Clinical Pediatrics

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Efficacy of Cephalexin Two vs. Three Times Daily vs. Cefadroxil Once Daily for Streptococcal
Tonsillopharyngitis
Correne D. Curtin, Janet R. Casey, Patrick C. Murray, Carolyn T. Cleary, William J. Hoeger, Steven M. Marsocci,
Marie Lynd Murphy, Anne B. Francis and Michael E. Pichichero
CLIN PEDIATR 2003 42: 519
DOI: 10.1177/000992280304200606

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 Efficacy of Cephalexin Two vs. Three
Times Daily vs. Cefadroxil Once Daily for
Streptococcal Tonsillopharyngitis
Correne D. Curtin, MD'
Janet R. Casey, MD'
Patrick C. Murray
Carolyn T. Cleary, MD'
William J. Hoeger, MD'
Steven M. Marsocci, MD'
Marie Lynd Murphy, MD'
Anne B. Francis, MD'
Michael E. Pichichero, MD1

Summary: The purpose of this study was to compare the bacteriologic and clinical efficacy of oral
cephalexin twice vs. three times daily vs. cefadroxil once daily as therapy for group A beta-hemolytic
streptococcal (GABHS) tonsillopharyngitis. A prospective open-label, observational cohort study
was conducted over 18 months (January 2000-June 2001). Children enrolled had an acute onset of
symptoms and signs of a tonsillopharyngeal illness and a laboratory-documented GABHS infection.
Follow-up examination and laboratory testing occurred 21 4 days following enrollment. Two ±

hundred seventy-one patients were enrolled (intent to treat group): 63 received cephalexin twice
daily, 124 received cephalexin three times daily, and 84 received cefadroxil once daily. Fifty-three
children did not return for the follow-up visit, leaving 218 patients in the per-protocol group: 54
cephalexin twice-daily treated, 94 cephalexin 3-times daily treated, and 70 cefadroxil once-daily
treated. In the per-protocol group, bacteriologic cure for those treated with cephalexin twice daily
was 87%, for cephalexin 3 times daily, it was 81% and for cefadroxil once daily it was 81% (p=0.61).
The clinical cure rate for cephalexin twice-daily treatment was 91 %; for three-times daily, it was 86%;
and for cefadroxil once daily, it was 84% (p=0.56). Because treatment allocation was not random-
ized, logistic regression analysis was used to adjust for treatment group differences. Younger age of
patient was significantly associated with bacteriologic (p=0.04) and clinical (p=0.01) failure indepen-
dent of treatment group but in the adjusted logistic model no differences were found among the
3 treatment regimens. Cephalexin dosed twice daily or three times daily and cefadroxil dosed
once daily appear equivalent in bacteriologic and clinical cure of GABHS tonsillopharyngitis.
Clin Pediatr. 2003;42:519-526

'Elmwood Pediatric Group, Rochester, New York. Introduction

Reprint requests and correspondence to: Michael E. Pichichero, MD, Elmwood Pediatric he of
American Academy
Group, University of Rochester Medical Center, 601 Elmwood Avenue, Box 672, Rochester, (
RedAAP)
Pediatrics
NY 14642. Book Committee states

2003 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A. that a 10-day course of a narrow-

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 Curtin et al.

