Cefaclor vs Amoxicillin in the Treatment of

Acute, Recurrent, and Chronic Sinusitis

Werner Huck, M(ASCP); Barbara D. Reed, MD, MSPH; Richard W. Nielsen, MD; Robert T. Ferguson, MD;
Dean W. Gray, MD; Glen K. Lund, MD; Dean H. ZoBell, MD; Mary Beth Moster

Background: The treatment of acute, recurrent, and chronic sinusitis remains

controversial because of the presence of a wide variety of aerobic and anaerobic
bacteria in the sinuses.
Design: This double-blind, randomized trial compared cefaclor with amoxicillin in
the treatment of acute, recurrent, and chronic maxillary sinusitis using clinical
evaluation, roentgenography, and microbiologic evaluation of antral aspirates.
Setting: Outpatient office of five otorhinolaryngologists in Salt Lake City, Utah.
Patients: One hundred eight adult patients with acute, recurrent, or chronic
maxillary sinusitis.
Intervention: Oral treatment with cefaclor (500 mg) twice daily or amoxicillin (500
mg) three times daily for 10 days.
Main Outcome Measure: Clinical response to treatment with cefaclor vs
amoxicillin.

Results: Fifty-six patients with acute sinusitis, 25 with recurrent sinusitis, and 15
with chronic sinusitis were evaluable. Although multiple organisms were common
in each group, patients with acute sinusitis were more likely to have Haemophilus
influenzae or Streptococcus pneumoniae, and patients with recurrent or chronic
sinusitis were more likely to have anaerobes in sinus aspirate. Whether treated with
cefaclor or amoxicillin, clinical improvement occurred in 86% of patients with
acute sinusitis and 56% of patients with recurrent sinusitis. Patients with chronic
sinusitis were too few to allow statistical analysis of the differences in outcome
between them and patients with recurrent or acute sinusitis. Resistance of the
cultured organisms to the study drug used was unrelated to treatment outcome.
Conclusions: The rate of clinical improvement was high in patients with acute
sinusitis but was less favorable in those with recurrent and chronic disease
regardless of the study drug used. The susceptibility of organisms isolated to the
study drugs was unrelated to outcome. (Arch Fam Med. 1993;2:497-503).

Sinusitisis a common problem in outpatient medicine and may be difficult to

recognize and treat. Untreated, the infection may result in continuing morbidity and
may progress to chronic sinusitis, ocular infections, and intracranial
complications.1-2 Hence, recognition of the disorder and prompt treatment with an
effective regimen are desired. Various factors may be related to the response to
treatment and the persistence of infection, such as anatomic abnormalities
(including nasal polyps, septal deviation, spur formation, and turbinate
hypertrophy), abnormal nasal glandular secretions,allergies, and the prior use of
antibiotics. However, the presence ofpathogenie bacteria in the sinus cavities has
been considered an important component of this problem; hence, the choice and
efficacy of various antimicrobial agents in the treatment regimen have been studied.
The preferred antimicrobial treatment for sinusitis remains controversial. Although
the most common bacterial causes of acute sinusitis are Haemophilus influenzae
and Streptococcus pneumoniae, patients, particularly those with recurrent or
chronic sinusitis, may harbor a wide variety of pathogens, including anaerobes and
organisms that produce a ß-lactamase enzyme. Susceptibilities of these organisms
to various antimicrobials differ greatly; therefore, the choice of the most appropriate
antibiotic therapy remains a challenge. Amoxicillin has traditionally been the drug
of choice in treatment of acute sinusitis because of its antibacterial activity against
most microbial agents found and its low cost. Despite the lack of US Food and Drug
Administration approval for an indication of sinusitis, cefaclor is commonly used,
primarily because of its enhanced spectrum of antibacterial coverage and greater
activity against ß-lactamase-producing organisms, including H influenzae,
Moraxella catarrhalis, and Staphylococcus aureus, than other cephalosporins. This
greater activity occurs despite hydrolysis of this antibiotic by ß-lactamase enzymes.
Furthermore, cefaclor concentrations in the maxillary sinus mucous membranes
after a 500 mg dose exceed the minimum inhibitory concentrations of most aerobic
isolates commonly associated with sinusitis, supporting the use of this antimicrobial
in sinusitis. The present study included the evaluation of the bacteriologie features
and antimicrobial susceptibilities of sinus fluid aspirates from patients with acute,
recurrent, or chronic sinusitis and compared the efficacy of two commonly used
antibiotics, amoxicillin and cefaclor, for the treatment of acute, recurrent, and
chronic sinusitis.

