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Amoxicillin concentration in pus from abscess caused by odontogenic infection
Gen. Pharmac. Vol. 25, No. 1, pp. 111-113, 1994 Copyright © 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved 0306-3623/94 $6.00 + 0.00
Pergamon
Amoxicillin Concentration in Pus from Abscess Caused by Odontogenic Infection YOSHIAKI AKIMOTO, 1 YOSHIKO MOCHIZUKI, 1 AKIO UDA, I HIROAKI OMATA, I JUN SHIBUTANI, ) HITOSHI NISHIMURA, 1 MASAMICHI KOMIYA, I KENJU KANEKO 1 and AKIRA FUJII 2 Departments of tOral Surgery 2 and 2Pharmacology, 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 17 May 1993)
Abstraet--l. Amoxicillinconcentration in pus from odontogenic infection was assayed and the concentrations were compared with MIC (minimum inhibitory concentration) of or-hemolytic streptococci isolated from odontogenic infection. 2. Measurable amoxicillin concentrations in serum and pus were found in all instances (n = 16). 3. The mean peak concentrations in serum and pus were found at identical times, 1.5 hr after administration, which were 5.92 and 0.90 pg/ml, respectively. 4. The mean concentration ratio of pus/serum the at the peak time was 0.15. 5. All amoxicillin concentrations in pus at the peak time exceeded the MIC for 90% of ~-hemolytic streptococci (0.25/Lg/ml).
INTRODUCTION Abscesses caused by odontogenic infection are common in oral surgery. Antimicrobial therapy is an essential treatment, and penicillins or cephalosorins are being used as the first choice. However, there is no study on the antibiotic concentration in the abscess in the oral region. Thus, the present study was undertaken to determine amoxicillin concentrations in human pus of abscesses caused by odontogenic infection and serum following a single oral administration of amoxicillin. Amoxicillin concentrations in pus were compared with MIC of ~t-hemolytic streptococci isolated from odontogenic infection. MATERIALS AND METHODS Sixteen patients, who had been diagnosed as having abscesses caused by odontogenic infection, were subjected to the present study. All cases were limited to acute abscesses, in which it was possible to aspirate at least 0.2 ml of pus with minimal probability of any significant contamination. Of the patients, 9 were female and 7 were male. The mean age of the patients was 41 years old (range, 16-68 years old) and the mean body weight was 57 kg (range, 42-76 kg). No patient had been receiving any treatment involving antimicrobial therapy for at least 2 weeks before the aspiration. Ill
Each non-fasting patient was given a single oral dose of amoxicillin (500 mg, two 250-mg capsules of amoxicillin) with 200ml of water. Pus sample, was aspirated at 1, 1.5 or 2 hr after administration of amoxicillin. An approx. 3-ml sample of blood was also taken from the antecubital vein of each patient. Samples of pus and blood were collected once from each patient. The maximum time lag between the sampling time and intended time was 3 min. Serum was obtained by centrifugation. The pus sample (0.2 ml), which was mixed with 1 part of 1% phosphate buffer, pH 6.0, was homogenized and centrifuged. The resulting supernatant and serum were subjected to assay. Amoxicillin concentration was measured by the paper disk method. The test organism was Micrococcus luteus ATCC 9341. Bacto Penassay Seed agar (Difco) was the assay medium. Standards for serum and pus assays were prepared with 1% phosphate buffer, pH 6.0, and 5 amoxicillin concentrations were assayed (range, 0.01--0.25 #g/ml). Susceptibility of 23 strains of or-hemolytic streptococci isolated from odontogenic infections for amoxicillin were determined by the standard microdilution method, using Mueller Hinton broth (Difco).
YOSrnAKI AKIMOTO et al.
112
Table 1, Amoxicillin concentrations in pus and serum, and pus-toserum amoxicillin concentration ratios following a single oral administration Amoxicillin concentration Sampling time (hr) I
1.5
2
Case No.