spectrum (first-generation) and cefadroxil once daily as 10- test) was performed. Patients
cephalosporin is an acceptable al- day treatment for GABHS tonsil- were deemed compliant by
ternative to penicillin for treat- lopharyngitis. parental report at the follow-up
ment of group A beta hemolytic visit if they assured the physician
streptococcal (GABHS) tonsil- that all medication had been
lopharyngitis.'1 The cephalo- Methods taken as prescribed.
sporins are particularly recom-
mended for persons allergic to Study Setting Analysis Groups
penicillin, noting however that The Elmwood Pediatric The intent-to-treat population
i'as many as 15% of penicillin-al- Group (EPG) is a private pedi- included all patients who were en-
lergic persons also are allergic to atric practice located in suburban rolled in the study meeting the in-
cephalosporins," which is perhaps Rochester, New York (greater clusion and exclusion criteria.
incorrect.2-6 The American Heart metropolitan population of 1 mil- The per-protocol population in-
Association (AHA) Committee on lion). The practice population is cluded all patients in the intent-to-
Rheumatic Fever recognizes representative of the economic, treat group who were compliant
cephalosporins as "acceptable al- racial, and ethnic diversity of sub- with treatment and returned for
ternatives" to penicillin, "particu- urban Rochester. During the cur- and completed the follow-up visit.
larly for penicillin-allergic individ- rent study, the group consisted of
uals."7 The AHA states that 20% 10 board-certified pediatricians Outcome Definitions
of penicillin-allergic persons are and 2 pediatric nurse practition- Bacteriologic outcomes were
also cephalosporin-allergic, which ers. There is a laboratory at the of- defined as eradication (cure) if
is also perhaps incorrect.2-6 The fice practice with Clinical Labora- the rapid antigen detection assay
AHA also notes that "narrow- tory Improvement Act (CLIA) or throat culture obtained at the
spectrum cephalosporins such as level III certification. follow-up visit was negative for
cefadroxil or cephalexin are GABHS or as failure if the test re-
probably preferable to the Study Design sult was positive for GABHS, both
broader-spectrum cephalospor- This was a prospective, open- irrespective of symptoms and
ins" for treatment of GABHS label, observational study con- signs. Clinical outcomes were clas-
tonsillopharyngitis. ducted over 18 months, January sified as success (cure) if the rapid
There are exceedingly few 2000 to June 2001. Children with antigen detection test or throat
studies in which different ce- acute onset of symptoms, signs, culture result obtained at the fol-
phalosporins have been com- and a laboratory-documented low-up was negative for GABHS
pared in the treatment of GABHS GABHS tonsillopharyngitis using and the patient had no symptoms
tonsillopharyngitis8-13 and none a rapid antigen detection test or a or signs of throat infection, or as
that have compared the AAP and throat culture were eligible for failure if the test result was posi-
AHA preferred agents-cepha- the study. Those children with a tive for GABHS and symptoms
lexin and cefadroxil. Further- history of penicillin, amoxicillin, and signs of throat infection were
more, cephalexin when first li- or cephalosporin allergy and present at the follow-up visit, or as
censed was indicated for GABHS those children with a history of a presumed carrier if the throat
tonsillopharyngitis using 4 times GABHS carriage were excluded culture result was positive and the
daily dosing; this schedule is a ma- from the study. The choice of an- patient was asymptomatic.
jor compliance barrier. Although tibiotic therapy and dosing fre-
the package insert for cephalexin quency was made according to Statistics
now states that cephalexin may be the preference and discretion of To assess possible differences
administered on an every 12-hour the child's physician, and the between treatment groups, chi-
schedule for 10 days for treatment doses were determined accord- square test for categorical data
of GABHS, we could find only 1 ing to the patient's weight. All pa- and the student t test for continu-
study where 4 versus 2 times daily tients were scheduled for a re- ous variables was used. A p value
dosing schedules were com- peat visit 21 4 days following
± less than 0.05 was considered sig-
pared.8 Therefore, in this study enrollment. At that time a his- nificant. Because the treatment
we compare the bacteriologic and tory, physical examination, and allocation was not randomized,
clinical efficacy of cephalexin repeat laboratory test (throat cul- logistic regression analysis was
given twice daily, or 3 times daily ture or rapid antigen detection done on the per-protocol dataset;

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 Cephalexin vs. Cefadroxil in Streptococcal Tonsillopharyngitis

in this analysis presumed GABHS to-treat study group; 63 received mirrored in the per-protocol
carriers at the end of treatment cephalexin twice daily, 124 re- group. No child refused to take
were deleted. Age of the patient, ceived cephalexin three times the antibiotic suspension, and no
antibiotic dose/kg of child daily, and 84 received cefadroxil parents acknowledged medica-
weight, number of GABHS infec- once daily. A description of the tion non-compliance; 53 did not
tions in the past year, days ill be- patient's age, gender, weight, return for the follow-up visit, leav-
fore the study visit, enlarged ton- symptoms, signs, and relevant ing 218 patients in the per-proto-
sillar size, and tonsillar exudates medical history are shown in col group; 54 cephalexin twice-
were the variables included with Table 1. The treatment groups daily group, 94 in the cephalexin
the treatment variable to predict were similar for all parameters ex- three-times-daily group, and 70 in
bacteriologic and clinical cure. cept antibiotic dose on a mg/kg the cefadroxil once-daily group.
calculation and there were statisti- In the per-protocol analysis
cal differences in the recording of the bacteriologic cure rate for
Results selected signs of tonsillopharyngi- children treated with cephalexin
tis inflammation (Table 1). The twice daily was 87%, for ce-
Two hundred seventy-one pa- similarities and differences seen phalexin three times daily-treated
tients were included in the intent- in the intent-to-treat group were children it was 81% and for ce-