PATIENTS AND METHODS

Patients with acute, recurrent, and chronic maxillary sinusitis were enrolled in this
randomized, double-blind study evaluating the efficacy of a 10-day course of oral
therapy with cefaclor compared with that of amoxicillin. Five boardcertified
otolaryngologists at the Ear, Nose, and Throat Center of Salt Lake City, Utah,
evaluated patients in this study between November 1985 and June 1987.
PATIENT POPULATION
Eligible patients were at least 15 years old; presented with symptoms of acute,
recurrent, or chronic maxillary sinusitis (facial pain and/or purulent nasal
discharge); and had a sinus roentgenogram consistent with maxillary sinusitis.
Excluded were patients with hepatic or renal disease, any condition that could
preclude evaluation of response to therapy, a necessity for other systemic antibiotics
between the pretherapy and posttherapy evaluations, hypersensitivity to
cephalosporins or penicillins, an inability to return for follow-up examinations, and
a history of successful or suppressive antimicrobial therapy for the sinus infection
preceding the pretherapy evaluation. Pregnant patients were also excluded.
Informed consent was obtained from each patient enrolled.
STUDY PROTOCOL
Patients were interviewed by an otolaryngologist and by the study coordinator at
the center, and the diagnosis of sinusitis was made based on symptoms, signs, and
roentgenographic findings. Roentgenographic demonstration (Waters view) of air-
fluid levels, opacity, and/or mucosal thickening at the lateral angle of the sinus was
considered to be consistent with the diagnosis of sinusitis. The chronicity of the
infection was defined as follows: for acute sinusitis, sinusitis with symptoms of
fewer than 14 days duration with no previous episodes in the last year; for recurrent
sinusitis, sinusitis accompanied by more than one episode per year of acute sinusitis
with clinical improvement between episodes; chronic sinusitis, nonresolving sinus
disease. All patients underwent antral puncture to obtain fluid for microbiologie
testing. After administration of local anesthesia and disinfection of the anterior
nares, puncture and aspiration were performed through the medial wall of the
antrum. Fluid, if present, was aspirated with a 5-mL syringe. If no fluid was
obtained, the sinus was irrigated with up to 2 mL of sterile, nonbacteriostatic saline.
Material obtained was immediately injected into a transport system suitable for
conveyance of anaerobic or facultative bacteria (BBL PortaCul, BBL Microbiology
Systems, Cockeysville, Md) and delivered within 4 hours of collection to a central
laboratory (Advanced Clinical Microbiology/Research, Salt Lake City, Utah).
Patients were randomly assigned to receive either cefaclor (500 mg) twice daily or
amoxicillin (500 mg) three times daily, each to be taken for 10 days. The twice-
daily dosing regimen for cefaclor was used because of the compliance advantages
of this schedule compared with dosing three times daily and the success and US
Food and Drug Administration approval of this regimen in other upper respiratory
bacterial infections such as otitis media and pharyngitis. To maintain blinding,
drugs and placebo were placed in identical capsules and given to patients in
identical bottles of 10 capsules each. The bottles were labeled "morning,"
"afternoon," and "evening." Placebo capsules were in the "afternoon" bottle for the
cefaclor group. Patients were reevaluated at two follow-up visits. The end-of-
therapy visit took place 0 hours through 48 hours after completion of therapy. The
posttherapy visit took place 6 days through 8 days after the end of therapy and
included roentgenography of the sinuses to assess improvement or recurrence of
disease.
MICROBIOLOGIC TESTING
For isolation of aerobic and facultative bacteria, 100 µL of aspirate or ìmgant was
inoculated onto Columbia sheep blood agar (BBL Microbiology Systems), onto
peptic digest agar for growth of Haemophilus species (MicroBio, Mesa, Ariz), and
into thioglycollate broth (BBL Microbiology Systems). The cultures were then
incubated at 37CC in an environment of 3% to 5% carbon dioxide for a maximum
of 5 days. For isolation of anaerobic organisms, 100 µL of sample was inoculated
onto prereduced Centers for Disease Control and Prevention anaerobic blood agar
(BBL Microbiology Systems) and incubated for up to 7 days at 37°C in an anaerobic
jar (Gas Pak, BBL Microbiology Systems). Anaerobic cultures were not examined
until after the first 48 hours of incubation to optimize recovery of potential oxygen-
labile anaerobes. A hypertonic broth procedure was used to maximize the recovery
of any atypical cell-wall deficient forms. Gram's stain was used to assess presence,
quantity, and type of bacteria as well as inflammatory cells. Pathogens were
identified using standard methods, and aerobic and facultative bacteria were tested
for susceptibility to cefaclor (cephalothin disk) and amoxicillin (ampicillin disk)
using the BauerKirby disk-diffusion test, according to guidelines of the National
Committee for Clinical Laboratory Standards.
EFFICACY ANALYSIS
Clinical response after therapy was assessed at each of the two follow-up visits for
patients with acute, recurrent, and chronic sinusitis. To qualify for the efficacy
analysis, patients were required to have a pretherapy roentgenogram positive for
sinusitis and a pretherapy sinus aspirate culture and to have complied with a return
visit for evaluation of symptomatic response to therapy. Patients who received
fewer than 5 days of therapy or who failed to attend the end-of-therapy visit were
considered unevaluable. The clinical responses were categorized by the physician
as improvement, relapse, or failure. Improvement was indicated by an end-of-
therapy clinical examination revealing the patient's signs and symptoms had
improved or resolved during therapy, relapse was indicated by the presence of signs
and symptoms that recurred by the end of therapy clinical evaluation, and failure
was indicated by obvious therapeutic failure by clinical examination at any time
during therapy. The study protocol did not include second antral aspirations after
therapy.
SAFETY ANALYSIS
All patients enrolled in the study who completed at least one follow-up visit were
included in the assessment of adverse events encountered any time during the study.
ANALYSIS OF DATA Frequency distributions of demographic characteristics,
symptoms, and historical information on the participants as well as microbiologie
results were calculated. Chisquare analysis of the associations between clinical
outcome (improvement, relapse, and failure) and the historical and microbiologie
findings were calculated. Odds ratios (ORs) and 95% confidence intervals were
determined when appropriate

