King Khalid National Guard Hospital
Pharmacy and Therapeutic Committee
Drug Evaluation
Drug Name: SPECTRACEF®
Requestor
1. Manufacture
Generic Name
Dr. Ahmad Abouzaid
Pharmaceutical, Inc., Lake Forest, IL
Cefditoren Pivoxil 200 mg tab.
2. Pharmacology-Therapeutic Class:
Cefditoren pivoxil is a semi-synthetic third generation cephalosporin antibiotic for oral
administration. It is a prodrug which is hydrolyzed by esterases during absorption, and the
drug is distributed in the circulating blood as active cefditoren.
3. Related Agents Already on Formulary:
 Penicillin VK.
 Cefuroxime.
 Clarithromycin.
 Amoxicillin-clavulanate.
 Cefpodoxime.
 Cefuroxime.
 Cefadroxil.
4. FDA Approved Indication:
 Pharyngitis / Tonsillitis.
 Acute Exacerbation of Chronic Bronchitis.
 Acute Maxillary Sinusitis.
 Community-Acquired Pneumonia.
 Uncomplicated Skin and Skin-Structure Infections.
5. Availability in the Kingdom:
Yes
No
6. Rationale for Formulary Addition:
1. Cefditoren gave the lowest MICs, a time–kill study of 12 pneumococcal strains with
varying drug susceptibilities showed that cefditoren, at 2 x MIC, gave 99% killing of all
strains after 12 h, with 99.9% killing after 24 h. Other cephalosporin gave similar kill
kinetics but at higher concentrations. At the MIC, had the lowest frequency of
spontaneous mutants compared with other drugs.
2. Objective Literature Evaluation:
Study (1)
Pharyngitis/Tonsillitis
a) The efficacy of cefditoren in the management of streptococcal pharyngitis was evaluated
in two double-blind, multicenter trials. Together, these trials involved 1011 adults with a
positive rapid antigen detection test for group a streptococci, complaints of sore throat,
and one or more additional symptoms (pharyngeal or tonsillar erythema or exudates,
cervical lymph node tenderness, or fever). Subjects were randomized to receive 10 days
of treatment with either oral cefditoren 200 mg twice/day or oral penicillin VK 250 mg 4
times/day. Clinical and microbiologic cure rates were evaluated at 4-7 days after the start
of therapy and 19-25 days after completion of therapy. Cure rates were determined by
routine bacterial culture and assessment of clinical signs and symptoms.Cefditoren was
superior to penicillin VK in bacteriologic response rates. After 4-7 days of therapy, the
bacteriologic response rate was 90% (329 of 364 patients) for the cefditoren group,
versus 83% (301 of 364 patients) for the penicillin VK group. After 19-25 days of therapy
the bacteriologic response rate was 85% (301 of 356 patients) for the cefditoren group
versus 77% (269 of 351 patients) for the penicillin VK group. All comparisons were
statistically significant (p<0.05). Adverse effects were mild to moderate in intensity, and
most required no action. The most frequently reported adverse events were diarrhea and
abdominal pain. Fewer than 1% of subjects in each treatment group discontinued
treatment due to adverse events.
b) A double-blind, parallel-group, multicenter study compared the effectiveness of cefditoren
pivoxil and penicillin VK against group A streptococci. Organisms were isolated from
throats of symptomatic patients aged 12 years or older. A total of 503 patients were
randomized to receive 10 days of therapy with either oral cefditoren 200 mg twice/day
(256 patients) or oral penicillin VK 250 mg 4 times/day (247 patients). Patients were
evaluated for the presence of streptococci at presentation (visit 1), and at two
convalescent visits, one at 14-17 days (visit 2) and the other at 29-35 days (visit 3) after
the start of treatment. Patients with pretreatment signs and symptoms of infection that
resolved or improved without additional antibiotic therapy were classified as clinically
cured. Compliance with the assigned regimen was assessed at visit 2 by pill count and
was defined as consumption of 80% of tablets. The researchers excluded 175 patients
from the study due to culture-negative S. pyogenes (106), noncompliance with therapy
(27), consumption of other antibiotics (17), or unavailable data at visit 2 or 3 (25).At the
second visit, S. pyogenes had been eradicated from 153 (95%) of 161 patients in the
cefditoren group versus 136 (81%) of 167 patients in the penicillin VK group (p<0.001). At
the third visit, S. pyogenes had been eradicated from 149 (93%) of 161 patients in the
cefditoren group versus 141 (84%) of 167 patients in the penicillin VK group (p=0.024).
