VA Class:AM200

AHFS Class:

• Erythromycins 8:12.12.04

Generic Name(s):

• Erythromycin Lactobionate

Erythromycin lactobionate is a macrolide antibiotic.

Reconstitution and Administration

Erythromycin lactobionate is administered by continuous or intermittent IV infusion. Because of the local irritative effects of erythromycin, the drug must not be administered rapidly by direct IV injection (IV push). The manufacturers state that continuous IV infusion with the drug is preferred to intermittent IV infusion because a slower infusion rate and lower erythromycin concentration is used; however, the drug may be administered by intermittent IV infusion at intervals not greater than every 6 hours. Oral erythromycin therapy should replace IV erythromycin lactobionate therapy as soon as possible.

Erythromycin lactobionate vials labeled as containing 500 mg or 1 g of erythromycin are initially reconstituted by adding 10 or 20 mL, respectively, of sterile water for injection without preservatives to provide a solution containing 50 mg/mL. No other diluent should be used to prepare this initial solution. (See Chemistry and Stability: Stability.) Prior to administration, the concentrated solution should be further diluted in glass or flexible plastic (Lifecare^®) containers of 0.9% sodium chloride injection, lactated Ringer's, or Normosol^®-R. Alternatively, IV solutions of 5% dextrose injection, 5% dextrose and lactated Ringer's, or 5% dextrose and 0.9% sodium chloride in glass or flexible plastic containers or Normosol^®-M or -R with 5% dextrose in glass containers may also be used if they are first buffered to a pH of 5.5 or higher using 4% sodium bicarbonate (Neut^®). (The manufacturers recommend addition of 1 mL of this buffer to every 100 mL of infusion solution.) For continuous IV infusion, the concentrated solution should be diluted to a concentration of 1 mg/mL. For intermittent IV infusion, the appropriate dose (one-fourth of the total daily dose) of the concentrated solution should be diluted to a concentration of 1-5 mg/mL and administered over 20-60 minutes. Not less than 100 mL of diluent should be used for preparing intermittent IV infusion solutions.

ADD-Vantage^® vials labeled as containing 500 mg or 1 g of erythromycin should be reconstituted according to the manufacturer's directions. Piggyback vials containing 500 mg of erythromycin are reconstituted by adding 100 mL of 0.9% sodium chloride injection, lactated Ringer's, or Normosol^®-R injection to provide a solution containing 5 mg/mL. Alternatively, 100 mL of 5% dextrose injection, 5% dextrose and lactated Ringer's, 5% dextrose and 0.9% sodium chloride, or Normosol^®-M or -R with 5% dextrose injection may be used if they are first buffered to a pH of 5.5 or higher using 1 mL of 4% sodium bicarbonate (Neut^®). Immediately after the diluent is added, the vial should be shaken well to enhance dissolution; lack of immediate agitation greatly increases the time required for complete dissolution. Solutions reconstituted in piggyback vials or ADD-Vantage^® containers are administered by intermittent IV infusion; one-fourth of the total daily dose is administered over 20-60 minutes.

Dosage

Dosage of erythromycin lactobionate is expressed in terms of erythromycin.

The usual dosage of erythromycin as the lactobionate for severe infections in adults and children is 15-20 mg/kg daily, given as a continuous IV infusion or by intermittent IV infusion in divided doses every 6 hours. Alternatively, a pediatric dosage of 300-600 mg/m² daily has been recommended. Dosages as high as 4 g daily have been used in very severe infections.

Pelvic Inflammatory Disease

Although erythromycin is not included in the current US Centers for Disease Control and Prevention (CDC) recommendations for the treatment of acute pelvic inflammatory disease (PID) caused by N. gonorrhoeae ,104 the manufacturers recommend a regimen of 500 mg of IV erythromycin every 6 hours for at least 3 days followed by 250 mg of erythromycin orally every 6 hours for 7 days for the treatment of these infections. However, some clinicians believe this oral dosage is inadequate and recommend 500 mg every 6 hours for 7-10 days.