RESULT
Between November 1985 andJune 1987,108 patients were enrolled in the study. Of
these, 54 received cefaclor and 54 received amoxicillin. Patients ranged in age from
16 to 73 years (mean age overall, 38.4 years; in the cefaclor-treated group, 35.3
years; and in the amoxicillin-treated group, 41.5 years), and 50 (46%) were male
(28 [52%] of those in the amoxicillin group and 22 [41%] of those treated with
cefaclor). Twenty eight (57%) of 49 evaluable cefaclor-treated patients and 28
(60%) of 47 évaluable amoxicillin-treated patients had acute sinusitis; 16 (33%) of
49 patients and nine (19%) of 47 patients, respectively, had recurrent sinusitis; and
five (10%) of 49 patients and 10 (21%) of 47 patients, respectively, had chronic
sinusitis. AU évaluable cefaclor-treated patients took the medication 10 days, as did
44 (94%) of 47 of those treated with amoxicillin (the other patients in the
amoxicillin treatment group completed 5 to 9 days of therapy).
EFFICACY ANALYSIS
Of the 108 enrolled patients, 49 (90.7%) of 54 cefaclortreated patients and 47
(87.0%) of 54 amoxicillin-treated patients qualified for efficacy analysis and were
considered évaluable. Reasons for disqualification from the efficacy analysis
included: no pretherapy roentgenogram (one amoxicillin-treated patient), a
pretherapy roentgenogram negative for sinusitis (one patient in each treatment
group), no pretherapy culture (one cefaclor-treated patient), and an assessment of
"unable to evaluate" for symptomatic response (three cefaclor-treated patients and
five amoxicillintreated patients). Patients with sinus aspirate or lavage samples
yielding one or more of 35 species of organisms included 43 (88%) of the 49
évaluable patients in the cefaclor group and 45 (96%) of 47 evaluable patients in
the amoxicillin group. Of the 56 évaluable patients with acute sinusitis, the most
prevalent organisms cultured were Streptococcus pneumoniae (18 patients [32%])
and H influenzae (13 patients [23%]) (Table I). Of the 21 patients with only one
organism isolated, S pneumoniae was isolated in eight (38%) and H influenzae was
isolated in two (10%). As shown in Table 1, no predominant pathogens were found
in patients with recurrent or chronic sinusitis, although the percentage of patients
with anaerobic isolates tended to be higher than in patients with acute disease (30%
compared with 16%; odds ratio, 2.24; P=.08) (Tables 1 and 2). In only one patient
was an anaerobe the only organism isolated. In patients with recurrent and chronic
disease, isolation of S. pneumoniae was unusual, occurring in two (8%) of 25
patients with recurrent disease and in none with chronic disease. Similarly, H
influenzae diminished in prevalence in patients with chronic disease. The
prevalence of multiple organisms found on culture was high but did not differ
significantly between those with acute, recurrent, or chronic sinusitis (Table 1).
Antimicrobial susceptibility testing was performed on aerobic isolates only. Despite
a higher prevalence of antimicrobial resistance among pathogens isolated from
patients in the amoxicillin group than from patients in the cefaclor group (26 [55%]
of 47 compared with five [10%] of 49; P=.0001), resistance was not associated with
poorer clinical outcomes. Furthermore, although 54 (61%) of 88 patients with
positive cultures were infected with multiple types of bacteria (Table 1), this was
not related to clinical outcome. The response to therapy was consistently better in
patients with acute sinusitis than in patients with recurrent and chronic sinusitis,
regardless of the presence of multiple or single isolates. Although anaerobes were
present in combination with aerobic organisms in 20 patients and tended to be more
common in recurrent and chronic cases, clinical outcome was not related to their
presence in the cefaclor or amoxicillin treatment groups, nor to their presence in the
acute, recurrent, or chronic sinusitis groups. Of the 96 évaluable patients, 67 (70%)
improved, two (2%) relapsed, and 27 (28%) failed to respond to therapy.
Stratification by chronicity is summarized in Table 2. As the chronicity of infection
increased, the percentage of patients who improved after therapy decreased in both
treatment groups. A statistically significant difference (P.20). Of 27 patients
classified as clinical failures after treatment, five (19%) showed improvement
roentgenographically, and 22 (81%) demonstrated either no improvement or
showed worsening on follow-up roentgenography.
SAFETY ANALYSIS
All 108 patients were included in the safety analysis. Adverse events during the
study period occurred in two (4%) of 54 patients treated with cefaclor (both patients
had vaginitis; neither patient discontinued therapy because of the event). In the
amoxicillin group, five (9%) of 54 patients had adverse events. These included
vaginitis (one patient), epistaxis (one patient), diarrhea and vaginitis (one patient),
edema (one patient), and herpes simplex (one patient). Symptoms resolved in the
patient who discontinued the study drug because of diarrhea and vaginitis.

