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Chronic Pain Syndrome
Penetration of Cefrnenoxime into Serum, Gynecologic Tissues, and Heart Valves
F.D. DASCHNER, M.D. E.E. PETERSEN, M.b. U.FRANK Freiburg, Federal Republic of Germany
D. HORNIG, M.D. Erlangen, Federal Republic of Germany
Twenty-nine women received 7 g of cefmendxime before abdominal or vaginal hysterectomy; 20 adult patients received 2 g of cefrnenoxime 24 hours and immediately before open heart surgery. In the gynecologic patients, peak cefmenoxime serum concentrations of 23.4 mg/llter were reached within dne to two hours after administration of the antibiotic. Cefmenoxlme concentrations in myometrium, endometrium, and salpinges also reached their peak one to two hours after administration. Two to three hours later tissue concentrations varied between 1.1 and 5.2 1'9/g; four hours after application, tissue concentrations were below detectable levels. Cefrnenoxime plasma and tissue concentrations were significantly higher in patients undergoing open heart surgery. Subcutaneous tissue and muscle concentrations varied between 2.7 and 38.0 #Lg/g. Cefmenoxime ,concentrations in cardiac valvular tissue were higher than those in muscle and fat. The present study was performed to determine the concentrations of cefmenoxime in serum, myometrium, endometrium, salpinges, subcutaneous tissue, muscle, and heart valves after an intravenous injection of 2 g. A further objective was to investigate whether cefmenoxime tissue concentrations are high enough to prevent postoperative wound infections after abdominal or open heart surgery. MATERIALS AND METHODS
From the Departments of Hospital Epidemiology and Gynecoiogy, University Hospital of Frelburg, Freiburg, Federai Republic of Germany, and the Department of Cardiac Surgery, University Hospital of Erlangen, Erlangen, Federal Republic of Germany. Requests for reprints should be addressed to Dr. F.D. Daschner, Department of Hospital Epidemiology, University Hospital of Freiburg, Hugstetter Str. 55, 7800 Freiburg, Federal Republic of Germany.
4
December 21, 1984
Twenty-nine women (mean age 43.8 years, mean body weight 64.9 kg) received 7 g of cefmenoxime intravenously as a 5-minute bolus injection at various times (one to two, two to three, three to four, four to five, five to six hours) before abdominal or vaginal hysterectomy. Twenty adult patients, all with normal renal function (mean age 53.3 years, mean body weight 73.1 kg) with valvular ot coronary heart disease were given 2 g of cefmenoxime as a 5-minute intravenous bolus injection between four hours and Immediately before surgery. The operations were always performed by the same surgical team. Informed consent was obtained from each patient. Venous blood and tissue samples were taken from each patient during the operation. All samples were deep frozen at -72°C immediately after collection and assayed within four to eight weeks. Cefmenoxime concentrations were assayed by an agar diffusion method with antibiotic medium number 2 (oxoid) supplemented with 2 g of natrium citrate per liter and Bacillus subtilis ATCC 6633 as test organism. Serum samples, diluted when necessary in pooled human serum, were assayed against standard samples in human seruin. Blood adhering to tissue samples was swabbed off with gauze and extracted with phosphate buffer pH 7, using a Coleworth stomacher number 80. The tissue assay was carried out against standard samples dissolved in phosphate buffer of pH 7.
The American Journal of Medicine
Volume
n
(suppl &A)
SYMPOSIUM ON CEFMENOXIME-DASCHNER ET AL
TABLE I
Plasma and Tissue Concentrations of Cefmenoxime in Gynecologic Bolus Injection of 7 g
Pa~ients
after a
Hours
Site Plasma Myometrium Endometrium Salpinges
1-2
2-3
3-4
4-5
5-6
23.4 ± 5.8· (3)t 7.6 ± 3.9 (3) 4.9 ± 4.9 (2) 8.2 ± 4.2 (3)
9.7 ± 2.3 (4) 3.6 ± 1.3 (6) 5.2 ± 3.6 (4) 3.1 ± 1.3 (6)
7.2 ± 2.8 (5) 2.9 ± 1.~ (5) 1.1 ± 0.8 (5) 2.1 ± 1.6 (4)
1.7 ± 0.5 (7) 0 (4) 0 (7) 0 (7)
0.9 ± 0.3 (7) 0 (7) 0 (7) 0 (7)
·oata are means ± standard deviation. tNumber of specimens assayed.