Cefditoren was superior to penicillin VK in the microbiologic eradication rates at both the
second and third visits, 91% (146 of 161 patients) versus 77% (128 of 167 patients,
p<0.001). Finally, a higher proportion of patients in the cefditoren group was classified as
clinically cured at visits 2 and 3. Nonetheless, the differences were not statistically
significant.
c) The efficacy of cefditoren in the management of streptococcal pharyngitis in children was
evaluated in a randomized, investigator-blind, multicenter, comparative trial. The trial
involved 503 children aged 3-11 years with symptomatic pharyngitis and/or tonsillitis, and
both a positive rapid antigen immunoassay and a positive culture for S. pyogenes. All
patients received 10 days of treatment with either cefditoren 3 mg/kg suspension
twice/day or penicillin VK 15 mg/kg suspension 3 times/day. Clinical and microbiologic
cure rates were determined at 4-7 days and at 19-25 days after therapy was completed,
based on signs and symptoms and routine bacterial cultures for S. pyogenes. At 4-7 days
after completion of therapy, clinical cure rates (defined as the percentage of patients
whose pretreatment signs and symptoms of infection resolved or improved without
requirement for additional therapy) were 93% for the cefditoren treatment arm (192 of 206
patients) versus 84% for the penicillin VK treatment arm (163 of 206 patients) (p<0.01). At
the same time point, pathogen eradication was achieved in 185 (90%) of 205 patients in
the cefditoren group versus 134 (67%) of 200 patients in the penicillin VK group
(p<0.001).At 19-25 days after completion of therapy, clinical cures were reported in 183
(92%) of 198 patients in the cefditoren group versus 137 (77%) of 179 patients in the
penicillin VK group (p<0.001). Pathogen eradication was achieved among 159 (81%) of
197 patients in the cefditoren group versus 108 (57%) of 191 patients in the penicillin VK
group (p<0.001).
Study (2)
Acute Exacerbation of Chronic Bronchitis
a) This is a multicenter study, double-blind randomize trial. The study involved 537 patients
with a history of chronic bronchitis who were randomized to receive a 10-day course of
either cefditoren pivoxil 200 or 400 mg twice/day or oral cefuroxime axetil 250 mg
twice/day. During the study, all drugs that were not antibiotics were allowed, as were
supportive nonpharmacologic measures. However, patients were not allowed to receive
an anticoagulant agent or a systemic corticosteroid in a dosage equivalent to prednisone
10 mg/day. Patients were evaluated at least once between days 3 and 5 of treatment,
within 48 hours after completion of treatment, and again at 7-14 days after completion of
treatment (test-of-cure). Cure was defined as resolution of pretreatment signs and
symptoms of infection, return to preinfection status, or improvement without the need for
additional antimicrobial therapy. Failure was defined as continuing or worsening signs
and symptoms or as improvement with the need for additional antimicrobial therapy after
at least 3 days of treatment. There were no statistically significant differences between
treatment groups with regard to clinical cure rates, resolution or improvement of
symptoms, or pathogen eradication rates. Clinical cure rates at 7-14 days after
completion of treatment were 82%, 86%, and 79% for the cefditoren 200 mg, cefditoren
400 mg, and cefuroxime groups, respectively. Eradication rates for the target pathogens
at 7-14 days after treatment were 73% for the cefditoren 200-mg group, 77% for the
cefditoren 400 mg-group, and 72% for the cefuroxime group. The groups did not differ
significantly in overall frequency of adverse events. Nonetheless, nausea was reported by
7% of subjects in the cefuroxime group versus 1% of those in the cefditoren 200-mg
group (p=0.006). The most commonly reported adverse events for all treatment arms
involved the gastrointestinal tract.
