CEFAZOLIN AND CEPHALEXIN LEVELS IN PROSTATIC TISSUE AND SERA AUSTIN S. LITVAK, M.D. CHARLES
D. FRANKS,
M.D.
STEPHEN
K. VAUGHT,
M.D.
J. WILLIAM
McROBERTS,
M.D.
From the Department of Surgery, Division of Urology, University of Kentucky Medical Center, Lexington, Kentucky
ABSTRACT -A study was carried out on 18 patients given cefazolin intramuscularly and 17 patients given cephalexin by mouth preoperatively prior to transurethral resection of the prostate. Prostatic tissue and serum levels of the two drugs were determined and contrasted with previously reported mean inhibitory concentrations. It was found that cefazolin was present in the sera and prostatic tissues in levels greater than was cephalexin and that cefazolin frequently exceeded the minimum inhibitory concentrations necessary fm sensitive organisms to be affected, whereas cephalexin did not. Therefore, it would appear that cefawlin would be preferable to cephalexin in treatment of acute bacterial prostatitis.
Recently cefazolin (Kefzol)*, a new parenteral cephalosporin, has become available for clinical use. The drug has broad-spectrum antibacterial activity, being effective against many grampositive and -negative organisms.’ Because the drug is particularly active against gram-negative bacteria, it has obvious appeal in treating urinary tract infections.2 Since the spectrum of antibacterial activity of cefazolin includes most of the causative organisms of bacterial prostatitis, a study was undertaken to determine the levels of cefazolin in the prostate gland. Cephalexin (Keflex)* was used as a comparative drug to determine relative drug concentrations, both in the serum and in the prostatic tissue. Cefazolin is a semisynthetic cephalosporin which reportedly produces high and more prolonged blood levels than either cephalothin or cephaloridine. It is also reported to have a longer Presented at Southeastern Section, American Urologic Association, Inc., Atlanta, Georgia, April 13, 1975. *Supported by a grant from Eli Lilly & Company.
UROLOGY
I
MAY 1976 / VOLUME
VII, NUMBER
5
half-life than either of these drugs. Cefazolin is distributed throughout many areas of the body but reaches its highest concentration in the kidney. It is excreted primarily unchanged by glomerular filtration, but there is also some slight degree of tubular secretion. Approximately 60 per cent of the drug is cleared from the serum in six hours in a normal person, while in those patients with a creatinine clearance below 20 ml. per minute the half life increases precipitously. The drug is 86 per cent protein-bound and is reported to show less renal toxicity than cephaloridine.3 Methods A comparison drug study was carried out on 35 male patients with significant prostatism secondary to benign prostatic hyperplasia who were about to undergo transurethral resection of the prostate. Renal function was normal in all. The patients were divided into two groups. Eighteen of the patients were given 500 mg. of cefazolin intramuscularly from forty-five minutes to two hours and forty-five minutes prior to the trans-
497
TABLE I. Number of patients demonstrating prostatic tissue and serum levels of cefazolin and cephalexin Levels
kg.)
Cefazolin 0 to 5 6 to 10
11 to 15 Over 15 TOTALS Cephalexin 0 to 5 6 to 10
11 to 15 Over 15 TOTALS
Serum No. of Patients
Prostate No. of Patients
1
4
0
9
_A 18
1
18
7 5
10 7
A17
-L 17
resection, and the other group of 17 patients received 500 mg. orally of cephalexin at 890 P.M. and at midnight the night prior to surgery and 500 mg. from forty minutes to two hours before surgery. Simultaneous specimens of prostate and blood were taken during the first part of the resection. The serum was separated from the blood sample by centrifugation and the prostatic chips, obtained at the time of drawing blood, and the sera were placed in a freezer following completion of the resection. Microbiologic assay of the activity of the antibiotics was carried out utilizing the disk plate method with Bacillus subtilis as the test organism. urethral
Findings The serum level of cefazolin was found to be 15 micrograms per milliliter or greater in all but one sample. The prostatic tissue levels in all patients but 4 who showed no drug present were noted to be 7 micrograms or better. In 1 of the 4 patients no drug was detected in the serum. Nine patients had levels from 6 to 10 micrograms per gram, 2 patients from 11 to 15 micrograms per gram, and 3 patients had more than 15 micrograms per gram (Table I). Among those patients who received cephalexin, it was noted that only 2 patients had a serum level more than 15 micrograms per milliliter. In 10 patients the prostatic levels obtained ranged from 0.5 to 5 micrograms per gram, and in 7 patients from 6 to 10 micrograms per gram. None of the patients had more than 10 micrograms per gram of cephalexin in the prostatic tissue (Table I).
