Erythromycin

Symposium on Antimicrobial Therapy

Erythromycin M arie J. Gribhle, M.B., Ch.B., F B.C .P .(C), * and Anthony W. Chow, MD., FB.C.P.(C)t

Erythromycin is currently thc most important of thc macrolidc antibiotics. It is produced by the actinomycete Streptomyces erythreHs and was introduced into clinical medicine in 1952 by McGuire and associates.'" Erythromycin has proved to be safe, effective therapy for a number of commonly encountered infections, and specific indications fc)r its use continue to increase. Erythromycin is composed of a macrocyclic lactone ring (macrolide) attached to two sugar moieties (Fig. 1). Erythromycin base is a bitter. crystalline compound that is poorly soluble in water, has a pK" of 8.8, and is rapidly inactivated by acid. Modifications of the drug and its pharmaceutical preparations have been made in an attempt to improve absorption and subsequent serum levels. This is achieved eithcr by providing an cnteric coating or a "film" coating to protect the erythromycin base from acid degradation or by preparing a salt, an ester, or the salt of an ester to modify the chemical structure. Five oral preparations and two intravenous watersoluble salts are available. Intramuscular injection is painful and not recommended. Like the other macrolide antibiotics, erythromycin acts at the level of the .50S ribosomal subnnit. In susceptible microorganisms, erythromycin inhibits RNAdependent protein synthesis by blockagc of transpeptidation and/or translocation reactions, without affecting synthesis of nucleic acid.''''') The antibacterial activity of lincomycin and chloramphenicol may bc interfered with by erythromycin because of competition f()r common binding sites. The action of erythromycin may be bactericidal or bacteriostatic. depcnding on microbial species, phase of growth, density of inoculum, and drug concentration. In addition, the activity of the drug increases markedly with increasing pH.:17

ANTIMICROBIAL SPECTRUM Erythromycin has a broad spectrum of antimicrobial activity. In vitro susceptibilities of some potential pathogens arc summarized in Table l. In addition, erythromycin has clinically useful activity against a number of other organisms including Treponema pallidHm, lIlany strains of rickettsiae and chlamydia, and several non*Senior Fellow, Division of IlIfl'ctiolls Disease, Department of Medicine, University of British Collllllhia and Vancouver General Hospital, Vallcouver, Canada tHead, Division of Infections Disease, alld Professor of I\:[cdicillc, University of British Columhia and Vancouver Ceneral Hospital, VallcolI\'('r, Canada

Medical Clinic.\' of North Ameri(;(/--Vol.

(;(i.

No. 1. Jallllar) 1982

79

80

MAHIE

Table 1.

J.

GHIIlHLE A1';1l A1';nlo1';Y

W.

CHOW

Antimicrohial Spectrum of El'!ltizromycin'l ..1173 r-..11~HvIAL

~lediall

Streptococcus I'ncllmoniac

n.os

StreptucoCCl/S lJ1lo!!,cncs

0.04

Str('piOC('CCllS viririalls

O.OG

Streptucoccus Jaecalis Staphylococcus aureus Staphylococcus epidermidis Coq/Hcbacterium diphtheriae Listeria nUJrwC!ltogenfs Actinomyces israelii Nocardia asteroides Neisseria gmwrrhocae Neisseria rneningitidis Brucella spp.

llemophilus influenzae Bordetella pertussis Campy{obacter Jetus ssI'. jejuni Legionella pueumophila Peptostrcptococcus spp. Clostridium perjringens C lostridiu11l telani

Bacteroides Jragilis

Bacteroides spp., not B Jragilis Fusobacterium spp.

MycohucteriulH kllHsasii

Mycoplasma pnellnumiae

C h{amyelia trachomatis

1.5 0.4 0.6 0.02 0.2 0.05 205 0.1 0.4 5 3.1 0.:3 1.(;

0.12 0.19 O.H

0.48 1.5

0.4 12 ..5 0.005 0 ..5

1!\"IIIBlTOHY COj'\CE:"JTBATIOI\ (jJ..l!illll)

