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Cefadroxil in the management of facial cellulitis of odontogenic origin
Cefadroxil in the management of facial cellulitis of odontogenic origin Charles B. Hanna Jr., DMD, Spartanburg, S.C. The objectives of this prospective single-blind trial were to compare the efficacy and safety of cefadroxil, 1 gm/day, and cephalexin, 250 mg four times a day, in the treatment of facial cellulitis of odontogenic origin. One hundred sixteen patients were screened for sensitivity to the assigned antibiotic and then randomly assigned treatment groups. Fifty-eight (100%) of the cefadroxil-treated patients and 57 (98%) of the cephalexin-treated patients were considered cured. Adverse reactions were noted in only two cefadroxil-treated patients and one cephalexin-treated patient. One patient from each group discontinued therapy prematurely; the patient who discontinued cephalexin was the only treatment failure in this study. This study found that cefadroxil administered once a day was therapeutically equivalent to cephalexin given four times a day. (ORAL SURC ORAL MED ORAL PATHOL 1991;71:496-8)
c
efadroxil and cephalexin are first-generation oral cephalosporins with a broad spectrum of activity against gram-positive cocci including staphylococci, group A /3-hemolytic streptococci, group B streptococci, and Streptococcus pneumoniae.lM3The firstgeneration cephalosporins generally have limited activity against gram-negative bacteria. However, cefadroxil has demonstrated in vitro bactericidal activity against Escherichia coli, Klebsiella sp., and Proteus mirabilis.4 The discovery of cefadroxil resulted from chemical manipulations of the aromatic ring common to several of the first-generation cephalosporins. The addition of a para-hydroxyl group on this ring of the cephalexin molecule gave rise to cefadroxil, which demonstrates two significant advantages over its counterparts. Unlike cephalexin and cephradine, absorption of cefadroxil is not affected by food, and its serum half-life is approximately twice that of either of the other two agents-t>5 Plasma levels of cefadroxil are detectable 12 hours after a 500 mg dose,whereas cephalexin and cephradine are undetectable 6 hours after a similar dose. Drug distribution studies have investigated the penetration of cefadroxil into various organs and tissues.Skin blisters are a model for the tissue penetration of anti-infectives. In this model the peak concentrations of cefadroxil were higher (fourfold) and more sustained than those of cephalexin6, 7 Also, tonsillar
7/35/23565 496
tissue levels of cefadroxil were higher than cephalexin (threefold)s and the 4-hour tissue concentration was 10 times abovethe minimum inhibitory concentration for /3-hemolytic streptococci.9 Correspondingly, cefadroxil has shown efficacy in open and controlled clinical trials in the treatment of skin and soft tissue infections, including cellulitis, folliculitis, furunculosis, impetigo, mastitis, pyoderma, and wound.s.‘O,’ ’ Results from once- or twice-daily dosing of cefadroxil were equal to those obtained with a regimen of cephalexin four times daily. Facial cellulitis of odontogenic origin is an infectious processarising from diseasedor necrotic dentition. By definition, it is a purulent inflammation of the loose subcutaneous tissue. The process may arise in bone, soft tissue, or both, and may manifest itself either intraorally or extraorally. Aerobic microbes, particularly streptococci, are the predominant pathogens isolated from culture material from endodontic cellulitis. Obligate anaerobes are seldom isolated.’ * Consequently, oral cephalosporins are good therapeutic agents for use in this indication. Two such agents, cefadroxil and cephalexin, recently were compared for their efficacy and safety in a study of patients with facial cellulitis, and the results are reported here. MATERIAL
AND METHODS
A total of 116 patients were entered into this investigator-blinded, comparative trial of cefadroxil, 1000 mg given once daily, and cephalexin, 250 mg given four times daily, for the treatment of facial cellulitis of odontogenic origin. The diagnosis of facial cellulitis was determined by clinical examination and the
Cefadroxil in endodontic cellulitis
Volume 71 Number 4
presence of intraoral or extraoral swelling. Photographic documentation, both intraoral and extraoral, was made before initiation of this trial and on study days 3 and 5. The infection site was first treated by means of surgical incision and drainage or extraction as needed. An adequate blood level of the assigned antibiotic was established by initiating therapy 12 hours before surgical procedures. Men and women 18 years of age or older were enrolled into this trial. The study protocol was approved by the institutional review board of Spartanburg Regional Medical Center, Spartanburg, S.C., and a stringent informed consent procedure was followed for all study participants. Use of all concomitant medications, with the exception of antibiotics, was permitted to continue. Any such medications were recorded on individual case record forms. Pregnant women and nursing mothers, and patients who had received antibiotic therapy in the previous 2 weeks, were excluded. Cultures from the infection site and sensitivity tests of the primary pathogen cultured were to be completed on day 0, before antibiotic therapy was started. On study days 3 and 5, a culture was to be taken only if infection persisted and culturable exudate was available. Dosing commenced on day 0, 12 hours before day 1 surgery, and continued for 4 days for a total of 5 days of treatment. At the conclusion of the trial the investigator assessedclinical efficacy on a 3point scale: cure, failure, and no change. RESULTS
