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Cephalexin concentrations in radicular granuloma following a single oral administration of 250- or 500-mg cephalexin
Pergamon
Gen. Pharmac. Vol.25,"No. 8, pp. 1563-1566, 1994 Copyright ~(': 1994ElsevierScienceLtd Printed in Great Britain.All rights reserved 0306-3623/94$7.00+ 0.00
0306-3623(94)00142-1
Cephalexin Concentrations in Radicular Granuloma Following a Single Oral Administration of 250- or 500-mg Cephalexin YOSHIAKI AKIMOTO,* AKIO UDA, HIROAKI OMATA, JUN SHIBUTANI, HITOSHI NISHIMURA, MASAMICHI KOMIYA, TOMONORI KAWANA, KENJI KANEKO, AKIRA FUJII, I TAKASHI KANEDA 2 and HIROTSUGU YAMAMOTO 3 Departments of Oral Surgery 2, tPharmaeology, ZRadiology and 3Pathology, Nihon University School of Dentistry at Matsudo, 2-870-1, Sakaecho-nishi, Matsudo, Chiba 271, Japan [Tel: 0473-68-6111; Fax: 0473-64-6295]
(Received 7 April 1994)
Abstract--1. Cephalexin concentrations in radicular granuloma and serum following a single oral administration of 250- or 500-mg cephalexin were measured by a paper disk method. 2. The highest concentration of cephalexin in radicular granuloma following administration of 250-mg cephalexin to nonfasting patients was observed at 2hr, and was 1.62#g/g. The mean cephalexin concentration ratio of radicular granuloma/serum at 2 hr was 0.35. 3. The highest concentrations of cephalexinin radicular granuloma followingadministration of 500-mg cephalexin to nonfasting and fasting patients occurred at 2 and 1.5 hr, and was 3.35 and 3.42#g/g, respectively. Mean cephalexinconcentration ratios of radicular granuloma/serum at 2 and 1.5 hr were 0.32 and 0.30, respectively. 4. All mean cephalexin concentrations in radicular granuloma following administration of 500-mg cephalexin to both fasting and nonfasting patients exceeded MIC for 90% (2 gg/ml) of clinicallyisolated strains of a-hemolytic streptococci. However, those concentrations obtained by 250-mgcephalexindid not exceed it. Key Words: Cephalexin, radicular granuloma, oral administration
INTRODUCTION Radicular granulomas accompanied by acute infection are often seen in dental practice. Antimicrobial therapy is an essential treatment for infected radicular granuloma. If there is insufficient antibiotic concentration in the infected site, the treatment will fail. Despite this, little attention has been paid to antibiotic concentration in radicular granuloma (Akimoto et al., 1988, 1992; Uda et al., 1989), and there is no study on oral cephalosporin. Thus, the present study was undertaken to determine the cephalexin concentrations in radicular granuloma and serum following a single oral administration of 250-mg cephalexin to nonfasting, 500-rag to nonfasting, or 500-mg to fasting patients. Cephalexin concen*To whom all correspondence should be addressed.
trations in radicular granuloma were compared with MIC of g-hemolytic streptococci isolated from odontogenic infection. Cephalexin has been used in dental practices, and cephalexin concentrations in human oral tissues following a single oral administration have been reported (Akimoto et ai., 1990). Therefore, the present experiment was restricted to the study of radicular granuloma in oral pathologic lesions.
MATERIALS AND METHODS
Patients Seventy-seven patients who underwent enucleation of radicular granuloma (granuloma) were tested in this study. Of the patients, 44 were female and 33 were male. The mean age of patients was 37 years old
1563
1564
YOSHIAKI AKIMOTOet al.
(range, 26--58 years old), and the mean weight was 55kg (range, 39-91 kg). All operations were performed under local anesthesia using 2% lidocaine with 1:80,000 epinephrine. All were without clinical signs of acute inflammation, and none had received any antimicrobial therapy for at least 1 week before the operation. In all cases, the clinical and roentgenologic diagnoses were verified by histological examinations.