Serum (#g/ml)
Pus (,u g/ml)
Pus-to-serum concentration ratio
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
5.60 10.40 4.10 1.50 1.30 8.00 2.80 4.80 7.80 6.20 6.20 5.60 1.60 3.30 2.60 6.80
0.27 0.63 0.70 0.10 0.15 1.41 0.42 0.58 1.16 0.91 1.19 0.97 0.31 0.73 0.42 1.09
0.05 0.06 0.17 0.07 0.12 0.18 0.15 0.12 0.15 0.15 0.19 0.17 0.19 0.22 0.16 0.16
RESULTS Amoxicillin concentrations in serum and pus, and the concentration ratio of pus-to-serum of each patient are summarized in Table 1. Measurable amoxicillin concentrations in pus were found in all instances (range, 0.10-1.41/~g/ml). The mean peak concentrations of amoxicillin in serum and pus occurred at identical times, 1.5hr after administration of amoxicillin. The mean peak concentrations (mean + SD) in serum and pus were 5.92 + 1.95 pg/ml (range, 2.80-8.00/lg/ml) and 0.90 + 0.36 pg/ml (range, 0.42-1.41 #g/ml), respectively (Table 2). The ratio (mean__ SD) of pusamoxicillin concentration-to-serum amoxicillin concentration at the mean peak time was 0.15 + 0.02 (range, 0.12-0.18) (Table 2). MIC for 90% of c~hemolytic streptococci of amoxicillin was 0.25/~g/ml. All amoxicillin concentrations in pus at the peak time exceeded the MIC for 90% for s-hemolytic streptococci. DISCUSSION There have been many previous studies on serum concentration after a single oral dose of 500 mg
Table 2. Mean amoxiciUin concentration in pus and serum, and mean pus-to-serum amoxicillin concentration ratios following a single oral administration Mean amoxillin concentration + SD Sampling time (hr) 1 1.5 2
Serum (/a g/ml)
Pus (#g/ml)
Mean pus-to-serum concentration ratio + SD
4.58 + 3.33 5.92+1.95 4.35+1.95
0.37 + 0.25 0.90+0.36 0.79+_0.33
0.09 + 0.04 0.15+0.02 0.18+_0.02
of amoxicillin, in which the peak serum concentration in the fasting state (5.9-10.8/~g/ml) is higher than that of the non-fasting state (5.1-8.0/~g/mi) (fasting state: Bodey and Nance, 1972; Crodon and Sutherland, 1971; Gordon et al., 1972; Miki et al., 1973; Neu et al., 1970, 1974; Philipson et al., 1975; Spyker et al., 1977; Ueda et al., 1973; Verbist, 1974; Welling et al., 1977) (non-fasting state: Akimoto et al., 1982, 1983; Miki et al., 1973; Nakagawa et al., 1973; Neu et al., 1970, 1974; Ueda et al., 1973; Welling et al., 1977). Furthermore, the peak time in the fasting state (1-2 hr) is earlier than that in the non-fasting state (1-3 hr). The present results (5.92/lg/ml) were similar to those of Spyker et al. (1977) (5.9 pg/ml), Akimoto et al. (1982, 1983) and Welling et al. (1977) (5.5-6pg/ml), which were obtained in the fasting and non-fasting states, respectively. Although amoxicillin was administered to non-fasting patient in the present study, each patient had a light meal because of the swelling of the abscess. Therefore, peak amoxicillin concentration and peak time in serum of the present study was similar to the reported concentrations in both fasting and nonfasting states. There are studies on amoxicillin concentrations in jaw cysts and jawbone following a single oral administration of amoxicillin (500mg) (Akimoto et aL, 1982). Cyst fluid-to-serum amoxicillin concentration ratios at the peak time were 0.22--0.27. The ratio of pus-to-serum (0.15) was lower than that of cyst fluid. Since the viscosity of pus was higher than that of cyst fluid, amoxicillin would show poor penetration into pus. Higher amoxicillin concentration in pus might be found in the early stages of abscess formation. The bacterium most commonly isolated from odontogenic infection are c~-hemolytic streptococci. All amoxicillin concentrations in pus at peak time exceeded MIC for 90% (0.25 #g/ml) for clinically isolated strains of s-hemolytic streptococci. Thus, effective amoxicillin concentrations in pus were found. In general, pus drainage is applied in practice. Since exact pus drainage can be performed because of the shallow location of most abscesses, it is advisable to combine this with a dosage of amoxicillin. In summary, since amoxicillin concentrations in pus following a single oral administration exceeded MIC for 90% of clinically isolated strains of ~hemolytic streptococci, amoxicillin may be a valuable agent for the treatment of odontogenic infection. However, when abscess formation is found, surgical drainage is advisable to be combined with dosage of amoxicillin.