Both treatment groups were comparable at baseline, as illustrated in Table I, with no statistically significant differences. The initial bacteriologic results for all patients indicated that the primary pathogen was sensitive to the assigned antibiotic. Therefore no patients were excluded from the analysis. The number of cultures available from days 3 and 5 was not sufficient to permit analysis, sothe efficacy assessment was basedsolely on the investigator’s blinded clinical evaluation at the end of treatment. Fifty-eight (100%) of the cefadroxil-treated patients and 57 (98%) of the cephalexin-treated patients were found to be cured. The difference between these two cure rates was not statistically significant (Fisher’s Exact Test, p = 1.O).Approximate binomial onesided 95% confidence limits were computed for the percentage of cures in each treatment group, with 1.7% as an estimate of the standard deviation of both percentages.The lower limit of the percentage cured by cefadroxil therapy was 97.2%, whereas that of cephalexin therapy was 95.5%. The sole failure in this study was in a 64-year-old woman who discontinued cephalexin after 36 hours of therapy. During the trial she had a mild episode of
Table
497
1.Summary of patient demographics Cefadroxil
No. of patients
Cephalexin
p value*
58
58
35
0.26
17-80
38 14 20-69
32 26
27 31
0.46
31 25 2
35 21 2
0.83
Age (~4
Mean SD Range Sex (No. of patients) M F
Race (No. of patients) White Black Other
14
*Two-tailed t test for age and Fisher’s Exact Test for sex and race.
cardiac arrhythmia, which was not considered to be related to study medication. The only other adverse effects were noted in two cefadroxil-treated patients. One patient had a mild skin rash on the forearm, which was believed to be related to the study drug. However, treatment was not interrupted and the patient was found to be cured on study day 5. The other patient noted mild episodesof dizziness and nausea.The investigator did not believe that these complaints were related to antibiotic therapy, but the patient did discontinue the study drug after 2 days. The patient was considered cured on study day 5. Use of concomitant pain medication was comparable for the two groups. Forty-four (76%) of the patients receiving cefadroxil and 41 (71%) receiving cephalexin were prescribed analgesics (no significant difference). Although steroids were permitted in this study, the only formulations used were oral contraceptives, which were taken by three patients receiving cefadroxil. DISCUSSION
This study of facial cellulitis supports previous clinical trials in other skin and soft tissue infections demonstrating that at equivalent doses,cefadroxil in a once-daily dosageregimen is as effective as cephalexin in multiple daily doses.‘0y‘I The once-daily dosage regimen has obvious utility in increasing patient compliance and therefore creating better antibiotic coverage over the course of treatment. Broad-spectrum oral cephalosporins are still somewhat limited in number, and early antibiotic intervention in infectious processes such as endodontic facial cellulitis can reduce morbidity and the need for parenteral antibiotic therapy in the hospital setting. The savings associated with such outpatient therapy is becoming increasingly important in the present era of cost constraints.
498
Hanna
ORAL SLRC ORAL MED ORAL
PATHOL
April 1991
The long serum half-life and rapid absorption of cefadroxil from the gastrointestinal tract without any effect on its uptake by food permits flexibility in its dosing schedule, which is not established for cephalexin. The prolonged tissue retention provides extended coverage through a course of therapy.ssI3 The favorable outcome of therapy in the cefadroxiltreated patient who discontinued medication after 2 days and two dosestends to corroborate this superior tissue retention. In contrast, the patient who discontinued cephalexin after receiving six dosesduring 36 hours was the only failure in this trial. In the treatment of endodontic facial cellulitis, first-generation cephalosporins have been cited as ideal choices because aerobic microbes, particularly streptococci, have been the predominant causative organisms isolated in investigations.12 The superior pharmacokinetic profile of cefadroxil, together with these clinical data, in turn offer an ideal choice in comparison with the other oral cephalosporins in its class.
