Long-term oral antibiotics for acne: Is laboratory monitoring necessary?

Therapv Long-term oral antibiotics for acne: Is laboratory monitoring necessary? Marcia S. Driscoll, PharmD, Marti Jill Rothe, MD, Lori Abrahamian, MD, and Jane M. Grant-Kels, MD Farmington, Connecticut Background: The roleof laboratory monitoring in patients receiving long-term oral antibiotics for acnevulgaris has not been clearly defined. Objective: Thepurpose ofourstudywas (l) to evaluate the literature for objective evidence on thevalue of routine laboratory monitoring of theasymptomatic patientreceiving oralantibiotics for acne and (2) to determine the utilization of laboratory monitoring of these patients by Connecticut dermatologists. Methods: We surveyed Connecticut dermatologists by phone and inquired aboutthe laboratorymonitoring performed in patients receiving long-term oral tetracycline, minocycline, or erythromycin for acne. Results: Eight published studies reported a totalof 777 patients who had laboratory monitoring at various frequencies while receiving oralantibiotics foracne. Onlyoneadverse drug reaction (ADR) was detected in a patient in whom mild hyperbilirubinemia developed. Of the 7S Connecticut dermatologists who participated in our survey, 48 (64%) perform some laboratory monitoring; 29% doso routinely, and 35% under special circumstances. Conclusion: Our literature review does notsupport routinelaboratory monitoring in all patients who receive long-term oral antibiotics for acne; rarely does such screening detect an ADR andthusdoes notjustify the costofsuch testing. A relatively smallproportion of Connecticut dermatologists check laboratorytestsmore frequently than appears necessary; inour opinion, laboratory monitoring should belimited to patients who may be at higher risk for an ADR. (J AM ACAD DERMATOL 1993;28:595-602.)

Systemic antibiotics have been used in the treatment of acne vulgaris for approximately 40 years. They remain a commonmodeof therapy because of their effectiveness and relativesafety with long-term use.1 The role of laboratory monitoring in patients receiving long-term systemic antibiotics has not been clearly defined. Since 1967 the Food and Drug Administration (FDA) has required pharmaceutical companies to include a statement concerning laboratory monitoring.in the product information listing for all tetracycline (TCN) drugs. A typical caveat reads as follows: "Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with tetracyclines.t'- In 1977 Sauer' proposed guidelines for monitoringpaFrom the Departmentof Medicine, Division of Dermatology, University of Connecticut Health Center. Reprint requests: Jane M. Grant-Kels, MD, University of Connecticut Health Center,MC-3933, Division ofDermatology, Farmington, CT 06030. Copyright@ 1993 by the American Academyof Dermatology, Inc. 0190-9622/93 $1.00 +.10 16/1/43735

tients receiving long-term TCN therapy: complete blood cell count (CBC) and 12-factor blood chemistry analysis after 2 years of therapy, and then every 2 years thereafter if the patient receives continuous therapy. In 1988, a surveyof medical directors of collegehealth servicesconcerning routine laboratory monitoring of patients with acne treated with long-term TCN revealedthat 37%routinely ordered laboratory tests." In this survey,35%ofthe clinicians obtained CBCs, 25% obtained liver function tests (LFTs), and 21% ordered both; the frequency of testing was variable and was often dependent on TCN dosage, duration of therapy, and/or concomitant medical conditions. This study did not inquire about laboratory monitoring of patients treated for acne with erythromycin, nor have any specificguidelines been published. It was our impressionthat there were considerable differences among dermatologistsin their laboratory evaluation of patients receivinglong-term oral antibiotics and indeed that some practitioners did not viewsuch testing as necessary in the typical young,

595

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596 Driscoll et al.

Table I. Connecticut dermatologists who perform laboratory monitoring of patients receiving long-term oral antibiotics for acne: Criteria for testing and testing schedules Total No. of dermatologists polled Total No. who performsome laboratory monitoring Monitor on a routine basis For all three drugs Only for minocycline Monitor under special circumstances Moderate to severe gastrointestinal symptoms Dependent on duration of use Only if high doses used Tested on one-timebasis Serious medical illness Patient concernedabout side effects

75 48/75 (64%) 22/75 (29%) 17/75 (23%) 5/75 (7%) 26/75 (35%) 9/75 (12%) 7/75 3/75 3/75 3/75 1/75

(9%) (4%) (4%) (4%) (1%)

healthy patient with acne. To assess the local standard of practice, we conducted a survey of dermatologists in Connecticut. In addition, we reviewed the literature on the adverse reactions to tetracyclines and erythromycins and focused on those adverse effects for which laboratory monitoring could be valuable and predictive.