Amoxicillin level in pus of oral infection
REFERENCES Akimoto Y., Kaneko K. and Tamura T. (1982) Amoxieillin concentrations in serum, jaw cyst, and jawbone following a single oral administration. J. Oral Maxillofac. Surg. 40, 287-293. Akimoto Y., Shibata T., Kaneko K., Fujii A. and Tamura T. (1983) Amoxicillin concentrations in human serum and gingiva following a single oral administration. IRCS Med. Sci. 11, 359-360. Bodey G. P. and Nance J. (1972) Amoxicillin: in vitro and pharmacological studies. Antimicrob. Agents Chemother. 1, 358-362. Croydon E. A. P. and Sutherland R. (1971)Alpha-aminohydroxybenzylpenicillin (BRL 2333), a new semisyntbetic penicillin: absorption and excretion in man. Antimicrob. Agents Chemother. 1970, 427-430. Gordon R. C., Regamay C. and Kirly W. M. M. (1972) Comparative clinical pharmacology of amoxicillin and ampicillin administered orally. Antimicrob. Agents Chemother. 1, 504-507. Miki F., Ozaki T., Hada M., Asai T., Kawai M. and Kubo K. (1973) Fundamental and clinical studies on amoxicillin. Chemother. (Tokyo)21, 1504-1516. Nakagawa K., Watanabe K., Kabe J., Fukui H., Suzuki T. and Fukui A. (1973) Clinical studies on amoxicillin. Chemother. (Tokyo)21, 1455-1462.
113
Neu H. C. (1974) Antimicrobial activity and human pharmacology of amoxicillin. J. Infect. Dis. 129, (Suppl.), S123-S131. Neu H. C. and Winshell E. B. (1970) Pharmacological studies of 6 [o ( - ) alpha-amino-para-hydroxyphenyllacetamido] penicillinic acid in human. Antimicrob. Agents Chemother. 1970, 423-426. Philipson A., Sabath L. D. and Rosner B. (1975) Sequence effect on ampicillin blood levels noted in an amoxicillin, ampicillin, and epicillin triple crossover study. Antimicrob. Agents Chemother. 8, 311-320. Spyker D. A., Rugloski R. J., Vann R. L. and O'Brien (1977) Pharmacokinetics of amoxicillin: dose dependence after intravenous, oral, and intramuscular administration. Antimicrob. Agents Chemother. 11, 132-141. Ueda Y., Matsumoto F., Saito A., Shimada J., Kobayashi C., Omori M., Shiba T., Yamaji T, and Saegusa M. (1973) Clinical and fundamental studies on amoxicillin. Chemother. (Tokyo)21, 1446-1454. Verbist L. (1974) Triple cross-over study on absorption and excretion of ampicillin, pivampicillin and amoxicillin. Antimicrob. Agents Chemother. 6, 588-593. Welling P. G., Huang H., Koch P, A., Craig W. A. and Madsen P. O. (1977) Effect of food on biovailability of ampicillin and amoxicillin in fasted and nonfasted subjects. 3. Pharm. Sci. 66, 549-552.