Range

0.001-0.2* 0.007-0.2* 0.02-3.1 * 0.1-> 100 0.00,5->100 0.2-> LOO 0.006-3.1 * O.1-(J.:3 0.2-0 . .5 0.2->200 0.005--1.0* 0.1-1.6 0.3-10 0.1-(; 0.02-1.6 0.2->2,5* 0.12-0.,5 0.02-0.4 0.1-6* 0.00(""-0.8 0.1-> LOO 0.02-.3.1 0.02->25 0.5--2 0.001-0.02 0.25--1

*Oecasonal clinical isolates may be more resistant

tuberculous mycobacteria especially Mycobacterium kansasii, M. scrofulaceum, and M. terrae."" vVhile thc Enterobacteriaeeae arc generally resistant to erythromycin, their sensitivity increases markedly at alkaline pH."7 Resistance to erythromycin among some pathogens that werc highly susceptihle previously are increasingly being reported. For example, 2.2 per cent of 8,654 clinical isolates of Group A strcptococci werc rcsistant to crythromycin in Alberta, Canada during the period of 1974 to 1977. 2" In Japan, more than 60 per cent of all strains of Group A streptococci isolated between 1974 and 1975 wcre resistant to erythromycin.'" These strains were cross-resistant to other macrolide antibiotics. This may be related to the Widespread use of erythromycin and other macrolides in Japan for treatment of patients with upper respiratory tract infections. Similarly, while most strains of Streptococcus pTleulIloniae are exquisitely sensitive to erythromycin, resistant isolates including some strains with a minimal inhibitory concentration (YlIC) of 2000 fLgiml have been reported. 2l 21 Resistant isolates of C orynehacterium diphtheriae have been reported from both the United States and Canada. lB. 12 All were nontoxigenic biotype mitis, isolated !i'om patients with cutaneous diphtheria. Most clinical isolates of Staphylococcus aureus are presently scnsitivc to erythromycin. However, resistant strains may emerge during therapy.",·"h.", These may exhibit one-step high level resistance to erythromycin alone, or cross-resistance to

81

ERYTlIHO\IYCIN

lincomycin, clindamycin and other macrolides, or '"dissociated resistance" as described by Garrod. l2

CLINICAL PHARMACOLOGY A variety of limiting factors, including those relating to drug equivalency (biologic and chemical) and specificity and sensitivity of analytic methodology, have particular relevance in thc case of erythromycin in view of the plethora of available formulations, the acid lability of the drug and its consequent chemical instability, and, most importantly, the consideration that much of the available phannacokinetic data is derived by microbiologic assays. These assays do not distinguish between the parent drug and its metabolites or between the free (h-ug and its protein-bound or unhydrolyzed f(Jr1ns. Erythromycin base has antibacterial activity; the esters are inactive until hydrolyzed back to fi-ee base." In the final analysis, the "therapeutic" plasma or tissue level is that which is associated with clinical efficacy.

Absorption and Serum Levels Peak serum levels obtained after administration of various erythromycin preparations (Table 2) are related to several factors, including the chemical structure, the coating, the number of doses, and whethcr the subject is fasting or fed. Considerable variation occurs among subjects and from study to study. Erythromycin base is absorbed intact. The time eourse and total amount of absorption is affected by the nature of the coating applied to erythromycin base and, for some preparations, by food intake. Excellent bioavailability has been demonstrated for enteric-coated erythromycin base in both the fasting and nonfasting states on single and multiple dosing regimens. 2fl'1 For this f(mnulation, mean peak serum levels are 0.73 J,Lg/ml at five hours after a single 250 mg dose in the fasting state. After multiple doses of 250 mg every six hours, peak levels are 1..5 J,Lg/ml in the fasting and nonhlsting states. 2".H7 Erythromycin stearate is absorbed as the base after dissociation in the duodenum. A single fasting dose of 250 mg results in a peak serum level of 0.82 J,Lg/ml at two hours. :VI ultiple doses produce peak levels of 1. 0 to 1.5 J,Lg/ml. "[).H7 Like erythromyein base, erythromycin stearate is acid-labile. Sig-

Table 2.