Legionnaires' Disease

Although the optimum dosage and duration of erythromycin for the treatment of Legionnaires' disease have not been established, dosages of 1-4 g daily in divided doses have been given alone or in conjunction with rifampin.105,106,107 A parenteral regimen usually is necessary for the initial treatment of severe Legionnaires' disease and the addition of rifampin is recommended during the first 3-5 days of therapy in severely ill and/or immunocompromised patients; after a response is obtained, rifampin can be discontinued and therapy changed to oral erythromycin.105,106,107 The duration of therapy in patients with Legionnaires' disease usually is 10-21 days.105,106,107

Anthrax

If erythromycin as the lactobionate is used as an alternative agent for the treatment of anthrax† caused by Bacillus anthracis susceptible to the drug, some clinicians recommend that adults receive an IV dosage of 15-20 mg/kg (up to 4 g) daily and that children receive 20-40 mg/kg daily given in divided doses every 6 hours.108 Although erythromycin has been suggested as an alternative to penicillin G for the treatment of naturally occurring or endemic anthrax in patients hypersensitive to penicillin G,108,111,112 limited or no clinical data are available to date regarding in vivo activity of erythromycin against B. anthracis and efficacy has not been evaluated in human or animal studies.109,110 Erythromycin is not considered a drug of choice for the treatment of anthrax that occurs as the result of exposure to anthrax spores in the context of biologic warfare or bioterrorism.109,110 For information on treatment of anthrax and recommendations for prophylaxis following exposure to anthrax spores, see Uses: Anthrax, in Ciprofloxacin 8:12.18.

Prevention of Perinatal Group B Streptococcal Disease

If erythromycin is used for intrapartum anti-infective prophylaxis for prevention of perinatal group B streptococcal (GBS) disease† in women with penicillin hypersensitivity who should not receive a β-lactam anti-infective, the CDC recommends that 500 mg of erythromycin be given IV every 6 hours until delivery.113 When indicated, such prophylaxis is initiated at the time of labor or rupture of membranes.113 Streptococcus agalactiae (group B streptococci) with resistance to erythromycin has been reported with increasing frequency.113 Therefore, clinical isolates obtained during GBS prenatal screening should be tested for in vitro susceptibility to erythromycin whenever use of the drug is being considered for prevention of perinatal GBS disease in women hypersensitive to penicillin.113 (See Uses: Prevention of Perinatal Group B Streptococcal Disease, in the Erythromycin General Statement 8:12.12.04.)

Pediatric Precautions

Some commercially available formulations of erythromycin lactobionate powder for injection contain benzyl alcohol as a preservative. Although a causal relationship has not been established, administration of injections preserved with benzyl alcohol has been associated with toxicity in neonates. Toxicity appears to have resulted from administration of large amounts (i.e., about 100-400 mg/kg daily) of benzyl alcohol in these neonates. Although use of drugs preserved with benzyl alcohol should be avoided in neonates whenever possible, the American Academy of Pediatrics states that the presence of small amounts of the preservative in a commercially available injection should not proscribe its use when indicated in neonates.

In several neonates with infections caused by Ureaplasma urealyticum who received IV administration of erythromycin lactobionate, adverse cardiac effects (e.g., bradycardia, hypotension, cardiac arrest, arrhythmias) requiring cardiopulmonary resuscitation have been reported.101,102,103 Some clinicians state that these adverse effects may depend on serum concentration and/or infusion rate of the drug.101,102,103 (See Cautions: Cardiac Effects, in the Erythromycins General Statement 8:12.12.04.) It has been suggested that prolonged IV infusion of erythromycin lactobionate (e.g., over 60 minutes) may reduce such adverse cardiac effects.102,103 However, it has been suggested that certain individuals may be at increased risk of developing erythromycin-induced adverse cardiac effects and that decreasing the rate of IV infusion may decrease but not eliminate the risk of such effects.101,103 Further study is needed to determine the pharmacokinetics and safety of erythromycin lactobionate in neonates.101,102,103

Chemistry and Stability

Chemistry

Erythromycin lactobionate occurs as white or slightly yellow crystals or powder having a faint odor and is freely soluble in water and in alcohol.

Stability

Erythromycin lactobionate powder for injection should be stored at a temperature less than 40°C, preferably between 15-30°C. Erythromycin lactobionate powder for injection has an expiration date of 4 years following the date of manufacture.

Erythromycin lactobionate sterile powder or powder for injection in 500-mg or 1-g vials must be initially reconstituted with sterile water for injection without preservatives, as the use of sodium chloride injection or other diluents containing inorganic salts will result in precipitation. The concentrated solution may then be diluted with a compatible IV solution. (See Dosage and Administration: Reconstitution and Administration.) No additional drugs or chemicals should be added to solutions of erythromycin lactobionate unless their effects on the chemical and physical stability of the solution have been determined; specialized references should be consulted for specific compatibility information. The stability of erythromycin lactobionate solutions depends on pH and is optimal at pH 6-8; acidic (pH less than 5.5) solutions of erythromycin lactobionate are unstable and rapidly lose their potency.

