D. Adam, Cefixime Study Group, U. Hostalek, K.

Tr6ster

5-Day Cefixime Therapy for Bacterial Pharyngitis and/or Tonsillitis:

Comparison with 10-Day Penicillin V Therapy
Summary: In an open, controlled, randomized multicenter study, 160 children suffering
from pharyngitis and/or tonsillitis were treated with either 8 mg cefixime/kg body weight
once daily for 5 days or 20,000 I.U. penicillin V/kg body weight t.i.d, for 10 days. One hun-
dred fifty-one children were evaluable for clinical efficacy. In the cefixime group, 65
(86.7%) children were cured, seven (9.3%) were significantly improved, one (1.3%) re-
lapsed and in two (2.7%) therapy failed. Of the patients treated with penicillin V, 69
(90.8%) were cured, five (6.6%) improved, one (1.3%) relapsed and in one (1.3%) thera-
py failed. Elimination of initial pathogens occurred in 57 (82.6%) patients treated with
cefixime and in 60 (88.2%) treated with penicillin V. At 3 to 4 weeks after the end Of
treatment, six relapses were seen in the cefixime group and eight in the penicillin V group.
Mild-to-moderate adverse events that were possibly related to the medication were seen
in four children treated with cefLxime and in five treated with penicillin V.

Introduction Patients and Methods

Antibiotic treatment of group A ~3-hemolytic streptococ-
cal pharyngitis and tonsillitis is traditionally continued for
at least 10 days to prevent such late complications as glom-
erulonephritis and rheumatic fever [1]. This recommenda-
tion is based on experience with penicillin V. The penicil-
lin concentrations in tonsillar tissue required for effective
elimination of streptococci can be attained only with rela-
tively high doses given for a comparatively long period of
time. ttowever, the number of reports of nonresponders to
penicillin V has been growing in recent years [1]. These
nonresponders are thought to be due to penicillin inacti-
vation by [3-1actamases of the normal tonsillopharyngeal
flora as well as to poor patient compliance with 10-day
treatment courses and to the relatively poor penetration of
penicillin V into tonsillar tissue [2].
Cefixime and other new oral cephalosporins have good ac-
tivity against group A streptococci, are highly resistant to
[3-1actamases [3,4], and attain therapeutic levels in tonsil-
lar tissue [5]. Ten-day treatment studies have compared
the efficacy of cefixime with that of penicillin V and re-
ported similar responses [6,7].
Clinical trials of less than 10 days' treatment of group A
streptococcal tonsillopharyngitis with cefixime [8] or oth-
er orat cephalosporins, [9,10] versus conventional 10-day
penicillin V therapy found that oral cephalosporin thera-
py for a reduced period of time was as effective as 10-day
penicillin V therapy. The objective of the present study,
therefore, was to evaluate the efficacy and safety of 5-day
cefixime therapy versus conventional 10-day penicillin V
therapy for group A streptococcal pharyngitis and/or ton-
sillitis, and to evaluate the clinical usefulness of a newly
developed cefixime ready-to-use suspension.
This open, controlled, randomized, multicenter trial was carried
out at 12 centers from December 1992 through March 1993. The
protocol had been approved by the Ethics Committee of the Baye-
rische Landes~irztekammer.
One hundred sixty children (1-12 years of age) with a clinical
diagnosis of bacterial pharyngitis and/or tonsillitis were enrolled
in this trial. A positive rapid strep A test was considered desir-
able before the start of therapy.
Exclusion criteria were known hypersensitivity to cephalospo-
rins or penicillins, evidence of viral infection, severe renal failure
(serum creatinine > 4.2 rag/100 ml), severe gastrointestinal disor-
ders with vomiting and/or diarrhea, antibiotic therapy within 3
days of the start of this trial, or concurrent treatment with anoth-
er antibiotic during this trial. Patients with bacterial isolates re-
sistant to cefixime or penicillin found at screening were also ex-
cluded and treated with different antibiotics.
After checking all criteria for inclusion and exclusion and taking
a careful history, informed consent was obtained from the
patients' parents (or legal guardians) and the children them-
selves (as far as possible). Patients then underwent an entry ex-
amination including the following items: clinical examination, re-
cording of all signs and symptoms, rapid test for group A 13-he-
molytic streptococci ("rapid strep A test"), throat (pharynx
and/or tonsils) swab for bacteriological testing, including suscep-
tibility testing, and recording of any drugs patients may have
been receiving concurrently.
Prof. D. Adam, M. D., Ph.D., Kinderklinik im Dr. von Haunerschen Kin-
derspital der Universit~it, Lindwurmstrasse 4, D-80337 Mtinchen; UIrike
Hostalek, M. D. Kristina TrOster, Ph.D., E. Merck, D-64271 Darmstadt,
Germany.
Correspondence to: Prof. D. Adam.