Tabl I

DEMOGRAPHIC DATA OF THE INTENT TO TREAT GROuUP

Patient Charactedstics Ciephalexin BIDX Cephalexin TID Cefadroxil OD
Paten
Chrctrstc
Ceh.xnBDearxlQ
No. of patients 63 124 84
Mean age, yr (range) 6.6 (1-17) 7.5 (2-19) 6.7 (2-14)
Gender (% males) 64 59 57
Antibiotic dose (mg/kg/day); mean S.D.* 39 + 12 31 ±10 31 ± 9
GABHS infections withinmpast year
0 episodes (%) 26 17 21
.1 episode (%) 74 83 79
Days ill before visit
< 2 days (%) 65 73 74
Sore throat (%) 91 92 89
Fever (%) 59 67 62
Heeadache (%) 65 66 60
Pharyngeal erythema (%) 100 95 98
Enlarged tonsillar size (M%) 70 56 48
Tonsillopharyngeal exudates (%): 54 57 71
Cervical lymrphadenopathy (%) 61 63 60

*Significant differences among treatment groups, p < 0.01.

tsignitcant differences among treament groups, p-0.02.
tSignificant differences among treament groups, p < 0.001.

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 Curtin et al.

fadroxil once daily it was 81% patient age on bacteriologic and not suggest that these antibiotics
(p=0.61) (Table 2). Similarly, the clinical outcome were similar would achieve an optimal effect
clinical cure rate for cephalexin when the variable of antibiotic on GABHS eradication when
twice daily treatment group dose on a mg/kg basis, number of doses twice or once daily are used,
(91%) was similar to the clinical GABHS infections in the past respectively, based on current
cure rate in the cephalexin three year, days ill before the study visit, pharmacokinetic/pharmacody-
times daily (86%) and cefadroxil enlarged tonsillar size and tonsil- namic (PK/PD models).29 Per-
once daily (84%) treatment lopharyngeal exudate were added haps the PK/PD model does not
groups, p=0.57 (Table 2). Analysis to the model. apply to GABHS tonsillopharyn-
of the intent-to-treat population gitis infections? The half-life of
gave similar results if patients who penicillin V in serum is 0.6
completed therapy but failed to Discussion hours28 and it can be dosed twice
return for follow-up were pre- daily3O-32 but not once daily33 and
sumed to experience bacterio- In private pediatric group
our still achieve a similar bacterio-
logic eradication and clinical practice setting we found in this logic cure rate as 3 or 4 times daily
cure. study that cephalexin twice daily, dosing.34-4O We identified one
In the adjusted logistic regres- cephalexin three times daily, and study in which cephalexin was ad-
treatment regimens
sion analysis, cefadroxil once daily produce a ministered twice vs. 4 times daily.8
were confirmed as not signifi- similar bacteriologic and clinical In that double-blind, random-
cantly different for bacteriologic cure of GABHS tonsillopharyngi- ized, controlled trial conducted at
(p=0.56) or clinical (p=0.51) tis. This result is consistent with the Oklahoma Children's Hospi-
cure. However, age of the patient cure rates observed in earlier tal involving a total of 65 children,
was found to be a significant pre- studies'426 where cephalexin was there was no difference in bacte-
dictor of the bacteriologic administered three or four times riologic or clinical cure for the
(p=0.01) and clinical (p=0.01) daily and where cefadroxil was ad- two dosing regimens. Five other
cure, with younger patients less ministered once or twice daily studies compared 2 cephalo-
frequently experiencing cure. (Table 3). sporins in the treatment of
The lack of differences among an- The serum half-life of GABHS tonsillopharyngitis;9-13
tibiotic treatments and the pres- cephalexin is 1.1 hours and for ce- 4 studies involved children and 1
ence of differences according to fadroxil is 1.5 hours,28 which does study was in adolescents and

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 Cephalexin vs. Cefadroxil in Streptococcal Tonsillopharyngitis

