CURRENT THERAPEUTIC RESEARCH VOL. 58, NO.

12, DECEMBER 1997

EFFICACY OF LINCOMYCIN VERSUS PENICILLIN AND CLARITHROMYCIN IN PATIENTS WITH ACUTE PHARYNGITIS/ TONSILLITIS CAUSED BY G R O U P A BETA-HEMOLYTIC STREPTOCOCCI AND A CLINICAL HISTORY OF R E C U R R E N C E
GERMAN ANGELI,1 JUAN FUKUDA,2 G. BELISARIO GALLEGOS,3 LILIANA LADUE,4 AROLDO MINITI,~ SAUL SUAREZ,e THELMA TUPASI,7 AND BERNARDO VIVAS1

1Centro Mddico Nueva Esparta, Bogota, Colombia, 2Departamento de Pediatrta, Hospital Nacional Cayetano Heredia, Lima, Peru, 3Facultad de Medicina, Universidad de Zulia, Maracaibo, Venezuela, 4Facultad de Medicina, Pontificia Universidad Cat6lica, Santiago, Chile, 5Out-Patient Department, Hospital das Clinicas, Facultade de Medicina, Sao Paulo University, Sao Paulo, Brazil, 6Hospital Regional de Trujillo, Trufillo, Peru, and 7Tropical Diseases Research Foundation, Makati Medical Center, Makati City, Philippines

ABSTRACT

This open-label, prospective, randomized, comparative, singlem a s k e d s t u d y was p e r f o r m e d a t e i g h t c e n t e r s i n t h e P h i l i p p i n e s a n d L a t i n A m e r i c a (Chile, Colombia, P e r u , Brazil, a n d V e n e z u e l a ) . T h e p u r p o s e o f t h i s s t u d y was t o a s s e s s t h e efficacy a n d t o l e r a b i l i t y o f t h r e e d i f f e r e n t a n t i b i o t i c r e g i m e n s for t h e t r e a t m e n t o f a c u t e phary n g i t i s / t o n s i l l i t i s as a r e s u l t o f g r o u p A b e t a - h e m o l y t i c s t r e p t o c o c c i (GABHS), a n d t o a s s e s s t h e r a t e o f r e c u r r e n c e s . C h i l d r e n ( a g e d 3 t o 15 y e a r s ) a n d a d u l t s w i t h a r e c e n t h i s t o r y o f t o n s i l l i t i s a s s o c i a t e d w i t h a p o s i t i v e r a p i d d i a g n o s t i c t e s t for g r o u p A s t r e p t o c o c c u s , l a t e r c o n f i r m e d b y p o s i t i v e c u l t u r e s f o r GABHS, w e r e r a n d o m i z e d t o o n e o f t h e following a n t i b i o t i c r e g i m e n s ( a c c o r d i n g t o p a t i e n t a g e ) for 10 days: ( 1 ) l i n c o m y c i n h y d r o c h l o r i d e c a p s u l e s o r s u s p e n s i o n : a d u l t s - - - t w o 500-mg c a p s u l e s t w o t i m e s a day ( B I D ) for 10 days; c h i l d r e n - - 6 0 mg/kg p e r day d i v i d e d BID for 10 days ( m a x i m u m dose, 1000 rag/d); ( 2 ) p h e n o x y m e t h y l p e n i c i l l i n c a p s u l e s o r s u s p e n s i o n : a d u l t s - - o n e 500-mg c a p s u l e t h r e e t i m e s a day ( T I D ) f o r 10 days; children---50 mg/kg p e r day divided TID f o r 10 days ( m a x i m u m dose, 1500 rag/d); ( 3 ) c l a r i t h r o m y c i n c a p s u l e s o r s u s p e n s i o n : a d u l t s - - o n e 250-mg c a p s u l e BID for 10 days; c h i l d r e n - - 7 . 5 mg/kg p e r day divided BID for 10 days ( m a x i m u m dose, 500 rag/d). A f t e r t h e i n i t i a t i o n o f t r e a t m e n t (12 t o 14 d a y s ) a n d 3 m o n t h s a f t e r c o m p l e t i o n , p a t i e n t s w e r e e v a l u a t e d t o a s s e s s clinical a n d m i c r o b i o l o g i c r e c u r r e n c e s . O u r r e s u l t s i n d i c a t e t h a t all d r u g s h a d s t a t i s t i c a l l y s i m i l a r clinical a n d b a c t e r i o l o g i c efficacy as well as t o l e r a b i l i t y for t h e t r e a t m e n t o f a c u t e GABHS p h a r y n g i t i s / t o n s i l l i t i s w i t h a clinical h i s t o r y o f r e c u r rence. K e y words: GABHS p h a r y n g i t i s / t o n s i l l i t i s , lincomycinp e n i c i l l i n- c l a r i t h r o m y c i n .

