VA Class:AM200

AHFS Class:

• Erythromycins 8:12.12.04

Associated Monographs

• Erythromycin

• Erythromycin Ethylsuccinate

• Erythromycin Lactobionate

• Erythromycin Stearate

Erythromycins are macrolide antibiotics that are active principally against gram-positive cocci and bacilli and to a lesser extent gram-negative cocci and bacilli; the drugs also exhibit activity against chlamydia, mycoplasma, ureaplasma, spirochetes, and mycobacteria.

Prior to initiation of erythromycin therapy, appropriate specimens should be obtained for identification of the causative organism and in vitro susceptibility tests. Use of erythromycin does not preclude the necessity for surgical procedures (such as incision and drainage) as needed. There does not appear to be a difference in clinical efficacy among the erythromycin derivatives when each is administered in appropriate doses. However, some clinicians believe that the risk of hepatotoxicity from the estolate derivative does not justify its use.

Streptococcal Infections

Erythromycin is used for the treatment of mild to moderately severe infections of the upper and lower respiratory tract, skin, and soft tissue caused by Streptococcus pyogenes (group A β-hemolytic streptococci). Erythromycin also is used to treat mild to moderately severe infections of the upper and lower respiratory tract caused by Streptococcus pneumoniae. Other macrolides (azithromycin, clarithromycin) generally are used orally as alternatives to first-line therapy with a natural penicillin for the treatment of mild to moderate upper and lower respiratory tract infections caused by susceptible S. pyogenes or S. pneumoniae when oral therapy of such infections is considered appropriate and when therapy with erythromycin or other less expensive anti-infectives would likely be less effective and/or associated with GI intolerance or noncompliance.

Pharyngitis and Tonsillitis

Erythromycin or other macrolides (azithromycin, clarithromycin) are used orally for the treatment of pharyngitis and tonsillitis caused by S. pyogenes (group A β-hemolytic streptococci).242,262,263,268,311,392,441,472 Although macrolides usually are effective in eradicating S. pyogenes from the nasopharynx, efficacy of the drugs in the subsequent prevention of rheumatic fever remains to be established.

Selection of an anti-infective agent for the treatment of S. pyogenes pharyngitis or tonsillitis should be based on the drug's spectrum of activity as well as the regimen's bacteriologic and clinical efficacy, potential adverse effects, ease of administration and patient compliance, and cost.243,311,392,441 No regimen has been found to date that effectively eradicates group A β-hemolytic streptococci in 100% of patients.392 Because penicillin has a narrow spectrum of activity, is inexpensive, and generally is effective, the US Centers for Disease Control and Prevention (CDC),243 American Academy of Pediatrics (AAP),311 American Academy of Family Physicians (AAFP),243 Infectious Diseases Society of America (IDSA),441 American Heart Association (AHA),392 American College of Physicians (ACP),243 and others472 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.441 Other anti-infectives (e.g., oral cephalosporins, oral macrolides) generally are considered alternative agents.243,311,392,441,472

A 10-day regimen of oral erythromycin usually is considered the preferred alternative for the treatment of streptococcal pharyngitis in patients hypersensitive to penicillin.243,311,392,441 It has been suggested that oral azithromycin offers an advantage over oral erythromycin in terms of improved GI tolerance and ease of administration (i.e., fewer daily doses and a 5-day regimen).392,434 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.441

Although strains of S. pyogenes resistant to erythromycin and other macrolides have been reported and may be prevalent in some areas of the world (e.g., Japan, Finland) and have resulted in treatment failures, the incidence of these resistant S. pyogenes in the US has been relatively low to date.311,392,441,446 (See Resistance.)

For additional information on treatment of S. pyogenes pharyngitis, see Pharyngitis and Tonsillitis under Gram-positive Aerobic Bacterial Infections: Streptococcus pyogenes Infections, in Uses in the Natural Penicillins General Statement 8:12.16.04.

Prophylaxis of Recurrent Rheumatic Fever

Oral erythromycin is used as an alternative to IM penicillin G benzathine, oral penicillin V potassium, and oral sulfadiazine or sulfisoxazole for prevention of recurrent attacks of rheumatic fever (secondary prophylaxis) in patients hypersensitive to penicillins and sulfonamides.311,392 The AHA and AAP recommend that patients with a well-documented history of rheumatic fever (including cases manifested solely by Sydenham's chorea) and those with evidence of rheumatic heart disease receive continuous antibiotic prophylaxis to prevent recurrent attacks.311,392 Continuous prophylaxis should be initiated as soon as the diagnosis of rheumatic fever or rheumatic heart disease is made, although patients with acute rheumatic fever should first receive the usual recommended anti-infective therapy for group A β-hemolytic streptococcal infections.311,392 In general, prevention of recurrent rheumatic fever requires long-term, continuous prophylaxis and the recommended duration depends on the presence or absence of residual heart damage 311,392 The risk of rheumatic fever recurrence decreases with increasing age and as the interval since the most recent attack increases.311,392 Patients without rheumatic heart disease are at lower risk of recurrence than patients with cardiac involvement. 311 The AHA recommends that patients who have had rheumatic fever without carditis receive secondary prophylaxis for at least 5 years or until the individual is 21 years of age (whichever is longer) and that those with rheumatic fever and carditis (but no clinical or echocardiographic evidence of residual heart disease) receive secondary prophylaxis for 10 years or well into adulthood (whichever is longer).392 The AHA recommends that those with rheumatic fever and carditis with residual heart disease (clinical or echocardiographic evidence of persistent valvar disease) receive secondary prophylaxis for at least 10 years since the last episode and at least until 40 years of a lifelong prophylaxis may be indicated in these patients.392

Anti-infective regimens used for the prophylaxis of recurrent rheumatic fever are inadequate for prophylaxis of bacterial endocarditis in adults and children with rheumatic valvular heart dysfunction undergoing certain dental and surgical procedures that put them at increased risk of endocarditis caused by viridans streptococci or certain GI, biliary, or genitourinary procedures that put them at risk of enterococcal endocarditis.311,392,436 Therefore, these individuals should receive short-term prophylaxis for prevention of bacterial endocarditis when indicated (see Uses: Prophylaxis of Bacterial Endocarditis in the Aminopenicillins General Statement 8:12.16.08).311,393,436 Individuals who have had rheumatic fever without evidence of valvar heart disease do not need additional short-term prophylaxis for prevention of bacterial endocarditis.311,392

When selecting anti-infectives for prophylaxis of recurrent rheumatic fever, the current recommendations published by the AHA should be consulted.392

Prevention of Perinatal Group B Streptococcal Disease

Parenteral erythromycin is used as an alternative to parenteral penicillin G or ampicillin for prevention of perinatal group B streptococcal (GBS) disease† in women who are hypersensitive to penicillin.246,311,415 Pregnant women who are colonized with GBS in the genital or rectal areas can transmit GBS infection to their infants during labor and delivery resulting in invasive neonatal infection that can be associated with substantial morbidity and mortality.246,415 Intrapartum anti-infective prophylaxis for prevention of early-onset neonatal GBS disease is administered selectively to women at high risk for transmitting GBS infection to their neonates.246,415

When intrapartum prophylaxis is indicated in the mother, penicillin G (5 million units IV initially followed by 2.5 million units IV every 4 hours until delivery) is the regimen of choice and ampicillin (2 g IV initially followed by 1 g IV every 4 hours until delivery) is the preferred alternative.246,415 When intrapartum prophylaxis to prevent GBS in the neonate is indicated in women who are hypersensitive to penicillins, the CDC recommends a regimen of IV clindamycin (900 mg IV every 8 hours until delivery) or IV erythromycin (500 mg IV every 6 hours until delivery) for those allergic to penicillins who are at high risk for anaphylaxis (e.g., those with a history of immediate penicillin hypersensitivity, such as anaphylaxis, angioedema, or urticaria; those with a history of asthma or other conditions that would make anaphylaxis more dangerous or difficult to treat, including individuals receiving β-adrenergic blocking agents).246,415 For those allergic to penicillins who are not at high risk for anaphylaxis, the CDC states that a regimen of IV cefazolin (2 g IV initially followed by 1 g IV every 8 hours until delivery) should be used since this cephalosporin has a narrow spectrum of activity and is associated with high intraamniotic concentrations.415

The fact that S. agalactiae (group B streptococci) with in vitro resistance to clindamycin and erythromycin have been reported with increasing frequency should be considered when choosing an alternative to penicillins.415 When use of erythromycin or clindamycin is being considered in a women hypersensitive to penicillin, in vitro susceptibility testing of clinical isolates obtained during GBS prenatal screening should be performed whenever possible to determine if the isolates are susceptible to these drugs.415 Strains of GBS resistant to erythromycin often are resistant to clindamycin, although this may not be evident in results of in vitro testing.415 If in vitro susceptibility testing is not possible, results are unknown, or isolates are found to be resistant to erythromycin or clindamycin, a regimen of vancomycin (1 g IV every 12 hours until delivery) should be used for intrapartum prophylaxis in women with penicillin allergy who are at high risk for anaphylaxis.415

For additional information on prevention of perinatal GBS disease, see Uses: Prevention of Perinatal Group B Streptococcal Disease, in the Natural Penicillins General Statement 8:12.16.04.

Prevention of Bacterial Endocarditis

Some macrolides (azithromycin, clarithromycin) have been recommended for prevention of α-hemolytic (viridans group) streptococcal bacterial endocarditis† in penicillin-allergic adults and children with congenital heart disease, rheumatic or other acquired valvular heart dysfunction (even after valvular surgery), prosthetic heart valves (including bioprosthetic or allograft valves), surgically constructed systemic pulmonary shunts or conduits, hypertrophic cardiomyopathy, mitral valve prolapse with valvular regurgitation and/or thickened leaflets, or previous bacterial endocarditis (even in the absence of heart disease) who undergo dental procedures that are likely to result in gingival or mucosal bleeding (e.g., dental extractions; periodontal procedures such as scaling, root planing, probing, and maintenance; dental implant placement or reimplantation of avulsed teeth; root-filling procedures; subgingival placement of antibiotic fibers or strips; initial placement of orthodontic bands; intraligamentary local anesthetic injections; routine professional cleaning) or minor upper respiratory tract surgery or instrumentation (e.g., tonsillectomy, adenoidectomy, bronchoscopy).436

While erythromycin previously was recommended by the AHA as an alternative to penicillins for prevention of bacterial endocarditis in penicillin-allergic patients,302 the AHA states that it no longer includes erythromycin in its recommendations because of adverse GI effects and the complicated pharmacokinetics of the various erythromycin formulations.436 However, the AHA states that practitioners who have successfully used an erythromycin (i.e., erythromycin ethylsuccinate, erythromycin stearate) for prophylaxis in individual patients may choose to continue using these agents.436 The AHA recognizes that its current recommendations for prophylaxis against bacterial endocarditis are empiric, since no controlled efficacy studies have been published, and that prophylaxis of endocarditis is not always effective. However, the AHA, the ADA, and most clinicians generally recommend routine use of prophylactic anti-infectives in patients at risk for bacterial endocarditis. A national registry established by the AHA in the early 1980s analyzed 52 cases of apparent failure of anti-infective prophylaxis against bacterial endocarditis; only 6 (12%) cases had received AHA-recommended prophylactic regimens.436,437 Erythromycin is not suitable for prophylaxis against bacterial endocarditis in patients undergoing GI, biliary, or genitourinary tract surgery or instrumentation because causative organisms are likely to be resistant to erythromycin. When selecting anti-infectives for prophylaxis of bacterial endocarditis, the current recommendations published by the AHA should be consulted.436

Acute Otitis Media

A fixed-combination preparation containing erythromycin ethylsuccinate and sulfisoxazole acetyl is used in children for the treatment of acute otitis media (AOM) caused by susceptible Haemophilus influenzae .264 Erythromycin is not effective when used alone for the treatment of H. influenzae infections.264

Macrolides (azithromycin, clarithromycin, the fixed combination of erythromycin ethylsuccinate and sulfisoxazole acetyl) are considered alternative agents and are not drugs of first choice for the treatment of AOM.483 These macrolides are recommended as alternatives for treatment of AOM in patients with type I penicillin hypersensitivity.483 The fixed combination of erythromycin ethylsuccinate and sulfisoxazole acetyl may not be effective for the treatment of AOM that fails to respond to amoxicillin since a high incidence of S. pneumoniae resistant to the fixed-combination drug has been reported.483 (For further information on treatment of AOM, see Uses: Otitis Media, in the Cephalosporins General Statement 8:12.06.)

