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Treatment of Urinary Tract Infections with Cephalexin
Vol. 106, November
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1971 by The Williams & Wilkins Co.
TREATMENT OF URINARY TRACT INFECTIONS WITH CEPHALEXIN KLAUS MOHRING, HELGE G. GENSTER
AND
PAUL 0. MADSEN*
From the Urology Section, Veterans Administration Hospital and the Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin
An oral antibiotic, cephalexin-, a cephalosporin-C derivative, has been developed. The almost complete absorption from the gastrointestinal tract, the high urine concentrations obtained following almost exclusive excretion via the kidneys, the broad-spectrum activity against common urinary pathogens and its reportedly low rate of side effects would indicate that cephalexin may be a promising antibiotic in the treatment of urinary tract infections. 1- 7 We have tested the efficacy and safety of cephalexin in the treatment of mainly chronic urinary tract infections and determined the concentration of the antibiotic in blood and urine of patients with normal and impaired renal function. MATERIALS AND METHOD
There were 121 male patients (average age of 69 years) with lower urinary tract infection and lower urinary tract obstruction of various etiology Accepted for publication December 1970. * Requests for reprints: Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705. 1 Braun, P., Tillotson, J. R., Wilcox, C. and Finland, M.: Cephalexin and cephaloglycin activity in vitro and absorption and urinary excretion of single oral doses in normal young adults. Appl. Microbial., 16: 1684, 1968. 2 Chou, T. S.: Isolation and identification of cephalexin from human urine. J. Med. Chem., 12: 925, 1969.
3 Gower, P. E. and Dash, C. H.: Cephalexin: human studies of absorption and excretion of new cephalosporin antibiotic. Brit. J. Pharmacol., 37:
738, 1969.
4 Kind, A. C., Kestle, D. G., Standiford, H. C. and Kirby, W. M. M.: Laboratory and clinical experience with cephalexin. Antimicrob. Agents Chemother., 8: 361, 1968. 5 Mohring, K., Pech, H. and Hartschuh, W.: Ergebnisse der oralen Cephalexinmedikation bei ambulanten Patienten mit akuten und chronischen Harnwegsinfektionen. Int. Z. Klin. Pharmakal. Ther. Toxik., in press. 6 Perkins, R. L., Carlisle, H. N. and Saslaw, S.: Cephalexin: in vitro bacterial susceptibility, absorption in volunteers, and antibacterial activity of sera and urine. Amer. J. Med. Sci., 266:
122, 1968. 7 Wick, W. E.: Cephalexin, a new orally absorbed cephalosporin antibiotic. Appl. Microbial.,
16: 765, 1967.
and degree treated with 250 mg. oral cephalexin 3 times daily for 14 days or 500 mg. 3 times daily for 14 days. During cephalexin therapy 45 patients underwent transurethral resection of the prostate or bladder. Diagnoses in all cases are noted in table 1. Most patients had been treated previously with other chemotherapeutic agents or antibiotics and, thus, many cases represented recurrent or persistent infections. Urine cultures were obtained before and at various intervals during and following treatment from midstream urine. Colony counts of more than 5,000 organisms per ml. were considered positive. There were 95 patients with normal renal function as indicated by blood urea nitrogen less than 30 mg. per cent and/or serum creatinine less than 1.5 mg. per cent and/or creatinine clearance more than 75 ml. per minute, whereas 26 patients had impaired renal function. The studies in the azotemic patients were carried out not only to evaluate the efficacy but also the possible accumulation of cephalexin as well as side effects. Almost all azotemic patients had indwelling catheters for various reasons (complete urinary retention, urinary incontinence and/or terminal stage of cancer). Therefore, it was expected that the effect of cephalexin on the urinary tract infection in these patients would be poor. All organisms isolated were tested for sensitivity against cephalexin and the other cephalosporin derivatives: cephaloglycin, cephaloridine and cephalothin, as well as against most commonly used antibiotics using disk sensitivity testing. A 30 µg. disk was used for cephalexin and an inhibition zone size of 16 mm. following overnight incubation was considered as the dividing point between sensitivity and resistance of the micro-organism. 1• 4 • 5- 9 Bio-assays of cephalexin in blood and urine were carried out by a cup-plate method using Sarcina lutea as test organism. Various laboratory analyses were done 8 Clark, H. and Turck, M.: In vitro and in vivo evaluation of cephalexin. Antimicrob. Agents Chemother., 8: 296, 1968. 9 Levison, M. E., Johnson, W. D., Thornhill, T. S. and Kaye, D.: Clinical and in vitro eval nation of cephalexin. J.A.M.A., 209: 1331, 1969.