3 Leitner F, McGregor MC, Pursiano TA. Comparative antibacterial spectrum of cefadroxil. J Antimicrob Chemother 1982;1O(suppl B): l-9. 4 Leitner F, Goodhines RA, Buck RE, Price KE. Bactericidal activity of cefadroxil, cephalexin, and cephradine in an in vitro pharmacokinetic model. J Antibiot 1979;32:718-26. 5 Pfeffer M, Jackson A, Ximenes J, Perche D Menezes J. Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob Agents Chemother 1977;11:331-8. 6. Simon C. Serum and skin blister levels of cefadroxil in comparison to cephalexin. Infection 1980;8(suppl 5):584-7. 7. Bernhardt LL. Tissue and fluid concentrations of cefadroxil monohydrate. J Int Med Res 1980;8(suppl 1):58-63. 8. Adam D, Krentle 0. Investigation on the diffusion of cefadroxil and cephalexin into tonsil tissues. Infection 1980; 5:580-3. 9. Helm SE, Ekedahl C. Comparative study of the penetration of penicillin V and cefadroxil into tonsils in man. J Antimicrob Chemother 1982;1O(suppl B):l21-3. IO. Ballantyne F. Cefadroxil in the treatment of skin and soft tissue infection. J Antimicrob Chemother 1982;1O(suppl B): 143-7. 11. Henness DM, Gordon WE. Effective once- or twice-daily treatment of skin and skin structure infections with a new cephalosporin (cefadroxil). Postgrad Med Comm 1979;41-7. 12. Matusow RJ. The flare-up phenomenon in endodontics: a clinical perspective and review. ORAL SURG ORAL MED ORAL
REFERENCES
13. Blumer JL, Goldford J. Rediscovering pharmacological values in antimicrobial therapy: cefadroxil in perspective. Drugs 1986;32(suppl 3):v-viii.
PATHOL
1. Tanrisever B, Santella PJ. Cefadroxil: a review of its antibacterial, pharmacokinetic and therapeutic properties in comparison with cephalexin and cephradine. Drugs 1986;32(suppl 3):1-16. 2. Buck RE, Price KE. Cefadroxil, a new broad-spectrum cephalosporin. Antimicrob Agents Chemother 1977;11:324-30.
1988:65:750-3.
Reprint requests to: Charles B. Hanna Jr., DMD 358 Serpentine Dr. Spartanburg, SC 29303
c
efadroxil and cephalexin are first-generation oral cephalosporins with a broad spectrum of activity against gram-positive cocci including staphylococci, group A /3-hemolytic streptococci, group B streptococci, and Streptococcus pneumoniae.lM3The firstgeneration cephalosporins generally have limited activity against gram-negative bacteria. However, cefadroxil has demonstrated in vitro bactericidal activity against Escherichia coli, Klebsiella sp., and Proteus mirabilis.4 The discovery of cefadroxil resulted from chemical manipulations of the aromatic ring common to several of the first-generation cephalosporins. The addition of a para-hydroxyl group on this ring of the cephalexin molecule gave rise to cefadroxil, which demonstrates two significant advantages over its counterparts. Unlike cephalexin and cephradine, absorption of cefadroxil is not affected by food, and its serum half-life is approximately twice that of either of the other two agents-t>5 Plasma levels of cefadroxil are detectable 12 hours after a 500 mg dose,whereas cephalexin and cephradine are undetectable 6 hours after a similar dose. Drug distribution studies have investigated the penetration of cefadroxil into various organs and tissues.Skin blisters are a model for the tissue penetration of anti-infectives. In this model the peak concentrations of cefadroxil were higher (fourfold) and more sustained than those of cephalexin6, 7 Also, tonsillar
7/35/23565 496
tissue levels of cefadroxil were higher than cephalexin (threefold)s and the 4-hour tissue concentration was 10 times abovethe minimum inhibitory concentration for /3-hemolytic streptococci.9 Correspondingly, cefadroxil has shown efficacy in open and controlled clinical trials in the treatment of skin and soft tissue infections, including cellulitis, folliculitis, furunculosis, impetigo, mastitis, pyoderma, and wound.s.