Infection 23 (1995) Suppl. 2 © MMV Medizin Verlag GmbH Mtinchen, Miinchen 1995 S 83
D. Adam et al.: Cefixime versus Penicillin V for Pharyngitis

Table 1 : Demographics of evaluable patients. from powder) per kg body weight t.i.d. 1 hour before meals for
10 days.
One to 5 days after the end of therapy, patients underwent a final
examination that included all items of the entry visit except the
No. Of patients 75 76 rapid strep A test, as well as recording of any adverse events that
Age (years) 2-11 1-12 may have occurred and evaluation of clinical efficacy (pre-post
Mean age (years) 5.5 5.4 comparison of signs and symptoms) and bacteriologic efficacy.
Mean weight (kg) 22.4 21.9 Patients were followed up at 3-4 weeks after the end of therapy
Gender (M~') 47/28 39/37 either by contacting the parents telephonically or by arranging a
Mean duration follow-up visit in order to record any signs and/or symptoms of
of therapy (days) 5.3 10.7 relapse. Bacteriologic testing was repeated if recurrence was sus-
pected.
Table 2: Entry diagnoses (evaluable patients). Bacteriologic testing of the throat (pharynx and/or tonsils) swab
included both the agar diffusion test and the agar dilution test. If
there were discrepancies between the two susceptibility testing
methods, the result of the dilution test was used because-this was
considered the more accurate. Susceptibility to cefixime in the
Tonsillitis 33 (44) 42 (55.3) agar diffusion test (in terms of inhibitory zone diameter in mm)
Pharyngitis 6 (8) 3 (3.9) was defined as follows: sensitive organisms >- 26 mm, intermedi-
Tonsillitis and ate-sensitivity strains 22-25 mm, resistant organisms -< 21 mm.
pharyngitis 36 (48) 31 (40.8) Agar diffusion test susceptibility to penicillin was defined as
Total 75 (100) 76 (100) follows: sensitive -> 28 mm, intermediate 20-27 mm, resistant
- 19 mm. Susceptibility to cefixime in the agar dilution test (in
terms of minimal inhibitory concentration in mgfl) was defined
Table 3: Causative organisms isolated before the start of thera- as follows: sensitive organisms -< 1 mg/1, intermediate strains 2
py (evaluable patients). mg/1, resistant organisms -> 4 mg/1. The respective MICs of
penicillin were -< 0.25 mg,q for sensitive strains, > 0.25 and -< 8 mg/1
for intermediate-sensitivity organisms, and > 8 rag/1 for resistant
strains.
Primary criteria of outcome were clinical efficacy and bacterio-
Group A logic efficacy of the study drugs. Clinical efficacy was defined in
B-hemolytic streptococci 68 (98.6) 68 (100) terms of change in clinical signs and symptoms after therapy ver-
Group G sus baseline findings. The efficacy end-point was complete elim-
[3-hemolytic streptococci 1 (1.4) ination of the signs and symptoms of infection present before
Total 69 (100) 68 (100) therapy or significant clinical improvement in the absence of
complete elimination of these signs and symptoms.
Bacteriologic efficacy of the study medication was defined as
Table 4: Clinical efficacy (evaluable patients). eradication of the causative organism(s) isolated before treat-
ment. The following organisms were considered causative:
Group A, C, and G [3-hemolytic streptococci, as well as Coryne-
bacterium haemolyticum and Staphylococc~ aureus, but the lat-
ter were not isolated in this study.
Complete elimination The secondary criterion of outcome was study medication safety
of signs and symptoms 65 (86.7) 69 (90.8) and tolerability.
Improvement 7 (9.3) 5 (6.6) Patients treated for the intended period of time were evaluated
Improvement and for efficacy, and all patients receiving at least one dose of their re-
recurrence 1 (1.3) 1 (1.3) spective study medication were evaluated for safety/tolerabitity.
Failure 2 (2.7) 1 (1.3) Results
Total 75 (100) 76 (100)
O n e h u n d r e d sixty patients were enrolled in the trial. Sev-
Recurrence 3-4 weeks enty-five of 80 c e f i x i m e - t r e a t e d patients w e r e evaluable
after end of therapy 6 (8) 8 (10.5) for clinical efficacy. T h r e e children w e r e t r e a t e d several
days longer than the r e q u i r e d 5 days; one patient could no
longer take the study m e d i c a t i o n b e c a u s e the r e a d y - t o - u s e
Patients were assigned a center-based consecutive patient num- suspension h a d t a k e n on a solid consistency; and a n o t h e r
ber as they entered the trial and received the respective medica- patient had d e v e l o p e d Criteria for exclusion. Seventy-six
tion. Based on a computer-generated randomization plan, pa-
of 80 penicillin-treated patients were e v a l u a b t e for clinical
tients were assigned to the treatment groups within each center.
Patients in the cefixime group received 8 mg of cefixime per kg efficacy. T h r e e children h a d p r e s e n t e d criteria for exclu-
body weight formulated as a ready-to-use oleaginous suspension sion, and one p a t i e n t failed to c o m e to the final visit at the
once daily for 5 days, while those of the penicillin group were ad- end of t h e r a p y and, t h e r e f o r e , could n o t be evaluated.
ministered 20,000 IU of penicillin V oral suspension (prepared T h e two t r e a t m e n t groups w e r e c o m p a r a b l e for patient