METHODS We contacted 120 Connecticut dermatologists by phone and inquired about their use of oral TCN, minocycline, and erythromycin for acne. Questions included what dosagerange was usually prescribed, and whether or not laboratory testswereperformed to monitorfor adverse drug reactions (ADRs) in patients receiving longterm therapy. If laboratory testing was performed, we asked why they chose to do so. We specifically inquired whether thisdecision was basedon whichantibiotic was used, dosage, duration of therapy, health of the patient, or the development of symptoms during the course of therapy. Wefurther inquired about the typesof tests performed, the frequency of testing, and what laboratory abnormalities, if any, were discovered in the course of monitoring.

RESULTS Of the 120 dermatologists contacted, 10 limited their practice to dermatopathology, dermatologic surgery, or dermatologic research. Of the remaining 110, 75 (68%) agreed to participate. Forty-eight (64%) stated that they perform some laboratory

monitoring of patients receiving long-term oral antibiotics for acne; 29% do so routinely, and 35% under special circumstances. Most dermatologists order a CBC, electrolytes, blood urea nitrogen (BUN), serum creatinine, and LFTs. Some dermatologists stated that they were aware of the cautionary statements (e.g., in the Physician's Desk Reference) that recommend laboratory monitoring in patients receiving long-term TCN. Most dermatologists stated that, on the basis of their own experience, long-term use of oral antibiotics for acne appeared to be safe, but still felt more secure with some periodic laboratory testing. Some dennatologists admitted that fear of malpractice probably has some influence on the decision to monitor. Dermatologists who perform laboratory testing vary in their criteria for testing and testing schedules (Table 1). Nine (12%) check laboratory values only if the patient develops moderate to severe gastrointestinal complaints. Seven (9%) stated that testing is dependent on the duration of therapy. Other criteria used include (1) high-dose therapy (minocycline >-200 mg/day or TCN >1 gm/day), (2) serious coexisting medical condition (e.g., diabetes mellitus, liver disease, kidney disease), or (3) patient expresses concern about ADRs. A few dermatologists order tests on a one-time basis after a certain duration of therapy, usually 6 months to I year. Only 2 of the 75 dermatologists interviewed stated that laboratory abnormalities were detected. One teenage patient had a marked elevation in serum glutamic oxaloacetic transaminase (SGOT) after 3 weeks of high-dose (1.5 gm/day) TCN therapy. LFTs were obtained because isotretinoin therapy was about to be started; the patient was asymptomatic and in good general health. TCN was discontinued, and 1 week later the SGOT was within normal range. The patient was not rechallenged with TCN. In a second case that occurred almost 10 years ago, routine laboratory tests ordered after 3 months of minocycline (l00 rug/day) therapy revealed an increase in LFTs in a healthy teenager. The dermatologist could not recall which LFTwas elevated, but only that the elevation was marked, and that the LFT normalized after minocycline was discontinued. When the drug was started again, a significant increase in LIT(s) was noted. LITERATURE REVIEW

We reviewed the literature on ADRs caused by TCN, minocycline, and erythromycin. We consid-