b) Cefditoren was compared with clarithromycin in a double-blind, multicenter study of 743
adult outpatients with acute exacerbation of chronic bronchitis. Subjects were considered
to have chronic bronchitis if they experienced a productive cough on most days for at
least 3 consecutive months in at least 2 consecutive years. Eligible subjects were
randomly assigned to receive a 10-day course of either oral cefditoren 200 or 400 mg
twice/day or clarithromycin 500 mg twice/day. Each patient's clinical status was evaluated
at least once during treatment (between days 3 and 5) and twice after treatment (within
48 hours and then between days 7 and 14 afterward [test-of-cure visit]). No statistically
significant differences emerged among treatment groups. Clinical cure rates at 7-14 days
after completion of treatment were 82%, 78%, and 83% for the cefditoren 200-mg,
cefditoren 400-mg, and clarithromycin 500-mg groups, respectively. During the same time
period, target pathogens were reported as eradicated in 74% of subjects in the cefditoren
200-mg group, 70% of subjects in the cefditoren 400-mg group, and 73% of subjects in
the clarithromycin group. The frequency of adverse effects was 27% for the cefditoren
200-mg group, 31% for the cefditoren 400-mg group, and 35% for the clarithromycin
group. The most commonly reported adverse events with cefditoren were diarrhea,
nausea, and among women, vaginal moniliasis. The most commonly reported adverse
event in the clarithromycin group was taste prevention; this affected 10% of subjects in
the clarithromycin group versus 2% of those in the cefditoren groups (p<0.001).
Cefditoren was associated with a higher frequency of vaginal moniliasis; this was
reported among 9% of women in the cefditoren 400-mg group versus 4% of women in the
clarithromycin group (p value not provided).
Study (3)
Acute Maxillary Sinusitis
A double-blind, multicenter trial compared cefditoren with amoxicillin-clavulanate in the
management of acute maxillary sinusitis. A total of 775 patients with sinus radiograph findings
supportive of acute maxillary sinusitis and signs and symptoms present for at least 7 days but
for no longer than 4 weeks were randomized to receive 10 days of treatment with either oral
cefditoren 200 mg or 400 mg twice/day or oral amoxicillin-clavulanate 875 mg twice/day.
Patients were evaluated within 48 hours after completion of therapy (posttherapy visit) and at
7-14 days after the last dose of study drug (follow-up visit). At the posttherapy visit for the
intent-to-treat analysis, 158 (69%) of 229 patients who had received cefditoren 200 mg were
rated as clinically cured, as were 161 (70%) of 229 patients who had received cefditoren 400
mg. Among the amoxicillin-clavulanate group, 167 (70%) of 240 patients were clinically cured.
At the follow-up visit, clinical cures were reported in 141 (62%) of 229 patients in the
cefditoren 200-mg group, 153 (66%) of 231 patients in the cefditoren 400-mg group, and 156
(65%) of 240 patients in the amoxicillin-clavulanate group. The frequency of adverse events
was 23%, 26%, and 24% for the cefditoren 200-mg, cefditoren 400-mg, and amoxicillinclavulanate groups, respectively. Of note, the frequency of vaginal moniliasis was significantly
lower in the group receiving cefditoren 200 mg than in the group receiving amoxicillinclavulanate (4% vs 11%, p</=0.05). In contrast, the frequency of nausea was significantly
lower in the group receiving amoxicillin-clavulanate than in the group receiving cefditoren 400
mg (2% vs 7%, p</=0.05.) There was no statistically significant difference between treatment
groups in the evaluable or intent-to-treat analysis.