RESULTS
In the group of gynecologic patients, peak cefmenoxime serum concentrations of 23.4 mg/liter were reached within one to two hours qfter administration of the antibiotic (Table I). Unfortunately, no specimens would be obtained earlier, at which time cefmenoxime serum concentrations would have been higher. The concentrations declined slowly thereafter. Concentrations of 7.2 mg/liter could still be measured three to four hours after administration; five to six hours after administration, only 0.9 mg/liter could be found (Table I). Cefmenoxime concentrations in myometrium, endometrium, and salpinges also reached their peak one to two hours after administration. Two to three hours later tissue concentrations varied between 1.1 and 5.2 mg/liter. Four hours after application, tissue concentrations were below detectable levels. Cefmenoxime penetrates equally well into myometrium, endometrium, and salpinges. Cefmenoxime plasma Cjnd tissue concentration were significantly higher in patients undergoing open heart surgery (Table II). Within four hours cefmenoxime plasma
TABLE II
concentrations declined from 134.9 to 11.6 mg/liter. Subcutaneous tissue and muscle concentrations varied between 2.7 and 38.0 ILglg. Cefmenoxime concentrations in cardiac valvular tissue were higher than those in muscle and fat. The decline in concentrations almost paralleled that in plasma, suggesting rapid diffusion and exchange of the antibiotic between plasma and valvular tissue. COMMENTS
The serum concentrations in the gynecologic patients were somewhat lower than those after bolus injection of 7 g of cefmenoxime in healthy male volunteers [1]. Cefmenoxime concentrations in plasma during cardiac bypass were higher than those in healthy adults, possibly because of decreased clearance during the operation. Cardiac bypC!SS seems to increase the serum half-life of cefmenoxime. Cefmenoxime concentrations in gynecologic tissues have to date been studied by Japanese investigators [2]. Cho et al [2] found that 60 to 135 minutes after Intravenous injection of 1 g of cefmenoxime, the concentrations
Plasma (mg/liter) and Tissue (/Lg/g) Concentrations of Cefmenoxime in Patients Undergoing Open Heart Surgery after a Bolus Injection of 2 g Hours
Plasma Subcutaneous tissue Muscle Heart valves
0-1
1.:.2
134.9 ± 18.4. (17)t 38.0 ± 6.8 (9) 34.4 ± 7.9 (8) 44.4±6.1 (8)
49.8 ± 5.5 (14) 19.8 ± 8.4 (5) 11.3 ± 4.0 (5) 28.8 ± 13.1 (9)
2,..3 20.7 ± (7) 7.4 ± (4) 4.1 ± (3) 14.3 ± (3)
3-4 4.2 3.1 2.1 5.4
15.1 ± (6) 4.5 ± (4) 6.5 ± (3) 5.5 ± (2)
5.8 2.8 3.5 1.1
4-5
5-6
11.6 ± 7.2 (4) 2.7 ± 2.1 (3) 1.4 ± 0.8 (3)
4.3 ± 0.7 (2)
p
(1)
1.1 (1) 3.3 (1)
·oata are means ± standard deviation. tNumber of specimens assayed.