S 84 Infection 23 (1995) Suppl. 2 © MMV Medizin Verlag GmbH Mfinchen, Mt~nchen 1995
 D. Adam et al.: Cefixime versus Penicillin V for Pharyngitis

demographics (Table 1) and entry diagnoses (Table 2). Table 5: Bacteriologic efficacy (evatuable patients)~
The causative organisms were group A [3-hemolytic strep-
tococci in over 98% of patients, as expected (Table 3).
However, six patients with a positive rapid strep A test at
the screening visit failed to have a positive throat swab.
Elimination 57 (82.6) 60 (88.2)
One child in the cefixime group had a positive culture for
group G streptococci. Persistence il (15.9) 7 (10.3)
The clinical efficacy of both study products was excellent. Change of pathogens 1 (1.4) 1 (1.5)
The clinical response rate (complete elimination of signs Total 69 (.100) 68 (100)
and symptoms or significant clinical improvement) was
96% in the cefixime group and 97.4% in the penicillin Table 6: Adverse events (all patients) with possible causal rela-
group (Table 4 ) . tionship to therapy.
Of the 137 causative organisms isolated before therapy,
82.6% were eradicated in the cef~ime group and 88.2% in
the penicillin group. Different organisms were isolated at
the end of therapy in 1.4% of patients in the cefixime
group and in 1.5% of children in the penicillin group. No. of patients with
Group A streptococci persisted after therapy in 15.9% of adverse events 4 (5.0) 5 (6.3)
cefixime-treated patients and in 10.3% of penicillin-treat- No. of adverse events 5 6
ed children (Table 5).
Recurrence within 3-4 weeks of the end of therapy was Abdominal pain 4 --
seen in six patients (8%) of the cefixime group and in eight Diarrhea 1 1
(10.5%) of the penicillin group. Vomiting -- 2
Both study products were well-tolerated. Four children Urticaria -- 1
(5%) ,of the cefixime group experienced a total of five ad- Pneumonia -- 1
verse events possibly related to the study medication, and
Diaper rash -- 1
five patients (6.3%) of the penicillin group had a total of
six adverse events (Table 6).
well as various other recent clinical trials have shown that
Discussion
modern oral cephalosporins achieve response rates similar
Both national and international medical associations con- to those established for 10-day penicillin V therapy but
tinue to recommend at least 10 days' antibiotic therapy for need not be continued for 10 days [8-10]. Shorter treat-
tonsillopharyngitis [1,11] in order to prevent such late ment courses and, with cefixime in particular, once daily
complications as rheumatic fever and glomerulonephritis. dosing are likely to enhance patient compliance and thus
A n d indeed, rheumatic fever, for instance, with the excep- have the potential to avoid nonresponse due t o p o o r ad-
tion of clusters reported from the USA, has in recent years herence to traditional penicillin therapy, while efficacy is
become a very rare event in most industrialized nations. A similar,
retrospective study conducted in the UK in 3,000 pharyn- Given the extremely low incidence of sequelae, the poten-
gitis patients found no cases of either glomerulonephritis tial risk of the development of such complications cannot
or rheumatic fever. In fact, there has not been a single re- be evaluated definitively on the basis of the currently
port of rheumatic fever from the UK for over 2 decades available studies. However, there was no case of either
[12]. No reliable epidemiological data are available on the rheumatic fever or glomerulonephritis in the 4-week fol-
incidence of these complications in Germany [13]. low-up periods of the two cefixime studies available to
The present cefixime ready-to-use suspension study as date.