Study (4)
Community-Acquired Pneumonia
Cefditoren was evaluated in a randomized, double-blind, multicenter, comparative trial
involving 851 ambulatory patients with radiologically documented community-acquired
pneumonia. Inclusion criteria were the presence of two or more of the following signs and
symptoms consistent with bacterial pneumonia: chest pain, cough, dyspnea, tachypnea,
cyanosis, purulent sputum production, and auscultatory findings such as rales or evidence of
pulmonary consolidation. In addition, subjects may have had fever or leukocytosis. Subjects
were randomly assigned to receive 14 days of treatment with one of the following three oral
regimens: cefditoren 200 mg twice/day, cefditoren 400 mg twice/day, or cefpodoxime 200 mg
twice/day. All subjects were evaluated at the posttreatment visit (</= 48 hrs after completion
of therapy) and at follow-up (7-14 days after completion of therapy). Microbiologic eradication
rates at both the posttreatment and the follow-up visits were higher for the cefpodoxime group
than for either cefditoren group. At the posttreatment visit, microbiologic eradication had
occurred in 134 (89%) of 151 patients in the cefditoren 200-mg group and 134 (89%) of 149
patients in the cefditoren 400-mg group compared with 134 (96%) of 140 patients in the
cefpodoxime group (p<0.05 for cefditoren 200 mg vs cefpodoxime 200 mg). At the follow-up
visit, microbiologic eradication had occurred in 132 (92%) of 144 patients in the cefpodoxime
group versus 124 (80%) of 155 patients in the cefditoren 200-mg group and 126 (86%) of 147
patients in the cefditoren 400-mg group (p<0.05 for cefditoren 200 mg vs cefpodoxime 200
mg). The frequency of treatment-related adverse effects was 19%, 22%, and 16% for the
cefditoren 200-mg group, cefditoren 400-mg group, and cefpodoxime 200-mg group,
respectively. Of note, the frequency of diarrhea was significantly lower in the cefpodoxime
200-mg group than in the cefditoren 400-mg group (3% vs 8%, p</=0.05). Rates of
discontinuation of therapy due to adverse effects were 4% for the cefditoren 200-mg group,
3% for the cefditoren 400-mg group, and 2% for the cefpodoxime 200-mg group.
Study (5)
Uncomplicated Skin and Skin-Structure Infections
a) Double-blind trial compared cefditoren with cefuroxime in the treatment of uncomplicated
skin and skin-structure infections. This trial involved 857 patients who received 10 days of
treatment with one of three oral regimens: cefditoren 200 mg twice/day, cefditoren 400
mg twice/day, or cefuroxime 250 mg twice/day. Subjects were followed for 7-14 days after
their last dose. Exclusion criteria were diabetes or vascular disease, chronic or underlying
condition at the infection site, wound secondary to thermal injury, and scalp or nail bed
infection. Cellulitis was the most common diagnosis (28% of patients), followed by wound
infection (25%). Staphylococcus aureus was the most reported causative skin pathogen
isolated before treatment, followed by Peptostreptococcus sp. Both cefditoren regimens
were equivalent to cefuroxime in treating uncomplicated skin and skin-structure
infections. Furthermore, cefditoren was well tolerated. Most adverse events were mild to
moderate in intensity and required no action. It should be noted that the frequency of
diarrhea and nausea was statistically significant in favor of cefuroxime (p value not
provided).
b) A double-blind study compared the efficacy of cefditoren with that of cefadroxil in the
treatment of uncomplicated skin and skin-structure infections. Of the study's 828
participants, 25% were diagnosed with cellulites, 24% had wound infections, and 13%
had simple abscess folliculitis. The remainder had other uncomplicated skin infections. All
subjects received 10 days of treatment with one of three oral regimens: cefditoren 200 mg
twice/day, cefditoren 400 mg twice/day, or cefadroxil 500 mg twice/day. Exclusion criteria,
causative organisms, and follow-up were similar to those of the study described above.[38]
Evaluation, consisting of site culture and assessment for the presence of two or more
signs and symptoms, was performed before therapy, after therapy (0-48 hrs after the last
dose), and at follow-up (7-14 days after the last dose). Cefditoren 200 mg twice/day was
superior to cefadroxil 500 mg twice/day in the overall eradication of skin pathogens. The
eradication rate was approximately 90% with both cefditoren dosages versus 81% with
cefadroxil (p<0.05).
7. Major Adverse Reaction:
 Diarrhea 11%-15%, nausea, and vaginal moniliasis.
 SPECTRACEF is contraindicated in patients with carnitine deficiency or inborn errors
of metabolism that may result in clinically significant carnitine deficiency, because use
of SPECTRACEF causes renal excretion of carnitine.