Respiratory Tract Infections

Erythromycin or other macrolides (azithromycin, clarithromycin) are used for the treatment of respiratory tract infections caused by Mycoplasma pneumoniae . Erythromycin also is used in the treatment of respiratory tract infections caused by C. pneumoniae (see Uses: Chlamydial Infections). Erythromycin or tetracyclines appear to be equally effective in shortening the duration of clinical symptoms and hastening radiographic improvement in adults with mycoplasmal pneumonia, despite failure to eradicate the pathogen from nasopharyngeal or sputum cultures. Although data are limited regarding efficacy for treatment of mycoplasmal pneumonia in children, some clinicians suggest that erythromycin is preferred for treating children with the infection.311

Although erythromycin usually is not effective for the treatment of respiratory tract infections caused by Haemophilus influenzae ,242,262,269 other macrolides (e.g., azithromycin, clarithromycin) are used for the treatment of pneumonia or acute exacerbations of chronic bronchitis caused by this bacterium.269 Limited evidence suggests that response to these macrolides in such infections is comparable to that observed with second or third generation oral cephalosporins (i.e., cefuroxime axetil, cefaclor, or cefixime).

Community-acquired Pneumonia

Erythromycin or other macrolides (azithromycin, clarithromycin) are used in the treatment of community-acquired pneumonia (CAP).269,270

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens; therapy may then be changed (if possible) to a pathogen-specific regimen based on results of in vitro culture and susceptibility testing, especially in hospitalized patients.269,270 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 ).269,270 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.269,270,276

The duration of CAP therapy depends on the causative pathogen, illness severity at the onset of anti-infective therapy, response to treatment, comorbid illness, and complications.269,270 CAP secondary to S. pneumoniae generally can be treated for 7-10 days 269 or 72 hours after the patient becomes afebrile.270 CAP caused by bacteria that can necrose pulmonary parenchyma generally should be treated for at least 2 weeks.270 Patients chronically treated with corticosteroids also may require at least 2 weeks of therapy.269 CAP caused by M. pneumoniae or C. Pneumoniae should be treated for 10-14 days.269,270

Outpatient Regimens for CAP

Pathogens most frequently involved in outpatient CAP include S. pneumoniae , Mycoplasma pneumoniae , Chlamydia pneumoniae , respiratory viruses, and H. influenzae (especially in cigarette smokers).269 Therefore, for empiric outpatient treatment of acute CAP in immunocompetent adults, the IDSA recommends monotherapy with an oral macrolide (azithromycin, clarithromycin, erythromycin), oral doxycycline, or an oral fluoroquinolone active against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin) and states that alternative empiric regimens include oral amoxicillin and clavulanate or certain oral cephalosporins (cefpodoxime, cefprozil, cefuroxime axetil).270 Because erythromycin does not provide coverage for H. influenzae , azithromycin or clarithromycin generally is preferred for empiric therapy if this organism is suspected.270

For outpatient treatment of CAP in immunocompetent adults without cardiopulmonary disease or other modifying factors that would increase the risk of multidrug-resistant S. pneumoniae or gram-negative bacteria, the American Thoracic Society (ATS) recommends an empiric regimen of monotherapy with azithromycin or clarithromycin or, alternatively, doxycycline.269 If H. influenzae are unlikely because the patient is a nonsmoker without cardiopulmonary disease, any macrolide (including erythromycin) could be used for these outpatients; however, azithromycin or clarithromycin are preferred since they have a lower incidence of adverse GI effects than erythromycin and require fewer daily doses which may improve compliance.269 For the outpatient treatment of immunocompetent adults with cardiopulmonary disease (congestive heart failure or chronic obstructive pulmonary disease [ COPD]) and/or other modifying factors that increase the risk for multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends a 2-drug empiric regimen consisting of a β-lactam anti-infective (e.g. oral cefpodoxime, oral cefuroxime axetil, high-dose amoxicillin, amoxicillin and clavulanate, parenteral ceftriaxone followed by oral cefpodoxime) and a macrolide or doxycycline or, alternatively, monotherapy with a fluoroquinolone active against S. pneumoniae (e.g., ciprofloxacin, ofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sparfloxacin, trovafloxacin [ risk of hepatic toxicity should be considered]).269 The CDC suggests that use of these oral fluoroquinolones in the outpatient treatment of CAP be reserved for when other anti-infectives are ineffective or cannot be used or when highly penicillin-resistant S. pneumoniae (i.e., penicillin MICs 4 mcg/mL or greater) are identified as the cause of infection.276 If ampicillin is used in the β-lactam and macrolide regimen, it will not provide coverage against H. influenzae and use of azithromycin or clarithromycin (rather than erythromycin) is recommended for the macrolide component.269

Inpatient Regimens for CAP

In addition to S. pneumoniae , other pathogens often involved in inpatient CAP are H. influenzae , enteric gram-negative bacilli, S. aureus , Legionella , M. pneumoniae , C. pneumoniae , and viruses.269 Patients with severe CAP admitted into the ICU may have Ps. aeruginosa infections (especially those with underlying bronchiectasis or cystic fibrosis) and Enterobacteriaceae often are involved.269 In addition, anaerobic infection should be suspected in patients with aspiration pneumonia or lung abscess.270

Inpatient treatment of CAP is initiated with a parenteral regimen, although therapy may be changed to an oral regimen if the patient is improving clinically, is hemodynamically stable, and able to ingest drugs.269,270 CAP patients usually have a clinical response within 3-5 days after initiation of therapy and failure to respond to the initial empiric regimen generally indicates an incorrect diagnosis, host failure, inappropriate anti-infective regimen (drug selection, dosage, route), unusual pathogen, adverse drug reaction, or complication (e.g., pulmonary superinfection, empyema).270

For empiric inpatient treatment of CAP in immunocompetent adults who require hospitalization in a non-ICU setting, the IDSA recommends a 2-drug regimen consisting of a parenteral β-lactam anti-infective (e.g., cefotaxime, ceftriaxone, ampicillin and sulbactam, piperacillin and tazobactam) and a macrolide (e.g., azithromycin, clarithromycin, erythromycin) or monotherapy with a fluoroquinolone active against S. pneumoniae (e.g., gatifloxacin, levofloxacin, moxifloxacin).270 For empiric inpatient treatment of CAP in immunocompetent adults who are hospitalized in a non-ICU setting and have cardiopulmonary disease (congestive heart failure or chronic obstructive pulmonary disease [ COPD]) and/or other modifying factors that increase the risk for multidrug-resistant S. pneumoniae or gram-negative bacteria, the ATS recommends a 2-drug regimen consisting of a parenteral β-lactam anti-infective (cefotaxime, ceftriaxone, ampicillin and sulbactam, high-dose ampicillin) and an oral or IV macrolide (azithromycin or clarithromycin; doxycycline can be used in those with macrolide sensitivity or intolerance) or, alternatively, monotherapy with an IV fluoroquinolone active against S. pneumoniae .269 If anaerobes are documented or lung abscess is present, clindamycin or metronidazole should be added to the regimen.269 For CAP patients admitted to a non-ICU setting who do not have cardiopulmonary disease or other modifying factors, the ATS suggests an empiric regimen of monotherapy with IV azithromycin; for those with macrolide sensitivity or intolerance, a 2-drug regimen of doxycycline and a β-lactam or monotherapy with a fluoroquinolone active against S. pneumoniae can be used.269

For inpatient treatment of CAP in immunocompetent adults who require hospitalization in an ICU, the IDSA recommends an empiric 2-drug regimen consisting of a β-lactam anti-infective (cefotaxime, ceftriaxone, ampicillin and sulbactam, piperacillin and tazobactam) and either a macrolide or a fluoroquinolone.270 For inpatient treatment of severe CAP in patients hospitalized in an ICU, the ATS recommends that those not at risk for Ps. aeruginosa infection receive a 2-drug empiric regimen consisting of an IV β-lactam anti-infective (cefotaxime, ceftriaxone) and either an IV macrolide (azithromycin) or IV fluoroquinolone.269 If risk factors for Ps. aeruginosa are present in patients with severe CAP admitted to an ICU, the ATS recommends an empiric regimen that includes 2 antipseudomonal agents and provides coverage for multidrug-resistant S. pneumonia and Legionella .269 Therefore, the ATS recommends that these patients receive a 2-drug empiric regimen that includes an IV antipseudomonal β-lactam anti-infective (e.g., cefepime, piperacillin and tazobactam, imipenem, meropenem) and an IV antipseudomonal fluoroquinolone (e.g., ciprofloxacin) or, alternatively, a 3-drug empiric regimen that includes one of the IV antipseudomonal β-lactams, an IV aminoglycoside, and either an IV macrolide (e.g., azithromycin) or an IV nonpseudomonal quinolone.269 When an IV macrolide is indicated, azithromycin usually is preferred over erythromycin because of ease of administration and lower incidence of adverse effects.269

Skin and Skin Structure Infections

Acute mild to moderate infections of the skin and soft tissue caused by Staphylococcus aureus have been treated with erythromycins, but resistance may develop during treatment. Azithromycin and clarithromycin also have been used in the treatment of skin and skin structure infections caused by Staphylococcus aureus or Streptococcus pyogenes and appear to have efficacy comparable to that of erythromycin or an oral cephalosporin.

Acne

Oral erythromycins are used with good results in the treatment of acne†.459 For information on the topical use of erythromycin in acne, see Erythromycin 84:04.04.

Amebiasis

Although the manufacturers state that oral erythromycin can be used for the treatment of intestinal amebiasis caused by Entamoeba histolytica ,242,262,263,268 a regimen of metronidazole or tinidazole followed by a luminal amebicide such as iodoquinol or paromomycin is recommended for the treatment of intestinal amebiasis.259,311

Anthrax

Erythromycin is used as an alternative agent in the treatment of anthrax†.218,227,472 Parenteral penicillins generally have been considered the drugs of choice for the treatment of naturally occurring or endemic anthrax caused by susceptible strains of Bacillus anthracis , including clinically apparent GI, inhalational, or meningeal anthrax and anthrax septicemia, although IV ciprofloxacin or IV doxycycline also are recommended.216,218,227,472 Erythromycin is suggested as an alternative to penicillin G for the treatment of naturally occurring or endemic anthrax in patients hypersensitive to penicillins.218,227

For the treatment of inhalational anthrax that occurs as the result of exposure to B. anthracis spores in the context of biologic warfare or bioterrorism, the CDC and the US Working Group on Civilian Biodefense recommend that treatment be initiated with a multiple-drug parenteral regimen that includes ciprofloxacin or doxycycline and 1 or 2 other anti-infectives predicted to be effective.216,347 Based on in vitro data, drugs that have been suggested as possibilities to augment ciprofloxacin or doxycycline in such multiple-drug regimens include chloramphenicol, clindamycin, rifampin, vancomycin, clarithromycin, imipenem, penicillin, or ampicillin.216,347 If meningitis is established or suspected, some clinicians suggest a multiple-drug regimen that includes ciprofloxacin (rather than doxycycline) and chloramphenicol, rifampin, or penicillin.216 Although there is evidence that erythromycin has in vitro activity against B. anthracis ,225,347 strains of the organism that were associated with cases of inhalational or cutaneous anthrax that occurred in the US (Florida, New York, District of Columbia) during September and October 2001 in the context of an intentional release of anthrax spores (biologic warfare, bioterrorism) had only intermediate susceptibility to erythromycin.347 Limited or no clinical data are available to date regarding in vivo activity of erythromycin against B. anthracis and the drug is not considered a drug of choice for the treatment or prophylaxis of anthrax that occurs as the result of exposure to anthrax spores in the context of biologic warfare or bioterrorism.216,347

IV anti-infective therapy is recommended for the initial treatment of clinically apparent GI, inhalational, or meningeal anthrax and anthrax septicemia and also is indicated for the treatment of cutaneous anthrax when there are signs of systemic involvement, extensive edema, or head and neck lesions; oral therapy may be adequate for mild, uncomplicated cutaneous anthrax.216,218,227

For additional information on treatment of anthrax and recommendations for prophylaxis following exposure to anthrax spores, see Uses: Anthrax, in Ciprofloxacin 8:12.18.