Administration of cephalexin, sampling procedure and preparation of analytical samples At 1 to 2 hr after breakfast or overnight fasting, each patient was given a single preoperative oral dose of 250- or 500-mg cephalexin with 200 ml of water. Seventy-seven patients were divided into three groups. Twenty-one patients in the nonfasting state were given 250-mg cephalexin. Twenty-one patients in a fasting state and 35 patients in a nonfasting state were given 500-mg cephalexin. Surgery was undergone to obtain the surgical specimens and blood samples at 1, 1.5, 2, 2.5 or 3 hr following administration. In order to obtain serum, approximately 3 ml of blood was also taken from the antecubital vein of each patient at the same collection time of surgical specimens. A single specimen of granuloma and blood sample was collected as a sample set from each patient. However, since the surgical specimen and blood sample were not able to be collected at an exactly identical time, they were collected within 3 min at the subjected time. The specimen of granuloma was agitated for approximately 3 sec in sterile saline to wash away the blood and then cut into small pieces. Three parts of 1% phosphate buffer (pH 6.0) were added to 40 mg of granuloma. The mixture was homogenized in an ice bath, and the resulting mixture was stored at 4°C for 18 hr to extract the cephalexin. The mixture was then centrifuged at 1500g for 15 min at 4°C. The serum, which was obtained from the blood sample by centrifugation, was diluted with the same buffer to factors of 1, 10, 50 and 100.
Bioassay Cephalexin concentration was measured by the paper disk method. The test organism was Micrococcus luteus A T C C 9341. Antibiotic Medium 1 (Difco) was the assay medium. Standards for granuloma and serum assays were prepared with 1% phosphate buffer (pH 6.0), and six different cephalexin concentrations were assayed (range, 0.05 to 3/zg/ml). All assays were performed in triplicate except for granuloma. All plates were incubated for 18 hr at 30°C, and the resulting growth inhibition zones were measured to a precision of 0.1 mm.
Bacteria and susceptibility test Twenty-five strains of s-hemolytic streptococci were obtained from oral infection. Determinations of antimicrobial susceptibility were performed by the standard microdilution method, in which pH-adjusted and cation-supplemented Mueller Hinton broth (Difco) was used. RESULTS
Cephalexin concentrations after 250-mg cephalexin to nonfasting patients Cephalexin concentrations in granuloma (n = 21) and serum (n = 21) were obtained at 1.5, 2 or 2.5 hr. Mean cephalexin concentrations (mean ± S D ) in granuloma and serum at each sampling time are shown in Table !. The highest concentrations of the granuloma and serum were observed at 2 and 1.5 hr, respectively, and were i.62 + 1.21/zg/g and 4.66___ 2.20/zg/ml, respectively. The means of the concentration ratios ( m e a n + S D ) of granuloma to serum cephalexin concentrations at 1.5 and 2 hr were 0.29 + 0.12 and 0.35 + 0.10, respectively (Table 1).
Cephalexin concentrations after 500-rag cephalexin to nonfasting patients Cephalexin concentrations in granuloma (n = 35) and serum (n = 35) were obtained at 1, i.5, 2, 2.5 or
Table 1. Cephalexin concentrations in serum and radicular granuloma in nonfasting subjects following a single oral administration of 250-mg cephalexin to nonfasting patients Mean cephalexin concentrations _+SD Mean concentration (range) ratio + SDt Serum Granuloma (range) Time* ( h r ) Numberof samples (,ug/ml) (/~g/g) Granuloma/serum 1.5 7 4.66 + 2.20 1.57 + 1.21 0.29 + 0.12 ( 1.29 - 7.20) (0.28 - 3.47) (0.12 - 0.51) 2 7 4.24 + 2.71 1.62 + 1.21 0.35 + 0.10 (0.80 - 7.71) (0.25 - 3.62) (0.22 - 0.50) 2.5 7 4.22 + 2.53 1.54 + 0.69 0.34 + 0.10 (1.80 - 8.13) (0.78 - 2.62) (0.21 - 0.53) *Hours after administration of cephalexin. tMean of each cephalexih concentration in granuloma divided by the respectiveconcentration in serum is expressed as a mean concentration ratio.