8. Cost Comparison:
Drug
Available Dosage
Forms
Cefuroxime
Clarithromycin
Cost/Treatment/Patient
(SR)
Estimated Cost Year
(SR)
Tablet:125 mg,
250 mg,
500 mg
44.35SR
86.55 SR
94.60 SR
22,175 SR
43,275 SR
47,300 SR
Tablet, film coated:
51.15 SR
25,575 SR
Tablet, chewable: 125,
200, 250, 400
44, 57 SR
22,285 SR
Capsule, as
monohydrate: 500 mg
Tablet, as
monohydrate: 1 g
17.35 SR
8,675 SR
Tab 200mg
203.5 SR
101,750 SR
250 mg, 500 mg
Amoxicillinclavulanate
Cefadroxil
Cefditoren
9. Summary:
Although clinical trials data show the lowest MIC than other drugs and had the lowest
frequency of spontaneous mutants, there is no significant difference between them. In (Study
1.a.) there were no significant differences between groups in the frequency of adverse effects.
The most commonly reported adverse effects with cefditoren and penicillin VK were
associated with the digestive system. These affected 14% patients who received cefditoren
and 11% of patients who received penicillin VK. Eight patients (3%) in each treatment group
withdrew from the study due to adverse effects. The authors concluded that oral cefditoren
administered for 10 days is an acceptable substitute for oral penicillin VK in suitable clinical
situations. In (Study1.b.) the authors concluded that cefditoren was well tolerated and
superior to penicillin in both clinical and microbiologic cure rates. Based on these results,
cefditoren holds promise as a therapeutic agent for managing streptococcal pharyngitis in
children. Nonetheless, cefditoren is not approved by the FDA for children; therefore, its use in
children under 12 years of age cannot be recommended. In (Study 2.a.) according to the
authors, cefditoren was comparable to cefuroxime in the treatment of acute exacerbation of
chronic bronchitis. Thus, cefditoren is an alternative to cefuroxime for this indication. In
(Study 2.b.) in light of these results, cefditoren appears to be comparable to clarithromycin in
the management of acute exacerbation of chronic bronchitis. A positive finding is that the
cefditoren treatment groups had a lower frequency of overall adverse events than the
clarithromycin group. Therefore, cefditoren provides a safe and effective alternative to
clarithromycin for this indication. In (Study 3) the authors concluded that both dosages of
cefditoren were equivalent to amoxicillin-clavulanate in the management of acute maxillary
sinusitis. In (Study 4) the authors concluded that cefditoren provided comparable efficacy to
cefpodoxime in the treatment of community-acquired pneumonia based on clinical cure rates
and eradication of respiratory pathogens. In (Study 5) the authors concluded that cefditoren
was as effective as cefadroxil and cefuroxime in treating clinical signs and symptoms of skin
infections.
In the other hand, prolonged treatment with the cefditoren is not recommended because of
the potential for clinical signs of carnitine deficiency to develop.
So, at this time cefditoren is recommended to remain non-formulary.
10. Recommendations:
 Formulary Status:
Approved
 Deletion From Formulary: None
Not Approved
11. Date Prepared: September 30, 2006
12. Prepared by: Alaa' Baqalaqel
13. Reviewed by:
References:
1. Spangler SK, Jacobs MR, Appelbaum PC. Time-kill studies on susceptibility of nine
penicillin-susceptible and -resistant pneumococci to cefditoren compared with nine other
-lactams. J Antimicrob Chemother 1997;39:141-8.
2. Karlowsky JA, Critchley IA, Draghi DC, Jones ME, Thornsberry C, Sahm DF. Activity of
cefditoren against -lactamase-positive and -negative Haemophilus influenzae and
Moraxella catarrhalis. Diagn Microbiol Infect Dis 2002;42:53-8.
3. Nagate T, Akashi T, Numata K, et al. In vitro and in vivo antibacterial activity and
pharmacokinetics of SC-002 and its derivative, SC-004: new oral cephalosporins.
Chemotherapy 2001;47:157-69.
4. Reinert R, Al-Lahham A, Lutticken R. In vitro activity of cefditoren against clinical isolates
of penicillin-susceptible and penicillin-intermediate strains of Streptococcus pneumoniae
isolated in Germany, 1992-1998. J Antimicrob Chemother 2001;48:279-81.
5. Fuchs PC, Barry AL, Brown SD. Susceptibility of Streptococcus pneumoniae and
Haemophilus influenzae to cefditoren, and provisional interpretive criteria. Diagn Microbiol
Infect Dis 2000;37:265-9.