Address correspondenceto: Dr. David Zambrano,Market RegionAsia, Pharmacia & Upjohn Asia Ltd, Room 1101-03,AlliedKsjima Building, 138 GloucesterRoad, Wanchai,Hong Kong. Received for publication on August 5, 1997. Printed in the U.S.A. Reproductionin whole or part is not permitted. 917 0011-393x/97/$3.50

L I N C O M Y C I N VS PENICILLIN A N D C L A R I T H R O M Y C I N IN PHARYNGITISfrONSILLITIS

INTRODUCTION

Group A beta-hemolytic streptococcal (GABHS) pharyngitis/tonsillitis remains one of the most frequent acute ambulatory infections, especially between the ages of 5 and 15 years. 1 Antibiotic therapy for streptococcal pharyngitis/tonsillitis is aimed not only toward symptomatic improvement of the acute infection and the prevention of suppurative complications but also toward the prevention of the subsequent occurrence of acute rheumatic fever. 2 Although acute tonsillitis traditionally has been considered a streptococcal disease, 3'4 recent literature s-12 has focused on the polymicrobial aspects of recurrent tonsillitis; furthermore, studies 6-12 have shown a disparity between the surface and the core of the tonsils, especially with beta-lactamase--producing bacteria (BLPB), which have been isolated from the core of the tonsils from 74% of patients. 6 BLPB m a y play a role in the persistence of the infectious process by rendering therapy with beta-lactam antibiotics ineffective.13'14 The administration of antimicrobials resistant to beta-lactamase may be more effective in treating recurrent GABHS tonsillitis. Penicillin, given orally or intramuscularly, is generally considered the drug of choice for the t r e a t m e n t of pharyngitis/tonsillitis and is the drug against which other regimens have most often been j u d g e d J 5 A full 10 days of oral therapy or a single injection of benzathine penicillin is required. 16 Other alternative antibiotics include the new macrolides that have prolonged half-lives, such as clarithromycin, an acid-stable, orally administered macrolide antimicrobial drug, structurally related to erythromycin. In these studies, 16'17 patients with streptococcal pharyngitis responded well to clarithromycin therapy, demonstrating both clinical cure and bacteriologic eradication. Treatment with clarithromycin was judged equivalent to t r e a t m e n t with erythromycin or phenoxymethylpenicillin. 17 Other available non-beta-lactam antibiotics are considered to be good alternatives to treat these infections, including lincomycin, which has been widely used and has shown excellent efficacy in eradicating streptococci from the throat of patients with GABHS pharyngitis/tonsillitis. 18 Some initial comparative studies have shown lincomycin to be as effective as penicillin and, in the case of recurrent infections, superior. 19'2 Since 1990, no prospective comparative study has been conducted with lincomycin in pharyngitis/tonsillitis. 21 We performed the present clinical trial to compare the bacteriologic and clinical efficacy and tolerability of three antibiotics (lincomycin vs penicillin vs clarithromycin) in the treatm e n t of patients with acute pharyngitis/tonsillitis caused by GABHS, who had a clinical history of recurrence of this illness, and to assess the recurrence rate in these patients for a period of up to 3 months after they completed 10 days of therapy.
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G. ANGELI ET AL.