Peak Serum Level~ of Erythnnnr/cin in Adults"'):!."" TI\IE :\FTEB

I'F\K LEYEI.S

PREPAHATI< >N

(\1(;)

IHHn'E

DOSE (liB)

HAN(;E ij.l).!;/!l,ll

Base

2.50 ,500 2.50 .500 2.50 ,500 .';00 ,50n :300 100(J

oral oral oral oral oral oral oral illtra\'t'IlOUS illtra\'(,1l011S illtravenous

·1 ·1 2-3 :3 2-4 :3 ..'5--4 0.'5--2 ..5

0.:3-0.7 O.:3-UJ

DOSE

Stearate Estolatc Ethylsllccillat(' LactohiOllatc Gluceptat('

*Total drug (eskr plus base) tFr('(' has('

(U-O.H

O.J-I.H IA-I.i* l.2*(1. Ii'1 \..';*(0(;'1"1 ~.H

2

2(; fHJ

82

MARIE

J.

GHIBIlLE AND ANTIIONY

\V. CIIOW

nificant decreases in bioavailability result when this product is administered with food. k7 Higher levels are also achieved if the stearate is taken with large volumes of water. Erythromycin estoZate is acid-stable. It is absorbed as the propionyl ester and subsequently is hydrolyzed to free base. The peak levels arc three to four times those attained after absorption of hase or stearate preparations; however, circulating levels comprise 70 to HO per cent unchanged estcr and only 20 to 30 per cent of the base. 7 The actual levels of base achieved are similar to those achieved by other oral preparations taken in the fasting state. Absorption of the estolate is not affected by food intake. In the United States, the FDA has initiated formal procedures to remove solid dosage forms of erythromycin estolate from the market. Liquid pediatric dosage forms arc still under consideration. Erythromycin ethy/succinate is absorbed unchanged and hydrolyzed hack to base." Drug levels and free base levels arc somewhat lower than those achieved with the estolate. Absorption of the ethylsuecinate preparation is enhanced by food. 20.>1 It appears that no one oral preparation of erythromycin proffers a significant advantage in terms of attainable serum levels of free base. This vicw is supported by a small numher of clinical studies comparing cfficacy of the various preparations in treatment of streptococcal pharyngitis and other respiratory infections of moderate severity.ll.Il.66

Erythromycin /actobionate and gluceptate are the intravenous preparations. Much higher serum levels arc achieved with these than with any oral preparations.

Distribution and Tissue Levels A fair body of data cxists relating to concentration of erythromycin in tissues and body fluids. In many of these studies, erythromycin was administered as the estolate or ethylsuecinatc, and the assays used do not discriminate hetween free base and inactive ester. Erythromycin penetrates well into most tissues and body fluids except for cerehrospinal fluid (Tahle 3). Note that concentrations achieved in the middle car in otitis media and in the sputum and sinus secretions are adequate to treat infections due to susceptible pneumococci and group A streptococci but are not adequate to consistently eradicate Hemophilus injlucnzae.

Excretion Erythromycin is concentrated by the liver and excreted into the bile in high concentrations, in the absence of biliary ohstruction. A proportion of ahsorbed drug may be N-demethylated in the liver. After oral administration of erythromycin, stool concentrations are high, representing both unahsorbed drug and hiliary excretion. It crosses the placenta, and high concentrations arc attained in hreast milk. The amount of erythromycin eliminated in urine is small and ranges from 4 per cent of an oral dose to 1.5 per cent of a parenteral dose. Clearance data suggest an active transport and/or net tuhular reabsorption of erythromycin. In anuric patients, the scrum half~lifC of erythromycin is prolonged to about five hours (normal halflife, 1.2 to 2.6 hours) and dosage change in renal hlilure is not necessary.') Erythromycin is not removed by hemodialysis or peritoncal dialysis.

PROPHYLAXIS AND THERAPY Erythromycin is the drug of choice for a number of infections and has a larger number of indications as an alternative drug to penicillin (Table 4). Treatment of

83

ERYTIIH()~IYCIN

Table:3.