Journal of the American Academy of Dermatology Volume 28, Number 4

ered only those ADRs for which laboratory monitoring could be useful, that is, adverse effects on the liver, kidney, and hematopoietic system. Adverse effects on the liver Tetracycline TCN was first noted to cause hepatotoxicity in seriously ill, hospitalized patientswhooftenreceived high (> 2 gm/day) intravenousdoses.o 6 Abnormal LFTs wereaccompaniedby nausea,vomiting, fever, abdominal pain, and jaundice, whichusuallybegan 4 to 10 days after initiation of therapy. This often producedterminal hypotensive shock." 8 The TCNs are intrinsic hepatotoxins and produce a microvesicular hepatic steatosis." Fatty liverdegeneration is dose-related and has been observed more often in patients who receive high doses, have renal or liver disease, or who are in their last trimester of pregnancy.v? When TCNs are used orally in young, healthy patients with acne, adversehepatic effects are rare. Delaney et al. 10 found no significant differences in LFTs between 76 control patients and 170 outpatientstreated withoxytetracycline forseveral months to severalyears. Coskey!' found no abnormalities in SGOT in 115outpatients after 1 to 3 years of treatment with TCN or erythromycin. In this study, 24 adolescent patients had serum alkalinephosphatase (AP) levels up to twice the normal adult level, but this age group may normally have APs three to six times the adult level.'! Sauer l2 conducted a retrospective review of laboratory tests performed in 325 patients receiving TCN for at least 3 years. Sixteen had a mild increase in total bilirubin (<2 mg/dl), most of which normalized despite continuous therapy. One 17-year-old girl had slight hyperbilirubinemia after 5 years of TCN therapy, shortlyafter the dosagewas increasedto 500 rug/day. Her highest total bilirubin levelwas 2.1 mg/dl; this returned to normal after discontinuationof TCN. On rechallenge, the bilirubin level again increased, and on withdrawal the level again normalized. Sixteen patients had elevations in AP, but most were mild and consistent with the levels normally observed in adolescents; one patient was also receiving acetohexamide, a drug known to produce an elevation in AP. Sauer'? conducted a prospective study of 75 patients in whom laboratory results were checked before initiating TCN therapy and after 12 months of continuous therapy. Four LFT abnormalities were

Driscoll et al. 597 found, but these wereconsidered insignificant, and the patients were asymptomatic. Baer et al." prospectively monitored LITs in 31 patients receiving high-dose (most received 2 gm/ day) TCN therapy for 3 to 31 months. One 21year-old asymptomatic man had a mildly elevated total and direct serum bilirubin level (1.7 and 0.5 mg/dl, respectively), and an SGOT of 52 ml.I/ml after 29 monthsof TCN (mean dosage 1 to 2 gm/ day). TCN was discontinued, and thesevalues normalized after I month. Minocycline Minocycline, a second-generation TCN derivative introduced in 1967, has been associated with hepatotoxicity similarto that described for intravenous TCN.15 In young, healthy patients with acne, severe adverse effects on the liver are rare. Two patients have beendescribed with exfoliative dermatitis and elevations in LFTs.l6 Thefirstwasa 16-year-old boy in whom fever, headache, malaise, rash,hepatomegaly and generalized lymphadenopathy developed after 4 weeks of therapy. All clinical and laboratory abnormalities resolved 1 month after discontinuation of minocycline. The second was a 17-year-old girl whoreceived minocyc1ine for 1 month and had a clinical presentation similar to that of the first patient. However, her liver function progressively deteriorated despite minocycline withdrawal. The patient underwent liver transplantation and subsequentlydied. However, etiologic factors other than minocycline needto be considered. Thispatient had recently returned from Kenya, where she took proguanil, chloroquine, and tablets containing tyrosine, copper, and para-aminobenzoic acid. She had also received immunizations against cholera, typhoid, and yellow fever. Liverbiopsy results were not provided in the case report. In 1990, Gorard17 reportedfever, malaise, myalgia, andelevated LFTs in a patient whoreceived minocycline, 50 mg daily, for 1 year. The patient's LFTs normalized before withdrawal of minocycline, but his symptoms were alleviated onlyafter the drug wasdiscontinued. In a prospective study, 11 patients treated with minocycline showed no difference between pretreatment LFTs and those measured 6 months later.IS Erythromycin Erythromycin preparations cause two different types of adverse effects in the liver. 19 Erythromycin administered orally or intravenously can cause benign increases in serum transaminases in up to 10%