Pergamon
Amoxicillin Concentration in Pus from Abscess Caused by Odontogenic Infection YOSHIAKI AKIMOTO, 1 YOSHIKO MOCHIZUKI, 1 AKIO UDA, I HIROAKI OMATA, I JUN SHIBUTANI, ) HITOSHI NISHIMURA, 1 MASAMICHI KOMIYA, I KENJU KANEKO 1 and AKIRA FUJII 2 Departments of tOral Surgery 2 and 2Pharmacology, 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 17 May 1993)
Abstraet--l. Amoxicillinconcentration in pus from odontogenic infection was assayed and the concentrations were compared with MIC (minimum inhibitory concentration) of or-hemolytic streptococci isolated from odontogenic infection. 2. Measurable amoxicillin concentrations in serum and pus were found in all instances (n = 16). 3. The mean peak concentrations in serum and pus were found at identical times, 1.5 hr after administration, which were 5.92 and 0.90 pg/ml, respectively. 4. The mean concentration ratio of pus/serum the at the peak time was 0.15. 5. All amoxicillin concentrations in pus at the peak time exceeded the MIC for 90% of ~-hemolytic streptococci (0.25/Lg/ml).
INTRODUCTION Abscesses caused by odontogenic infection are common in oral surgery. Antimicrobial therapy is an essential treatment, and penicillins or cephalosorins are being used as the first choice. However, there is no study on the antibiotic concentration in the abscess in the oral region. Thus, the present study was undertaken to determine amoxicillin concentrations in human pus of abscesses caused by odontogenic infection and serum following a single oral administration of amoxicillin. Amoxicillin concentrations in pus were compared with MIC of ~t-hemolytic streptococci isolated from odontogenic infection. MATERIALS AND METHODS Sixteen patients, who had been diagnosed as having abscesses caused by odontogenic infection, were subjected to the present study. All cases were limited to acute abscesses, in which it was possible to aspirate at least 0.2 ml of pus with minimal probability of any significant contamination. Of the patients, 9 were female and 7 were male. The mean age of the patients was 41 years old (range, 16-68 years old) and the mean body weight was 57 kg (range, 42-76 kg). No patient had been receiving any treatment involving antimicrobial therapy for at least 2 weeks before the aspiration. Ill
Each non-fasting patient was given a single oral dose of amoxicillin (500 mg, two 250-mg capsules of amoxicillin) with 200ml of water. Pus sample, was aspirated at 1, 1.5 or 2 hr after administration of amoxicillin. An approx. 3-ml sample of blood was also taken from the antecubital vein of each patient. Samples of pus and blood were collected once from each patient. The maximum time lag between the sampling time and intended time was 3 min. Serum was obtained by centrifugation. The pus sample (0.2 ml), which was mixed with 1 part of 1% phosphate buffer, pH 6.0, was homogenized and centrifuged. The resulting supernatant and serum were subjected to assay. Amoxicillin concentration was measured by the paper disk method. The test organism was Micrococcus luteus ATCC 9341. Bacto Penassay Seed agar (Difco) was the assay medium. Standards for serum and pus assays were prepared with 1% phosphate buffer, pH 6.0, and 5 amoxicillin concentrations were assayed (range, 0.01--0.25 #g/ml). Susceptibility of 23 strains of or-hemolytic streptococci isolated from odontogenic infections for amoxicillin were determined by the standard microdilution method, using Mueller Hinton broth (Difco).
YOSrnAKI AKIMOTO et al.
112
Table 1, Amoxicillin concentrations in pus and serum, and pus-toserum amoxicillin concentration ratios following a single oral administration Amoxicillin concentration Sampling time (hr) I
1.5
2
Case No.