Bartonella Infections

Oral erythromycin or oral azithromycin has been used in conjunction with IM or IV ceftriaxone for the treatment of bacteremia caused by Bartonella quintana † (formerly Rochalimaea quintana ).460 B. quintana , a gram-negative bacilli, can cause cutaneous bacillary angiomatosis, trench fever, bacteremia, endocarditis, and chronic lymphadenopathy.460,461,462,463 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.460,461,463 Optimum anti-infective regimens for the treatment of infections caused by B. quintana have not been identified,460,462,463 and various drugs have been used to treat these infections, including doxycycline, erythromycin, azithromycin, chloramphenicol, or cephalosporins.311,462,463,472 There is evidence that these infections tend to persist or recur and prolonged therapy (several months or longer) usually is necessary.460,463

The possible role of macrolides in the treatment of infections caused by Bartonella henselae (formerly Rochalimaea henselae ) (e.g., cat scratch disease, bacillary angiomatosis, peliosis hepatitis) has not been determined.464,465 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 probably is indicated in immunocompromised patients.311,464,465,466 Anti-infectives also are indicated in patients with B. henselae infections who develop bacillary angiomatosis, neuroretinitis, or Parinaud's oculoglandular syndrome.311,464,465,466 While the optimum anti-infective regimen for the treatment of cat scratch disease or other B. henselae infections has not been identified, some clinicians recommend use of erythromycin, azithromycin, doxycycline, ciprofloxacin, rifampin, co-trimoxazole, gentamicin, or third generation cephalosporins.311,464,465,466,472

HIV-infected individuals (especially severely immunosuppressed individuals) are at unusually high risk for severe disease caused by Bartonella and relapse or reinfection sometimes occurs following initial treatment of these infections.420 Therefore, although data are insufficient to make firm recommendations, the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) suggest that long-term suppression with erythromycin or doxycycline be considered to prevent recurrence of Bartonella infection in HIV-infected patients.420

Campylobacter Infections

The CDC,272 IDSA,271 and AAP311 consider oral erythromycin a treatment of choice for symptomatic enteric infections caused by Campylobacter jejuni †. Azithromycin and fluoroquinolones (e.g., ciprofloxacin) also are recommended for these infections;272,311,472 tetracycline also can be used for patients 8 years of age or older.311

When initiated early in the course of the Campylobacter infection, erythromycin or azithromycin shortens the duration of illness and prevents relapse.311 Both of these macrolides usually eradicate the organism from the stool within 2-3 days; in patients with gastroenteritis, the recommended duration of therapy is 5-7 days.311

Chancroid

Oral erythromycin is used for the treatment of chancroid† (genital ulcers caused by H. ducreyi ).228,248,472 While a few erythromycin-resistant isolates of H. ducreyi were reported in Asia more than a decade ago, similar isolates have not been reported elsewhere.256

The CDC228 and others248 state that a single oral dose of azithromycin, a single IM dose of ceftriaxone, a 3-day regimen of oral ciprofloxacin (contraindicated in pregnant or lactating women), or a 7-day regimen of oral erythromycin are the regimens of choice for the treatment of chancroid. 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 treatment as well as those who are HIV-negative or circumcised.228,248 Because data on efficacy of the single-dose azithromycin and ceftriaxone regimens for the treatment of chancroid in patients with HIV infection are limited, the CDC recommends that these regimens be used in HIV patients only if follow-up can be ensured; some experts recommend that HIV-infected individuals with chancroid receive the 7-day erythromycin regimen.228

In the US, chancroid usually occurs in discrete outbreaks, but the disease is endemic in some areas.228 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.228 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.228 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.228 Ideally, diagnostic evaluation of patients with genital ulcers should include a serologic test for syphilis and either darkfield examination or direct immunofluorescence test for T. pallidum , culture for H. ducreyi , and culture or antigen test for HSV.228 A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that is not widely available.228 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.228 While the presence of a painful ulcer and tender inguinal adenopathy occur in about one-third of chancroid patients and suggests a diagnosis of chancroid, the additional presence of suppurative inguinal adenopathy is a clearer indication of the disease.228

Patient Follow-up and Management of Sexual Partners

The CDC recommends that all patients diagnosed with chancroid be tested for HIV and, if initial tests for syphilis and HIV are negative, the tests repeated 3 months later.228 Patients with chancroid should be examined 3-7 days after initiation of anti-infective therapy.228 If the regimen was effective, symptomatic improvement in the ulcers is evident within 3 days and objective improvement is evident within 7 days.228 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 regimen, the strain of H. ducreyi is resistant to the anti-infective agent used, or the patient is HIV seropositive.228

The time required for complete healing is related to the size of the ulcer; large ulcers may require more than 2 weeks to heal.228 Healing of ulcers may be slower in uncircumcised men who have ulcers under the foreskin.228 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.228 While needle aspiration of buboes is a simpler procedure, incision and drainage of buboes may be preferred.228

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.228

Chlamydial Infections

Oral erythromycin is used for the treatment of urethritis caused by Ureaplasma urealyticum in adult males and for the treatment of uncomplicated urethral, endocervical, or rectal infections caused by Chlamydia trachomatis in adults in whom tetracyclines and azithromycin are contraindicated or not tolerated. Oral erythromycin also is used for the treatment of chlamydial urogenital infections during pregnancy and for the treatment of chlamydial pneumonia in infants. The AAP, CDC, and other clinicians also recommend oral erythromycin for the treatment of initial episodes and recurrences of chlamydial conjunctivitis in neonates.228,248,311

Although oral erythromycin has not been evaluated extensively in culture-confirmed cases, the drug is used as an alternative to doxycycline for the treatment of genital, inguinal, or anorectal infections caused by lymphogranuloma venereum serotypes of C. trachomatis †.228,248,311

Urogenital Chlamydial Infections in Adults and Adolescents

For the treatment of urogenital chlamydial infections in nonpregnant adults and adolescents, the CDC and other clinicians recommend a single dose of oral azithromycin or a 7-day regimen of oral doxycycline.228,248 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.228,248 Erythromycin is less effective than either azithromycin or doxycycline and GI effects associated with the drug may discourage patient compliance with the regimen.228 To maximize compliance with 7-day regimens, the CDC recommends that the drugs be dispensed on site and that the first dose be taken under supervision.228

Individuals with HIV infection who also are infected with chlamydia should receive the same treatment regimens recommended for other individuals with chlamydial infections.228

Patient Follow-up and Management of Sexual Partners

Since azithromycin and doxycycline regimens are highly effective for the treatment of urogenital chlamydial infections, a test of cure probably is unnecessary in patients who receive one of these regimens unless symptoms persist or reinfection is suspected; however, a test of cure should be considered 3 weeks after completion of an erythromycin regimen.228

Patients being treated for chlamydial infection should be instructed to refer their sexual partner(s) for evaluation and treatment, and to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen.228 In addition, to minimize the risk of reinfection, patients should be instructed to abstain from sexual intercourse until after all their sexual partners are cured.228 Although the CDC acknowledges that the exposure intervals are somewhat arbitrary, they recommend that individuals who had sexual contact with the chlamydia patient within 60 days before the onset of symptoms or diagnosis in the patient should be evaluated and treated.228 If the patient reports that the last sexual contact occurred more than 60 days prior to the onset of symptoms or diagnosis, their most recent sexual partner should be treated.228

Chlamydial Infections during Pregnancy

The CDC recommends that urogenital chlamydial infections in pregnant women be treated with a 7-day regimen of oral erythromycin base or oral amoxicillin; alternative regimens recommended by the CDC for the treatment of urogenital chlamydial infection in pregnant women are a 14-day regimen of oral erythromycin base or ethylsuccinate, a 7-day regimen of erythromycin ethylsuccinate, or a single dose of oral azithromycin.228 Other clinicians recommend that urogenital chlamydial infections in pregnant women be treated with a 7-day regimen of oral amoxicillin or, alternatively, a single oral dose of azithromycin or a 7-day regimen of oral erythromycin.248 Repeat testing, preferably by culture, 3 weeks after completion of therapy is recommended since none of these regimens is highly effective and since frequent adverse effects associated with erythromycin may discourage compliance.228

Chlamydial Infections in Neonates and Infants

C. trachomatis infection in neonates usually occurs as the result of exposure to the mother's infected cervix.228 Perinatal C. trachomatis infection initially involves mucous membranes of the eye, oropharynx, urogenital tract, and rectum and usually becomes apparent when conjunctivitis develops 5-12 days after birth;228 however, asymptomatic oropharyngeal, genital tract, and rectal infections can occur in neonates.228 C. trachomatis also is a common cause of subacute, afebrile pneumonia occurring in children 1-3 months of age.228 Because a neonate with chlamydial infection has acquired the organism from their mother, both the mother and her sexual partner(s) should be evaluated and treated for chlamydia following a diagnosis in the neonate.228

If erythromycin is used for the treatment of chlamydial infections in neonates, the risk of infantile hypertrophic pyloric stenosis (IHPS) should be considered248,311 and the child's parents or caregivers should be informed about the potential risks of developing IHPS and signs of IHPS.311

Chlamydial Ophthalmia Neonatorum

A 14-day regimen of oral erythromycin base or ethylsuccinate is a preferred or alternative regimen of choice for the treatment of ophthalmia neonatorum caused by C. trachomatis .228,248,311 The neonate should receive appropriate follow-up to ensure that the infection resolves; a second course of erythromycin may be necessary since the drug is effective in approximately 80% of cases.228,311 The AAP suggests that oral sulfonamides be used in neonates who cannot tolerate erythromycin.311 Although data on use of other macrolides (e.g., azithromycin, clarithromycin) for the treatment of neonatal chlamydial infections are limited, there is some evidence that a 3-day regimen of oral azithromycin may be effective for the treatment of chlamydial ophthalmia neonatorum;228 some clinicians consider azithromycin the regimen of choice.248 Topical anti-infectives are inadequate for the treatment of chlamydial ophthalmia neonatorum and are unnecessary when appropriate systemic anti-infective therapy is given.228,311

While universal topical prophylaxis using topical anti-infectives (i.e., 1% tetracycline ophthalmic ointment, 0.5% erythromycin ophthalmic ointment, silver nitrate 1% ophthalmic solution) is recommended for all neonates as soon as possible after birth to prevent gonococcal ophthalmia neonatorum, these topical anti-infectives do not prevent perinatal transmission of C. trachomatis from mother to infant.228,311 Infants born to mothers with untreated chlamydial infection are at high risk for infection; however, parenteral prophylaxis in these infants is not indicated since the efficacy of such prophylaxis is unknown.228 These infants should be monitored to ensure appropriate treatment if chlamydial infection develops.228 The possibility of a chlamydial infection should be considered in any infant 30 days of age or younger who develops conjunctivitis; ocular exudate from infants being evaluated for chlamydial conjunctivitis also should be tested for N. gonorrhoeae .228