Zusammenfassung: 5 Tage CefLxim zur Behandlung der bakte-
riellen Pharyngitis und/oder Tonsillitis: Vergleich mit 10 Tagen
Penicillin V. Im Rahmen einer offenen, randomisierten, kon-
trollierten Multizenterstudie wurden 160 Kinder mit Pharyngi-
tis und/oder Tonsillitis entweder mit 8 mg Cefixim/kg KOrper-
gewicht einmal t/iglich 5 Tage oder mit 20 000 IE Penicillin V/kg
K6rpergewicht dreimal t~iglich10 Tage lang behandetti Die Be-
urteilung der klinischen Wirksamkeit war bei 51 K!ndern mOg-
lich. In der Cefixim-Gruppe wurden 65 Kinder (86,7%) geheilt,
bei sicben Kindern (9,3%) trat eine erhebliche Besserung ein,
bei einem Kind (1,3%) kam es zu einem Rezidiv, bei zwei Kin-
dern (2,7%) war die Behandlung erfolglos. Unter Behandlung
mit Penicillin V trat in 69 F~illen (90,8%) Heilung ein, in ftinf
F/illen (6,6%) Besserung, in einem Fall (1,3%) trat ein Rezidiv
auf, in einem Fall' (1,3%) wurde die Behandlung als effolglos
beurteilt. Bei 57 (82,6%) der mit Cefixim und bei 60 (88,2%)
der mit Penicillin V behandelten Kinder wurden die ursprting-
lichen Erreger eliminiert. 3-4 Wochen nach Behandlungsende
wurden in der Cefixim-Gruppe sechs und in der Penicillin V-
Gruppe acht Rezidive festgestetlt. Bei vier der mit Cefixim und
fiinf der mit Penicillin V behandelten Kinder wurden Neben-
wirkungen beobachtet, die m6glicherweise auf die medika-
ment6se Therapie zurtickzuftthren sind.