Cephalexin in radicular granuioma
1565
Table 2. Cephalexin concentrations in serum and radicular granuloma following a single oral administration of 500-rag cephalexin to nonfasting patients Mean cephalexin concentrations + SD (range) Time* (hr)
Number of samples
1
7
1.5
7
2
7
2.5
7
3
7
Serum (#g/ml)
Gsanuloma (#g/g)
Mean concentration ratio +- SDf (range) Granuloma/serum
9.69 +_4.17
2.79 +-2.12
0.26 + 0.12
(2.51 - 15.33)
(0.33 - 7.1 I)
(0.09 - 0.49)
9.96 +- 5.19 ( I . 8 0 - 17.03) 9.42 __.4.83 (2. I 0 - 15.00) 8.48 _+ 3.70 (2.56- 14.18) 6.80 _ 3.66 ( 1 . 8 9 - 11.81)
3.34 +- 1.38 (0.26-6.30) 3.35 +- 2.09 (0.20 - 6.20) 3.07 + 1.41 ( I . 3 3 - 5.53) 2.78 +- 1.76 (0.36-4.13)
0.32 + 0.10 (0.14-0.46) 0.32 + 0.12 (0.25 - 0.52) 0.38 + 0.08 (0.25-0.52) 0.39 +- 0.14 (0.19-0.63)
*Hours after administration of cephalexin. ?Mean of each cephalexin concentration in granuloma divided by the respective concentration in ~d~rum is expressed as mean concentration ratio.
3 hr. Mean cephalexin concentrations (mean + SD) in granuloma and serum at each sampling time are shown in Table 2. The highest concentrations of the granuloma and serum were observed at 2 and 1.5 hr, respectively, and were 3.35 + 2.09#g/g and 9.96+ 5.19gg/ml, respectively. The means of the concentration ratios (mean + SD) of granuloma to serum cephalexin concentrations at 1.5 and 2 hr were 0.32 + 0.10 and 0.32 +0.12, respectively (Table 2).
MIC MICs of 25 strains of ~-hemolytic streptococci for cephalexin ranged from 0.12 to 64#g/ml and MIC for 90% was 2 #g/ml. All mean cephalexin concentrations in granuloma following administration of 500-rag cephalexin to both fasting and nonfasting patients exceeded the MIC for 90% of a-hemolytic streptococci. However, those obtained by 250-rag cephalexin did not exceed it.
Cephalexin concentrations after 500-mg cephalexin to fasting patients Cephalexin concentrations in granuloma (n = 21) and serum (n = 21) were obtained at 1, 1.5 or 2 hr. Mean cephalexin concentrations (mean +__SD) in granuloma and serum at each sampling time are shown in Table 3. The highest concentrations of the granuloma and serum were observed at 1.5 and 1 hr, respectively, and were 3.42-t-1.68#g/g and 11.54 -I- 4.45/xg/ml, respectively. The means of the concentration ratios (mean + SD) of granuloma to serum cephalexin concentrations at 1 and 1.5 hr were 0.31 + 0.11 and 0.30_ 0.07, respectively (Table 3).
DISCUSSION Comparing the highest cephalexin concentrations in serum and granuloma following a single oral administration of 500-rag cephalexin to nonfasting and fasting patients, the fasting patients showed higher concentrations of both serum and granuioma than those obtained by the nonfasting patients. However, the differences between those of nonfasting and fasting patients were not significant. Cephalexin concentrations in gingiva and mandibular bone following a single oral administration of
Table 3. Cephalexin concentrations in serum and radicular granuloma following a single oral administration of 500-rag cephalexin to fasting patients Mean cephaiexin concentrations 5: SD (range)
Mean concentration ratio +- SDf (range)
Time*
Number of samples
I
7
1.5
7
2
7
Serum (#g/ml)
Granuloma (/Jg/g)
Granuloma/serum
11.54+4.45 (4.26-- 17.00) 1 I.17 __ 3.97 (5.69-- 16.60) 8.60+-4.14 (3.65 -- 15.80)
3.12+_0.99 (1.94--4.59) 3.42 __. 1.68 (2.08--6.81) 2.84+- 1.15 ( 1.97 -- 5.53)
0.31 __.0.II (0.18 -- 0.55) 0.30 + 0.07 (0.19--0.41) 0.36+-0.10 (0.22 -- 0.54)
*Hours after administration of cephalexin. ?Mean of each cephalexin concentration in granuloma divided by the respective concentration in serum is expressed as mean concentration ratio.
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YOSHIAKI AKIMOTOet al.