R Noefere C:e halexmn or

N. Authors. yr Agn I~mily
Da Dose Schedule Cefadroil Percen Cure*
14 Stiermatn tl al. 1970 500 mg TlID 90
10 x
15 Disney et all 1971 Cphalexin 3044-0 mg/k TID 81
16 Stilermanet a 1972 Cephalexin 1,500 mg 89
Cephalex'in
17 Gau et al. 1972 2W:mg
20-40 TID 96
18 Rabinoichet al. 1973
Cephalexin
2,000;mg 010 100
19
Cephalexin
Mten et al. 1974 Cephlaexin
CtephJalkexin 2,000 mg QID 97
20 Disne eal. 1992 ; 27 mg/kg¢ aID 93
21 Ginsberg et al. 1980 Cefadroxil 30mg TID 93
22 Ginsbemrget al 01982 30 mg/k BID 86
CefadroxilI!t
23 Henness, 1982 Cefdroxil
Cefadroxil 30 mg/kg BID 86
;Cefdroxil
24 Pichichero d al. 1987 QD 90
Cefdroxil
25 Stromberg tet al. -198 1,000-200 mg IBID 97
Cefaroxilj
26 Hoim et al. 1991 BID 98
27 Miovwicetima. 1991 25mg/k BID 93
*Pemt cure dei*d asbater ologi dition at end of treatment.
QD once daily, BID Wiedtil, lID -three times daily, OID = four times dail.l

adults. In all but 1, the drugs pro- AHA7 erroneously caution that ies with n's of 69 to 255).2 Second-
duced similar bacteriologic and 15% to 20% of penicillin-allergic and third-generation cephalo-
clinical outcomes. patients are also cephalosporin-al- sporins have been linked to a
A concern of pediatricians is lergic. In those studies, which the lower incidence of allergic reac-
the potential for allergic cross-re- AAP and AHA possibly relied on, tions.5650 A recent study investi-
activity in children who are con- the penicillin allergy was not con- gated 187 children and adoles-
sidered penicillin allergic.41-43 On firmed with skin tests, the cents whose adverse reactions to
the basis of chemical structure cephalosporin skin test reagent was amoxicillin (or amoxicillin/clavu-
and degradation of the penicillins contaminated with penicillin, and lanate) or oral cephalosporin,4 or
and cephalosporins, differing many of the cephalosporin reac- both, were sufficient to preclude
conclusions about the likelihood tions may not have been immuno- further use.451 Fifty-four peni-
of cross-sensitivity may be logically mediated. More recent cillin or amoxicillin reactors with
reached.44-49 Patients with histo- studies suggest cross-sensitivity to positive skin test results or oral
ries of penicillin allergy have first generation cephalosporins in challenges received 83 courses of
demonstrated a potential for in- patients with a history of peni- cephalosporins uneventfully in
creased hypersensitivity to first- cillin allergy occurs less fre- prospective follow-up.
generation cephalosporins.3,42,49 quently than widely thought Because this was not a ran-
Citing early studies and subse- (4.4% across 7 small studies with domized, controlled trial there
quent reviews, the AAP' and n's of 3 to 62; 7.1 % across 3 stud- are several limitations that should

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 Curtin et al.

be acknowledged. The selection fadroxil, given once daily and trolled study of cephalexin twice ver-
of the antibiotic was at the discre- cephalexin, given twice or thrice sus four-times daily. Infection. 1984;

tion of the physician seeing the daily, are equally efficient in both 12:181-184.
patient. This occurred in a consis- bacteriologic and clinical cure of 9. Barbhaiya RH, Shukla UA, Gleason
GABHS tonsillopharyngitis in CR, et al. Phase I study of multiple-
tent manner by each investigator
dose cefprozil and comparison with
according to his/her preference children. cefaclor. Antimicrob Agents Chemother
for a particular antibiotic and reg- 1990;34:1 198-1203.
imen; therefore selection bias did 10. McCarty JM, Renteria A, Doyle CA,
not likely occur because more or Acknowledgments Durham SJ, Hamilton H, Wilber RB,
less ill patients were not more or for the Cefprozil Multicenter Study
less likely to see any particular The Department of Biostatis- Group. Cefprozil vs. cefaclor in the
physician. Secondly, in keeping tics, University of Rochester as- treatment of pharyngitis and tonsilli-
with the general treatment ap- sisted in data analysis. This study tis. Infect Med. 1992; 9 (Suppl C) :33-43.
proach advocated at EPG52,53 and was supported by the Elmwood 11. Randolph M. Clinical comparison of
by others,29 cephalosporin treat- Pediatrics Research Fund. once-daily cefadroxil and thrice-daily
ment in this study was used more cefaclor in the treatment of strepto-
often as a treatment for patients coccal pharyngitis. Chemotherapy.
with recurrent GABHS tonsil- 1988;34:512-518.
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