Concentrations of Erythromycin in Tissues and Body Fluids C{)NCENTHATI()~ (r-.lC/I\fUT

Mean Pcak

SITE

PREPARATIOK

Saliva Tonsil Tissu{'

stearate estolate ethylsucdnate lactobionate stearate ethyl succinate ethylsuccinate estolate stearate estolate intravenous*

0.8 0.9 0.4.5 2.6

oral* estolate estolate estolate estolate intravenolls* base

0.3

Sputum Middle Ear (secretory otitis) (acute otitis) Sinus SecretioIls Cerehrospinal Flllid (meningitis) Synovial Fluid Aqueous Breast Milk Fetal Blood Amniotic Fluid

Prostatic Fluid

Ejaculum Bile (unobstructed) (partial obstruction) (colllplete obstrudioll) Pancreatic Juice (dogs) Feces

lactohionatc

lactobionate lactobionate illtravenOllS* oral*

1.2 0.8 4.2 1.2 I.H

Range

0.3-2.3 0.2-1.3 0.9-8.4 0.3-5 0.2-4.2 0.2-1.0 1.6-8.0 0.1-3.0

TISSUE TO SERL'M BATH)

HEFEHENCES

0.1-1.0 0.3 0.5 1.5--5

10 34 34 51 16 77

1.0 0.6 0.6 0.5

6 59

0.1-0.8

0.07-0.2.5

3 HH

0.2-0.5 0.04-0.13

0.25

:30 O.O(j

0.36 0.35

0--0.12 0.32-0.39 0.2-0.9

Hl 5 0 1.:3 4HO

0.5--2.4

(j

62 56 8H (jO

0.4 0.2 10

60 69 2

[,5

1.5 15 HH 88

*Preparatioll not spt'cified tConcentrations attained after standard doses (sce Table 3)

pneumonia due to Mycoplasma pneumoniae with erythromycin reduces the duration 'of illness and accelerates radiologic clearing of pulmonary infiltrates';:] hut does not hasten eradication of the organism fi'om the host. 72 Present practice is to treat M. pneulnoTliae pneumonia for five to seven days with erythromycin; however, administration f(H' a longer period (up to three weeks) has been recommended f()r severe infections. "C) Erythromycin is believed to be the most active available agent in treatment of Legionnaires' disease. " In the immunocompromised host with Legionnaires' disease, oral administration of erythromycin has hiled, 13.6H and intravenous administration of 2 gm per day is recommended. Treatment of Chlamydia tracho1ltatis pneumonia in infants with erythromycin ethylsuccinate (50 mg/kg/day, f()r two to three weeks) has resulted in symptomatic improvement in five to seven days and negative cultures hy nine days. S In addition, erythromycin is probahly the drug of choice f()r C. traclwmatis inclusion conjunctivitis in inhmts, hut further data are needed regarding optimal dosage and duration of therapy. Erythromycin may also have a role in therapy of genital C. trachomatis infections in adults, especially during pregnancy. Enteritis and enterocolitis due to Cam]lylohacter fetus ssp. jejuni is usually a benign and self~limited illness, and no controlled trials of therapy have heen conducted. Occasionally, more severe diarrhea, prolonged diarrhea, or recurrent relapses may justify therapy, and oral erythromycin has been successfully used'! Approximately I) to 10 per cent of strains may he resistant to erythromycin."2H! A 10 day course of erythromycin is recommended by the American Academy

84

MAHlE

Table 4.

J.

(;HIBHLE Mm AI\TllOI\Y

W.

CHOW

Major Uses of Erytltrolllllcill

INlJlf:.'\TH)N

DHlIC

t:rythrom"cin as Vrug of Choice Mycoplm:mw pncul1umiuc pn(~tlm()llia Lcgiollllain's'dis{"asc Pertussis Dipththeria~disease

--carrier state

Erythrasma Carnl'ylobactcr fetus ssI'. j"jllni enteritis inlill1tile Chlamydia trachornatis pneumonia

Erythrmnycin as Alajor Aiternafice Groups A, H, C, G streptococcal infection S. pneu17loniac infection Syphilis 1°,2°, latent <1 yr latent> 1 yr, 3° Rheumatic ft'vcr proph ylaxis Endocarditis prophylaxis (dental procedures)

Alfl:nwtin: Drug

0.5 qm qid pot X 7~21 days 0 ..5 gm-1.0 'I 'lid pot X 21 days 0 ..5 gm 'lid po X 10 days 0 ..5 gm qid po X 10 days 0.5 gm 'lid po X IO days 0.25 gm tid po X 21 days 0.5 gill 'lid po X 7 days:j:

TetracyclilH'