Following reconstitution of conventional vials of the drug with sterile water for injection to a concentration of 50 mg/mL, solutions of erythromycin lactobionate have a pH of 7 and are stable for 2 weeks when refrigerated at 2-8°C or for 24 hours at room temperature. Following further dilution of this concentrated solution to 1-5 mg/mL in 0.9% sodium chloride injection, lactated Ringer's, Normosol^®-R, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride, 5% dextrose and lactated Ringer's, or Normosol^®-M or -R with 5% dextrose, stability of the resultant solutions is variable and depends on several factors, including the IV infusion solution, type of container, resultant pH, and temperature. Because these diluted solutions are not suitable for prolonged storage and because of the variability of specific stability information, the manufacturers state, as a general guide, that the solutions should be completely administered within 8 hours after dilution. Alternatively, the manufacturers can provide more specific stability information. For example, diluted solutions are stable at 22-28°C for 24 hours in glass or flexible plastic (Lifecare^®) containers of lactated Ringer's or buffered (see Dosage and Administration: Reconstitution and Administration) 5% dextrose injection.

Piggyback vials of erythromycin lactobionate that have been reconstituted to a concentration of 5 mg of erythromycin per mL with 0.9% sodium chloride injection, lactated Ringer's, or Normosol^®-R or with buffered solutions of 5% dextrose injection, 5% dextrose and lactated Ringer's, 5% dextrose and 0.9% sodium chloride, or Normosol^®-M or -R with 5% dextrose should be used within 8 hours if stored at room temperature or 24 hours if refrigerated at 2-8°C. Reconstituted erythromycin lactobionate solutions in piggyback vials may be frozen at -20° to -10°C within 4 hours of preparation and stored for 30 days. Frozen solutions of the drug should be thawed in the refrigerator and used within 8 hours after thawing is complete; thawed solutions must not be refrozen.

When reconstituted as directed in 0.9% sodium chloride injection or 5% dextrose injection, solutions prepared from ADD-Vantage^® vials of erythromycin lactobionate should be completely administered within 8 or 2 hours, respectively. ADD-Vantage^® vials of the drug that have been connected to an ADD-Vantage^® diluent container but not activated for dissolution can be stored at room temperature for up to 30 days.

Additional Information

For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of erythromycin lactobionate, see the Erythromycins General Statement 8:12.12.04.

Only references cited for selected revisions after 1984 are available electronically.

101. Farrar HC, Walsh-Sukys C, Kyllonen K et al. Cardiac toxicity associated with intravenous erythromycin lactobionate: two case reports and a review of the literature. Pediatr Infect Dis J . 1993; 12:688-91. [PubMed 8018130]

102. Sims PJ, Waites KB, Crouse DT. Erythromycin lactobionate toxicity in preterm neonates. Pediatr Infect Dis J . 1994; 13:164-5. [PubMed 8190550]

103. Farrar HC, Walsh-Sukys C, Kyllonen K et al. Erythromycin lactobionate toxicity in preterm neonates. Pediatr Infect Dis J . 1994; 13:166.

104. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines 2002. MMWR Morb Mortal Wkly Rep . 2002; 51(No. RR-6):1-78. [Fulltext MMWR]

105. Stout JE, Yu VL. Legionellosis. N Engl J Med . 1997; 337:682-7. [PubMed 9278466]

106. Edelstein PH. Legionnaires' disease. Clin Infect Dis . 1993; 16:741-9. [PubMed 8329504]

107. Committee on Infectious Diseases, American Academy of Pediatrics. 2000 Red book: report of the Committee on Infectious Diseases. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000:364-5.

108. Dixon TC, Maselson M, Guillemin J et al. Anthrax. N Engl J Med . 1999; 341:815-26. [PubMed 10477781]

109. Centers for Disease Control and Prevention. Update: investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep . 2001; 50:909-19. [PubMed 11699843]

110. Inglesby TV, O'Toole T, Henderson DA et al for the Working Group on Civilian Biodefense. Anthrax as a biological weapon, 2002. Updated recommendations for management. JAMA . 2002; 287:2236-52. [PubMed 11980524]

111. US Army Medical Research Institute of Infectious Disease. USAMRIID's medical management of biologic casualties handbook. 4th ed. USAMRIID: Fort Detrick, MD; 2001 Feb.

112. Turnball PCB. Guidelines for surveillance and control of anthrax in human and animals. 3rd ed. Geneva, Switzerland: World Health Organization, Department of Communicable Diseases Surveillance and Response. Publication N. WHO/EMC/ZSI./98.6. 1998. From WHO website. [Web]

113. Centers for Disease Control and Prevention. Prevention of perinatal group B streptococcal disease: revised guidelines from CDC. MMWR Morb Mortal Wkly Rep . 2002; 51(RR-11):1-22. [Fulltext MMWR]