6. Fernandez-Roblas R, Lopez JC, Ramos JM, Gimeno M, Coronel P, Soriano F. In vitro
activity of cefditoren against clinical isolates of penicillin-susceptible and resistant strains
of Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitides. J
Antimicrob Chemother 1996;37:1038-9.
7. Thornsberry C. Karlowsky JA, Kelly LJ, et al. Comparative activity of cefditoren and other
oral -lactams against nonpneumococcal streptococci. Chemotherapy 2001;47: 332-43.
8. Gooch W, Marsh D, Stickler T, Hunt B. Cefditoren is safe and effective treatment of
streptococcal pharyngitis [abstr]. In: Programs and abstracts of the 40th annual
interscience conference on antimicrobial agents and chemotherapy. Washington, DC:
American Society for Microbiology, 2000:95.
9. Poling T, Agre K, Marsh D, Kidd S, Hunt B. Cefditoren is effective treatment for
streptococcal pharyngitis [abstr]. In: Program and abstracts of the 39th annual
interscience conference on antimicrobial agents and chemotherapy. Washington, DC:
American Society for Microbiology, 1999:714.
10. Kaplan EL, Tucker RM, Poling TL, Marsh D, Chou C. A multicenter comparison of
cefditoren pivoxil and penicillin VK. J Resp Dis 2001;22(suppl 8):60-4.
11. Block SL, Hedrick JA, Hom R. Stickler T, Chou C. Cefditoren vs penicillin for
streptococcal pharyngitis in children [abstr]. In: Program and abstracts of the 41st annual
interscience conference on antimicrobial agents and chemotherapy. Washington, DC:
American Society for Microbiology, 2001:1538.
12. Henry DC, Poling TL, Bettis RB, Hunt BJ, Cyganowski M, Hom RC. A double-blind,
randomized study of cefditoren vs cefuroxime for AECB. J Resp Dis 2001;22(suppl 8):6974.
13. Ramirez JA, Tucker RM, Bettis RB, Cyganowski M, Hunt BJ. Treating acute
exacerbations of chronic bronchitis. J Resp Dis 2001;22(suppl 8):75-80.
14. Bettis R, Agre K, Williamson S, Stickler T, Hunt B. Safety and efficacy of cefditoren in
acute bacterial exacerbation of chronic bronchitis [abstr]. In: Program and abstracts of the
39th annual interscience conference on antimicrobial agents and chemotherapy.
Washington, DC: American Society for Microbiology, 1999:711.
15. Tucker R, Rhudy J, Hom R, Hunt B, Cyganowski M. Safety and efficacy of cefditoren in
acute exacerbation of chronic bronchitis (AECB) [abstr]. In: Programs and abstracts of the
40th annual interscience conference on antimicrobial agents and chemotherapy.
Washington, DC: American Society for Microbiology, 2000:91.
16. Millikan L, Hahn H, Hom R, Hunt B, Kidd S. Cefditoren is safe and effective treatment for
uncomplicated skin and skin structure infections [abstr]. In: Programs and abstracts of the
40th annual interscience conference on antimicrobial agents and chemotherapy.
Washington, DC: American Society for Microbiology, 2000:99.
17. Hebert A, Bucko A, Bell V, Hunt B. Cefditoren is safe and effective in the eradication of
common pathogens in uncomplicated skin and skin structure infections (USSI) [abstr]. In:
Programs and abstracts of the 40th annual interscience conference on antimicrobial
agents and chemotherapy. Washington, DC: American Society for Microbiology,
2000:105.
18. Chow J, Russell M, Volk S, Chou C. Efficacy of cefditoren pivoxil (CDTR) vs amoxicillinclavulanate (AMX-CLV) in acute maxillary sinusitis (AMS) [abstr]. In: Program and
abstracts of the 40th annual interscience conference on antimicrobial agents and
chemotherapy. Washington, DC: American Society for Microbiology, 2000:87.
19. Le Roux J, La Fata J, Volk R, et al. Cefditoren is effective treatment for communityacquired pneumonia in adults [abstr]. In: Program and abstracts of the 41st annual
interscience conference on antimicrobial agents and chemotherapy. Washington, DC:
American Society for Microbiology, 2001:852.
20. Chi JC, ed. Drug topics red book. Montvale, NJ: Medical Economics Company, 2002.