500-mg cephalexin to nonfasting subjects have been reported (Akimoto et al., 1990); concentration ratios (tissue/serum) at the peak times of tissues were 0.53 in gingiva and 0.19 in mandibular bone. Compared with the present results, granuloma (0.32) was lower than that of gingiva, and higher than that of mandibular bone. The radicular granuloma is an inflammatory connective tissue and antibiotic concentration in inflamed connective tissue depends on the degree of inflammation (Akimoto et al., 1982). Although the specimens of granuloma were collected from patients without clinical signs of acute inflammation, the degree of chronic inflammation varied among the specimens. This would lead to greater variation of cephalexin concentration in granuloma. There are three studies about the concentrations of antibiotics in radicular granuloma following oral administration. Akimoto et al. (1988, 1992) and Uda et al. (1989) reported on ampicillin from talampicillin, ampicillin from bacampicillin, and josamycin, in which mean concentration ratios of granuloma/ serum ampicillin and josamycin concentrations were 0.22, 0.27 and 0.64, respectively. Cephalexin (0.32) was higher than those of ampicillin and was lower than that of josamycin. This result is explained by using a physicochemical property such as the partition coefficient. The partition coefficients of cephalexin, ampicillin, and josamycin in the system of n-octyl alcohol and 1/15 M phosphate buffer (pH 7.2) were 0.66, 0.39 and 1370, respectively. Since cephalexin and ampicillin have lower lipophilic properties than those ofjosamycin, and cephalexin has a slightly higher lipophilic property than that of ampicillin, it is reasonable that there were differences in the concentration ratios. All mean cephalexin concentrations in granuloma following administration of 500-mg cephalexin to both fasting and nonfasting patients exceeded MIC for 90% (2#g/ml) of clinically isolated strains of s-hemolytic streptococci. However, those obtained by 250-mg cephalexin did not exceed the MIC for 90%. Since cephalexin showed an early elimination (Lecaillon et al., 1980; Pfeffer et al., 1977); higher cephalexin concentration in serum after multiple dosings was not obtained. This suggests that there is no possibility of obtaining more than the MIC for
90% after multiple dosings of 250-mg cephalexin. Thus, 500-mg cephalexin should be given for the treatment of periapicai infection. In conclusion, cephalexin concentrations in granuloma and serum following a single oral administration were measured by the paper disk method. The highest mean concentrations of cephalexin in granuloma following administration of 250-mg cephalexin to nonfasting, 500-mg cephalexin to nonfasting, and 500-mg cephalexin to fasting patients were 1.62, 3.35 and 3.42 pg/g, respectively. The mean concentration ratios of granuloma/serum at the highest granuloma concentrations were 0.35, 0.32, and 0.30, respectively. Mean cephalexin concentrations in granuloma following administration of 500-rag cephalexin to both nonfasting and fasting patients exceeded MIC for 90% for clinically isolated strains of or-hemolytic streptococci. However, those obtained by 250-mg cephalexin did not exceed the MIC for 90%. REFERENCES
Akimoto Y., Kaneko K., Fujii A. and Yamamoto H. (1992) Ampicillin concentrations in human radicular granuloma following a single oral dose of bacampicillin. J. Oral Maxillofac. Surg. 50, 11 13. Akimoto Y., Kaneko K. and Tamura T. (1982) Amoxicillin concentrations in serum, jaw cyst, and jawbone following a single oral administration. J. Oral Maxillofac. Surg. 40, 287-293. Akimoto Y., Nishimura H., Komiya M., Kaneko K., Fujii A. and Tamura T. (1988) Ampicillin concentrations in human dental granuloma after a single oral administration of talampicillin. Antimicrob. Agents Chemother. 32, 566-567. Akimoto Y., Uda A., Omata H., Shibutani J., Nishimura H., Komiya M., Kaneko K. and Fujii A. (1990) Cephalexin concentrations in human serum, gingiva, and mandibular bone following a single oral administration. Gen. Pharmac. 21,621~23. Lecaillon J. B., Hirtz J. L., Schoeller J. P., Humbert G. and Vischer W. (1980) Pharmacokinetic comparison of cefroxadin (CGP 9000) and cephalexin by simultaneous administration to humans. Antimierob. Agents Chemother. 18, 656~500. Pfeffer M., Jackson A., Ximenes J. and Menezes J. P. D. (1977) Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob. Agent Chemother. 11, 331-338. Uda A., Omata H., Shibutani J., Nishimura H., Komiya M., Akimoto Y., Kaneko K. and Fujii A. (1989) Josamycin concentrations in human dental granuloma after a single oral administration of josamycin. Gen. Pharmac. 20, 823-825.