‘O,’ ’ Results from once- or twice-daily dosing of cefadroxil were equal to those obtained with a regimen of cephalexin four times daily. Facial cellulitis of odontogenic origin is an infectious processarising from diseasedor necrotic dentition. By definition, it is a purulent inflammation of the loose subcutaneous tissue. The process may arise in bone, soft tissue, or both, and may manifest itself either intraorally or extraorally. Aerobic microbes, particularly streptococci, are the predominant pathogens isolated from culture material from endodontic cellulitis. Obligate anaerobes are seldom isolated.’ * Consequently, oral cephalosporins are good therapeutic agents for use in this indication. Two such agents, cefadroxil and cephalexin, recently were compared for their efficacy and safety in a study of patients with facial cellulitis, and the results are reported here. MATERIAL
AND METHODS
A total of 116 patients were entered into this investigator-blinded, comparative trial of cefadroxil, 1000 mg given once daily, and cephalexin, 250 mg given four times daily, for the treatment of facial cellulitis of odontogenic origin. The diagnosis of facial cellulitis was determined by clinical examination and the
Cefadroxil in endodontic cellulitis
Volume 71 Number 4
presence of intraoral or extraoral swelling. Photographic documentation, both intraoral and extraoral, was made before initiation of this trial and on study days 3 and 5. The infection site was first treated by means of surgical incision and drainage or extraction as needed. An adequate blood level of the assigned antibiotic was established by initiating therapy 12 hours before surgical procedures. Men and women 18 years of age or older were enrolled into this trial. The study protocol was approved by the institutional review board of Spartanburg Regional Medical Center, Spartanburg, S.C., and a stringent informed consent procedure was followed for all study participants. Use of all concomitant medications, with the exception of antibiotics, was permitted to continue. Any such medications were recorded on individual case record forms. Pregnant women and nursing mothers, and patients who had received antibiotic therapy in the previous 2 weeks, were excluded. Cultures from the infection site and sensitivity tests of the primary pathogen cultured were to be completed on day 0, before antibiotic therapy was started. On study days 3 and 5, a culture was to be taken only if infection persisted and culturable exudate was available. Dosing commenced on day 0, 12 hours before day 1 surgery, and continued for 4 days for a total of 5 days of treatment. At the conclusion of the trial the investigator assessedclinical efficacy on a 3point scale: cure, failure, and no change. RESULTS
Both treatment groups were comparable at baseline, as illustrated in Table I, with no statistically significant differences. The initial bacteriologic results for all patients indicated that the primary pathogen was sensitive to the assigned antibiotic. Therefore no patients were excluded from the analysis. The number of cultures available from days 3 and 5 was not sufficient to permit analysis, sothe efficacy assessment was basedsolely on the investigator’s blinded clinical evaluation at the end of treatment. Fifty-eight (100%) of the cefadroxil-treated patients and 57 (98%) of the cephalexin-treated patients were found to be cured. The difference between these two cure rates was not statistically significant (Fisher’s Exact Test, p = 1.O).Approximate binomial onesided 95% confidence limits were computed for the percentage of cures in each treatment group, with 1.7% as an estimate of the standard deviation of both percentages.The lower limit of the percentage cured by cefadroxil therapy was 97.2%, whereas that of cephalexin therapy was 95.5%. The sole failure in this study was in a 64-year-old woman who discontinued cephalexin after 36 hours of therapy. During the trial she had a mild episode of
Table
497
1.Summary of patient demographics Cefadroxil
No. of patients
Cephalexin
p value*
58
58
35
0.26
17-80
38 14 20-69
32 26
27 31
0.46
31 25 2
35 21 2
0.83
Age (~4
Mean SD Range Sex (No. of patients) M F
Race (No. of patients) White Black Other
14
*Two-tailed t test for age and Fisher’s Exact Test for sex and race.