Chlamydial Pneumonia in Infants

A 14-day regimen of oral erythromycin base or ethylsuccinate is a preferred or alternative regimen for the treatment of chlamydial pneumonia in infants.228,248,311 The infant should receive appropriate follow-up to ensure that the pneumonia resolves; a second course of erythromycin may be necessary since the drug is effective in approximately 80% of cases.228,311 Some clinicians suggest that a 3-day regimen of azithromycin is the regimen of choice for chlamydial pneumonia in neonates.248

Urogenital Chlamydial Infections in Children

For the treatment of urogenital chlamydial infections in children who weigh less than 45 kg, the CDC recommends a 14-day regimen of oral erythromycin base or ethylsuccinate.228 For the treatment of urogenital chlamydial infections in children younger than 8 years of age who weigh at least 45 kg, the CDC recommends a single 1-g dose of oral azithromycin; for those 8 years of age or older, the CDC recommends a single-dose azithromycin regimen or a 7-day regimen of oral doxycycline.228 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 erythromycin or azithromycin.311 Follow-up cultures are necessary to ensure that treatment has been effective.228

Lymphogranuloma Venereum

A 21-day regimen of oral erythromycin base is recommended as an alternative regimen for the treatment of lymphogranuloma venereum† caused by invasive serotypes of C. trachomatis (serovars L1, L2, L3).228,248,311 A 21-day regimen of oral doxycycline generally is considered the regimen of choice for lymphogranuloma venereum;228,248 erythromycin can be used as an alternative and is the preferred regimen for pregnant and lactating women.228 Although oral azithromycin also may be effective, the CDC states that clinical safety and efficacy data are lacking.228 Effective treatment cures the infection and prevents ongoing tissue damage, although tissue reaction can result in scarring.228 Aspiration of buboes or incision and drainage may be necessary to prevent the formation of inguinal/femoral ulcerations.228

The CDC recommends that individuals who had sexual contact with the lymphogranuloma venereum patient should be examined, tested for urethral or cervical chlamydial infection, and treated if they had sexual contact with the patient within 30 days prior to onset of symptoms in the patient.228

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.228

Chlamydia psittaci Infections

While tetracyclines are the drugs of choice for the treatment of C. psittaci infections (psittacosis),311,451,472 erythromycin is an alternative for the treatment of psittacosis when tetracyclines are contraindicated (e.g., in pregnant women, children younger than 9 years of age).311,451

Diphtheria

Erythromycin is used as an adjunct to diphtheria antitoxin in the treatment of respiratory tract infection caused by Corynebacterium diphtheria (diphtheria).261,311,454,455,474 Erythromycin also is used for prevention of diphtheria in close contacts of patients with diphtheria and to eliminate the diphtheria carrier state.261,311,454,455 Although cutaneous diphtheria generally is caused by nontoxigenic strains of C. diphtheriae , some clinicians recommend that patients with cutaneous infections receive a 10-day regimen of anti-infective therapy in addition to thorough cleansing of the lesions; use of diphtheria antitoxin in these patients also is recommended by some clinicians since toxic sequelae have occurred in some patients with cutaneous lesions.311

Use of diphtheria antitoxin is the most important aspect of treatment of respiratory diphtheria.261,311,454,455 (See Diphtheria Antitoxin 80:04.) Anti-infective therapy may eliminate C. diphtheriae from infected sites, prevent spread of the organism and further toxin production, and prevent or terminate the diphtheria carrier state; however, anti-infectives appear to be of no value in neutralizing diphtheria toxin and should not be considered a substitute for antitoxin therapy.311,454,455 For the adjunctive treatment of diphtheria, erythromycin may be given orally or IV; alternatively, a parenteral regimen of penicillin G or penicillin G procaine can be used.261,311,455 Patients usually are no longer contagious 48 hours after initiation of anti-infective therapy.261 Eradication of C. diphtheriae should be confirmed by 2 consecutive negative cultures following completion of anti-infective therapy.261,311,455 Because diphtheria infection often does not confer immunity, active immunization with a diphtheria toxoid preparation (see 80:08) should be initiated or completed during convalescence.311,455

For prevention of diphtheria, the CDC,261 US Public Health Service Advisory Committee on Immunization Practices (ACIP),455 and AAP311 recommend that, irrespective of their immunization status, all household or other close contacts of individuals with suspected or proven diphtheria should have samples taken for C. diphtheriae culture, receive anti-infective prophylaxis, and be kept under surveillance for evidence of the disease for 7 days.261,311,455 Although efficacy of anti-infectives in preventing secondary disease is presumed and not proven, prophylaxis should be initiated promptly and should not be delayed pending culture results.311,454,455 The CDC, ACIP, and AAP recommend that either a single IM dose of penicillin G benzathine or 7-10 days of oral erythromycin be used for chemoprophylaxis in contacts of patients with diphtheria.261,311,455 Erythromycin may be slightly more effective,454,455 but IM penicillin G benzathine may be preferred when there are concerns about compliance.261,454,455 In addition, contacts who are inadequately immunized against diphtheria (i.e., have previously received less than 3 doses of diphtheria toxoid) or whose immunization status is unknown should receive an immediate dose of an age-appropriate diphtheria toxoid preparation and the primary immunization series should be completed according to the recommended schedule.261,455 Contacts who are fully immunized should receive an immediate booster dose of an age-appropriate diphtheria toxoid preparation if it has been 5 years or longer since their last booster dose.261,311 The ACIP and AAP state that use of diphtheria antitoxin in unimmunized close contacts is not recommended because of the risks associated with the antitoxin and because there is no evidence that such therapy has any additional benefit for contacts who receive recommended prophylaxis with penicillin G benzathine or erythromycin.311,455

Erythromycin can be used to eliminate the diphtheria carrier state in individuals known to carry toxigenic strains of C. diphtheriae .311,454,455 The ACIP and AAP recommend that carriers receive prophylaxis with either penicillin G benzathine or erythromycin in the regimen recommended for prophylaxis of close contacts of patients with diphtheria.311,455 Follow-up cultures should be obtained at least 2 weeks after completion of the regimen; individuals who continue to harbor C. diphtheriae after either penicillin G benzathine or erythromycin therapy should receive an additional 10 day course of oral erythromycin and additional follow-up cultures should be obtained.311,454,455

Gonorrhea and Associated Infections

Erythromycin has been used as an alternative to the preferred regimens (e.g., a single dose of oral azithromycin or a 7-day regimen of oral doxycycline) for the treatment of coexisting chlamydial infections in adults and adolescents receiving treatment for gonorrhea.228 Gonorrhea frequently is associated with coexisting chlamydial infection; however, cephalosporins, spectinomycin, and most single-dose quinolone regimens used for the treatment of gonorrhea are ineffective for the treatment of chlamydial infection.228 Because of the risks associated with untreated coexisting chlamydial infection, the CDC and most clinicians recommend that adults and adolescents being treated for uncomplicated gonorrhea or disseminated gonococcal infection also receive an anti-infective regimen effective for presumptive treatment of uncomplicated urogenital chlamydial infection.228,248,311 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 urogenital chlamydial infection in some populations.228 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 .228 Since the cost of presumptive treatment of chlamydia is less than the cost of testing for presence of chlamydia, routine dual therapy without chlamydial testing can be cost-effective for populations in which coinfection with chlamydia has been reported in 10-30% of patients with N. gonorrhoeae infection.228 In areas where the rate of coinfection with chlamydia is low and chlamydial testing is widely available, some clinicians may prefer to test for chlamydia rather than treat presumptively; however, presumptive treatment is indicated for patients who may not return for test results.228

In the treatment of gonococcal infections in children, routine presumptive treatment of chlamydia with erythromycin or tetracycline therapy is not currently included in the CDC recommendations, but the CDC states that children being treated for gonorrhea should be evaluated for coexisting Chlamydia trachomatis infection.228 The AAP recommends presumptive treatment of chlamydial infections for all children beyond the neonatal period being treated for uncomplicated vulvovaginal, urethral, or pharyngeal gonorrhea, epididymitis, proctitis, or disseminated gonococcal infections, including meningitis and endocarditis.311 The AAP suggests that children who weigh less than 45 kg receive erythromycin or azithromycin for presumptive treatment of coexisting chlamydial infection and that children who weigh 45 kg or more and are 8 years of age or older receive azithromycin or doxycycline.311

While IV erythromycin lactobionate followed by oral erythromycin base or stearate is recommended by some manufacturers for the treatment of acute pelvic inflammatory disease (PID) caused by N. gonorrhoeae ,242,262,263 erythromycins are not included in current CDC recommendations for the treatment of PID.228

Topical erythromycin is used for prophylaxis of ophthalmia neonatorum caused by N. gonorrhoeae .228,311 (See Uses in Erythromycin 52:04.04.)

Granuloma Inguinale (Donovanosis)

Erythromycin or azithromycin has been used orally in the treatment of donovanosis† caused by Calymmatobacterium granulomatis .228,450 The CDC recommends that donovanosis be treated with regimen of oral co-trimoxazole or oral doxycycline or, alternatively, a regimen of oral ciprofloxacin , oral erythromycin, or oral azithromycin.228 Anti-infective treatment of donovanosis should be continued until all lesions have healed completely; a minimum of 3 weeks of treatment usually is necessary.228,450 If lesions do not respond within the first few days of therapy, some experts recommend that a parenteral aminoglycoside (e.g., 1 mg/kg of gentamicin IV every 8 hours) be added to the regimen.228 Erythromycin is recommended for the treatment of donovanosis in pregnant and lactating women;228,450 addition of a parenteral aminoglycoside (e.g., gentamicin) to the regimen should be strongly considered in these women.228 Although azithromycin also may be effective for the treatment of donovanosis in pregnant women, clinical safety and efficacy data are lacking.228 Anti-infective treatment appears to halt progressive destruction of tissue, although prolonged duration of therapy often is required to enable granulation and re-epithelization of ulcers.228 Despite effective anti-infective therapy, donovanosis may relapse 6-18 months later.228

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 considered in HIV-infected patients.228

Legionnaires' Disease

Erythromycin (with or without rifampin) is used for the treatment of Legionnaires' disease caused by Legionella pneumophila .242,262,263,268,270,311,452,453,472 Macrolides or fluoroquinolones generally are considered the drugs of choice for the treatment of pneumonia caused by L. pneumophila and doxycycline or co-trimoxazole are alternatives.270,311,452,453,472 A parenteral regimen usually is necessary for the initial treatment of severe Legionnaires' disease and the addition of oral rifampin is recommended during the first 3-5 days of macrolide or doxycycline therapy in severely ill and/or immunocompromised patients; after a response is obtained, rifampin can be discontinued and therapy changed to an oral regimen.311,452,453 Some clinicians suggest that azithromycin may be the preferred macrolide for the treatment of severe Legionnaires' disease270 and may also be preferred for empiric therapy in patients with severe community-acquired pneumonia (CAP) that may be caused by Legionella .269,452 (See Community-acquired Pneumonia under Uses: Respiratory Tract Infections.)

Mycobacterium avium Complex (MAC) Infections

Although erythromycin is not used in the treatment of mycobacterial infections, other macrolides (azithromycin, clarithromycin) are used in the treatment and prevention of Mycobacterium avium complex (MAC) infections.416,417,418,420,422,423,424,425,426,427 For information on the use of azithromycin and clarithromycin in the prevention and/or treatment of MAC infections, including see the individual monographs on these drugs and see Management of Other Mycobacterial Diseases: Mycobacterium avium Complex (MAC) Infections, in the Antituberculosis Agents General Statement.