December 21, 1984
Thl! American Journal of Medicine
Volume 77 (suppl SA)
5
SYMPOSIUM ON CEFMENOXIME-DASCHNER ET AL
in myometrium varied between 10.0 and 5.4 JLglg and in endometrium between 10.5 and 5.9 JLglg. Concentrations in ~glpinges were as high as those in myometrium and endometrium. In heart valves, cefmenoxime reaches concentrations substantially higher than those in muscle and subcutaneous fat. These results compare favorably with previous pharmacokinetic studies of cephradine, cefamandole, cefsulodin, gentamicin, and piperacillin [3-6]. Therefore, vascularity of the heart valves does not seem to determine cefmenoxime tissue concentrations. Cefmenoxime has excellent in vitro activity against most organisms causing gynecologic infections or infections after open heart surgery [7 -1 0]. The 90 percent minimal inhibitory concentration (MIC) for Escherichia coli is
0.12 mg/liter, for Klebsiella pneumoniae 0.125 mg/liter, for C:nterobacter cloacae 0.5 mg/liter, for indole-positive Proteus strains and Staphylococcus aureus strains 2 mg/ml. Cefmenoxime concentrations in gynecologic tissues are, for at least three hours after application, above the MIC for most organisms isolated from gynecologic infections, except enterococci and some gram-negative species such as Pseudomonas aeruginosa. Cefmenoxime is not the antibiotic of first choice in the treatment of gramnegative anaerobic infections. Cefmenoxime heart valve concentrations seem to be high enough for treatment of patients with endocarditis caused by Staphylococcus aureus, S. epidermidis, and most gram-negative bacterial species and also for prophylaxis of postoperative infection after open heart surgery.
REFERENCES 1.
2.
3.
4.
5.
6
Granneman RG, Senello LT, Steinberg FJ, Sonders RC: Intramuscular and intravenous pharmacokinetics of cefmenoxime, a new broad-spectrum cephalosporin, in healthy subjects. Antimicrob Agents Chemother 1982; 21: 141-145. Cho N, Fukunaga K, Kunii M: Fundamental and clinical studies of cefmenoxime (SCE-1365) in the field of obstetrics and gynecology. Chemother (Tokyo) 1981; 29(suppl1): 930-940. Daschner F, Eschenbruch E, Me!l B, Bayer E, Schmuziger M: Penetration of gentamicin into heart valves; subcutaneous tissue and muscle of patients undergoing open-heart surgery. J Cardiovas Surg 1981; 22: 581 '-584. Daschner F, Langmaack H, Spillner H, Admadi A, Schlosser V: Penetration of cephradine into heart valves, subcutaneous tissue and muscle of patients undergoing open-heart surgery. J Antimicrob Chemother 1979; 5: 711-715. Daschner F, Metz B, Spillner G, Buzello W, Schlosser V: Concentration of cefamandole and cefsulodin in serum, heart valves, subcutaneous tissue and muscle of patients undergoing open-heart surgery. J Infect Dis 1980; 142: 290.
December 21, 1984
The American Journal of Medicine
Daschner F, Just M, Spillner G, Schlosser V: Penetration of piperacillin into cardiac valves, subcutaneous and muscle tissue of patients undergoing open-heart surgery. J Antimicrob Chemother 1982; 9: 489-492. 7. Kesado T, Watanabe K, Asahi Y, lsono M, Ueno K: Susceptibilities of anaerobic bacteria to N-Formimidoyl Thienamycin (MK0787) and to other antibiotics. Antimicrob Agents Chemother 1982; 21: 1016-1022. 8. Khan MY, Siddiqui Y, Simpson ML, Gruninger RP: Comparative in vitro activity of cefmenoxime, cefotaxime, cefuroxime, cefoxitin, and penicillin against Neisseria gonorrhoeae. Antimicrob Agents Chemother 1981; 20: 681-682. 9. Stamm JM, Girolami RL, Shipkowitz NL, Bower RB: Antimicrobial activity of cefmenoxime (SCE~1365). Anti111icrob Agents Chemother 1981; 19: 454-460. 10. Tsuchiya K, Kondo M, Kida M, et al: Cefmenoxime (SCE-1365), a: novel broad-spectrum cephalosporin: in vitro and in vivo antipacterial ·activities. Antimicrob Agents Chemother 1981 ; 19: 56-65. 6.