PATIENTS

AND METHODS

This trial was an open-label, multicenter, prospective, randomized, singlemasked study designed to compare treatments of patients with signs and symptoms of tonsillitis/pharyngitis caused by GABHS. Eight centers from six countries participated in the study. Children aged 3 to 15 years and adults were eligible if they had a clinical diagnosis of acute streptococcal tonsiUitis/pharyngitis including at least four of the following six signs/ symptoms: t e m p e r a t u r e >37.5 C, erythema, exudate, t e n d e r cervical lymphadenopathy, sore throat, or dysphagia. A positive rapid diagnostic test for GABHS was required to be included in the study, and this rapid direct test had to be confirmed by a throat culture positive for GABHS for the patient to be considered assessable. The infection had to be acute (duration ~<1 week), and patients had to have a history of at least two episodes of d o c u m e n t e d p h a r y n g e a l or tonsillar infections within 12 months preceding the study that were associated with one or more of the signs and symptoms mentioned previously. The other conditions of participation were willingness to participate voluntarily, and the ability to take oral medication. All patients (or parents) provided written informed consent for study participation. Patients were ineligible if (1) they had a history of sensitivity to clindamycin, lincomycin, beta-lactam antibiotics, erythromycin, clarithromycin, or any other macrolide; (2) they had any concomitant infection that could interfere with t r e a t m e n t evaluation; (3) they had previous antimicrobial therapy within 48 hours, preexisting diarrhea, or recent history of chronic lower-bowel disease (within 10 years); (4) they were previously enrolled in another investigational study; (5) they had a recent (<1 year) history of renal or hematologic disease; (6) they were pregnant or lactating; or (7) they had a recent (<1 year) history of GABHS-positive pharyngeal/ tonsillar rapid test or culture but had no clinical symptoms of tonsillitis/ pharyngitis (carriers). A rapid identification test for GABHS was performed on all patients at screen utilizing a Unipath Clearview Strepto A kit (Unipath Ltd., Bedford, United Kingdom). If a negative test was obtained, the patient was not enrolled. If the patient had a positive rapid identification of GABHS, a tonsillar swab was obtained for culture. A single culture specimen was obtained from the posterior pharynx before administration of study drug. A positive culture was defined as 10 or more colonies per high-power field. GABHS were present on the culture plate. A throat specimen for culture was obtained using a throat swab that was passed over both sides of the posterior pharynx and the uvula. The recommended culture medium was sheep blood agar. All culture that was negative at 24 hours was reincubated for another 24 hours. Reduced oxygen tension, which potentially enhances identification of GABHS, was at919

LINCOMYCIN VS PENICILLIN AND CLARITHROMYCIN IN PHARYNGITIS?rONSILLrrIs

tempted by stabbing the agar after the sample was streaked or by using a coverglass pressed onto the primary zone of inoculation. GABHS were identified by the bacitracin method. The streptococci obtained on culture were saved for subsequent typing when possible. The cultures for streptococci were repeated at end of treatment (Days 12 to 14) and at any time from the end of treatment through posttreatment if patients presented with recurrence of signs and symptoms. (Cultures for GABHS were not required at posttreatment if patients showed no signs or symptoms of pharyngitis/tonsillitis.)

Treatment Regimens
Outpatients who fulfilled inclusion criteria were randomly assigned to one of the following three treatments: (1) Lincomycin hydrochloride capsules or suspension (according to patient age): adults--two 500-rag capsules two times a day (BID) for 10 days; children--60 mg/kg per day divided BID for 10 days (maximum dose, 1000 mg/d). (2) Phenoxymethylpenicillin capsules or suspension (according to patient age): adults--one 500-mg capsule three times a day (TID) for 10 days; children--50 mg/kg per day divided TID for 10 days (maximum dose, 1500 mg/d). (3) Clarithromycin capsules or suspension (according to patient age): adults---one 250-mg capsule BID for 10 days; children--7.5 mg/kg per day divided BID for 10 days (maximum dose, 500 mg/d). The initial treatment was given for approximately 3 days, but was terminated early if the patient's condition deteriorated or if severe adverse reactions occurred. Patients were supplied with blisters or bottles containing medication. One blister or bottle contained sufficient medication for 4 days of treatment for one patient and was given at screen. The second blister or bottle was provided at the Day 4 visit to patients with a positive culture to complete 10 days of therapy. The antibiotic therapy was administered for 10 days (20 doses of lincomycin or clarithromycin, and 30 doses of phenoxymethylpenicillin). Patients were assigned to one of the three treatment groups based on a series of random code tables kept in envelopes provided by the sponsor. The random table of numbers was supplied by Pharmacia & Upjohn Company, Kalamazoo, Michigan. Equal numbers of patients were assigned to the three groups. Patient numbers were assigned sequentially. Study numbers assigned to patients who withdrew from the study or were considered nonassessable were not reassigned to another patient. The single-masked procedure involved two physicians: one screened patients for study eligibility, evaluated the clinical status of patients, col920