COMMENT
Study of the efficacy of treatment in acute, recurrent, and chronic sinusitis remains
difficult because of the difficulty of diagnosis, the invasiveness of tests used to
document organisms present, and the coexistence of numerous factors that may
affect the risk of infection and resolution, such as anatomic differences, allergies,
exposure to irritants and toxins, and concomitant use of other medications.1
However, improved recognition of the types, numbers, and resistances of the
organisms present in the sinus cavities and the association or lack of association
between these findings and clinical outcome using different treatment modalities is
needed if improved treatment recommendations are to be developed. This study
compared the clinical efficacy of two commonly used antibiotics for the treatment
of sinusitis, cefaclor and amoxicillin, in conjunction with a comprehensive
evaluation of the aerobic and anaerobic bacteriologie status of the sinus aspirate to
assess these relationships. The most common bacterial causes of acute sinusitis, as
demonstrated in this study and others, are H influenzae and S pneumoniae.
However, 19 (34%) of 56 patients had other organisms present, including M
catarrhalis, S aureus, and others (Table 1). Several factors may be present that could
alter the probability of eradication of the infection, such as the presence of anaerobic
bacteria, ß-lactamase-producing organisms, concurrent infection with multiple
bacterial types, and antibiotic sensitivities of the bacteria present. Although these
findings may be more common in recurrent and chronic infections, they may also
be seen in acute sinusitis, and the effect on clinical outcome has not been well
characterized. In this study, the clinical outcome rate for patients with acute sinusitis
was comparable to those of other investigators. Wald et al found virtually identical
efficacy rates for cefaclor and amoxicillin in pediatrie patients with acute disease.
In our study, patients with recurrent or chronic sinusitis exhibited poor clinical
response rates regardless of study drug used. The effect on clinical outcome of the
presence of anaerobic organisms, ß-lactamase-producing organisms, multiple
concurrent organisms, and susceptibilities of the organisms to the study drugs will
be discussed.