498
Comment Utilizing the results obtained in a previous study in determining the minimum inhibitory concentrations for cefazolin,4 it was noted that the following gram-negative bacteria, Escherichia coli, Enterobacter aerogenes, Klebsiella species, and Proteus mirabilis were sensitive to minimum inhibitory concentrations of 4 micrograms per milliliter or more. Enterobacter cloacae, Proteus morganii, rettgeri, and vulgaris, as well as all Pseudomonas species tested were resistant to minimum inhibitory concentrations of cefazolin lower than 32 micrograms per milliliter. Cephalexin, on the other hand, was found to have in vitro minimum inhibitory concentrations in sera to E. coli, Klebsiella, and enterobacter species that ranged from 12.5 micrograms to 25 micrograms per milliliter. However, at this level, not all strains were inhibited.5 It has been difficult to obtain hard data on a dry weight basis of prostatic tissues in determining the amount of antibiotics truly present. However, in this study, even allowing for the washing effects of irrigating fluid, it becomes clear that there is a definite difference in the amount of the two antibiotics in the prostate. Recognizing that in the inflamed prostate, the pH and pK change to inhibit penetrance of the antibiotics in the prostate,6 one can hypothesize that given similar circumstances cefazolin will penetrate the prostate and provide a greater concentration of available drug than will cephalexin. Because of the difference of in vitro minimum inhibitory concentrations obtained for the two drugs, it would appear that cefazolin would be a more suitable antibiotic which could penetrate the prostate in levels that would be clinically effective in eradicating infection. Lexington,
Kentucky 40506 (DR. LITVAK)
References 1. Eli Lilly and Company: Kefzol (cefazolin sodium), Drug Information Form, 1973. 2. ISHIYAIV~A, S., et al. : Absorption, tissue concentration, and organ distribution of cefazolin, J. Antimicro. Agents Chemother. 10:476(1970). 3. GIUSTI, D. L.: The cephalosporins, J. Drug Intelligence Clin. Pharm. 7: 252 (1973). 4. Clinical Investigation Manual: Cefazolin Sodium, Indidianapolis, Eli Lilly and Co., 1974, p. 9. 5. MEYERS, B. R., et al.: Cephalexin: microbiological effects and pharmacologic parameters in man, Clin. Pharmacol. Ther. 10:810 (1968). 6. MEARES, E. M., JR.: Prostatitis: a review, Urol. Clin. N. America 2: 11 (1975).
UROLOGY
/ MAY 1976 / VOLUME
VII, NUMBER 5
D. FRANKS,
M.D.
STEPHEN
K. VAUGHT,
M.D.
J. WILLIAM
McROBERTS,
M.D.
From the Department of Surgery, Division of Urology, University of Kentucky Medical Center, Lexington, Kentucky
ABSTRACT -A study was carried out on 18 patients given cefazolin intramuscularly and 17 patients given cephalexin by mouth preoperatively prior to transurethral resection of the prostate. Prostatic tissue and serum levels of the two drugs were determined and contrasted with previously reported mean inhibitory concentrations. It was found that cefazolin was present in the sera and prostatic tissues in levels greater than was cephalexin and that cefazolin frequently exceeded the minimum inhibitory concentrations necessary fm sensitive organisms to be affected, whereas cephalexin did not. Therefore, it would appear that cefawlin would be preferable to cephalexin in treatment of acute bacterial prostatitis.
Recently cefazolin (Kefzol)*, a new parenteral cephalosporin, has become available for clinical use. The drug has broad-spectrum antibacterial activity, being effective against many grampositive and -negative organisms.’ Because the drug is particularly active against gram-negative bacteria, it has obvious appeal in treating urinary tract infections.2 Since the spectrum of antibacterial activity of cefazolin includes most of the causative organisms of bacterial prostatitis, a study was undertaken to determine the levels of cefazolin in the prostate gland. Cephalexin (Keflex)* was used as a comparative drug to determine relative drug concentrations, both in the serum and in the prostatic tissue. Cefazolin is a semisynthetic cephalosporin which reportedly produces high and more prolonged blood levels than either cephalothin or cephaloridine. It is also reported to have a longer Presented at Southeastern Section, American Urologic Association, Inc., Atlanta, Georgia, April 13, 1975. *Supported by a grant from Eli Lilly & Company.