Serum (#g/ml)
Pus (,u g/ml)
Pus-to-serum concentration ratio
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
5.60 10.40 4.10 1.50 1.30 8.00 2.80 4.80 7.80 6.20 6.20 5.60 1.60 3.30 2.60 6.80
0.27 0.63 0.70 0.10 0.15 1.41 0.42 0.58 1.16 0.91 1.19 0.97 0.31 0.73 0.42 1.09
0.05 0.06 0.17 0.07 0.12 0.18 0.15 0.12 0.15 0.15 0.19 0.17 0.19 0.22 0.16 0.16
RESULTS Amoxicillin concentrations in serum and pus, and the concentration ratio of pus-to-serum of each patient are summarized in Table 1. Measurable amoxicillin concentrations in pus were found in all instances (range, 0.10-1.41/~g/ml). The mean peak concentrations of amoxicillin in serum and pus occurred at identical times, 1.5hr after administration of amoxicillin. The mean peak concentrations (mean + SD) in serum and pus were 5.92 + 1.95 pg/ml (range, 2.80-8.00/lg/ml) and 0.90 + 0.36 pg/ml (range, 0.42-1.41 #g/ml), respectively (Table 2). The ratio (mean__ SD) of pusamoxicillin concentration-to-serum amoxicillin concentration at the mean peak time was 0.15 + 0.02 (range, 0.12-0.18) (Table 2). MIC for 90% of c~hemolytic streptococci of amoxicillin was 0.25/~g/ml. All amoxicillin concentrations in pus at the peak time exceeded the MIC for 90% for s-hemolytic streptococci. DISCUSSION There have been many previous studies on serum concentration after a single oral dose of 500 mg
Table 2. Mean amoxiciUin concentration in pus and serum, and mean pus-to-serum amoxicillin concentration ratios following a single oral administration Mean amoxillin concentration + SD Sampling time (hr) 1 1.5 2
Serum (/a g/ml)
Pus (#g/ml)
Mean pus-to-serum concentration ratio + SD
4.58 + 3.33 5.92+1.95 4.35+1.95
0.37 + 0.25 0.90+0.36 0.79+_0.33
0.09 + 0.04 0.15+0.02 0.18+_0.02
of amoxicillin, in which the peak serum concentration in the fasting state (5.9-10.8/~g/ml) is higher than that of the non-fasting state (5.1-8.0/~g/mi) (fasting state: Bodey and Nance, 1972; Crodon and Sutherland, 1971; Gordon et al., 1972; Miki et al., 1973; Neu et al., 1970, 1974; Philipson et al., 1975; Spyker et al., 1977; Ueda et al., 1973; Verbist, 1974; Welling et al., 1977) (non-fasting state: Akimoto et al., 1982, 1983; Miki et al., 1973; Nakagawa et al., 1973; Neu et al., 1970, 1974; Ueda et al., 1973; Welling et al., 1977). Furthermore, the peak time in the fasting state (1-2 hr) is earlier than that in the non-fasting state (1-3 hr). The present results (5.92/lg/ml) were similar to those of Spyker et al. (1977) (5.9 pg/ml), Akimoto et al. (1982, 1983) and Welling et al. (1977) (5.5-6pg/ml), which were obtained in the fasting and non-fasting states, respectively. Although amoxicillin was administered to non-fasting patient in the present study, each patient had a light meal because of the swelling of the abscess. Therefore, peak amoxicillin concentration and peak time in serum of the present study was similar to the reported concentrations in both fasting and nonfasting states. There are studies on amoxicillin concentrations in jaw cysts and jawbone following a single oral administration of amoxicillin (500mg) (Akimoto et aL, 1982). Cyst fluid-to-serum amoxicillin concentration ratios at the peak time were 0.22--0.27. The ratio of pus-to-serum (0.15) was lower than that of cyst fluid. Since the viscosity of pus was higher than that of cyst fluid, amoxicillin would show poor penetration into pus. Higher amoxicillin concentration in pus might be found in the early stages of abscess formation. The bacterium most commonly isolated from odontogenic infection are c~-hemolytic streptococci. All amoxicillin concentrations in pus at peak time exceeded MIC for 90% (0.25 #g/ml) for clinically isolated strains of s-hemolytic streptococci. Thus, effective amoxicillin concentrations in pus were found. In general, pus drainage is applied in practice. Since exact pus drainage can be performed because of the shallow location of most abscesses, it is advisable to combine this with a dosage of amoxicillin. In summary, since amoxicillin concentrations in pus following a single oral administration exceeded MIC for 90% of clinically isolated strains of ~hemolytic streptococci, amoxicillin may be a valuable agent for the treatment of odontogenic infection. However, when abscess formation is found, surgical drainage is advisable to be combined with dosage of amoxicillin.