Volume 77 (suppl 6A)
F.D. DASCHNER, M.D. E.E. PETERSEN, M.b. U.FRANK Freiburg, Federal Republic of Germany
D. HORNIG, M.D. Erlangen, Federal Republic of Germany
Twenty-nine women received 7 g of cefmendxime before abdominal or vaginal hysterectomy; 20 adult patients received 2 g of cefrnenoxime 24 hours and immediately before open heart surgery. In the gynecologic patients, peak cefmenoxime serum concentrations of 23.4 mg/llter were reached within dne to two hours after administration of the antibiotic. Cefmenoxlme concentrations in myometrium, endometrium, and salpinges also reached their peak one to two hours after administration. Two to three hours later tissue concentrations varied between 1.1 and 5.2 1'9/g; four hours after application, tissue concentrations were below detectable levels. Cefrnenoxime plasma and tissue concentrations were significantly higher in patients undergoing open heart surgery. Subcutaneous tissue and muscle concentrations varied between 2.7 and 38.0 #Lg/g. Cefmenoxime ,concentrations in cardiac valvular tissue were higher than those in muscle and fat. The present study was performed to determine the concentrations of cefmenoxime in serum, myometrium, endometrium, salpinges, subcutaneous tissue, muscle, and heart valves after an intravenous injection of 2 g. A further objective was to investigate whether cefmenoxime tissue concentrations are high enough to prevent postoperative wound infections after abdominal or open heart surgery. MATERIALS AND METHODS
From the Departments of Hospital Epidemiology and Gynecoiogy, University Hospital of Frelburg, Freiburg, Federai Republic of Germany, and the Department of Cardiac Surgery, University Hospital of Erlangen, Erlangen, Federal Republic of Germany. Requests for reprints should be addressed to Dr. F.D. Daschner, Department of Hospital Epidemiology, University Hospital of Freiburg, Hugstetter Str. 55, 7800 Freiburg, Federal Republic of Germany.
4
December 21, 1984
Twenty-nine women (mean age 43.8 years, mean body weight 64.9 kg) received 7 g of cefmenoxime intravenously as a 5-minute bolus injection at various times (one to two, two to three, three to four, four to five, five to six hours) before abdominal or vaginal hysterectomy. Twenty adult patients, all with normal renal function (mean age 53.3 years, mean body weight 73.1 kg) with valvular ot coronary heart disease were given 2 g of cefmenoxime as a 5-minute intravenous bolus injection between four hours and Immediately before surgery. The operations were always performed by the same surgical team. Informed consent was obtained from each patient. Venous blood and tissue samples were taken from each patient during the operation. All samples were deep frozen at -72°C immediately after collection and assayed within four to eight weeks. Cefmenoxime concentrations were assayed by an agar diffusion method with antibiotic medium number 2 (oxoid) supplemented with 2 g of natrium citrate per liter and Bacillus subtilis ATCC 6633 as test organism. Serum samples, diluted when necessary in pooled human serum, were assayed against standard samples in human seruin. Blood adhering to tissue samples was swabbed off with gauze and extracted with phosphate buffer pH 7, using a Coleworth stomacher number 80. The tissue assay was carried out against standard samples dissolved in phosphate buffer of pH 7.
The American Journal of Medicine
Volume
n
(suppl &A)
SYMPOSIUM ON CEFMENOXIME-DASCHNER ET AL
TABLE I
Plasma and Tissue Concentrations of Cefmenoxime in Gynecologic Bolus Injection of 7 g
Pa~ients
after a
Hours
Site Plasma Myometrium Endometrium Salpinges
1-2
2-3
3-4
4-5
5-6
23.4 ± 5.8· (3)t 7.6 ± 3.9 (3) 4.9 ± 4.9 (2) 8.2 ± 4.2 (3)
9.7 ± 2.3 (4) 3.6 ± 1.3 (6) 5.2 ± 3.6 (4) 3.1 ± 1.3 (6)
7.2 ± 2.8 (5) 2.9 ± 1.~ (5) 1.1 ± 0.8 (5) 2.1 ± 1.6 (4)
1.7 ± 0.5 (7) 0 (4) 0 (7) 0 (7)
0.9 ± 0.3 (7) 0 (7) 0 (7) 0 (7)
·oata are means ± standard deviation. tNumber of specimens assayed.