Infection23 (1995) Suppl. 2 © MMV MedizinVerlag GmbH Mttnchen,MUnchen1995 S 85

D. A d a m et al.: Cefixime versus Penicillin V for Pharyngitis
References
1. Empfehlungen der Deutschen Gesellschaft fiir Piidiatrische Infek-
tiologie (DGPI): Antibiotikatherapie der A-Streptokokken Tonsil-
lopharyngitis. Pfidiatr. Prax. 44 (1992) 256-258.
2. Brook, I.: The role of S lactamase producing bacteria in the persis-
tence of streptococcal tonsillar infection. Rev. Infect. Dis. 6 (1984)
601.-607.
3. Soussy, C. J., Meyran, M., Duval, J.: Comportement antibact4rien du
c6fixime. Presse M~d. 18 (1989) 1546-1550.
4. Sanders, C. C.: t3-Lactamase stability and in vitro activity of oral
cephalosporins against strains possessing welI-characterized mech-
anisms of resistance. Antimicrob. Agents Chemother. 33 (1989)
1313-1317.
5. B6gu6, P., Garab6dian, N., Quinet, B., Baron, S.: Diffusion amygda-
lienne du c6fixime chez l'enfant. Presse M6d. 18 (1989) 1593-1595.
6. Block, S. L., Hedrick, J. A., Tyler, R. D.: Comparative study of the
effectiveness of cefixime and penicillin V for the treatment of strep-
tococcal pharyngitis in children and adolescents. Pediatr. Infect. Dis.
J. 11 (1992) 919-925.
7. Adam, D., Cefixlm Studiengruppe, Hostalek, U.: Wirksamkeit und
Vertr~iglichkeit yon Cefixim im Vergleich zu Penicillin V bei bakte-
rieller Pharyngitis und Tonsillitis bei Kindern. Klin. P~diatr. 206
(1994) 26-29.
Q&A
Q. H a v e y o u f o u n d in y o u r c o u n t r y t h a t t h e r e is an increas-
ing r a t e o f g r o u p A s t r e p t o c o c c a l p h a r y n g i t i s ?
A . I d o n ' t t h i n k so. I w o u l d s a y t h a t d o c t o r s a r e l o o k i n g
m o r e f o r c u l t u r e s n o w , t h e y a r e b e t t e r t r a i n e d , so it is o n -
ly a v i r t u a l e n h a n c e m e n t of t h e r a t e o f positivity.
N 86
8. Peyramond, D., Tigaud, S., Bremard-Oury, C., Scheimberg, A.: Mul-
ticenter comparative trial of cefixime and phenoxymethylpenicillin
for group A [3-hemolytic streptococcal tonsillitis. Curr. Ther. Res. 55
(Suppl. A) (1.994) 14-21.
9. Portier, H., Chavanet, P., Gouyon, J. B., Guetat, F.: Five day treat-
ment of pharyngotonsillitis with cefpodoxime proxetil. J. Antimi-
crob. Chemother. 26 (Suppl. E) (1990) 79-85.
10. Pichichero, M. E., Gooch, W. M., Rodriquez, W., Blumer, J. L.,
Aronoff, S. C., Jacobs, R. F., Musser, J. M.: Effective short-course
treatment of acute group A 13-hemolytic streptococcal tonsillo-
pharyngitis. Arch. Pediatr. Adolesc. Med. 148 (1994) 1053-1060.
i1. Shulman, S. T., Amren, D. P., Bisno, A. L., Dajani, A. S., Duraek, D.
T., Gerber, M. A., Kaplan, E. L., Millard H. D., Sanders W. E.,
Schwartz R. H., Watanaknnakorn Ch.: Prevention of rheumatic fe-
ver. Circulation 70 (1984) 1118A-1122A.
12. Davey, P.: Assessing the cost-effectiveness of antibiotic treatment of
pharyngitis and acute otitis media. Curr. Ther. Res. 55 (Suppl. A)
(1994) 2-1,3.
13. Pannenbecker, J.: Welche Inzidenz hat das akute rheumatische Fie-
ber in Deutschland? Fortschr. Antimikrob. Antineoplast. Chemo-
ther, 12 (1993) 517-520,
Q. I h a v e a q u e s t i o n a b o u t t h e r e c u r r e n c e . W e r e t h e r e c u r -
r e n c e s d e p e n d e n t o n t h e p e r s i s t e n c e o f [3-hemolytic s t r e p -
t o c o c c i a f t e r t r e a t m e n t ? T h a t is, if t h e o r g a n i s m p e r s i s t e d ,
are those the ones that accounted for the recurrences 3
weeks later?
A . Yes. It was t h e s a m e strain, t h e s a m e type.
Infection 23 (1995) Suppl. 2 © MMV Medizin Verlag GmbH Miinchen, Miiuchen 1995