Nongonococcal Urethritis

Oral erythromycin228,242,248,262,263 or oral azithromycin228 is used for the treatment of nongonococcal urethritis. While C. trachomatis is a frequent cause of nongonococcal urethritis, these infections can be caused by Ureaplasma urealyticum or Mycoplasma genitalium ; Trichomonas vaginalis and HSV also are possible causes of nongonococcal urethritis.228 The CDC currently considers a single oral dose of azithromycin or a 7-day regimen of oral doxycycline the regimens of choice for the treatment of nongonococcal urethritis.228 Alternative regimens recommended by the CDC are a 7-day regimen of oral erythromycin base or ethylsuccinate or a 7-day regimen of oral ofloxacin or levofloxacin.228 Patients with persistent or recurrent urethritis who were not compliant with the treatment regimen or were reexposed to untreated sexual partner(s) should be retreated with the initial regimen.228 If the patient has recurrent and persistent urethritis, was compliant with the regimen, and reexposure can be excluded, the CDC recommends an additional 7-day regimen of oral erythromycin given in conjunction with a single 2-g dose of oral metronidazole.228

Pertussis

Erythromycin is considered the drug of choice for the treatment of Bordetella pertussis infection (pertussis, whooping cough) and for prevention in contacts of patients with pertussis.253,261,311,455,457,472

According to CDC data, there were an average of 2900 cases of pertussis each year in the US from 1980-1990; however, the incidence of pertussis has been gradually increasing during the last decade.261 In 2000, there were 7867 reported cases (the largest number since 1967).261 While pertussis can occur at any age, approximately 43% of reported cases that occurred in the US during 1997 were reported in children younger than 5 years of age and 24% were reported in infants younger that 6 months of age.311 Susceptible infants and young children who have not been completely immunized against pertussis frequently are infected by older siblings or adult contacts who may have mild or atypical illness.311,456 According to CDC surveillance data for 1997-2000, there was about a 60% increase in the incidence rate of pertussis in adolescents and adults compared with incidence rates reported for these age groups in 1994-1996.261 This may reflect a true increase or may reflect improvements in recognition and diagnosis of pertussis among older individuals.261 The CDC suggests that healthcare providers consider pertussis in the differential diagnosis when evaluating adults with acute cough that has lasted at least 7 days, particularly if the cough is paroxysmal and associated with posttussive vomiting and/or whooping.456

Transmission of pertussis can be reduced by prompt diagnosis and treatment of index cases and administration of prophylaxis to close contacts.311,455,456 Use of erythromycin therapy during the catarrhal stage of pertussis may ameliorate the disease, but usually has no discernible effect on the course of the illness if initiated after paroxysms are established; however, anti-infective treatment even at the paroxysmal stage is recommended to limit the spread of the organism to others.261,311 The CDC, AAP, and other clinicians recommend anti-infective prophylaxis for all household and other close contacts (e.g., those in childcare) of individuals with pertussis, regardless of age or vaccination status.261,311,455,456 Prophylaxis should be administered as soon as possible after first contact with the index case; prophylaxis administered 21 days or longer after first contact is considered to be of limited value.456 In addition to anti-infective prophylaxis, all close contacts younger than 7 years of age who are not fully immunized against pertussis should receive the remaining required doses of a preparation containing pertussis vaccine (using minimal intervals between doses) and those who are fully immunized but have not received a vaccine dose within the last 3 years should receive a booster dose of a pertussis vaccine preparation.261

The CDC,261 ACIP,455 AAP,311 and others456 generally recommend a 14-day regimen of oral erythromycin for the treatment of pertussis or for prevention in susceptible contacts. While nasopharyngeal cultures usually become negative for B. pertussis within 5 days of initiation of anti-infective therapy311 and a 7- or 10-day regimen of erythromycin has been effective for the treatment of pertussis in some patients,311,458 prophylaxis failures and bacteriologic relapse of pertussis have been reported with erythromycin regimens shorter than 14 days.250,251,253,255,458 There is some limited evidence that 5-7 days of azithromycin or clarithromycin may be effective for the treatment of pertussis; however, additional study is needed.311

Some clinicians suggest that erythromycin estolate is the preferred erythromycin for the treatment or prevention of pertussis, since it may be better tolerated and because prophylaxis failures and delays or failures in eradication of B. pertussis have been reported with some other forms of erythromycin (e.g., erythromycin ethylsuccinate or stearate).250,251,254,311 However, other clinicians suggest that these other erythromycin preparations can be used if adequate dosage is administered and patient compliance is ensured.250,251,252,253 An association between oral erythromycin and infantile hypertrophic pyloric stenosis (IHPS) has been reported in infants younger than 6 weeks of age who received the drug for prophylaxis of pertussis; however, a causal relationship has not been clearly established.311,229,230 Because additional study is needed to determine whether erythromycin contributed to these reported cases of IHPS and because only limited information is available regarding alternatives for prophylaxis and treatment of pertussis (e.g., azithromycin, clarithromycin, co-trimoxazole), the AAP continues to recommend use of erythromycin for prophylaxis or treatment of pertussis when indicated and states that parents of neonates should be informed about the potential risks of developing IHPS and signs of IHPS.311

Although the clinical importance is unclear, erythromycin-resistant strains of B. pertussis have been reported rarely in the US.457 If a patient with pertussis does not improve with erythromycin therapy, nasopharyngeal cultures should be obtained and in vitro susceptibility testing performed to determine if the isolate is resistant to the drug.311

Spirochetal Infections

Lyme Disease

Erythromycin, azithromycin, or clarithromycin has been used in the treatment of early Lyme disease†,214,310,311,394,395,397,399,472,473,476,477,478 a spirochetal disease caused by tick-borne Borrelia burgdorferi .214,274,311,394,395,396,472,473,475,477 However, some evidence in patients with early Lyme disease suggests that certain macrolides (e.g., azithromycin, erythromycin) may be less effective than penicillins or tetracyclines,214,274,310,311,394,397,473,475,476 and the IDSA, AAP, and other clinicians recommend that macrolide antibiotics not be used as first-line therapy for early Lyme disease.265,274,331,472,475

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.214,267,274,331,472,475 Therapy with a macrolide antibiotic generally is recommended for the treatment of early Lyme disease in patients who are allergic to or intolerant of penicillins and cephalosporins and in whom tetracyclines are contraindicated (e.g., pregnant or lactating women and children younger than 8-9 years of age).214,274,311,394,395,397,399,472,473,475 While therapy with clarithromycin (500 mg twice daily for 21 days) appeared to be effective in resolving manifestations of early Lyme disease in a limited number of patients in an open-label study,266 the IDSA and other clinicians state that macrolide antibiotics should be reserved for patients who are intolerant of amoxicillin, doxycycline, and cefuroxime axetil214,331,475 and that patients treated with macrolides should be monitored closely.214

The IDSA, AAP, and other clinicians recommend that patients with more severe forms or late complications of Lyme disease generally receive a higher dosage, more prolonged therapy, and/or parenteral anti-infectives (e.g., IV ceftriaxone, IV cefotaxime, or IV penicillin G for 2-4 weeks).214,274,311,314,394,395,396,397,398,399,400,401,402,472,473,474,475,477

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

The manufacturers suggest that oral erythromycin can be used for the treatment of primary syphilis.262,263,268 Although the CDC previously suggested use of oral erythromycin as an alternative agent for the treatment of primary or secondary syphilis in nonpregnant adults and adolescents hypersensitive to penicillins, erythromycin is less effective than other possible penicillin alternatives275 and is no longer included in CDC recommendations for the treatment of any form of syphilis in adults or adolescents (including primary, secondary, latent, or tertiary syphilis or neurosyphilis).228 Penicillin G is the drug of choice for the treatment of all stages of syphilis.228,248 Although efficacy is not well documented, the CDC states that use of oral doxycycline or oral tetracycline or, possibly, oral azithromycin, can be considered in nonpregnant adults and adolescents with primary, secondary, or early latent syphilis who are hypersensitive to penicillin.228 However, if compliance and follow-up cannot be ensured, these patients should be desensitized and treated with penicillin G.228 (For information on skin testing to document penicillin hypersensitivity and desensitization procedures, see Cautions: Hypersensitivity Reactions in the Natural Penicillins General Statement 8:12.16.04.) Use of penicillin alternatives (e.g., doxycycline, ceftriaxone, azithromycin) for the treatment of syphilis in HIV-infected individuals has not been studied and should be undertaken with caution.228

Erythromycin is no longer recommended by the CDC, AAP, or other clinicians for the treatment of syphilis in pregnant women who are hypersensitive to penicillin since numerous treatment failures (including in the fetus) have been reported with the drug.228,247,248,249,311 There are no proven alternatives to penicillin G for the treatment of syphilis during pregnancy, and pregnant women with a history of penicillin hypersensitivity should be desensitized, if indicated, and treated with penicillin G.228,248 Because erythromycin administered during pregnancy cannot be considered a reliable cure for the fetus, neonates born to a woman who received such treatment during pregnancy should be treated with penicillin G for presumed congenital syphilis.311

Erythromycin is not included in CDC recommendations for the treatment of presumed or documented congenital syphilis in neonates or for congenital syphilis in older infants and children.228 The CDC and AAP state that data are insufficient regarding efficacy of nonpenicillin regimens (e.g., ceftriaxone) for the treatment of syphilis in pediatric patients.228 Therefore, if treatment for syphilis is necessary in a neonate or child who has a history of penicillin hypersensitivity or who has developed an allergic reaction presumed to be related to penicillin, they should be desensitized and treated with penicillin G.228,311

Preoperative Intestinal Antisepsis

Oral erythromycin base is used in conjunction with oral neomycin sulfate as an adjunct to mechanical cleansing of the large intestine for intestinal antisepsis prior to elective colorectal surgery.237,262 For perioperative prophylaxis in patients undergoing colorectal surgery, many clinicians recommend a regimen of IV cefotetan or IV cefoxitin; a regimen of IV cefazolin and IV metronidazole; or a regimen of oral erythromycin and oral neomycin.237 It has been suggested that the oral regimen may be as effective as the parenteral regimens for patients undergoing elective colorectal surgery.237 Many clinicians use both the oral regimen and a parenteral regimen for perioperative prophylaxis in patients undergoing colorectal surgery;237,257 however, it is unclear whether this combined regimen is more effective than use of either an oral or parenteral regimen alone.237 In a randomized, prospective study in patients undergoing elective colorectal surgery, the overall incidence of intra-abdominal septic complications in those who received mechanical bowel preparation and an oral regimen (erythromycin and neomycin) alone was similar to that in those who received both the oral regimen and a parenteral regimen (cefoxitin); however, the incidence of abdominal wound infection was higher in those who received the oral regimen alone (14.6%) than in those who received the combined oral and parenteral regimen (5%).258

Other Uses

For more information on the uses of azithromycin and clarithromycin, see the individual monographs in 8:12.12.92. For topical uses of erythromycins, see 52:04.04 and 84:04.04.

Administration

Erythromycin base, stearate, ethylsuccinate, and estolate are administered orally. Erythromycin lactobionate is administered by continuous or intermittent IV infusion. In general, the oral route of administration is preferred and should replace the parenteral route as soon as possible.

Dosage

The duration of erythromycin therapy is dependent on the type of infection. In infections caused by Streptococcus pyogenes (β-hemolytic streptococci), therapy should be continued for at least 10 days. When oral erythromycin therapy is used for prophylaxis or treatment of β-hemolytic streptococcal infections, the importance of strict adherence to the prescribed dosage regimen must be stressed to the patient.

Dosage in Renal Impairment

Since renal excretion is not a major route of elimination of erythromycin and prolongation of serum half-life of the drug is not clinically important, dosage modifications are not necessary for patients with impaired renal function.

With the exception of the estolate, erythromycins are considered among the least toxic anti-infectives and serious adverse effects are rare.