RESULTS
In the group of gynecologic patients, peak cefmenoxime serum concentrations of 23.4 mg/liter were reached within one to two hours qfter administration of the antibiotic (Table I). Unfortunately, no specimens would be obtained earlier, at which time cefmenoxime serum concentrations would have been higher. The concentrations declined slowly thereafter. Concentrations of 7.2 mg/liter could still be measured three to four hours after administration; five to six hours after administration, only 0.9 mg/liter could be found (Table I). Cefmenoxime concentrations in myometrium, endometrium, and salpinges also reached their peak one to two hours after administration. Two to three hours later tissue concentrations varied between 1.1 and 5.2 mg/liter. Four hours after application, tissue concentrations were below detectable levels. Cefmenoxime penetrates equally well into myometrium, endometrium, and salpinges. Cefmenoxime plasma Cjnd tissue concentration were significantly higher in patients undergoing open heart surgery (Table II). Within four hours cefmenoxime plasma
TABLE II
concentrations declined from 134.9 to 11.6 mg/liter. Subcutaneous tissue and muscle concentrations varied between 2.7 and 38.0 ILglg. Cefmenoxime concentrations in cardiac valvular tissue were higher than those in muscle and fat. The decline in concentrations almost paralleled that in plasma, suggesting rapid diffusion and exchange of the antibiotic between plasma and valvular tissue. COMMENTS
The serum concentrations in the gynecologic patients were somewhat lower than those after bolus injection of 7 g of cefmenoxime in healthy male volunteers [1]. Cefmenoxime concentrations in plasma during cardiac bypass were higher than those in healthy adults, possibly because of decreased clearance during the operation. Cardiac bypC!SS seems to increase the serum half-life of cefmenoxime. Cefmenoxime concentrations in gynecologic tissues have to date been studied by Japanese investigators [2]. Cho et al [2] found that 60 to 135 minutes after Intravenous injection of 1 g of cefmenoxime, the concentrations
Plasma (mg/liter) and Tissue (/Lg/g) Concentrations of Cefmenoxime in Patients Undergoing Open Heart Surgery after a Bolus Injection of 2 g Hours
Plasma Subcutaneous tissue Muscle Heart valves
0-1
1.:.2
134.9 ± 18.4. (17)t 38.0 ± 6.8 (9) 34.4 ± 7.9 (8) 44.4±6.1 (8)
49.8 ± 5.5 (14) 19.8 ± 8.4 (5) 11.3 ± 4.0 (5) 28.8 ± 13.1 (9)
2,..3 20.7 ± (7) 7.4 ± (4) 4.1 ± (3) 14.3 ± (3)
3-4 4.2 3.1 2.1 5.4
15.1 ± (6) 4.5 ± (4) 6.5 ± (3) 5.5 ± (2)
5.8 2.8 3.5 1.1
4-5
5-6
11.6 ± 7.2 (4) 2.7 ± 2.1 (3) 1.4 ± 0.8 (3)
4.3 ± 0.7 (2)
p
(1)
1.1 (1) 3.3 (1)
·oata are means ± standard deviation. tNumber of specimens assayed.