757
758
MOHRING, GENSTER AND MADSEN
·,
NO TREATMENT
40 Patients
100
- . 36 Patients
TREATMENT WITH CEPHALEXIN ORALLY 14 OAYS
33 Patients 750mg/Day' 0
50
50Patient1' -
"
___.j
======·.-:.,.,-~
~ 4 1 Patients
1500mg/Ooy - • 45Patients
0 DAY OF CULTURE.
7th
ISi
14th
I0-45th
Fm. 1. Course of urinary tract infection in untreated control group and in 2 comparable patient groups with normal renal function treated with 250 mg. cephalexin 3 times daily or 500 mg. 3 times daily for 2 weeks. before and immediately following completion of the treatment with cephalexin: urinalysis, complete blood count, blood urea nitrogen, serum creatinine, alkaline phosphatase and serum glutamic oxaloacetic transaminase.
1. Diagnoses in 121 patients with urinary
tract infection
Prostatic hypertrophy Cancer of prostate Cancer of bladder Epididymitis, prostatitis Hydronephrosis, pyelonephritis N eurogenic bladder Bladder calculi Bladder diverticulum Urethral stricture
20 "j
.,ui
~ "':I. ~
TABLE
15
lo: a::
!z
i ~
Totals
Normal Renal Function
Impaired Renal Function
51
7
10 3 3 0 6
1 3 1 3
0 0 0
95
26
14 7
8
4
10
~
RESULTS
z
The in vitro sensitivity and the bacteriological response to treatment in 95 patients with normal renal function were noted (table 2). We found no statistically significant difference between results from treatment with 750 mg. daily and 1,500 mg. daily. Another measure of the efficacy of cephalexin in the treatment of chronic urinary tract infection was the percentage of patients infected during and following cephalexin treatment as compared to an untreated control group of 40 patients undergoing transurethral resection of the prostate, all infected at the time of the operation (fig. 1). This group of patients had been followed 1 to 2 years prior to the cephalexin study but since the 2 groups represent the same type of patients they were considered comparable.10
§
iw
5
i ,_l DAY OF TREATMENT
I 7 14
-½l-½7'°'14-!-----'-l,',7:'-l,..f4---{
I 7 14
I 7 14
700
700
700
1500
1000
CREATINNE CLEARANCE 75.9 ±S.E. ml/min :t.5.0
53.3 t6.0
260
74.1
22.1
CEPHALEXIN
ffiQ/DAY
NUMBER OF PATIENTS
6
:!-3.8
tB.6
±50
9
Fm. 2. Cephalexin serum concentrations in patients with normal renal function, slightly impaired renal function and poor renal function as expressed by creatinine clearance. Cephalexin doses were 250 mg. 3 times daily for 14 days or 500 mg. 3 times daily for 14 days. All blood samples were obtained 2 hours following administration of medication at 9 a.m. Slight accumulation of cephalexin in blood is seen in patients with poor renal function treated for 14 days with 1,500 mg. daily.