GI Effects

The most common adverse effects of oral erythromycins are GI and are dose related. Erythromycin stimulates smooth muscle and GI motility. Abdominal pain and cramping occur frequently. Nausea, vomiting, and diarrhea have also occurred, especially after large doses. Occasionally, stomatitis, heartburn, anorexia, melena, pruritus ani, and reversible mild acute pancreatitis have occurred.

Clarithromycin causes less stimulation of GI smooth muscle motility than erythromycin in animals, and adverse GI effects appear to occur less frequently with clarithromycin or azithromycin than with oral erythromycin therapy.

Hepatic Effects

Hepatic dysfunction, with or without jaundice, has occurred in patients receiving oral or parenteral erythromycin.217,222,224 Erythromycin estolate may rarely produce hepatotoxicity in the form of reversible cholestatic hepatitis. Erythromycin estolate-induced hepatotoxicity, which occurs mainly in adults, is most likely to appear in patients who receive the drug for longer than 10 days or in repeated courses of therapy. Therefore, use of the drug in these circumstances should be avoided. Erythromycin estolate-induced hepatotoxicity is generally considered to be a hypersensitivity reaction to the propanoate ester linkage at the 2" position of the drug. However, reversible cholestatic hepatitis similar to that reported with erythromycin estolate has also been reported rarely with erythromycin ethylsuccinate.217,223 Some clinicians suggest that use of erythromycin estolate and erythromycin ethylsuccinate should be avoided in patients with a history of hepatitis associated with erythromycin therapy.217

Local Effects

Venous irritation and thrombophlebitis have occurred following IV administration of erythromycin lactobionate. The manufacturer states that pain and vessel trauma can be minimized if dilute solutions of the drug are administered by continuous infusion or by intermittent infusion slowly over 20-60 minutes.

Cardiac Effects

Prolongation of the QT interval and development of ventricular arrhythmias, including atypical ventricular tachycardia (torsades de pointes), have been reported rarely with oral or IV erythromycin.260,305,306,307,308,360,362,376,481 Most reported cases have involved IV administration of the drug; limited data suggest that these adverse cardiac effects may depend on serum concentrations and/or rate of infusion of the drug.260,305,306,307,308,360,362,376,481 Erythromycin has exhibited concentration-dependent, reversible effects on cardiac conduction in electrophysiologic studies in humans and in Purkinje fibers isolated from dogs similar to those exhibited by class IA antiarrhythmic agents such as quinidine.305,308,360,376 Erythromycin prolongs the QT interval and blocks the potassium channel encoded by the human ether-a-gogo-related gene (HERG).481

It has been suggested that erythromycins be used with caution in patients at risk for QT prolongation and/or accumulation of the anti-infective, particularly when the drug is administered IV.305,306,307,308,360,361,362,376 Some clinicians suggest that decreasing the rate of IV infusion of erythromycin may reduce the risk of cardiac toxicity; however, decreasing the rate may not eliminate the risk, and discontinuance of the drug may be necessary.360,362 Additional study and experience are needed to elucidate further the mechanisms and possible risk factors for the development of this toxicity.360,361,362

There is some evidence that concomitant use of erythromycin with drugs that inhibit metabolism of the anti-infective may be associated with an increased risk of sudden cardiac death.481 In a population-based study that evaluated the association between erythromycin and the risk of sudden death from cardiac causes (usually ventricular tachyarrhythmia) using data for deaths occurring in a Tennessee Medicaid cohort from 1988-1993, the incidence of sudden death from cardiac causes was twice as high in those who received oral erythromycin during the study period than in those who received no anti-infectives.481 Concomitant use of oral erythromycin (a drug metabolized by the cytochrome P-450 [CYP] isoenzyme 3A) with drugs that inhibit CYP3A (e.g., fluconazole, ketoconazole, itraconazole, diltiazem, verapamil) increased the risk of sudden death from cardiac causes by a factor of 5.481 When the effect of specific CYP3A inhibitors was evaluated, calcium-channel blocking agents (diltiazem, verapamil) accounted for nearly all the person-years of follow-up and all cases of sudden death from cardiac causes.481 Prior use of erythromycin or prior use of CYP3A inhibitors was not associated with an increased risk.481 Therefore, it has been suggested that concomitant use of erythromycin and drugs that are potent inhibitors of CYP3A should be avoided.481 (See Drug Interactions.)

Other Adverse Effects

Mild allergic reactions including urticaria, skin eruptions, and rash have occurred with erythromycin therapy. Serious allergic reactions including anaphylaxis have also been reported. Although a causal relationship was not definitely established, Stevens-Johnson syndrome occurred in at least one patient receiving oral erythromycin.244

Ototoxicity consisting of bilateral hearing loss, in at least one case irreversible, has been reported rarely with erythromycin lactobionate, stearate, or ethylsuccinate.212,213,323 Tinnitus, alone or with vertigo, has also been reported rarely.212,213 Ototoxicity has generally occurred in patients with impaired renal or hepatic function and/or in those who were receiving high dosages of erythromycin (e.g., 4 g/day or more).212,213 Although hearing loss usually has been reversible following dosage reduction or discontinuance of the drug,212 sensorineural hearing loss that had not resolved after a follow-up period of at least 23 weeks also has been reported in a geriatric patient with underlying hepatic disease who received 2 g of IV erythromycin daily.323 Hypotension has been reported rarely in patients receiving erythromycin therapy.326

Although a causal relationship to erythromycin lactobionate has not been established, nervous system effects including seizures, hallucinations, confusion, and vertigo have occurred rarely during therapy with the drug.

Precautions and Contraindications

Following prolonged or repeated erythromycin therapy, overgrowth of nonsusceptible bacteria or fungi may occur. Appropriate therapy should be instituted if such infection occurs. Because Clostridium difficile -associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by overgrowth of toxin-producing clostridia has been reported with the use of broad-spectrum anti-infective agents, it should be considered in the differential diagnosis of patients who develop diarrhea during anti-infective therapy.313 Colitis may range in severity from mild to life-threatening.364,377 Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include sigmoidoscopy, appropriate bacteriologic studies, and treatment with fluid, electrolyte, and protein supplementation as indicated.313,467,468,469,470,471 If colitis is severe or is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.313,364,377,467,468,469,470,471 Other causes of colitis also should be considered.313

Erythromycins are contraindicated in patients with a history of hypersensitivity reactions to the drugs. When astemizole and terfenadine were commercially available in the US, erythromycins were contraindicated in patients receiving these antihistamines.315,320 Concomitant administration of other macrolide antibiotics (e.g., clarithromycin) also was contraindicated in patients receiving terfenadine or astemizole since macrolides may impair metabolism of the antihistamines, potentially resulting in serious cardiotoxicity.298,315,318,324,325,329,403,404,439 (See Drug Interactions: Astemizole and Terfenadine.) Concomitant administration of cisapride and erythromycin or clarithromycin is contraindicated since these macrolides are expected to produce substantially increased plasma concentrations of unchanged cisapride and increase the potential for serious adverse effects (e.g., life-threatening cardiac arrhythmias) associated with the drug.422,479

Erythromycin estolate is contraindicated in patients with hepatic dysfunction or preexisting liver disease. Other erythromycins should be used with caution in patients with impaired hepatic function or impaired biliary excretion. In addition, monitoring of serum erythromycin concentrations and modification of dosage when indicated may be advisable in these patients. The manufacturer of erythromycin gluceptate recommends monitoring hepatic function when the patient is receiving high doses or prolonged therapy.

Mutagenicity and Carcinogenicity

Long-term (2-year) studies in rats using oral erythromycin base or erythromycin ethylsuccinate have not shown any evidence of tumorigenicity.242 Studies have not been performed to date to evaluate the mutagenic potential of erythromycin.242

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in female rats using oral erythromycin base at levels up to 0.25% of the diet prior to and during mating, during gestation, and through weaning of 2 successive litters have not revealed evidence of teratogenicity.242 Erythromycin has been reported to cross the placenta in humans; however, fetal plasma concentrations are generally low.298 There are no adequate and controlled studies to date using erythromycin in pregnant women, and the drug should be used during pregnancy only when clearly needed.242 However, oral erythromycin is used for the treatment of urogenital chlamydial infections in pregnant women.228,248 Erythromycin estolate is not recommended for this use because of the potential adverse effects on mother and fetus.228,248

Fertility

Reproduction studies in male and female rats using oral erythromycin base at levels up to 0.25% of the diet have not revealed evidence of impaired fertility.242

Lactation

Because erythromycin is distributed into milk, the drug should be used with caution in nursing women.242

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Erythromycin, apparently through inhibition of cytochrome P-450 (CYP) microsomal enzyme systems,352 can reduce the hepatic metabolism of some drugs including carbamazepine,358,378,379,380,381,382,383,384,385 cyclosporine,357,386,387,388,389 hexobarbital, phenytoin, alfentanil,354,355,390 disopyramide,309,351,353 lovastatin,359,391 and bromocriptine,349,350,356 thereby decreasing elimination and increasing serum concentrations of these drugs. In patients receiving concomitant erythromycin, serum concentrations of drugs metabolized by cytochrome P-450 microsomal enzyme systems should be monitored closely and dosage adjusted if necessary.349,350,351,352,357,358

Erythromycin is metabolized by CYP3A and concomitant use with drugs that inhibit the CYP3A isoenzyme may result in increased erythromycin plasma concentrations.481 There is some evidence that concomitant use of oral erythromycin with drugs that inhibit CYP3A (i.e., fluconazole, ketoconazole, itraconazole, diltiazem, verapamil) is associated with an increased incidence of sudden death from cardiac causes,481 presumably because of increased plasma erythromycin concentrations resulting in an increased risk of QT prolongation (a dose-associated effect of erythromycin) and serious ventricular arrhythmias.481 Therefore, it has been suggested that concomitant use of erythromycin and drugs that are potent inhibitors of CYP3A should be avoided.481

Anti-infective Agents

Although in vitro studies have shown varying degrees of additive or synergistic effects against some organisms when erythromycin was used in conjunction with penicillins, streptomycin, sulfonamides, rifampin, or chloramphenicol, the clinical importance of these reports has not been established. Antagonism of bactericidal activity has been observed between erythromycin and clindamycin in vitro. In addition, antagonism has been reported when a bacteriostatic drug was administered with a bactericidal drug, but antagonism has not been convincingly documented clinically.