UROLOGY
I
MAY 1976 / VOLUME
VII, NUMBER
5
half-life than either of these drugs. Cefazolin is distributed throughout many areas of the body but reaches its highest concentration in the kidney. It is excreted primarily unchanged by glomerular filtration, but there is also some slight degree of tubular secretion. Approximately 60 per cent of the drug is cleared from the serum in six hours in a normal person, while in those patients with a creatinine clearance below 20 ml. per minute the half life increases precipitously. The drug is 86 per cent protein-bound and is reported to show less renal toxicity than cephaloridine.3 Methods A comparison drug study was carried out on 35 male patients with significant prostatism secondary to benign prostatic hyperplasia who were about to undergo transurethral resection of the prostate. Renal function was normal in all. The patients were divided into two groups. Eighteen of the patients were given 500 mg. of cefazolin intramuscularly from forty-five minutes to two hours and forty-five minutes prior to the trans-
497
TABLE I. Number of patients demonstrating prostatic tissue and serum levels of cefazolin and cephalexin Levels
kg.)
Cefazolin 0 to 5 6 to 10
11 to 15 Over 15 TOTALS Cephalexin 0 to 5 6 to 10
11 to 15 Over 15 TOTALS
Serum No. of Patients
Prostate No. of Patients
1
4
0
9
_A 18
1
18
7 5
10 7
A17
-L 17
resection, and the other group of 17 patients received 500 mg. orally of cephalexin at 890 P.M. and at midnight the night prior to surgery and 500 mg. from forty minutes to two hours before surgery. Simultaneous specimens of prostate and blood were taken during the first part of the resection. The serum was separated from the blood sample by centrifugation and the prostatic chips, obtained at the time of drawing blood, and the sera were placed in a freezer following completion of the resection. Microbiologic assay of the activity of the antibiotics was carried out utilizing the disk plate method with Bacillus subtilis as the test organism. urethral
Findings The serum level of cefazolin was found to be 15 micrograms per milliliter or greater in all but one sample. The prostatic tissue levels in all patients but 4 who showed no drug present were noted to be 7 micrograms or better. In 1 of the 4 patients no drug was detected in the serum. Nine patients had levels from 6 to 10 micrograms per gram, 2 patients from 11 to 15 micrograms per gram, and 3 patients had more than 15 micrograms per gram (Table I). Among those patients who received cephalexin, it was noted that only 2 patients had a serum level more than 15 micrograms per milliliter. In 10 patients the prostatic levels obtained ranged from 0.5 to 5 micrograms per gram, and in 7 patients from 6 to 10 micrograms per gram. None of the patients had more than 10 micrograms per gram of cephalexin in the prostatic tissue (Table I).
498
Comment Utilizing the results obtained in a previous study in determining the minimum inhibitory concentrations for cefazolin,4 it was noted that the following gram-negative bacteria, Escherichia coli, Enterobacter aerogenes, Klebsiella species, and Proteus mirabilis were sensitive to minimum inhibitory concentrations of 4 micrograms per milliliter or more. Enterobacter cloacae, Proteus morganii, rettgeri, and vulgaris, as well as all Pseudomonas species tested were resistant to minimum inhibitory concentrations of cefazolin lower than 32 micrograms per milliliter. Cephalexin, on the other hand, was found to have in vitro minimum inhibitory concentrations in sera to E. coli, Klebsiella, and enterobacter species that ranged from 12.5 micrograms to 25 micrograms per milliliter. However, at this level, not all strains were inhibited.5 It has been difficult to obtain hard data on a dry weight basis of prostatic tissues in determining the amount of antibiotics truly present. However, in this study, even allowing for the washing effects of irrigating fluid, it becomes clear that there is a definite difference in the amount of the two antibiotics in the prostate. Recognizing that in the inflamed prostate, the pH and pK change to inhibit penetrance of the antibiotics in the prostate,6 one can hypothesize that given similar circumstances cefazolin will penetrate the prostate and provide a greater concentration of available drug than will cephalexin. Because of the difference of in vitro minimum inhibitory concentrations obtained for the two drugs, it would appear that cefazolin would be a more suitable antibiotic which could penetrate the prostate in levels that would be clinically effective in eradicating infection. Lexington,
Kentucky 40506 (DR. LITVAK)
References 1. Eli Lilly and Company: Kefzol (cefazolin sodium), Drug Information Form, 1973. 2. ISHIYAIV~A, S., et al. : Absorption, tissue concentration, and organ distribution of cefazolin, J. Antimicro. Agents Chemother. 10:476(1970). 3. GIUSTI, D. L.: The cephalosporins, J. Drug Intelligence Clin. Pharm. 7: 252 (1973). 4. Clinical Investigation Manual: Cefazolin Sodium, Indidianapolis, Eli Lilly and Co., 1974, p. 9. 5. MEYERS, B. R., et al.: Cephalexin: microbiological effects and pharmacologic parameters in man, Clin. Pharmacol. Ther. 10:810 (1968). 6. MEARES, E. M., JR.: Prostatitis: a review, Urol. Clin. N. America 2: 11 (1975).
UROLOGY
/ MAY 1976 / VOLUME
VII, NUMBER 5
