthard 2016]).

Secondary prophylaxis: 500 to 600 mg daily in combination with ethambutol; may discontinue when patient has completed ≥12 months of therapy, has no signs/symptoms of MAC disease, and has sustained (>6 months) CD4 count >100 cells/mm3 in response to ART

Pulmonary disease (nodular/bronchiectatic disease) in non-HIV-infected patients (off-label use): 500 to 600 mg 3 times weekly in combination with rifampin and ethambutol; continue treatment until patient is culture negative on therapy for 1 year (ATS/IDSA [Griffith 2007])

Pulmonary disease (severe nodular/bronchiectatic or cavitary disease) in non-HIV-infected patients (off-label use): 250 to 300 mg once daily in combination with a rifamycin plus ethambutol; continue treatment until patient is culture negative on therapy for 1 year. May also consider addition of 3-times-weekly amikacin or streptomycin early in therapy (ATS/IDSA [Griffith 2007]).

Pulmonary disease in patients with cystic fibrosis (off-label use): 250 to 500 mg once daily in combination with rifampin and ethambutol; continue for 12 months beyond culture conversion. Note: Intermitted dosing (3 times weekly) is not recommended for patients with cystic fibrosis (Floto 2016)

Mycoplasma genitalium (off-label use) (Falk 2015; CDC [Workowski 2015]): Oral:

Single-dose regimen: 1 g as a single dose

Extended-dose regimen: 500 mg on day 1, followed by 250 mg once daily on days 2 through 5

Nontuberculous mycobacterial disease (off-label use): Oral:

Mycobacterium abscessus pulmonary disease in patients with cystic fibrosis: 250 to 500 mg once daily in combination with amikacin plus one or more additional IV antibiotic based on tolerability and drug susceptibility for 3 to 12 weeks, followed by a continuation phase of azithromycin 250 to 500 mg once daily in combination with inhaled amikacin with 2 to 3 additional antibiotics (eg, minocycline, clofazimine, moxifloxacin, linezolid) (Floto 2016).

M. abscessus skin, soft tissue, or bone infections: 250 mg once daily in combination with an IV antibiotic (eg, amikacin, cefoxitin, imipenem); duration depends on severity and site of infection (ATS/IDSA [Griffith 2007]).

Pelvic inflammatory disease (PID): IV: 500 mg as a single dose for 1 to 2 days, follow IV therapy by the oral route with a single daily dose of 250 mg to complete a 7-day course of therapy.

Pertussis (off-label use) (CDC 2005): Oral: 500 mg on day 1 followed by 250 mg daily on days 2 to 5 (maximum: 500 mg daily).

Pharyngitis (including susceptible group A streptococci), tonsillitis (as an alternative agent in penicillin-allergic patients): Oral: 12 mg/kg (maximum: 500 mg) on day 1 followed by 6 mg/kg (maximum: 250 mg) once daily on days 2 through 5. Note: Regimen is also recommended by the Infectious Disease Society of America (IDSA) (Shulman 2012).

Pneumonia, community-acquired: Note: For empiric therapy, may need to use in combination with other appropriate agents (depending on disease severity and/or risk factors for drug-resistant pathogens). Treat for ≥5 days (patients should be afebrile for 48 to 72 hours and clinically stable prior to discontinuation) (IDSA/ATS [Mandell 2007]).

Oral: Outpatient: 500 mg on day 1 followed by 250 mg once daily on days 2 to 5. More severe pneumonia (requiring inpatient treatment) should be treated with 500 mg once daily for duration of therapy.

ER suspension (Zmax): 2 g as a single dose.

Oral, IV: Inpatient: 500 mg once daily.

Prevention of exacerbations of chronic obstructive pulmonary disease (COPD) (off-label use): Oral: 250 mg once daily (Albert 2011) or 500 mg 3 times weekly (Uzun 2014). Note: Duration of prophylaxis in clinical studies was 1 year (Albert 2011; Uzun 2014).

Prevention of pulmonary exacerbations in patients with noncystic fibrosis bronchiectasis (off-label use): Oral: 500 mg 3 days per week. Note: Duration of treatment in clinical trial was 6 months; durations >6 months have not been evaluated. Trial patients had ≥1 exacerbation in the past year, no macrolide treatment for >3 months in the past 6 months, and were screened for nontuberculous mycobacterial infection prior to treatment (Wong 2012). A more selective approach for patients with functionally mild disease has been suggested (Wilson 2012).

Prophylaxis against infective endocarditis (off-label use): Oral: 500 mg 30 to 60 minutes prior to the procedure. Note: American Heart Association (AHA) guidelines now recommend prophylaxis only in patients undergoing invasive procedures and in whom underlying cardiac conditions may predispose to a higher risk of adverse outcomes should infection occur. As of April 2007, routine prophylaxis for GI/GU procedures is no longer recommended by the AHA.