Antifungal Agents

In a population-based study, concomitant use of oral erythromycin and drugs that inhibit CYP3A (i.e., fluconazole, ketoconazole, itraconazole) was associated with an increased incidence of sudden death from cardiac causes.481 Concomitant use of erythromycin and these drugs presumably increases plasma erythromycin concentrations resulting in an increased risk of QT prolongation (a dose-associated effect of erythromycin) and serious ventricular arrhythmias.481 Concomitant use of erythromycin and fluconazole, ketoconazole, or itraconazole should be avoided.481

Astemizole and Terfenadine

Erythromycin may interact with astemizole and terfenadine (both drugs no longer commercially available in the US), resulting in potentially serious adverse cardiovascular effects.298,315,318,324,325,329 Some evidence indicates that erythromycin may alter the metabolism of astemizole and terfenadine, probably via inhibition of the cytochrome P-450 microsomal enzyme system.315,316,317,318,324,325,328,405 (See Drug Interactions and Cautions: Cardiovascular Effects and Precautions and Contraindications, in the Antihistamines General Statement 4:00.) While erythromycin has been shown to decrease markedly the clearance of the active carboxylic acid metabolite of terfenadine, the effect of the macrolide on unchanged terfenadine concentrations has not been fully elucidated,315,317,318,319 but appears to show interindividual variation.318,406 In studies in extensive metabolizers of dextromethorphan or debrisoquin, erythromycin markedly impaired clearance of the active metabolite of terfenadine in all such individuals but produced measurable effects on unchanged terfenadine in only one-third of these individuals.318,406 In addition, erythromycin is known to inhibit the enzyme system responsible for astemizole's metabolism.324,325

Prolongation of the QT interval and ventricular tachycardia, including torsades de pointes, have been reported in some patients receiving astemizole324,325 or terfenadine298,315,318,328,329 concomitantly with erythromycin or the structurally related macrolide troleandomycin (no longer commercially available in the US). Rarely, cardiac arrest and death have been reported in patients receiving erythromycin and terfenadine concomitantly.298 Therefore, when terfenadine and astemizole were commercially available in the US, these antihistamines were contraindicated in patients receiving erythromycin, clarithromycin, or troleandomycin.315,320,324,439 In addition, concomitant administration of astemizole or terfenadine and azithromycin also was not recommended,315,316,321,322,324,325,407,408,409,410 although limited data suggested that azithromycin did not alter the metabolism of terfenadine.411,412,413

Carbamazepine

Concomitant use of erythromycin and carbamazepine in adults or children has resulted in increased serum concentrations of carbamazepine and subsequent signs of carbamazepine toxicity (e.g., ataxia, dizziness, drowsiness, vomiting).210,220,221 Studies in adults indicate that erythromycin can substantially decrease serum clearance of carbamazepine, presumably by inhibiting hepatic metabolism of the drug.210,220 Patients receiving erythromycin and carbamazepine concomitantly should be monitored for evidence of carbamazepine toxicity; carbamazepine dosage should be reduced when necessary.210,220,221 Some clinicians suggest that use of an alternative anti-infective agent, instead of erythromycin, may be necessary in patients receiving carbamazepine.221

Cardiac Drugs

Concomitant use of erythromycin and digoxin has resulted in increased serum concentrations of digoxin,298,299 and initiation of erythromycin therapy in several patients receiving disopyramide reportedly has been associated with elevated serum disopyramide concentrations, QT-interval prolongation, and polymorphic ventricular tachycardia.309

In at least one patient, concomitant administration of oral quinidine sulfate and IV erythromycin lactobionate resulted in increased serum quinidine concentrations and possible quinidine toxicity including asymptomatic, nonsustained ventricular tachycardia.393 It has been suggested that quinidine concentrations and ECGs be monitored closely if erythromycin is used concomitantly with quinidine.393

Calcium-channel Blocking Agents

In a population-based study, concomitant use of oral erythromycin and drugs that inhibit CYP3A (i.e., diltiazem, verapamil) was associated with an increased incidence of sudden death from cardiac causes.481 There was no increase in sudden cardiac death when oral erythromycin was used with calcium-channel blocking agents that do not inhibit CYP3A to a clinically important extent (e.g., nifedipine).481 Concomitant use of erythromycin and diltiazem or verapamil presumably increased plasma erythromycin concentrations resulting in an increased risk of QT prolongation (a dose-associated effect of erythromycin) and serious ventricular arrhythmias.481 In addition, erythromycin (a CYP3A inhibitor) is likely to increase plasma concentrations of diltiazem or verapamil leading to an increased risk of adverse effects associated with these drugs.481 Concomitant use of erythromycin and diltiazem or verapamil should be avoided.481

Cisapride

Oral or IV erythromycin markedly inhibit cytochrome P450 enzymes that metabolize cisapride (CYP3A4) and increase plasma cisapride concentrations, which may increase the potential for serious adverse effects (e.g., life-threatening cardiac arrhythmias) associated with the drug.422,479,480 (See Cautions: Precautions and Contraindications.)

Clozapine

In one patient stabilized on clozapine (800 mg daily), concomitant administration of oral erythromycin therapy (250 mg 4 times daily) appeared to precipitate a tonic-clonic seizure, possibly by interfering with metabolism of the drug.273

Cyclosporine

Concomitant use of erythromycin and cyclosporine may result in substantial increases in blood or plasma concentrations of cyclosporine231,232,233,234,235,236 and subsequent signs of cyclosporine toxicity (e.g., nephrotoxicity).232,233,234 Studies in healthy adults indicate that erythromycin can substantially decrease plasma clearance of cyclosporine,235 presumably by inhibiting hepatic metabolism of the drug,231,232,233,234,236 although the exact mechanism remains to be clearly determined.231,232,233,234,235,236 Erythromycin and cyclosporine should be used concomitantly with caution, and patients should be monitored for evidence of cyclosporine toxicity.231,232,233,234,236 Renal function and blood or plasma concentrations of cyclosporine should be monitored when erythromycin therapy is administered or discontinued in patients receiving cyclosporine or vice versa, and cyclosporine dosage adjusted appropriately as necessary.231,232,233,234,236

Ergot Alkaloids

Concomitant administration of erythromycin and ergotamine reportedly may induce ischemic reactions, dysesthesia, and peripheral vasospasm.297,298

Midazolam and Triazolam

Erythromycin may alter pharmacokinetics of midazolam.332,333 Following concomitant administration of erythromycin with oral midazolam (an oral dosage form of midazolam currently is not available in the US) in healthy individuals, oral bioavailability of midazolam increased, resulting in substantial increases in peak plasma concentrations and half-life and fourfold increases in the area under the plasma concentration-time curve (AUC) of midazolam.333 Pharmacokinetics of IV midazolam were not affected to the same extent by concomitant administration of erythromycin as were those of oral midazolam; however, clearance of IV midazolam was decreased by 54% and half-life and volume of distribution of IV midazolam were increased.333 Although the mechanism of these interactions is unknown,332 it has been suggested that erythromycin may decrease hepatic metabolism of midazolam.332,333,334,335 In these individuals, erythromycin potentiated the sedative effect of oral midazolam and, to a lesser extent, that of IV midazolam, and also altered substantially the psychomotor effects of midazolam.333 Some clinicians suggest that erythromycin not be used in patients receiving oral midazolam or, alternatively, dosage of oral midazolam be reduced by 50-75%.333 Patients should be observed carefully and dosage of IV midazolam should be adjusted in individuals receiving erythromycin concomitantly.333

Concomitant use of erythromycin apparently decreases clearance of triazolam and could increase the pharmacologic effects of the drug.238,239,332 A study in healthy adults indicates that peak serum concentration, elimination half-life, and area under the serum concentration time-curve (AUC) of triazolam are increased by about 50%, clearance of triazolam is decreased by about 50%, and the apparent volume of distribution of the drug is decreased by about 30% when erythromycin is given concomitantly.238,332 Patients receiving erythromycin and triazolam concomitantly should be monitored closely; a reduction in triazolam dosage may be necessary.239

It is not known whether concomitant administration of erythromycin with other benzodiazepines results in similar alterations of pharmacokinetics of the benzodiazepines.332

Theophylline

Concomitant use of erythromycin in patients receiving high dosage of theophylline has resulted in decreased clearance of theophylline, elevated serum theophylline concentrations, and a prolonged serum half-life of the bronchodilator.210,220,221 An interaction may be most likely to occur in patients receiving an erythromycin dosage greater than 1.5 g daily for more than 5 days.210 Patients receiving theophylline should be closely monitored for signs of theophylline toxicity when erythromycin is administered concomitantly; serum theophylline concentrations should be monitored and dosage of the bronchodilator reduced if indicated.210,220,221

Although further study is needed and the clinical importance has not been determined to date, there is some evidence that concomitant administration of erythromycin and theophylline can also result in decreased serum erythromycin concentrations210,220,221 and subtherapeutic concentrations of erythromycin may occur.336

Warfarin

Initiation of erythromycin therapy in some patients stabilized on warfarin has resulted in prolongation of prothrombin time and bleeding.210,211,220,221 Increased anticoagulant effect may be more pronounced in geriatric patients. The exact mechanism(s) of this interaction has not been clearly established, but erythromycin may inhibit hepatic metabolism of warfarin.210,211,220,221 Prothrombin time should be monitored more closely than usual in patients receiving warfarin when erythromycin therapy is initiated, and warfarin dosage should be adjusted as necessary.211,220,221

Laboratory Test Interferences

Erythromycin may falsely elevate concentrations of urinary catecholamines, 17-hydroxycorticosteroids, and 17-ketosteroids. The drug may interfere with colorimetric assays resulting in falsely increased AST (SGOT) and ALT (SGPT) concentrations. Falsely elevated AST concentrations without liver injury may result due to erroneous measurement of unidentified metabolites of erythromycin in colorimetric determinations.

Erythromycin may decrease serum folate assay results if a microbiologic method is used since the drug can inhibit the growth of Lactobacillus casei ; results are unaffected if the chromatographic procedure of Landon is used. The presence of erythromycin in the blood may interfere with the etiologic diagnosis of mycoplasmal pneumonia by masking a rise in the titer of the tetrazolium reduction inhibition neutralizing antibody to Mycoplasma pneumoniae.

Mechanism of Action

Erythromycin is usually bacteriostatic, but it may be bactericidal in high concentrations or against highly susceptible organisms.

Erythromycin inhibits protein synthesis in susceptible organisms by binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of erythromycin is the same as that of other macrolides (e.g., azithromycin, clarithromycin) and the same as that of clindamycin, lincomycin, and chloramphenicol.

Erythromycin exerts its effect only against multiplying organisms. Only un-ionized erythromycin is believed to penetrate susceptible bacteria, and penetration increases in an alkaline environment as the pK_a of the drug is approached. Erythromycin generally penetrates the cell wall of gram-positive bacteria more readily than that of gram-negative bacteria, and gram-positive organisms may accumulate 100 times more erythromycin than do gram-negative organisms.

Spectrum

Erythromycin is active in vitro against gram-positive cocci (staphylococci and streptococci) and gram-positive bacilli including Bacillus anthracis, Corynebacterium , Clostridium , Erysipelothrix , and Listeria monocytogenes. Erythromycin also is active in vitro against some gram-negative cocci ( Neisseria ) and some gram-negative bacilli, including some strains of Haemophilus influenzae, Legionella pneumophila, Pasteurella , and Brucella. Some strains of Chlamydia , Actinomyces , Mycoplasma pneumoniae , Ureaplasma urealyticum , Rickettsia, Treponema , and Entamoeba histolytica are inhibited by erythromycin. Erythromycin also has some in vitro activity against Mycobacterium kansasii and M. scrofulaceum . Enterobacteriaceae (e.g., Escherichia coli , Enterobacter , Klebsiella , Proteus , Salmonella , Shigella ) and Pseudomonas usually are resistant to erythromycin, as are viruses and fungi.

There is a wide range of minimal inhibitory concentrations (MICs) reported for erythromycin, but generally in vitro erythromycin concentrations of less than 1 mcg/mL inhibit the majority of strains of susceptible staphylococci, streptococci, Moraxella catarrhalis (formerly Branhamella catarrhalis ), Clostridium , Erysipelothrix , Listeria , Bacillus , Actinomyces , and Mycoplasma pneumoniae. Higher concentrations may be required to inhibit some strains of Enterococcus faecalis (formerly Streptococcus faecalis ) and certain strains of Corynebacterium , Neisseria , Haemophilus , Brucella , Pasteurella , Bordetella , and mycobacteria.