cardiac arrhythmia, which was not considered to be related to study medication. The only other adverse effects were noted in two cefadroxil-treated patients. One patient had a mild skin rash on the forearm, which was believed to be related to the study drug. However, treatment was not interrupted and the patient was found to be cured on study day 5. The other patient noted mild episodesof dizziness and nausea.The investigator did not believe that these complaints were related to antibiotic therapy, but the patient did discontinue the study drug after 2 days. The patient was considered cured on study day 5. Use of concomitant pain medication was comparable for the two groups. Forty-four (76%) of the patients receiving cefadroxil and 41 (71%) receiving cephalexin were prescribed analgesics (no significant difference). Although steroids were permitted in this study, the only formulations used were oral contraceptives, which were taken by three patients receiving cefadroxil. DISCUSSION
This study of facial cellulitis supports previous clinical trials in other skin and soft tissue infections demonstrating that at equivalent doses,cefadroxil in a once-daily dosageregimen is as effective as cephalexin in multiple daily doses.‘0y‘I The once-daily dosage regimen has obvious utility in increasing patient compliance and therefore creating better antibiotic coverage over the course of treatment. Broad-spectrum oral cephalosporins are still somewhat limited in number, and early antibiotic intervention in infectious processes such as endodontic facial cellulitis can reduce morbidity and the need for parenteral antibiotic therapy in the hospital setting. The savings associated with such outpatient therapy is becoming increasingly important in the present era of cost constraints.
498
Hanna
ORAL SLRC ORAL MED ORAL
PATHOL
April 1991
The long serum half-life and rapid absorption of cefadroxil from the gastrointestinal tract without any effect on its uptake by food permits flexibility in its dosing schedule, which is not established for cephalexin. The prolonged tissue retention provides extended coverage through a course of therapy.ssI3 The favorable outcome of therapy in the cefadroxiltreated patient who discontinued medication after 2 days and two dosestends to corroborate this superior tissue retention. In contrast, the patient who discontinued cephalexin after receiving six dosesduring 36 hours was the only failure in this trial. In the treatment of endodontic facial cellulitis, first-generation cephalosporins have been cited as ideal choices because aerobic microbes, particularly streptococci, have been the predominant causative organisms isolated in investigations.12 The superior pharmacokinetic profile of cefadroxil, together with these clinical data, in turn offer an ideal choice in comparison with the other oral cephalosporins in its class.
3 Leitner F, McGregor MC, Pursiano TA. Comparative antibacterial spectrum of cefadroxil. J Antimicrob Chemother 1982;1O(suppl B): l-9. 4 Leitner F, Goodhines RA, Buck RE, Price KE. Bactericidal activity of cefadroxil, cephalexin, and cephradine in an in vitro pharmacokinetic model. J Antibiot 1979;32:718-26. 5 Pfeffer M, Jackson A, Ximenes J, Perche D Menezes J. Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob Agents Chemother 1977;11:331-8. 6. Simon C. Serum and skin blister levels of cefadroxil in comparison to cephalexin. Infection 1980;8(suppl 5):584-7. 7. Bernhardt LL. Tissue and fluid concentrations of cefadroxil monohydrate. J Int Med Res 1980;8(suppl 1):58-63. 8. Adam D, Krentle 0. Investigation on the diffusion of cefadroxil and cephalexin into tonsil tissues. Infection 1980; 5:580-3. 9. Helm SE, Ekedahl C. Comparative study of the penetration of penicillin V and cefadroxil into tonsils in man. J Antimicrob Chemother 1982;1O(suppl B):l21-3. IO. Ballantyne F. Cefadroxil in the treatment of skin and soft tissue infection. J Antimicrob Chemother 1982;1O(suppl B): 143-7. 11. Henness DM, Gordon WE. Effective once- or twice-daily treatment of skin and skin structure infections with a new cephalosporin (cefadroxil). Postgrad Med Comm 1979;41-7. 12. Matusow RJ. The flare-up phenomenon in endodontics: a clinical perspective and review. ORAL SURG ORAL MED ORAL
REFERENCES
13. Blumer JL, Goldford J. Rediscovering pharmacological values in antimicrobial therapy: cefadroxil in perspective. Drugs 1986;32(suppl 3):v-viii.
PATHOL
1. Tanrisever B, Santella PJ. Cefadroxil: a review of its antibacterial, pharmacokinetic and therapeutic properties in comparison with cephalexin and cephradine. Drugs 1986;32(suppl 3):1-16. 2. Buck RE, Price KE. Cefadroxil, a new broad-spectrum cephalosporin. Antimicrob Agents Chemother 1977;11:324-30.
1988:65:750-3.
Reprint requests to: Charles B. Hanna Jr., DMD 358 Serpentine Dr. Spartanburg, SC 29303