G. ANGELI ET AL.

lected samples for culture, and assessed bacteriologic results throughout the study; the other distributed medication to the patient, completed drug accountability, and counseled patients to refrain from discussing anything about their medication with the other physician. The physician assigned to distribute medication opened the envelope containing the random code and assigned patients to one of the three treatments. The single-masked physician evaluator was retained for the duration of the study. In case of emergency, another previously assigned physician (not the masked evaluator) identified and treated the specific patient. Each center was provided with a separate random code list. All medications taken concomitantly during the study were recorded. The use of nonstudy antibiotics during treatment (up through Days 12 to 14) disqualified patients from participation in the study. Only acetaminophen was allowed if a patient required symptomatic treatment. After Days 12 to 14, alternative antibiotic therapy was permitted as needed. Patients were scheduled to return to the study sites at Day 4 after the initiation of therapy for clinical evaluation and 2 days after the end of drug therapy (Day 12) for clinical and bacteriologic assessments. Drug therapy was stopped in patients from whom GABHS was not isolated from the pretreatment throat culture. Clinical efficacy was determined independently of microbiologic outcome on the basis of signs and symptoms. Assessable patients were categorized during Day 4 and Day 12 according to the following criteria: (1) clinical cure: all signs and symptoms resolved; (2) clinical failure: patients who remained symptomatic at the end of treatment; and (3) side-effect failure: patients who experienced side effects from study medication that necessitated early withdrawal from the study. Bacteriologic efficacy was defined as either a success (initial culture was positive, Day 12 culture was negative) or a failure (GABHS persisted on culture at posttherapy visit [Day 12]). Information regarding adverse effects was elicited at each follow-up visit by questioning the patient. All side effects (related or unrelated) were recorded on a medical event form. The investigator was required to classify events as serious or nonserious and to judge whether the side effect was related to the protocol medication. All patients who received any study medication were included in the safety analysis. Statistical A n a l y s i s After completion of the study, descriptive statistics, analysis of variance, and categorical analysis techniques were applied to compare the treatment groups with regard to the following: demographics (age, sex, race, body weight, height, and underlying disease); efficacy (development of complications, presence of infections, physician evaluation of therapeu921

L I N C O M Y C I N VS PENICILLIN A N D C L A R I T H R O M Y C I N IN PHARYNGITISfrONSILLITIS

tic responses, and bacteriologic response); and tolerability (types and ratio of adverse reactions). The primary efficacy measures were clinical outcome and bacteriologic outcome. Tolerability was evaluated by listing reported side effects for each treatment group. All statistical tests were two-sided. Statistical analyses were performed by using SAS Version 6.08 (SAS Institute, Inc., Cary, North Carolina) at a level of significance of 0.05. 22 Clinical and efficacy variables were tested for statistical significance by means of the chi-squared test. The analysis of the continuous variable (temperature) was performed by means of analysis of variance methods for the full model if interaction was of interest, or by using Student's t test if the basic model was appropriate.
RESULTS