Gen. Pharmac. Vol.25,"No. 8, pp. 1563-1566, 1994 Copyright ~(': 1994ElsevierScienceLtd Printed in Great Britain.All rights reserved 0306-3623/94$7.00+ 0.00
0306-3623(94)00142-1
Cephalexin Concentrations in Radicular Granuloma Following a Single Oral Administration of 250- or 500-mg Cephalexin YOSHIAKI AKIMOTO,* AKIO UDA, HIROAKI OMATA, JUN SHIBUTANI, HITOSHI NISHIMURA, MASAMICHI KOMIYA, TOMONORI KAWANA, KENJI KANEKO, AKIRA FUJII, I TAKASHI KANEDA 2 and HIROTSUGU YAMAMOTO 3 Departments of Oral Surgery 2, tPharmaeology, ZRadiology and 3Pathology, Nihon University School of Dentistry at Matsudo, 2-870-1, Sakaecho-nishi, Matsudo, Chiba 271, Japan [Tel: 0473-68-6111; Fax: 0473-64-6295]
(Received 7 April 1994)
Abstract--1. Cephalexin concentrations in radicular granuloma and serum following a single oral administration of 250- or 500-mg cephalexin were measured by a paper disk method. 2. The highest concentration of cephalexin in radicular granuloma following administration of 250-mg cephalexin to nonfasting patients was observed at 2hr, and was 1.62#g/g. The mean cephalexin concentration ratio of radicular granuloma/serum at 2 hr was 0.35. 3. The highest concentrations of cephalexinin radicular granuloma followingadministration of 500-mg cephalexin to nonfasting and fasting patients occurred at 2 and 1.5 hr, and was 3.35 and 3.42#g/g, respectively. Mean cephalexinconcentration ratios of radicular granuloma/serum at 2 and 1.5 hr were 0.32 and 0.30, respectively. 4. All mean cephalexin concentrations in radicular granuloma following administration of 500-mg cephalexin to both fasting and nonfasting patients exceeded MIC for 90% (2 gg/ml) of clinicallyisolated strains of a-hemolytic streptococci. However, those concentrations obtained by 250-mgcephalexindid not exceed it. Key Words: Cephalexin, radicular granuloma, oral administration
INTRODUCTION Radicular granulomas accompanied by acute infection are often seen in dental practice. Antimicrobial therapy is an essential treatment for infected radicular granuloma. If there is insufficient antibiotic concentration in the infected site, the treatment will fail. Despite this, little attention has been paid to antibiotic concentration in radicular granuloma (Akimoto et al., 1988, 1992; Uda et al., 1989), and there is no study on oral cephalosporin. Thus, the present study was undertaken to determine the cephalexin concentrations in radicular granuloma and serum following a single oral administration of 250-mg cephalexin to nonfasting, 500-rag to nonfasting, or 500-mg to fasting patients. Cephalexin concen*To whom all correspondence should be addressed.
trations in radicular granuloma were compared with MIC of g-hemolytic streptococci isolated from odontogenic infection. Cephalexin has been used in dental practices, and cephalexin concentrations in human oral tissues following a single oral administration have been reported (Akimoto et ai., 1990). Therefore, the present experiment was restricted to the study of radicular granuloma in oral pathologic lesions.
MATERIALS AND METHODS
Patients Seventy-seven patients who underwent enucleation of radicular granuloma (granuloma) were tested in this study. Of the patients, 44 were female and 33 were male. The mean age of patients was 37 years old
1563
1564
YOSHIAKI AKIMOTOet al.
(range, 26--58 years old), and the mean weight was 55kg (range, 39-91 kg). All operations were performed under local anesthesia using 2% lidocaine with 1:80,000 epinephrine. All were without clinical signs of acute inflammation, and none had received any antimicrobial therapy for at least 1 week before the operation. In all cases, the clinical and roentgenologic diagnoses were verified by histological examinations.