10 Genster, H. G. and Madsen, P. 0.: Urinary tract infections following transurethral prostatec-
759
TREATMENT OF URINARY TRACT INFECTIONS WITH CEPHALEXIN
The results from bio-assays of urine and blood in patients with normal and impaired renal function at 2 dose levels are seen in figure 2. Some accumulation of the drug in patients with impaired renal function is noted when the creatinine clearance is less than 50 ml. per minute.11 Cephalexin in doses of 750 mg. a day has considerable clinical effect in the treatment of urinary tract infections. Au increase in dosage does not seem to improve the clinical results. The 750 mg. dose was divided into 3, 250 mg. doses and during this regimen urine concentrations of cephalexin in all 24-hour urine portions were higher than 100 µg. per ml. in patients with normal renal function (a veragc 325 µg. per ml.) and higher than 65 µg. per ml. in all patients with impaired renal function (average 198 µg. per ml.). Therefore, this urine concentration should easily be bactericidal to any organism showing sensitivity to the 30 µg. test disk. 1 • 4 · 6 - 9 , 12 This explains the good correlation between the bacteriological results and the in vitro testing. The results of in vitro cephalexin testing corresponded well to similar results for cephaloglycin, cephalothin and cephaloridine. In a few cases discrepancies between the sensitivity pattern of the 4 antibiotics were found but for practical purposes sensitivity testing to only one of these antibiotics would be sufficient. The relatively unsatisfactory clinical response is explained by the chronic and recunent nature of the infections. Approximately 25 per cent of patients with normal renal function and 50 per cent of patients with impaired renal function had more than 1 infecting micro-organism at some time during treatment. This explains why satisfactory bacteriological results in azotemic patients were only obtained in 6 of 13 strains considered sensitive to cephalexin and in only 2 of 15 strains considered resistant. In only 1 of 26 patients with impaired renal function was a completely sterile urine obtained and a total of 21 new micro-organisms, all resistant to cephalexin, appeared in the urine of these patients during treatment. Side effects. Cephalexin was well tolerated. In 1 patient the treatment had to be discontinued tomy: with special reference to the use of antimicrobials. J. Urol., 104: 163, 1970. 11 Kabins, S. A., Kelner, B., Walton, E. and Goldstein, E.: Cephalcxin therapy as related to renal function. Amer. J. l\led. Sci., 259: 133, 1970. 12 Griffith, IL S. and Black, H. R.: Cephalexin: a new antibiotic. Clin. Med., 75: 14, 1968.
2. Bacteriological response to cephalexin treatment in 95 patients with normal renal function (119 micro-organisms isolated)
TABU~
No. Strains Eradi·· cated or Reduced During Treatment*
E.coli Proteus mirabilis Klebsiella-Aerobacter Pseudomonas Proteus morganii Streptococcus faecalis Staphylococcus
Totals
f,,
31 19
9 0 13 8
80
26 17
0
g 0
0 13 8
73 (91%)
15 7 0
39
15 (38%)
Less than .5,000 colonies per milliliter.
because of a generalized skin rash probably caused by the drug. In 1 patient there was a slight transient increase in the serum glutamic oxaloacetic transaminase value. Ko other toxic effects on renal function, hepatic function and bone marrow activity as estimated by the previously mentioned tests were noted. No noticeable side effects were seen in any patients with impaired renal function despite the described accumulation. Development of resistance. Only 4 micro-organisms (3.4 per cent) considered sensitive to cephalexin before treatment developed resistance during the treatment (2 Proteus strains and 2 Escherichia coli strains). DISCUSSION
In our study the total amount of excreted cephalexin was only 50 to 60 per cent of the administered dose. The reason for this could be that the patients were not fasting, resulting in a recovery loss of approximately 10 per cent, and that almost all our patients were old. These old patients may have lowered gastrointestinal absorption. The relatively low blood values of cephalexin 2 hours following administration support this assumption. Since our were carried out almost 1 month after the samples had been taken we also may have a potency loss of an additional 10 per cent despite deep freezing of the specimens. 1 • 6 • 12 • 13 In 4 normal, young, 13 Thornhill, T. S., Levison, M. E., Johnson, W. D. and Kaye, D.: In vitro antimicrobial activity and human pharmacology of cephalexin, a
760
MOHRING, GENSTER AND MADSEN
non-fasting volunteers in whom the bio-assays were carried out immediately after obtaining the urine samples we were able to recover from 90 to 100 per cent of the ingested cephalexin, confirming the results of other investigators. 1- 3 , 12 SUMMARY
There were 121 male patients with chronic lower urinary tract infection treated with oral new orally absorbed cephalosporin C antibiotic. Appl. Microbiol., 17: 457, 1969.
cephalexin (750 mg. or 1,500 mg. per day for 12 days). Cephalexin was of considerable value in the treatment of urinary tract infections. An increase in dose from 750 to 1,500 mg. cephalexin daily did not influence clinical results. Cephalexin was tolerated well in patients with normal as well as in patients with impaired renal function with minimal side effects, although some accumulation of cephalexin in the serum of the latter was noted.