A total of 387 patients entered the study and received some protocol drug: 134 (35%) in the lincomycin group, 129 (33%) in the penicillin group, and 124 (32%) in the clarithromycin group. Table I shows the number of patients in each group completing various study stages, and Table II describes the reasons that potential patients could not be assessed. Of the 387 initial patients, 121 patients (31%) could not be assessed: 83 (21%) patients (28 in the lincomycin group, 27 in the penicillin group, and 28 in the clarithromycin group) had negative pretreatment culture results for GABHS. These patients were deemed ineligible after treatment began and were dropped from the study after the Day 4 visit. In addition, 4 patients (1%) failed to meet entry criteria (2, 1, and 1 in the lincomycin, penicillin, and clarithromycin groups, respectively), 12 patients (3%) failed to follow protocol (eg, because they had received additional antibiotic therapy) (7, 4, and 1 in the same respective groups), 4 patients (1%) were evaluated beyond the window of evaluation (0, 2, and 2

Table I. No. (%) of patients completing each study stage.

Treatmenl Groups Stage Lincomycin (n = 134) Penicillin (n = 129) Clarithromycin (n = 124) Total (N = 387)

Clinical evaluation Microbiologic evaluation (Days 12 to 14) Posttreatment evaluation (3 months)

91 (34) 89 (34) 68 (33)

88 (33) 87 (34) 72 (35)

87 (33) 83 (32) 64 (31)

266 (100) 259 (100) 204 (99)*

* Does not total 100% because of rounding.

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G. ANGELI ET AL.

Table II. No. (%) of patients who could not be evaluated. Treatment Groups Reason Lincomycin (n = 134) Penicillin (n = 129) Clarithromycin (n = 124) Total (N = 387)

Negativepretreatmentculture Failedto meetentry criteria Failedto follow protocol (eg, additiona/antibiotictherapy) Beyondwindows of evaluation Missed Day 12 to 14 visit Total

28 (21) 2 (1) 71i l 0 6 43 )

27 (21) 1 (1) 411l 2 7 41 )

28 (23) 1 (1) 11! 2 l 5 37 )

83 (21) 4 (1) 12/i l 4 18 121 )

in the same respective groups), and 18 patients (5%) missed the visit on Days 12 to 14 (6, 7, and 5 in the same respective groups). Of the 387 patients enrolled, 266 (69%) who adhered to all protocol features were included in the primary efficacy analysis: 91 (34%) in the lincomycin group, 88 (33%) in the penicillin group, and 87 (33%) in the clarithromycin group (Table III). No significant differences were observed among treatment groups with respect to age, body weight, sex, race, body temperature, or pharyngotonsillar erythema (Table III). Three hundred eighty-three (99%) of the 387 patients had at least two episodes of pharyngotonsillitis in the preceding 12 months. All of the 387 patients enrolled in the study were included in the safety analysis.
Table III. Demographic characteristics of patients included in the primary efficacy analysis according to treatment group.* Characteristic Lincomycln (n = 91) Penicillin (n = 88) Clarithromycin (n = 87)

Age Mean Range Bodyweight (kg) Range Sex (%) Male Race(%) Hispanic Oriental/Asian White Black Mean bodytemperature, axillary (C) Pharyngotonsillarerythema(%)

17.5 3-60 47.0 10-115 39 61 }6;I 15 12 (13) 3 (3) 38.1 90 (99)

19.0 3-60 49.3 13-92 38 61 }~l 13 11 (13) 3 (3) 38.1 87 (99)

18.0 5-56 45.0 12-86 37 (43) 59 (68) 15 (17) 10 (12) 3 (3) 38.01 86 (99)

* No significantdifferenceswerefound amongtreatmentgroupswith respectto any of the characteristics indicated.Percentageshavebeenrounded,

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LINCOMYCIN VS PENICILLIN AND CLARITHROMYCIN IN PHARYNGITISfrONSILLITIS

On the basis of the six symptoms, investigators were asked to assess each patient's clinical response 22 days after the end of drug therapy (Days 12 to 14); the overall response rate was 83% (Table IV). The three groups showed clinical responses that did not show statistically significant differences among them (Table IV). When noting the bacteriologic eradication of GABHS bacteria 2 days after completion of drug therapy, the overall response rate (95%) was higher (Table V). No statistically significant differences were detected among the three groups with respect to microbiologic eradication or persistence. Two hundred four patients could be evaluated 3 months after completion of the t r e a t m e n t to assess clinical and microbiologic recurrences (Table VI). None of the patients in the lincomycin or clarithromycin group reported clinical or bacteriologic recurrences: however, two patients in the penicillin group showed clinical and microbiologic recurrences. Another patient in the penicillin group had a positive GABHS culture b u t was free of clinical symptoms at the end of treatment (Table VI).