Administration of cephalexin, sampling procedure and preparation of analytical samples At 1 to 2 hr after breakfast or overnight fasting, each patient was given a single preoperative oral dose of 250- or 500-mg cephalexin with 200 ml of water. Seventy-seven patients were divided into three groups. Twenty-one patients in the nonfasting state were given 250-mg cephalexin. Twenty-one patients in a fasting state and 35 patients in a nonfasting state were given 500-mg cephalexin. Surgery was undergone to obtain the surgical specimens and blood samples at 1, 1.5, 2, 2.5 or 3 hr following administration. In order to obtain serum, approximately 3 ml of blood was also taken from the antecubital vein of each patient at the same collection time of surgical specimens. A single specimen of granuloma and blood sample was collected as a sample set from each patient. However, since the surgical specimen and blood sample were not able to be collected at an exactly identical time, they were collected within 3 min at the subjected time. The specimen of granuloma was agitated for approximately 3 sec in sterile saline to wash away the blood and then cut into small pieces. Three parts of 1% phosphate buffer (pH 6.0) were added to 40 mg of granuloma. The mixture was homogenized in an ice bath, and the resulting mixture was stored at 4°C for 18 hr to extract the cephalexin. The mixture was then centrifuged at 1500g for 15 min at 4°C. The serum, which was obtained from the blood sample by centrifugation, was diluted with the same buffer to factors of 1, 10, 50 and 100.
Bioassay Cephalexin concentration was measured by the paper disk method. The test organism was Micrococcus luteus A T C C 9341. Antibiotic Medium 1 (Difco) was the assay medium. Standards for granuloma and serum assays were prepared with 1% phosphate buffer (pH 6.0), and six different cephalexin concentrations were assayed (range, 0.05 to 3/zg/ml). All assays were performed in triplicate except for granuloma. All plates were incubated for 18 hr at 30°C, and the resulting growth inhibition zones were measured to a precision of 0.1 mm.
Bacteria and susceptibility test Twenty-five strains of s-hemolytic streptococci were obtained from oral infection. Determinations of antimicrobial susceptibility were performed by the standard microdilution method, in which pH-adjusted and cation-supplemented Mueller Hinton broth (Difco) was used. RESULTS
Cephalexin concentrations after 250-mg cephalexin to nonfasting patients Cephalexin concentrations in granuloma (n = 21) and serum (n = 21) were obtained at 1.5, 2 or 2.5 hr. Mean cephalexin concentrations (mean ± S D ) in granuloma and serum at each sampling time are shown in Table !. The highest concentrations of the granuloma and serum were observed at 2 and 1.5 hr, respectively, and were i.62 + 1.21/zg/g and 4.66___ 2.20/zg/ml, respectively. The means of the concentration ratios ( m e a n + S D ) of granuloma to serum cephalexin concentrations at 1.5 and 2 hr were 0.29 + 0.12 and 0.35 + 0.10, respectively (Table 1).
Cephalexin concentrations after 500-rag cephalexin to nonfasting patients Cephalexin concentrations in granuloma (n = 35) and serum (n = 35) were obtained at 1, i.5, 2, 2.5 or
Table 1. Cephalexin concentrations in serum and radicular granuloma in nonfasting subjects following a single oral administration of 250-mg cephalexin to nonfasting patients Mean cephalexin concentrations _+SD Mean concentration (range) ratio + SDt Serum Granuloma (range) Time* ( h r ) Numberof samples (,ug/ml) (/~g/g) Granuloma/serum 1.5 7 4.66 + 2.20 1.57 + 1.21 0.29 + 0.12 ( 1.29 - 7.20) (0.28 - 3.47) (0.12 - 0.51) 2 7 4.24 + 2.71 1.62 + 1.21 0.35 + 0.10 (0.80 - 7.71) (0.25 - 3.62) (0.22 - 0.50) 2.5 7 4.22 + 2.53 1.54 + 0.69 0.34 + 0.10 (1.80 - 8.13) (0.78 - 2.62) (0.21 - 0.53) *Hours after administration of cephalexin. tMean of each cephalexih concentration in granuloma divided by the respectiveconcentration in serum is expressed as a mean concentration ratio.