ANAEROBIC ORGANISMS
In both adults and children, anaerobic bacteria have been found in approximately
10% of cases of acute sinusitis and in 28% to 100% of patients with chronically
inflamed sinuses. Studies using sensitive techniques for the identification of
anaerobes suggest polymicrobial infections are common, with approximately two
anaerobes and one aerobe isolated per patient evaluated, although anaerobes may
be the only isolate in as many as half of the patients. Su et al found that the presence
of anaerobes in the sinus fluid distinguished patients with chronic sinusitis from
controls, while the presence of aerobes was less discriminating. Furthermore,
anaerobes commonly produce ß-lactamase, suggesting antimicrobial resistance
may be a more common factor in these persistent cases. In the present study,
aspirates from patients with recurrent and chronic disease were more likely to
contain anaerobes and less likely to yield S pneumoniae than were those from
patients with acute disease. The response to treatment was not significantly
different between those with mixed anaerobic/aerobic infections and those without
anaerobic infection. Furthermore, recurrence rates in each clinical group (acute,
recurrent, and chronic sinusitis) did not differ if anaerobes were present or absent.
However, neither cefaclor nor amoxicillin covers anaerobic organisms well. Hence,
further study is needed to assess the role of these organisms in persistent disease.
RESISTANCE OF THE ORGANISM(S) TO THE ANTIBIOTIC USED
Isolated organisms were more likely to be resistant to amoxicillin (26 [55%] of 47
patients) than to cefaclor (five [10] of 49 patients), regardless of whether the patient
had acute, recurrent, or chronic sinusitis. Nevertheless, no significant difference in
clinical response to therapy was found between the two study drugs, which were
used in 10-day courses. Twenty-two (33%) of 67 patients responding to therapy had
cultures yielding isolates resistant to their study drug. Although several
investigators have found an association between clinical efficacy and the in vitro
susceptibility of pathogens isolated, the findings of this study and others illustrate
that clinical improvement is often not directly related to the in vitro susceptibility
found. This may reflect the role of other factors associated with sinusitis, such as
anatomic abnormalities, allergies, immunologie abnormalities. The therapeutic
effect of antral puncture is also documented, and may contribute to the response
score independent ofantibiotic choice.

ß-LACTAMASE-PRODUCING ORGANISMS
Organisms producing ß-lactamase are reported with increasing frequency, with
18% to 42% of H influenzae, organisms and most M catarrhalis organisms
producing this type of enzyme. Two previous reports suggest that 20% to 26% of
cases of chronic sinusitis may involve ß-lactamase-producing organisms. Such
organisms may become more prevalent after treatment with other antibiotics. In the
present study, seven (35%) of 20 of H influenzae isolates produced ß-lactamase
enzyme, and all isolates ofM catarrhalis produced ß-lactamase. Theoretically, the
presence of these organisms at the site of infection could have an inhibitory effect
on ß-lactamase-susceptible antibiotics, which could be inactivated by the enzyme.
Previous studies have shown an increased resistance ofgroup A ß-hemolytic
Streptococcus to penicillin in the presence of ß-lactamase-producing organisms.
Although cefaclor is more resistant than amoxicillin to ß-lactamase degradation, the
lack of difference in clinical outcome between cefaclor and amoxicillin may reflect
a therapeutic effect of antral puncture. The efficacy of cefaclor compared with
amoxicillin in patients without such a procedure is less clear

MULTIPLE ORGANISMS
Previous studies suggest that approximately one third of sinus infections are caused
by multiple organisms, regardless of the chronicity of the infection. In the present
study, approximately 63 aspirates (58.3%) were positive for more than one
organism regardless of the chronicity of the infection. Improvement rates did not
significantly differ between patients with acute sinusitis who received cefaclor and
those who received amoxicillin, even when multiple organisms were present.
Patients presenting with recurrent disease, however, showed higher favorable
response rates to therapy when only one pathogen was isolated from the sinus
aspirate. This was true irrespective of study drug used. Further study is needed to
assess whether the presence of specific organisms, as opposed to numbers of
organisms, is responsible for this finding.

LIMITATIONS
This study demonstrated similar clinical outcomes in patients with acute sinusitis
regardless of whether amoxicillin or cefaclor was used. However, the antral
puncture performed at the initial visit may have contributed to this outcome.
Because antral puncture is not routinely recommended for patients with acute
sinusitis, outcome may vary in patients who do not undergo this procedure.
Furthermore, not all patients with sinusitis treated at the study site during the study
period were enrolled. Reasons for nonenrollment included lack of physician or
patient time for participation (estimated as 25% of patients not enrolled) and patient
refusal (estimated as 75% of patients not enrolled). Whether patients who chose to
participate differed in severity of disease from those who declined to participate or
those who did not meet inclusion criteria is unknown. This, and enrollment at a
specialty, referral practice, would bias the study in the direction of more severe
cases than may be the usual case in a primary-care setting. The proportion of
patients with acute sinusitis who improved clinically after treatment with cefaclor
or amoxicillin was high compared with those with recurrent or chronic sinusitis.
The presence of multiple types of organisms, ß-lactamase-producing organisms,
and resistance to the study drugs were not statistically associated with clinical
outcome in response to treatment. The response of sinusitis to antimicrobial
treatment involves more than susceptibility of the pathogens to the antibiotic
therapy used. Further study of treatment protocols for sinusitis is needed to assess
these other factors.