50 mglkgldav in 4 doses

Sulfisoxazole

X

Hitllllpin & Ery,throlTlYC'lll Ampicillill

Penicillin C Pellicillin (; ~'tin()cycline

14--21 days

0.25--0.5 gm 'lid po 0.25--0.5 gm 'lid pot 0 ..5 gm 'lid po X 1.5 days 0 ..5 gm 'lid po X 30 days§ 0.25 gm bid po 1. 0 gm po 1-2 hr bet(lw procedure; then 0.5 gm 'lid

Vrug ofClwice Penicillin G Penicillin C Penicillin Penicillin G Penicillin G

'Usual pediatric dosage: :30--50 mg/kglday in four to six divided doses PO, or Hl-20 mglkglday ill three to limr divided doses IV tIntravenous route should be used in serious illness :j:Dose and duration of theapy 1I0t established; sce text §Eflectivcncss uncertain ill 3° syphilis

of Pediatrics as the treatment of choice for pertussis. 6 ' vVhile no effect has been demonstrated on the course of the disease, the ability of erythromycin to clear Bordetella pertussis from the nasopharynx is well established.· 7 Erythromycin has also been used with some success as chemoprophylaxis for pertUSSiS," although no large-scale controlled trials of antimicrobial prophylaxis far pertussis have been published. Erythromycin has been used extensively for the treatment of diphtheria and diphtheria carriers. In acute infections, antitoxin remains the primary therapeutic modality. Erythromycin is highly effective in eradicating C. diphtheriae from the nasopharynx within 48 to 72 hours ..3:\ A 10 day course of therapy is recommended because of an unacceptably high relapse rate after a brider course of treatment.:;3 Erythromycin resistant C. diphtheriae isolated from patients with cutaneous diphtheria have been reported. tu Erythrasma, a superficial skin infection caused by Corynebacterium minutissimum, is dramatically eradicated by erythromycin. (;9 Acute otitis media caused by S. pneumoniae and Group A streptococci may be effectively treated by oral erythromycin. However. in acute otitis media caused by H. injluenzae, the concentration of erythromycin achieved in the middle ear may be insufficient to eradicate the organism. Combinations of erythromycin ami sulfanamides (usually triple sulfonamide, 90 mg/kg/day) have been successflllly used and shown to be comparable to ampicillin and amoxicilJin, regardless of causative orga-

EI\YTlIIl()~IY(:IN

85

nism.'o Such comhinations relllain effective against J3-lactalllase-producing 1I. infiuenzae.

The combination of erythromycin base and neomycin has becn successful in reducing the number of infectious eomplications of elective eolorectal surgery. '7 The suecess of this regimen results at least in part from the reductioll in numbers of aerobic and anaerobic organisms in the colonic contents of the subjects. However, these doses of erythromycin base should result in significant tissue levels of erythromycin, which may be a eontributing factor in the reduction of wound infection. The use of erythromycin as an important alternative drug to penieillin in a variety of infections is well established and has been reviewed in detail elsewhere.:n ,8'; Note that erythromycin is no longer regarded as adequate therapy for gonococcal infection. Erythromycin has also been used as an alternative agent in the therapy of anthrax, 6' Listeria morlOcytogenes infections,' and actinomycosis.,1H Erythromycin has been effective when given in combination with ampicillin in the treatment of Nocardia asteroides infections, and in vitro synergy for this combination has been demonstrated. 2H Chronic bacterial prostatitis has responded to prolonged therapy with erythromycin. 12 Urinary tract infections due to gram-negative bacilli that might require the use of toxic agents may occasionally be treatcd with erythromycin and urinary alkalinizing agents. [)O Of historical interest, erythromycin has in vitro amebicidal activity, and clinical studies in acute and chronic amebiasis have demonstrated cure rates as high as 87 per cent. :l.1 Single reports have reported clinical efficacy of erythromycin in leptospirosis,21 Q fever,22 and psittacosis. 1H A recent double-blind comparative trial has demonstrated efficacy for a topical formulation of erythromycin base in acne vulgaris. 0.0 Some limited therapeutie trials with erythromycin, usually in eombination with other drugs, have indicated promise in therapy of certain non tuberculous myeobacterial infections. ",; Failure of erythromycin therapy in staphylococcal infections has been wcll documented n and in view of the availability of more effective agents, erythromycin should not be used alone in treatmcnt of serious staphylococcal infections. Erythromycin in combination with a penicillin may be synergistic against S. aureus .,1.'.11 In staphylococcal infections of only mild or moderate severity, erythromycin is an acceptable alternative agent.