Tolerability
The safety data are based on a total of 387 patients who received some protocol drug in the study. Sixty-nine adverse medical events were reported: 22 in the lincomycin group, 19 in the penicillin group, and 28 in the clarithromycin group (Table VII). No statistically significant difference was observed among the three treatment groups with respect to the proportion of patients having at least one side effect. The most common side effects were diarrhea (19), abdominal pain (14), and pharyngitis (8). Diarrhea was the most common side effect in the lincomycin and penicillin groups, whereas abdominal pain was the most common side effect in the clarithromycin group. The incidence rates for the most frequently observed medical events did not differ between children and adults. None of these side effects were serious with the exception of severe arthritis reported by
Table IV. No. (%) of patients included in the primary efficacy analysis at the end of treatment (Days 12 to 14). Treatmenl Group* Category Lincomycin* (n = 91) Penicillin* (n = 88) Clarithromycin* (n = 87) Total (N = 266)

Clinical cure Clinical failuret

731280 / 18

77/881 11

711821 16 18 t

2211?~l 45

* Differences among the three treatment groups with respectto age, sex, body weight, race, body temperature, and pharyngotonsillar erythemawere not statistically significant. t Comprises failures and improvements. One patient was considered to be a side-effect failure and included in the clinical failure category.
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G. ANGELI ET AL.

Table V. No. (%) of patients with microbiologic eradication or persistence a t the end of t r e a t m e n t (Days 12 to 14).

Treatment Group Category Lincomycin (n = 89) Pencillin (n = 87) Clarlthromycin (n = 83) Total (N = 259)

Microbiologic eradication* Microbiologic persistence*

87 (98) 2 (2)

79 (91) 8 (9)

80 (96) 3 (4)

246 (95) 13 (5)

* Difference among the three treatment groups in microbiologic eradication and persistence was not statistically significant. one male patient in the clarithromycin group at the end of treatment (Days 10 to 12); the patient was discontinued from the study and fully recovered with no residual effects. The event was not considered to be drug related.
DISCUSSION

The present study was performed in patients with acute recurrent GABHS pharyngitis/tonsillitis. No attempt was made to determine the actual incidence of anaerobes and other BLPB in our patient population because those pathogens are more frequently found in the core of the tonsils than on the surface. 5-9 We also did not perform the study on pure acute GABHS pharyngitis/tonsillitis because lincomycin is not recommended as first-line therapy for the acute indication. The present study confirmed that a significant percentage of patients enrolled with symptoms and signs of an acute bacterial infection had negative cultures (83 of 387 [21%]).
Table VI. No. (%) of p a t i e n t s e v a l u a t e d for clinical a n d microbiologic recurrences a t 3 months.

Treatment Group Category Lincomycin (n = 8 ) 6 Penicillin (n = 72) Clarithromycin (n = 64) Total (N = 204)

Clinical and microbiologic recurrences Symptom-free No microbiology performed GABHS eradication GABHS present Symptoms present No microbiology performed GABHS eradication GABHS present

0 (0) 37154/ 22 32 0 (0) 4{i 5 I 0

2 (3) 41/57 / 21 29 2 (3) 31i 2 I 1 *

0 (0) 38/591 17 4 (6) 1{i 4 I 0

2 (1) 116 {ii/ 60 6 814 11 / 1 (<1)

GABHS = group A beta-hemolytic streptococci. * One female patient had clinical symptoms and GABHSat posttreatment but failed to meet the definition for recurrence because, even though she was GABHSculture positive, she was free of symptoms at the end of treatment.
925

LINCOMYCIN VS PENICILLIN AND CLARITHROMYCIN IN PHARYNGITISfIY)NSILLITIS

Table VII. No. (%) of adverse medical events.*

Treatment Group

Ab om,na, pa,n

Pharyngitis Upper respiratory infection Vomiting

Rhinitis

Diarrhea 91;/ '/i/

Medical Event Lincomycin (n = 134) Penicillin (n = 129)