598 Driscoll et al. of patients; these mayor may not recur on rechallenge. The second type is reversible cholestatic jaundice in up to 2%to 4%of patients. It is believed to be a hypersensitivity reaction and occurs more frequently in patients treated with erythromycin estolate. However, all erythromycin preparations can cause cholestatic jaundice.2D-22 Complete recovery usually occurs within a few weeks after discontinuation of erythromycin .P In a prospective study by Caskey, 11 there were no abnormalities in LFTs in 115 patients, some of whom (exact number not stated) were receiving erythromycin. Other studiesoferythromycinuse for acne have not includedroutine monitoringof LFTs; none has reported erythromycin-induced cholestatic jaundice. I I, 24-26The rarity oferythromycin-induced cholestatic jaundice in patients treated for acne is most likelythe effectof age;the mean age ofpatients in whom this ADR develops is 40 years. Fewer than 20% are younger than 20 years of age.22 Adverse effects on the kidney Tetracycline TCNs commonly cause an increase in BUN because of their antianabolic effects. 27 However, patients usually do not have an increase in serum creatinine, that is, renal insufficiency doesnot occur.I:28 Patients with renal insufficiency, who may accumulate high serum levels of TCN, may have a worsening of their renal insufficiency.P' In addition, hospitalized patients treated withboth diureticsand TCN had BUN increasethree timesmore frequentlythan patients treated with diuretics alone.29 The azotemia develops severaldays after initiationof therapy and resolves rapidly after withdrawal. In a prospective study, Delaney et al.l o found no significantdifferences in BUN between 170patients treated with oxytetracycline and 76 untreated control subjects. In the prospective study by Coskey,!' there were no abnormalities in BUN or serum creatinine after 1 to 3 yearsof treatment. Albuminuria occurred in four patients, but it was not attributed to drug therapy. In the retrospective review by Sauer,12 of 325 patients who received at least 3 years of TCN treatmen t, only four had a minor elevationin BUN. A subsequent prospective study by Sauer" found no change in BUN in 75 patients after 1 year of continuous TCN therapy. In a prospective study of high-dose TCN therapy by Baer et a1.,14 31 patients had no changes in "kidney function studies."

Journal of the American Academy of Dermatology Ap ril 1993

Minocycline Adverse effectson the kidneyoccur uncommonly with minocycline. In two patients hypersensitivity reactionsdeveloped whichresulted in kidney failure. The first was treated with high-dose oral minocycline for an upper respiratory tract infection.r? and the second case was a 16-year-old boy treated with low-dose minocycline. He had a rash, lymphadenopathy, and renal failure." Only one study evaluated renal function prospectively in patients receiving minocycline for acne;noneof the 11 patients had changes in BUN or serum creatinine after 6 months of therapy. IS Erythromycin Nephrotoxicity associated with erythromycin is rare. One case of erythromycin-induced interstitial nephritis has been reported in a patient treated for tonsillitis.F When patients treated with erythromycin for acne are considered, no abnormalities in BUN or serum creatinine after 1 to 3 years of treatment have been reported.II Adverse effects on the hematopoietic system

Tetracycline Adverse hematologic changes associated with TeN therapy are rare.? In 1960, Witten et al.33 reviewed the cases of almost 100 patients treated for acne with TCN and other antibiotics. Nineteen received only TCN; the abnormalities found were not considered significant. Osment and Hammack'" conducted a prospective study of 22 patients with acne treated with TCN for 15 to 315 days; seven untreated patients with acne served as controls. A decreasefrom the pretreatment count of white blood cells (WBCs) occurred in 18 patients, and in th ree of seven control patients. Only three of the 18 patients had a WBC count slightly below the lower limit of normal, compared with none of the control patients. In the study by Coskey.!' mild leukopenia developed in 12of 115patients receiving variousoral antibiotics for acne, including TCN. However, no baseline CBCs were checked, and the author states that it was difficult to assess whether leukopenia was caused by the antibiotic, viral infections, or was normal. In the retrospective review of 325 patients by Sauer.P five abnormalities in the WBC count occurred, but none was consideredsignificant. In his prospectivestudy, Sauer' ' reported that 2 of 75 patients had mild insignificant neutrophilia. In the study by Baer et al.,14 none of the 31 patients re-

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Driscoll et al. 599

Table II. Laboratory abnormalities detected through routine monitoring in asymptomatic patients treated for acne vulgaris with tetracycline, minocycline, and erythromycin Laboratory monitoring No. of patients

Author(s)

Tests

Delaney et al. lo

170 AP, bili, Group I: 50 SGPT, Group 2: 120 BUN, U/A

Coskey!'

115

Sauer'?