December 21, 1984
Thl! American Journal of Medicine
Volume 77 (suppl SA)
5
SYMPOSIUM ON CEFMENOXIME-DASCHNER ET AL
in myometrium varied between 10.0 and 5.4 JLglg and in endometrium between 10.5 and 5.9 JLglg. Concentrations in ~glpinges were as high as those in myometrium and endometrium. In heart valves, cefmenoxime reaches concentrations substantially higher than those in muscle and subcutaneous fat. These results compare favorably with previous pharmacokinetic studies of cephradine, cefamandole, cefsulodin, gentamicin, and piperacillin [3-6]. Therefore, vascularity of the heart valves does not seem to determine cefmenoxime tissue concentrations. Cefmenoxime has excellent in vitro activity against most organisms causing gynecologic infections or infections after open heart surgery [7 -1 0]. The 90 percent minimal inhibitory concentration (MIC) for Escherichia coli is
0.12 mg/liter, for Klebsiella pneumoniae 0.125 mg/liter, for C:nterobacter cloacae 0.5 mg/liter, for indole-positive Proteus strains and Staphylococcus aureus strains 2 mg/ml. Cefmenoxime concentrations in gynecologic tissues are, for at least three hours after application, above the MIC for most organisms isolated from gynecologic infections, except enterococci and some gram-negative species such as Pseudomonas aeruginosa. Cefmenoxime is not the antibiotic of first choice in the treatment of gramnegative anaerobic infections. Cefmenoxime heart valve concentrations seem to be high enough for treatment of patients with endocarditis caused by Staphylococcus aureus, S. epidermidis, and most gram-negative bacterial species and also for prophylaxis of postoperative infection after open heart surgery.
REFERENCES 1.
2.
3.
4.
5.
6
Granneman RG, Senello LT, Steinberg FJ, Sonders RC: Intramuscular and intravenous pharmacokinetics of cefmenoxime, a new broad-spectrum cephalosporin, in healthy subjects. Antimicrob Agents Chemother 1982; 21: 141-145. Cho N, Fukunaga K, Kunii M: Fundamental and clinical studies of cefmenoxime (SCE-1365) in the field of obstetrics and gynecology. Chemother (Tokyo) 1981; 29(suppl1): 930-940. Daschner F, Eschenbruch E, Me!l B, Bayer E, Schmuziger M: Penetration of gentamicin into heart valves; subcutaneous tissue and muscle of patients undergoing open-heart surgery. J Cardiovas Surg 1981; 22: 581 '-584. Daschner F, Langmaack H, Spillner H, Admadi A, Schlosser V: Penetration of cephradine into heart valves, subcutaneous tissue and muscle of patients undergoing open-heart surgery. J Antimicrob Chemother 1979; 5: 711-715. Daschner F, Metz B, Spillner G, Buzello W, Schlosser V: Concentration of cefamandole and cefsulodin in serum, heart valves, subcutaneous tissue and muscle of patients undergoing open-heart surgery. J Infect Dis 1980; 142: 290.
December 21, 1984
The American Journal of Medicine
Daschner F, Just M, Spillner G, Schlosser V: Penetration of piperacillin into cardiac valves, subcutaneous and muscle tissue of patients undergoing open-heart surgery. J Antimicrob Chemother 1982; 9: 489-492. 7. Kesado T, Watanabe K, Asahi Y, lsono M, Ueno K: Susceptibilities of anaerobic bacteria to N-Formimidoyl Thienamycin (MK0787) and to other antibiotics. Antimicrob Agents Chemother 1982; 21: 1016-1022. 8. Khan MY, Siddiqui Y, Simpson ML, Gruninger RP: Comparative in vitro activity of cefmenoxime, cefotaxime, cefuroxime, cefoxitin, and penicillin against Neisseria gonorrhoeae. Antimicrob Agents Chemother 1981; 20: 681-682. 9. Stamm JM, Girolami RL, Shipkowitz NL, Bower RB: Antimicrobial activity of cefmenoxime (SCE~1365). Anti111icrob Agents Chemother 1981; 19: 454-460. 10. Tsuchiya K, Kondo M, Kida M, et al: Cefmenoxime (SCE-1365), a: novel broad-spectrum cephalosporin: in vitro and in vivo antipacterial ·activities. Antimicrob Agents Chemother 1981 ; 19: 56-65. 6.
Volume 77 (suppl 6A)