Clarithromycin (n = 124)

Total (N = 387)
1,

33 2 1
1

4~ 1 1
2

19/;/
3

3/~/

8 4 5

Asthenia 1 0 ~/~/ 2 Gastroenteritis 0 1 l/~/ 2 Nausea 0 1 2 Cough 11i/ eli / ~/~/ 3/i / Dyspepsia 0 0 2 Bronchospasm 0 1 2 Rash 0 1 Arthritis 0 o t, t t/;~/ Grouptotals 22 (16) 19(~5) 28(23) 69 * Onlythoseeventsthatwerereportedby morethan0.5%of all patientson all visitsare shown. 1 Onemalepatienton clarithromycin reportedseverearthritisandwasdiscontinued the study. from
The present study confirms penicillin as a highly effective antibiotic for the treatment of GABHS pharyngitis/tonsillitis. We did not note the high failure rates observed with this antibiotic in developed countries in the past 2 decades. 23-26 It is possible that because our patients were enrolled in developing countries they might have been less exposed to the indiscriminate use of antibiotics. The present results with clarithromycin are similar to those of other recently published studies. O'Neill et a127 and Vogel 2s reported clinical success rates of 90% and 97%, respectively, in patients with tonsillitis in open-label studies. In comparative studies against penicillin or erythromycin, four studies 29-32 that used the same doses as we used in the present study demonstrated success rates between 80% and 96%. Lincomycin has been used orally TID in most studies for this indication. Because pharmacokinetic studies have shown that a single 1000-mg dose of lincomycin given orally in adults produces serum levels for 12 hours, which achieved an above average minimum inhibitory concentration (MIC) for streptococci, 33 we proposed to use 500 mg BID in the present study. The 60 mg]kg per day dose, the highest recommended for children, was selected for this study because it is the only one to achieve serum levels above the MIC for GABHS for more than 12 hours18; after 12 hours in both adults and children, the average blood level was 1 ~g/mL, whereas the MIC for GABHS was between 0.05 and 0.5 mg/mL, ls'33 These two lincomycin doses produce different average blood concentrations (eg, in a 70-kg adult, 2000 mg/70 kg per day = 28 mg/kg per day, whereas in a 10-kg child, 600 mg/10 kg per day = 60 mg/kg per day). Because the 926

G. ANGELIET AL.

different doses produce the same blood level after 12 hours, we can assume that children metabolize the drug much faster than adults, ls'Sa although different formulation characteristics might also account for this difference. In the present study, the new lincomycin regimen for both children and adults achieved success rates similar to those for clarithromycin and penicillin. The three regimens evaluated in the present study were well tolerated. Gastrointestinal disturbances were the most common side effects reported in the study groups, with diarrhea being more frequent in the lincomycin group and penicillin group and abdominal pain more common in the clarithromycin group. Previous studies on large numbers of patients reported similar patterns of the most common side effects for lincomyCin, 34'35 penicillin, 3e and clarithromycin. 37 All the side effects reported here were mild (with one exception in the clarithromycin group), and the differences among t r e a t m e n t groups were not statistically significant. Side-effect incidence rates were comparable in children and adults. Although a pharmacoeconomic evaluation was not performed in the present study because of significant price differences in the various antibiotics in different countries, a full t r e a t m e n t of penicillin or lincomycin on average would be less expensive than clarithromycin and produce similar success rates.
CONCLUSION

Lincomycin at the doses used in the present study showed similar clinical and bacteriologic success rates when compared with clarithromycin and penicillin for the treatment of acute and recurrent GABHS pharyngitis/ tonsillitis. The new BID doses of lincomycin were effective for the treatment of these infections. After 30 years, lincomycin continues to be a safe and effective t r e a t m e n t for acute and recurrent GABHS pharyngitis/ tonsillitis.

Acknowledgment
This study has been supported financially by a grant from Pharmacia & Upjohn Co., Kalamazoo.
References:
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