325

AP, bili, SGOT, BUN, creatinine, total protein, albumin, calcium, chol, uric acid, CBC, glucose, U/A AP, bili, SGOT, BUN, total protein, albumin, calcium, chol, uric acid, CBC, with diff, phosphorus, glucose

Timing and frequency of tests

Group 1: 0,1, 3, 6, 12 and 24 rna after Rx initiated Group 2: every 3 mo or annually after Rx >2 yr Various frequencies in pts treated for 1 to 3 yr

Test abnormalities found

Drug regimen

No. of abnormalities considered ADR

Oxytetracycline, 0 250 mg b.i.d.

o

Tetracycline 12: WBC or count erythromycin, <4500/ 250 mg mm' b.i.d. (in 4: Albuminuria majorityof pts)

o

Initial tests Tetracycline, after Rx for various >3 yr with dosages, tests but usually repeated at 250 mg yearly bid. intervals if possible (212 pts tested once, 83 tested twice, 22 tested three times, and one tested eight times)

I: Total bili 2.1 mg/dl

15: Transient or mild increase in total bili 1: WBC count 3900/mm3 4: WBC count 11,30014,150/mm3 4: Mild elevation in BUN (highest 31 mg/dl)

o

o o o a

ADR, Adverse drug reaction; AP, alkaline phosphatase; bili, bilirubin; BUN, blood urea nitrogen; CBC, complete blood cell count; chol, cholesterol;

CPK, creatininephosphokinase; diff, differential; ESR, erythrocyte sedimentation rate; LDlI, lacticdehydrogenase; LFrs, liver function tests; lyles, electrolytes; pt. patient; Rx, treatment; SGOT, serumglutamicoxaloacetic transaminase; SGPT, serumglutamic pyruvic transaminase; 1'FTs, thyroid function tests; UIA, urinalysis; WBC, white blood cellcount. Continued Oil page600

ceiving high-dose oral TCN had abnormalities in CBCs. In a case-history study of 68,596 patients treated with TCN (for a variety of indications, with variable dosageregimens,for variable durations), no case of a hematologic adverse effect was documented.35

Minocycline Hematologic adverse effects caused by minocycline are rare. In a double-blind study of 45 healthy volunteers receiving minocycline (100 mg twice daily for 5 days) and 44 control subjects receiving placebo, the 18men in the minocycline group had a

Journal of the American Academy of Dermatology April 1993

600 Driscoll et al. Table II. Cont'd. Laboratory monitoring

Author(s)

Sauer':'

Baer et a1. 14

No. of patients

75

31

Tests

AP, bili, SGOT, BUN, total protein, albumin, calcium, chol, uric acid, CBC with diff, phosphorus, glucose

LFTs, kidney function tests, CBC, CPK,U/A

Timingand frequency of tests

oand 12 mo after Rx initiated

0, then every 3 to 6 mo in patients treated for 3 to 33 rno

significant decrease in WBC count compared with the 23 male control subjects." In a study of 11 patients treated with low-dose minocyclinefor acne, no significant changes between pretreatment CBCs and those measured 6 months later were observed. 18

Erythromycin Adverse hematologic effects caused by erythromycin are limited to two reported cases of immune hemolytic anemia, in young chi1dren. 3?, 38 A casehistory study indicated no abnormalities in more than 50,000 patients treated with erythromycin." Table II summarizes the laboratory abnormalities detected through routine monitoring in asymptomatic patients treated for acne with oral tetracycline, minocycline, and erythromycin.

Drug regimen

Tetracycline, 250mg b.i.d. (average dosage)

Tetracycline, 500 mg q.i.d.

Test abnormalities found

No. of abnormalities considered ADR

1: Total bili increased from 1.1 to 1.2 mg/dl after I yr 1: AP of 305 rnU/ml 1: SGOT increase from 105 to 125 mU/ml, but heavy alcohol use 1: LDH 260 rnU/ml 2: Mild increase in neutrophils I: Elevated CPK 1: Elevated CPK, mild elevation SGOT (42 mtl/ml), mild elevation in total and direct bili 0.7 and 0.5 mg/dl), pt asymptomatic

0

0 0

0 0 0

0

DISCUSSION

Our literature review does not support the practice of routine laboratory monitoring in healthy, young patients treated with oral TCN, minocyc1ine, or erythromycin for acne. The current FDA recommendations for laboratory monitoring were first proposed in 1967 and were based on the severe ADRs that occurred in seriously ill, hospitalized patients who received high-dose intravenous TCN, had underlying renal or hepatic insufficiency, or were in their third trimester of pregnancy. In patients treated for acne, adverse effects on the hepatic, renal, and hematopoietic systems are rarely associated with TCN, minocycline, or erythromycin therapy. The serious adverse effects of these drugs do not have an