Cephalexin in radicular granuioma
1565
Table 2. Cephalexin concentrations in serum and radicular granuloma following a single oral administration of 500-rag cephalexin to nonfasting patients Mean cephalexin concentrations + SD (range) Time* (hr)
Number of samples
1
7
1.5
7
2
7
2.5
7
3
7
Serum (#g/ml)
Gsanuloma (#g/g)
Mean concentration ratio +- SDf (range) Granuloma/serum
9.69 +_4.17
2.79 +-2.12
0.26 + 0.12
(2.51 - 15.33)
(0.33 - 7.1 I)
(0.09 - 0.49)
9.96 +- 5.19 ( I . 8 0 - 17.03) 9.42 __.4.83 (2. I 0 - 15.00) 8.48 _+ 3.70 (2.56- 14.18) 6.80 _ 3.66 ( 1 . 8 9 - 11.81)
3.34 +- 1.38 (0.26-6.30) 3.35 +- 2.09 (0.20 - 6.20) 3.07 + 1.41 ( I . 3 3 - 5.53) 2.78 +- 1.76 (0.36-4.13)
0.32 + 0.10 (0.14-0.46) 0.32 + 0.12 (0.25 - 0.52) 0.38 + 0.08 (0.25-0.52) 0.39 +- 0.14 (0.19-0.63)
*Hours after administration of cephalexin. ?Mean of each cephalexin concentration in granuloma divided by the respective concentration in ~d~rum is expressed as mean concentration ratio.
3 hr. Mean cephalexin concentrations (mean + SD) in granuloma and serum at each sampling time are shown in Table 2. The highest concentrations of the granuloma and serum were observed at 2 and 1.5 hr, respectively, and were 3.35 + 2.09#g/g and 9.96+ 5.19gg/ml, respectively. The means of the concentration ratios (mean + SD) of granuloma to serum cephalexin concentrations at 1.5 and 2 hr were 0.32 + 0.10 and 0.32 +0.12, respectively (Table 2).
MIC MICs of 25 strains of ~-hemolytic streptococci for cephalexin ranged from 0.12 to 64#g/ml and MIC for 90% was 2 #g/ml. All mean cephalexin concentrations in granuloma following administration of 500-rag cephalexin to both fasting and nonfasting patients exceeded the MIC for 90% of a-hemolytic streptococci. However, those obtained by 250-rag cephalexin did not exceed it.
Cephalexin concentrations after 500-mg cephalexin to fasting patients Cephalexin concentrations in granuloma (n = 21) and serum (n = 21) were obtained at 1, 1.5 or 2 hr. Mean cephalexin concentrations (mean +__SD) in granuloma and serum at each sampling time are shown in Table 3. The highest concentrations of the granuloma and serum were observed at 1.5 and 1 hr, respectively, and were 3.42-t-1.68#g/g and 11.54 -I- 4.45/xg/ml, respectively. The means of the concentration ratios (mean + SD) of granuloma to serum cephalexin concentrations at 1 and 1.5 hr were 0.31 + 0.11 and 0.30_ 0.07, respectively (Table 3).
DISCUSSION Comparing the highest cephalexin concentrations in serum and granuloma following a single oral administration of 500-rag cephalexin to nonfasting and fasting patients, the fasting patients showed higher concentrations of both serum and granuioma than those obtained by the nonfasting patients. However, the differences between those of nonfasting and fasting patients were not significant. Cephalexin concentrations in gingiva and mandibular bone following a single oral administration of
Table 3. Cephalexin concentrations in serum and radicular granuloma following a single oral administration of 500-rag cephalexin to fasting patients Mean cephaiexin concentrations 5: SD (range)
Mean concentration ratio +- SDf (range)
Time*
Number of samples
I
7
1.5
7
2
7
Serum (#g/ml)
Granuloma (/Jg/g)
Granuloma/serum
11.54+4.45 (4.26-- 17.00) 1 I.17 __ 3.97 (5.69-- 16.60) 8.60+-4.14 (3.65 -- 15.80)
3.12+_0.99 (1.94--4.59) 3.42 __. 1.68 (2.08--6.81) 2.84+- 1.15 ( 1.97 -- 5.53)
0.31 __.0.II (0.18 -- 0.55) 0.30 + 0.07 (0.19--0.41) 0.36+-0.10 (0.22 -- 0.54)
*Hours after administration of cephalexin. ?Mean of each cephalexin concentration in granuloma divided by the respective concentration in serum is expressed as mean concentration ratio.
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YOSHIAKI AKIMOTOet al.