Amoxicillin level in pus of oral infection
REFERENCES Akimoto Y., Kaneko K. and Tamura T. (1982) Amoxieillin concentrations in serum, jaw cyst, and jawbone following a single oral administration. J. Oral Maxillofac. Surg. 40, 287-293. Akimoto Y., Shibata T., Kaneko K., Fujii A. and Tamura T. (1983) Amoxicillin concentrations in human serum and gingiva following a single oral administration. IRCS Med. Sci. 11, 359-360. Bodey G. P. and Nance J. (1972) Amoxicillin: in vitro and pharmacological studies. Antimicrob. Agents Chemother. 1, 358-362. Croydon E. A. P. and Sutherland R. (1971)Alpha-aminohydroxybenzylpenicillin (BRL 2333), a new semisyntbetic penicillin: absorption and excretion in man. Antimicrob. Agents Chemother. 1970, 427-430. Gordon R. C., Regamay C. and Kirly W. M. M. (1972) Comparative clinical pharmacology of amoxicillin and ampicillin administered orally. Antimicrob. Agents Chemother. 1, 504-507. Miki F., Ozaki T., Hada M., Asai T., Kawai M. and Kubo K. (1973) Fundamental and clinical studies on amoxicillin. Chemother. (Tokyo)21, 1504-1516. Nakagawa K., Watanabe K., Kabe J., Fukui H., Suzuki T. and Fukui A. (1973) Clinical studies on amoxicillin. Chemother. (Tokyo)21, 1455-1462.
113
Neu H. C. (1974) Antimicrobial activity and human pharmacology of amoxicillin. J. Infect. Dis. 129, (Suppl.), S123-S131. Neu H. C. and Winshell E. B. (1970) Pharmacological studies of 6 [o ( - ) alpha-amino-para-hydroxyphenyllacetamido] penicillinic acid in human. Antimicrob. Agents Chemother. 1970, 423-426. Philipson A., Sabath L. D. and Rosner B. (1975) Sequence effect on ampicillin blood levels noted in an amoxicillin, ampicillin, and epicillin triple crossover study. Antimicrob. Agents Chemother. 8, 311-320. Spyker D. A., Rugloski R. J., Vann R. L. and O'Brien (1977) Pharmacokinetics of amoxicillin: dose dependence after intravenous, oral, and intramuscular administration. Antimicrob. Agents Chemother. 11, 132-141. Ueda Y., Matsumoto F., Saito A., Shimada J., Kobayashi C., Omori M., Shiba T., Yamaji T, and Saegusa M. (1973) Clinical and fundamental studies on amoxicillin. Chemother. (Tokyo)21, 1446-1454. Verbist L. (1974) Triple cross-over study on absorption and excretion of ampicillin, pivampicillin and amoxicillin. Antimicrob. Agents Chemother. 6, 588-593. Welling P. G., Huang H., Koch P, A., Craig W. A. and Madsen P. O. (1977) Effect of food on biovailability of ampicillin and amoxicillin in fasted and nonfasted subjects. 3. Pharm. Sci. 66, 549-552.