Borrelia burgdorferi , the causative organism of Lyme disease, reportedly may be inhibited in vitro by erythromycin concentrations of 0.01-1 mcg/mL or less.240,289,290,292,293,296 Minimum bactericidal concentrations of erythromycin for B. burgdorferi generally have ranged from 0.04-0.16 mcg/mL.279,293,301

Erythromycin has in vitro activity against Bacillus anthracis .225,226 Anti-infectives are active against the germinated form of B. anthracis , but are not active against the organism while it is still in the spore form.215 Results of in vitro susceptibility testing of 11 Bacillus anthracis isolates that were associated with cases of inhalational or cutaneous anthrax that occurred in the US (Florida, New York, District of Columbia) during September and October 2001 in the context of an intentional release of anthrax spores (biologic warfare, bioterrorism) indicate that these strains had erythromycin MICs of 1 mcg/mL.347 Based on interpretive criteria established for staphylococci, these strains are considered to have intermediate susceptibility to erythromycin.347 Limited or no data are available to date regarding in vivo activity of erythromycin against B. anthracis or use of the drug in the treatment of inhalational anthrax.347

Erythromycin is active in vitro against Helicobacter pylori (formerly Campylobacter pylori or C. pyloridis ), an organism associated with the development of duodenal and gastric ulcers.337,338,339,340,341,342,343,429,430,431,432,433 However, in vivo efficacy of the drug against this organism has been poor, possibly as a result of inactivation of the drug by stomach acid and/or the rapid development of resistance when erythromycin is used alone for H. pylori infections.337,338,343,344

In general, clarithromycin displays in vitro activity similar to or greater than that of erythromycin against erythromycin-sensitive organisms; azithromycin and erythromycin have comparable activity against most gram-positive organisms (e.g., streptococci and staphylococci) but azithromycin is more active against gram-negative organisms (e.g., M. catarrhalis , Neisseria gonorrhoeae , Hemophilus influenzae ).

For more information on the spectra of activity of azithromycin and clarithromycin, see the individual monographs in 8:12.12.92.

In Vitro Susceptibility Testing

Because there are differences in the spectra of activity and potency of the various macrolides, in vitro susceptibility to these drugs must be tested individually. When the disk-diffusion procedure is used, separate drug-specific disks should be used to test susceptibility to azithromycin, clarithromycin, and erythromycin.

The Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]) states that, if results of in vitro susceptibility testing indicate that a clinical isolate is susceptible to erythromycin, then an infection caused by this strain may be appropriately treated with the dosage of the drug recommended for that type of infection and infecting species, unless otherwise contraindicated.346 If results indicate that a clinical isolate has intermediate susceptibility to erythromycin, then the strain has a minimum inhibitory concentration (MIC) that approaches usually attainable blood and tissue concentrations and response rates may be lower than for strains identified as susceptible.346 Therefore, the intermediate category implies clinical applicability in body sites where the drug is physiologically concentrated or when a high dosage of the drug can be used.346 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.346 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to erythromycin, the strain is not inhibited by systemic concentrations of the drug achievable with usual dosage schedules and/or MICs fall in the range where specific microbial resistance mechanisms are likely and efficacy has not been reliable in clinical studies.346

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to erythromycin, a disk containing 15 mcg of the drug should be used.346

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus or Enterococcus with growth inhibition zones of 23 mm or greater are susceptible to erythromycin, those with zones of 14-22 mm have intermediate susceptibility, and those with zones of 13 mm or less are resistant to the drug.346

When testing susceptibility of Streptococcus , including S. pneumoniae , according to CLSI standardized procedures using Mueller-Hinton agar (supplemented with 5% defibrinated sheep blood), those with growth inhibition zones of 21 mm or greater are susceptible to erythromycin, those with zones of 16-20 mm have intermediate susceptibility, and those with zones of 15 mm or less are resistant to the drug.346

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to CLSI standardized procedures using CLSI interpretive criteria, Staphylococcus or Enterococcus with MICs of 0.5 mcg/mL or less are susceptible to erythromycin, those with MICs of 1-4 mcg/mL have intermediate susceptibility, and those with MICs of 8 mcg/mL or greater are resistant to the drug.346

When susceptibility of Streptococcus , including S. pneumoniae , is tested according to CLSI standardized procedures using cation-adjusted Mueller-Hinton broth (with 2-5% lysed horse blood), those with MICs of 0.25 mcg/mL or less are susceptible to erythromycin, those with MICs of 0.5 mcg/mL have intermediate susceptibility, and those with MICs of 1 mcg/mL or greater are resistant to the drug.346

Resistance

Resistant strains of Haemophilus influenzae , Corynebacterium diphtheriae , and staphylococci, particularly S. aureus , have developed during therapy with erythromycin.

Erythromycin-resistant strains of streptococci, including Streptococcus pyogenes (group A β-hemolytic streptococci), group B streptococci, S. pneumoniae , and viridans streptococci have been reported.440,441,442,443,444,445,446,447,448,449 In some areas of the world (e.g., Taiwan, Japan, Spain), a large percentage (up to 14-83%) of streptococcal isolates have been reported to be resistant to erythromycin.442,443,444 In Finland, the incidence of erythromycin resistance in S. pyogenes increased from about 13% in 1990 to 19% in 1993; however, by 1996, the incidence had decreased to 8.6% and this decrease was attributed in part to a nationwide effort to restrict use of erythromycin in outpatients with minor respiratory tract or skin infections.440 The incidence of erythromycin-resistant streptococci in the US has been relatively low to date;392,441,446 analysis of clinical isolates at some US medical centers indicate that up to 7% of S. pyogenes 446 and 7-16% of group B streptococci445,449 are resistant to erythromycin.

Resistance to erythromycin develops stepwise at a rate less than or equal to that with natural penicillins. Resistance usually is not a major problem in short-term erythromycin therapy, but may be clinically important if erythromycins are used frequently or in large quantities.

Cross-resistance generally occurs among the macrolides, including azithromycin, clarithromycin, and erythromycin. Some cross-resistance occurs between macrolides and clindamycin and lincomycin. Erythromycin exhibits a dissociated type of resistance, characteristic of macrolides, in which the presence of erythromycin can influence in vitro susceptibility testing. For example, strains of organisms that are resistant to erythromycin but susceptible to other macrolides or lincomycin may show resistance to these drugs if erythromycin also is present. This phenomenon may be the result of altered metabolism in the organism induced by erythromycin or of competition between erythromycin and lincomycin for the ribosomal binding site.

Pharmacokinetics

Absorption

Absorption of orally administered erythromycins occurs mainly in the duodenum. The bioavailability of the drugs is variable and depends on several factors including the particular erythromycin derivative, the formulation of the dosage form administered, acid stability of the derivative, presence of food in the GI tract, and gastric emptying time.

Gastric acidity causes partial inactivation of some of these drugs, with the degree of inactivation depending on the acid stability of the particular derivative and dosage form. Erythromycin base is highly susceptible to gastric acid inactivation, and commercially available tablets are coated with acid-resistant (enteric) coatings or are buffered to protect the drug from gastric acidity. Results of one in vitro study indicate that the stearate is also highly susceptible to gastric acid inactivation. Erythromycin ethylsuccinate is partially dissociated in the intestine where both erythromycin and the undissociated ester are absorbed; in the blood, the ester is partially hydrolyzed to release free erythromycin. The estolate is acid stable because of the presence of the lauryl sulfate moiety. Erythromycin estolate dissociates in the upper intestine, liberating the inactive propanoate ester which is absorbed and partially hydrolyzed in the blood to release free erythromycin.

Single oral doses of the erythromycins generally produce peak serum concentrations within 1-4 hours. Higher peak serum concentrations are achieved when the drugs are given orally in 4 doses daily than following single doses. In general, oral administration of 250 mg of erythromycin as the base, estolate, or stearate, or 400 mg of erythromycin as the ethylsuccinate, 4 times daily maintains antibacterial serum concentrations of 0.1-2 mcg/mL. Higher serum concentrations have been reported to occur in patients receiving erythromycin estolate than in those receiving other derivatives. However, since as much as 80% of the drug in plasma is the inactive propanoate ester and the assay procedure causes hydrolysis of the ester, the apparently greater plasma concentrations achieved with the estolate are not necessarily indicative of greater antibacterial activity. Mean peak serum concentrations of about 0.6 mcg/mL reportedly occur 1.5-2 hours after a single 50-mg IM dose of erythromycin ethylsuccinate in children, or 1-4 hours after a single 100-mg IM dose in adults. Following IV administration of 200 mg of erythromycin lactobionate, peak serum concentrations of 3-4 mcg/mL have been reported.

Distribution

Erythromycin is widely distributed into most body tissues and fluids. Following oral or parenteral administration of the drug, most tissues except the brain have erythromycin concentrations that are higher and persist longer than serum concentrations. Only low concentrations of erythromycin (2-13% of serum concentrations) are distributed into CSF. In patients with otitis media, erythromycin appears in the middle ear exudate in concentrations generally 50% of concurrent serum concentrations; however, these concentrations may not be sufficient to inhibit all strains of H. influenzae. Concentrations of erythromycin in prostatic fluid and semen are approximately 33% of concurrent serum concentrations. In patients with normal liver function, erythromycin is concentrated in the liver and bile.

Erythromycin base is 73-81% bound and erythromycin estolate is approximately 96% bound to serum proteins.219

Erythromycin crosses the placenta, achieving fetal serum concentrations 5-20% of maternal serum concentrations. Erythromycin is distributed into milk in concentrations about 50% of plasma concentrations.

Elimination

The serum half-life of erythromycin in patients with normal renal function is usually 1.5-2 hours, but may range from 0.8-3 hours. In anuric patients, the serum half-life may be prolonged to 6 hours, but this is not considered to be clinically important. Although there are few data on the serum half-life of erythromycin in patients with impaired hepatic function, the possibility that the half-life may be prolonged should be considered. In one single-dose study, the terminal elimination half-life in adults with alcoholic liver disease was similar to that in healthy adults, but the initial distribution half-life was slightly prolonged and average and peak serum concentrations were higher in those with alcoholic liver disease.

Erythromycin is partly metabolized by cytochrome P-450 (CYP) isoenzyme 3A4 in the liver by N -demethylation to inactive, unidentified metabolites.482 Erythromycin is mainly excreted unchanged via bile. Some reabsorption follows biliary excretion. Small amounts of erythromycin are also excreted in urine. Only small amounts of erythromycin are removed by hemodialysis.

Chemistry and Stability

Chemistry

Erythromycin is a macrolide antibiotic produced by Streptomyces erythreus. Erythromycin is a weak base that readily forms salts and esters with organic acids. The pK_a of erythromycin base is 8.9. Erythromycin has a bitter taste, and the stearate salt, the ethylsuccinate ester, and the sodium lauryl sulfate salt of the propanoate ester (estolate) have been developed in an attempt to overcome the taste. In addition, many commercially available tablets of the various derivatives are film-coated to mask the taste or enteric-coated to protect the drugs from inactivation by gastric acidity. Erythromycin base, stearate, ethylsuccinate, and estolate are poorly soluble in water; erythromycin lactobionate is freely soluble in water.

Azithromycin and clarithromycin are semisynthetic macrolide antibiotics structurally and pharmacologically related to erythromycin. Azithromycin, an azalide, differs structurally from erythromycin by the addition of a methyl-substituted nitrogen atom into the lactone ring; clarithromycin differs from erythromycin only by the methylation of a hydroxyl group at the 6 position on the lactone ring. These structural modifications in azithromycin and clarithromycin result in improved resistance to acid degradation and enhanced tissue penetration compared with erythromycin.

Tacrolimus is a macrolide antibiotic produced by Streptomyces tsukubaensis 365,366,367,368,371,373,374,375 that exhibits only limited antimicrobial activity;371,373 the drug is employed for its immunosuppressive effects (e.g., to prevent rejection in allograft recipients).365,366,367,368,369,370,371,372,374,375 (See Tacrolimus 92:44.)

Stability

Erythromycin lactobionate is reported to be physically incompatible with many drugs, but the compatibility depends on several factors (e.g., the concentration of the drugs, specific diluents used, temperature). Stability of erythromycin lactobionate solutions is dependent on pH and is optimal at pH 6-8; loss of antibacterial activity occurs rapidly when the pH is less than 5.5. Specialized references should be consulted for specific compatibility information.

For more information on the chemistry and stability of azithromycin and clarithromycin, see the individual monographs in 8:12.12.92.

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