Prophylaxis against sexually transmitted diseases following sexual assault (off-label use): Oral: 1 g as a single dose in combination with ceftriaxone (plus metronidazole or tinidazole) (CDC [Workowski 2015])

Shigella dysentery type 1 (off-label use): Oral: 1,000 to 1,500 mg once daily for 1 to 5 days (WHO 2005)

Syphilis, primary and secondary (off-label use): Oral: 2,000 mg as a single dose. Note: Because of the possibility of resistance and treatment failure, azithromycin should be used with caution and should not be used to treat syphilis in patients with HIV, pregnant women, or in the MSM population (CDC [Workowski 2015]).

Toxoplasma gondii encephalitis (treatment) in HIV-infected patients (off-label use): Oral: 900 to 1,200 mg once daily in combination with pyrimethamine and leucovorin for at least 6 weeks, followed by a chronic maintenance therapy regimen (HHS [OI adult 2016])

Traveler's diarrhea (off-label use): Oral: 1,000 mg as a single dose or 500 mg once daily for 1 to 3 days with or without concomitant loperamide (ACG [Riddle 2016]; CDC 2015; Ericsson 2007; Tribble 2007). Note: Increased nausea may occur with the 1,000 mg single dose regimen (Tribble 2007). Three-day course of 500 mg is the preferred regimen for dysentery or febrile diarrhea (ACG [Riddle 2016]).

Urethritis/cervicitis (nongonococcal): Oral: 1 g as a single dose

Refer to adult dosing.

Azithromycin is predominantly hepatically eliminated; however, there is no dosage adjustment provided in the manufacturer's labeling, Use with caution due to potential for hepatotoxicity (rare); discontinue immediately for signs or symptoms of hepatitis.

Injection (Zithromax): Prepare initiation solution by adding 4.8 mL of sterile water for injection to the 500 mg vial (resulting concentration: 100 mg/mL). Use of a standard syringe is recommended due to the vacuum in the vial (which may draw additional solution through an automated syringe).

The initial solution should be further diluted to a concentration of 1 mg/mL (500 mL) to 2 mg/mL (250 mL) in NS, D5W, or LR.

IV: Infuse over 1 hour (2 mg/ml infusion) or over 3 hours (1 mg/ml infusion). Not for IM or IV bolus administration.

Oral: Immediate release suspension and tablet may be taken without regard to food; extended release suspension should be taken on an empty stomach (at least 1 hour before or 2 hours following a meal), within 12 hours of reconstitution.

Concerns related to adverse effects:

• Hypersensitivity reactions: Allergic reactions (eg, angioedema, anaphylaxis, Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported (rare), including fatalities; reappearance of allergic reaction may occur shortly after discontinuation of symptomatic treatment without further azithromycin exposure.

• Altered cardiac conduction: Macrolides (especially erythromycin) have been associated with rare QTc prolongation and ventricular arrhythmias, including torsade de pointes; consider avoiding use in patients with prolonged QT interval, congenital long QT syndrome, history of torsade de pointes, bradyarrhythmias, uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, uncompensated heart failure, or concurrent use of Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval.

• Cardiac risk: A retrospective cohort study done in Tennessee Medicaid patients demonstrated an increased cardiac risk with azithromycin relative to amoxicillin or ciprofloxacin, and similar risk compared to levofloxacin; notably, increased cardiac mortality (an estimated 47 additional deaths per 1 million 5-day courses of treatment compared to amoxicillin) was associated with higher baseline cardiovascular risk (Ray 2012); however, these data may not be generalizable to the population as a whole (Ray 1989). In another retrospective population study of US veterans, azithromycin was shown to significantly increase the risk of mortality and arrhythmia on days 1 to 5, but not on days 6 to 10 after dispensing the prescription (Rao 2014). In contrast, 2 additional large retrospective cohort studies did not demonstrate an increased risk of cardiovascular events, including all-cause mortality or cardiovascular death (Svanstrom 2013, Mortensen 2014). The implications of these data have yet to be determined.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD); CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Gonorrhea/syphilis: May mask or delay symptoms of incubating gonorrhea or syphilis, so appropriate culture and susceptibility tests should be performed prior to initiating a treatment regimen.

• Hepatic impairment: Use with caution in patients with preexisting liver disease; hepatocellular and/or cholestatic hepatitis, with or without jaundice, hepatic necrosis, failure, and death have occurred. Discontinue immediately if symptoms of hepatitis occur (malaise, nausea, vomiting, abdominal colic, fever).

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; exacerbation and new onset of symptoms have occurred.

• Renal impairment: Use with caution in patients with severe renal impairment (GFR <10 mL/minute); increased gastrointestinal adverse effects may occur.

Special populations:

• Infants: Use of azithromycin in neonates and infants (treatment up to 42 days of life) has been associated with infantile hypertrophic pyloric stenosis (IHPS); observe for non-bilious vomiting or irritability with feeding (Eberly 2015).

Dosage form specific issues:

• Oral suspensions: Immediate release and extended release suspensions are not interchangeable.