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Driscoll et al. 601

Table II. Cont'd. Laboratory monitoring

Author(s)

Hubbell et aI.[8

Witten et al.33

Osment and

Hammack-"

No. of patients

20

19

22

Tests

LFTs, Iytes, BUN,

Test

Timingand frequency of tests

o and 6 mo after Rx initiated

creatinine, TFTs, uric acid, CBC with diff, glucose, serum immunoglobulins Various CBC frequencies in pts treated from 1 to 12 mo 0, then every CBC, reticulocyte 6 wk in pts treated for count, ESR upt0315 days

asymptomatic period during which early detection can lead to prevention or amelioration of the reaction. Most serious ADRs are idiosyncratic and are best detected after the development of symptoms. The stron gest rationale for routine laboratory monitoring is in a patient with a concomita nt medical condition known to cause a higher risk for an ADR. For example, BUN, serum creatinine, and electrolytes should be monitored when using TCN in a patient with renal insufficiency. Laboratory monitoring would also be justified in a patient who has nausea, vomiting, severe abdominal pain, or malaise, which suggest a hypersensitivity reaction . In our survey of Connecticut dermatologists, 64% stated that they perform some type of laboratory monitoring in patients receiving long-term oral antibiotics for acne; their decision to monitor is based on clinical information and perhaps to some extent on the desire to protect themselves against malpractice claims. In our opinion, these dermatologists order laboratory tests more frequently than appears justified on the basis of our literature review. In addition, the cost oflaboratory monitoring can be large if the cost of repeated testing and staff and patient time is considered.

abnormalities found

Drug regimen

. Minocycline, 50 mg b.i.d. (9 pts) Tetracycline, 250 mg bid. (I I pts) Tetracycline, lowdose

Tetracycline, 250 mg bid.

No. of abnormalities considered ADR

0

0

3:WBC 4500/mm3 9: Mild increase in WBC

0

3: Mild decrease in WBCto <5000/

0

0

mm!

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25. HughesBR,MurphyCE, BarnettJ, et al.Strategyof acne therapy with long-term antibiotics. Br J Dermatol 1989; 121 :623-8. 26. WanskerB.Antibiotics and pustulocystic acne. Arch DermatoI1961;84:96-8. 27. Appel GB, Neu He. The nephrotoxicity of antimicrobial agents (second of three parts). N Engl J Moo 1977; 296:722-8. 28. KeenanTD, Blacklock H, Little PJ, et al. Aggravation of renal functional impairment by tetracycline. N Z Moo J 1973;78:164-6. 29. Report from the Boston Collaborative Drug Surveillance Program. Tetracycline and drug-attributed rises in blood urea nitrogen. JAMA 1972;220:377-9. 30. Walker RG, Thomson NM, Dowling JP, et al. Minocycline-induced interstitial nephritis. Br Med J 1979;1:524. 31. Wilkinson SP, Stewart WK, Spiers EM, et al. Protracted systemic illness: an interstitial nephritis dueto minocycline. Postgrad Moo J 1989;65:53-6. 32. Rosenfeld J, Gura V, Boner G, et al. Interstitial nephritis with acute renal failure after erythromycin. Br Med J 1983;286:938-9. 33. Witten VH, SulzbergerMB,Krasner F. Blood countsand long-term antibiotic therapy. JAMA 1960;173:1458-61. 34. OsmentLS, Hammack W1.The long-term useoftetracyclineinacne vulgaris: effect on blood elements. SouthMed J 1970;63:1156-8. 35. Danielson DA, Douglas SW III, HerzogP, et al. Drug-induced blood disorders. lAMA 1984;252:3257-60. 36. Fanning WL, Gump DW, Sofferman RA. Side elfects of minocycline: a double-blind study. Antimicrob Agents Chemother 1977;11:712-7. 37. Wong KY, Boose GM, Issitt CH. Erythromycin-induced hemolytic anemia. J Pediatr 1981 ;98:647-9. 38. NanceSJ, LadischS, Williamson TL, et al.Erythromycininduced immune hemolytic anemia. Vox. Sang 1988; 55:233-6.