500-mg cephalexin to nonfasting subjects have been reported (Akimoto et al., 1990); concentration ratios (tissue/serum) at the peak times of tissues were 0.53 in gingiva and 0.19 in mandibular bone. Compared with the present results, granuloma (0.32) was lower than that of gingiva, and higher than that of mandibular bone. The radicular granuloma is an inflammatory connective tissue and antibiotic concentration in inflamed connective tissue depends on the degree of inflammation (Akimoto et al., 1982). Although the specimens of granuloma were collected from patients without clinical signs of acute inflammation, the degree of chronic inflammation varied among the specimens. This would lead to greater variation of cephalexin concentration in granuloma. There are three studies about the concentrations of antibiotics in radicular granuloma following oral administration. Akimoto et al. (1988, 1992) and Uda et al. (1989) reported on ampicillin from talampicillin, ampicillin from bacampicillin, and josamycin, in which mean concentration ratios of granuloma/ serum ampicillin and josamycin concentrations were 0.22, 0.27 and 0.64, respectively. Cephalexin (0.32) was higher than those of ampicillin and was lower than that of josamycin. This result is explained by using a physicochemical property such as the partition coefficient. The partition coefficients of cephalexin, ampicillin, and josamycin in the system of n-octyl alcohol and 1/15 M phosphate buffer (pH 7.2) were 0.66, 0.39 and 1370, respectively. Since cephalexin and ampicillin have lower lipophilic properties than those ofjosamycin, and cephalexin has a slightly higher lipophilic property than that of ampicillin, it is reasonable that there were differences in the concentration ratios. All mean cephalexin concentrations in granuloma following administration of 500-mg cephalexin to both fasting and nonfasting patients exceeded MIC for 90% (2#g/ml) of clinically isolated strains of s-hemolytic streptococci. However, those obtained by 250-mg cephalexin did not exceed the MIC for 90%. Since cephalexin showed an early elimination (Lecaillon et al., 1980; Pfeffer et al., 1977); higher cephalexin concentration in serum after multiple dosings was not obtained. This suggests that there is no possibility of obtaining more than the MIC for
90% after multiple dosings of 250-mg cephalexin. Thus, 500-mg cephalexin should be given for the treatment of periapicai infection. In conclusion, cephalexin concentrations in granuloma and serum following a single oral administration were measured by the paper disk method. The highest mean concentrations of cephalexin in granuloma following administration of 250-mg cephalexin to nonfasting, 500-mg cephalexin to nonfasting, and 500-mg cephalexin to fasting patients were 1.62, 3.35 and 3.42 pg/g, respectively. The mean concentration ratios of granuloma/serum at the highest granuloma concentrations were 0.35, 0.32, and 0.30, respectively. Mean cephalexin concentrations in granuloma following administration of 500-rag cephalexin to both nonfasting and fasting patients exceeded MIC for 90% for clinically isolated strains of or-hemolytic streptococci. However, those obtained by 250-mg cephalexin did not exceed the MIC for 90%. REFERENCES
Akimoto Y., Kaneko K., Fujii A. and Yamamoto H. (1992) Ampicillin concentrations in human radicular granuloma following a single oral dose of bacampicillin. J. Oral Maxillofac. Surg. 50, 11 13. Akimoto Y., Kaneko K. and Tamura T. (1982) Amoxicillin concentrations in serum, jaw cyst, and jawbone following a single oral administration. J. Oral Maxillofac. Surg. 40, 287-293. Akimoto Y., Nishimura H., Komiya M., Kaneko K., Fujii A. and Tamura T. (1988) Ampicillin concentrations in human dental granuloma after a single oral administration of talampicillin. Antimicrob. Agents Chemother. 32, 566-567. Akimoto Y., Uda A., Omata H., Shibutani J., Nishimura H., Komiya M., Kaneko K. and Fujii A. (1990) Cephalexin concentrations in human serum, gingiva, and mandibular bone following a single oral administration. Gen. Pharmac. 21,621~23. Lecaillon J. B., Hirtz J. L., Schoeller J. P., Humbert G. and Vischer W. (1980) Pharmacokinetic comparison of cefroxadin (CGP 9000) and cephalexin by simultaneous administration to humans. Antimierob. Agents Chemother. 18, 656~500. Pfeffer M., Jackson A., Ximenes J. and Menezes J. P. D. (1977) Comparative human oral clinical pharmacology of cefadroxil, cephalexin, and cephradine. Antimicrob. Agent Chemother. 11, 331-338. Uda A., Omata H., Shibutani J., Nishimura H., Komiya M., Akimoto Y., Kaneko K. and Fujii A. (1989) Josamycin concentrations in human dental granuloma after a single oral administration of josamycin. Gen. Pharmac. 20, 823-825.