Adverse Reactions Erythromycin is one of the safest antimicrobial agents in clinical use. Adverse reactions are not life-threatening and are rare, with the exception of irritative effects. Dose-related gastrointestinal upsets (epigastric distress, nausea, vomiting, and diarrhea) occur most commonly. Thrombophlebitis occurs with intravenous administration but can be minimized by slower administration of dilute solutions. Hypersensitivity reactions such as skin rash, fever, and eosinophilia are unusual. The most serious toxicity of erythromycin is a characteristic syndrome of ehole static hepatitis, which was first reported in 1961." Ninety-three per eent of the cases oeeurred following administration of the estolate,2(; but the syndrome has also been indueed by the ethylsuecinate. 7(;,H8,"[) The majority of these reactions have occurred in patients 12 years of age and older. Since the estolate appears to offer no benefits to offset this risk of hepatotoxicity, the FDA's Bureau of Drugs is moving to remove solid dosage forms of erythromycin estolatc for clinical use. 26 Reversible sensorineural hearing loss has been rarely associated with the use

86

MARIE

J.

CRIIlBLE A!'iD A!'iTlIONY W. CHOW

of high doses of erythromycin, KO usually in the presence of renal failure and via the intravenous route. Hypertrophic pyloric stenosis developed in five infants during administration of erythromycin estolate. 27 Pseudomembranous colitis associated with oral erythromycin has been reported.:li

Drug Interactions Concurrent use of erythromycin and theophylline may be associated with an increase in theophylline scrum levels and possible toxicity.",·5 An apparent interaction between erythromycin and warfarin sodium, with potentiation of hypoprothrombinemia, has been reported. 5 Erythromycin and certain other macrolide antibiotics may lower the maintenance dose of glucoeorticoids required by severely asthmatic patients. 70 The following drugs have been reported to be incompatible with intravenously administered erythromycin: vitamins B complex and C, cephalothin, tetracycline, chloramphenicol, colistin, heparin, metraminol, and diphenylhydantoin. 73

Interference with Laboratory Tests The presence of erythromycin in body fluids may produce artifactual alterations in clinical laboratory tests. False elevations are reported for urinary catecholamines, urinary 17 -hydroxycorticosteroids, 55 and fill' colorimetric determination of SCOT levels. The latter false-positive elevation of SCOT must be distinguished from hepatotoxicity. Serum folate levels may be falsely decreased when a bioassay is used but are not affected when a chromatographic procedure is employed. ,.5 Falsely depressed urinary estriollevels during erythromycin therapy has also been reported. 30

CONCLUSION Recent advances in our ability to isolate and identify the specific etiologic agents in a number of newly defined clinical syndromes have greatly enhanced the therapeutic usefulness of erythromycin. Compared to only a decade ago, several important new indications for erythromycin have emerged in clinical medicine: treatment for Legionnaires' disease, C. trachomatis infections, and eampylobacter enteritis. The potential value of erythromycin in Ureaplasma urealyticum infections is under study. In addition, two new investigational macrolides structurally similar to erythromycin Oosamycin and rosaramycin) have recently been introduced for clinical trials. These newer analogues have the potential advantage of enhanced in vitro activity, fewer gastrointestinal side effects, and reduced likelihood of induced macrolide resistance during therapy. On the other hand, erythromycin is no longer recommended as a suitable alternative to penicillin for treatment of gonorrhea. The hepatotoxicity of erythromycin estolate has been firmly established, and the solid form of this preparation may soon be removed from clinical use. It remains to he seen whether resistance to erythromycin will evolve as a major therapeutic problem as a result of markedly increased usage of this important macrolide in the next decade. ACKNOWLEDGMENT

We thank Brenda Costa and Jean Wong fin their assistanee in the preparation of this article.

87

ERYTHRO~IYCI"

REFERENCES 1. Armstrong, D.: Listeria 1IL01IOCytOgCIH:S. III Mandell, C. L., Donf(las, H. G., and Bennett,.I. E. (eek): Principles and Practice of Infectious Diseases. New York, J. Wiley, 1979, p. i(i26.

2, Armstrong, 3.

4. .5. 6. 7.

8. 9. 10. 11. 12.

J.

R., Cook, F. E., and HobisOll,

J.

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