THE JOURNAL OF UROLOGY
Printed in U.S.A.
Copyright© 1971 by The Williams & Wilkins Co.
TREATMENT OF URINARY TRACT INFECTIONS WITH CEPHALEXIN KLAUS MOHRING, HELGE G. GENSTER
AND
PAUL 0. MADSEN*
From the Urology Section, Veterans Administration Hospital and the Department of Surgery, University of Wisconsin School of Medicine, Madison, Wisconsin
An oral antibiotic, cephalexin-, a cephalosporin-C derivative, has been developed. The almost complete absorption from the gastrointestinal tract, the high urine concentrations obtained following almost exclusive excretion via the kidneys, the broad-spectrum activity against common urinary pathogens and its reportedly low rate of side effects would indicate that cephalexin may be a promising antibiotic in the treatment of urinary tract infections. 1- 7 We have tested the efficacy and safety of cephalexin in the treatment of mainly chronic urinary tract infections and determined the concentration of the antibiotic in blood and urine of patients with normal and impaired renal function. MATERIALS AND METHOD
There were 121 male patients (average age of 69 years) with lower urinary tract infection and lower urinary tract obstruction of various etiology Accepted for publication December 1970. * Requests for reprints: Veterans Administration Hospital, 2500 Overlook Terrace, Madison, Wisconsin 53705. 1 Braun, P., Tillotson, J. R., Wilcox, C. and Finland, M.: Cephalexin and cephaloglycin activity in vitro and absorption and urinary excretion of single oral doses in normal young adults. Appl. Microbial., 16: 1684, 1968. 2 Chou, T. S.: Isolation and identification of cephalexin from human urine. J. Med. Chem., 12: 925, 1969.
3 Gower, P. E. and Dash, C. H.: Cephalexin: human studies of absorption and excretion of new cephalosporin antibiotic. Brit. J. Pharmacol., 37:
738, 1969.
4 Kind, A. C., Kestle, D. G., Standiford, H. C. and Kirby, W. M. M.: Laboratory and clinical experience with cephalexin. Antimicrob. Agents Chemother., 8: 361, 1968. 5 Mohring, K., Pech, H. and Hartschuh, W.: Ergebnisse der oralen Cephalexinmedikation bei ambulanten Patienten mit akuten und chronischen Harnwegsinfektionen. Int. Z. Klin. Pharmakal. Ther. Toxik., in press. 6 Perkins, R. L., Carlisle, H. N. and Saslaw, S.: Cephalexin: in vitro bacterial susceptibility, absorption in volunteers, and antibacterial activity of sera and urine. Amer. J. Med. Sci., 266:
122, 1968. 7 Wick, W. E.: Cephalexin, a new orally absorbed cephalosporin antibiotic. Appl. Microbial.,
16: 765, 1967.
and degree treated with 250 mg. oral cephalexin 3 times daily for 14 days or 500 mg. 3 times daily for 14 days. During cephalexin therapy 45 patients underwent transurethral resection of the prostate or bladder. Diagnoses in all cases are noted in table 1. Most patients had been treated previously with other chemotherapeutic agents or antibiotics and, thus, many cases represented recurrent or persistent infections. Urine cultures were obtained before and at various intervals during and following treatment from midstream urine. Colony counts of more than 5,000 organisms per ml. were considered positive. There were 95 patients with normal renal function as indicated by blood urea nitrogen less than 30 mg. per cent and/or serum creatinine less than 1.5 mg. per cent and/or creatinine clearance more than 75 ml. per minute, whereas 26 patients had impaired renal function. The studies in the azotemic patients were carried out not only to evaluate the efficacy but also the possible accumulation of cephalexin as well as side effects. Almost all azotemic patients had indwelling catheters for various reasons (complete urinary retention, urinary incontinence and/or terminal stage of cancer). Therefore, it was expected that the effect of cephalexin on the urinary tract infection in these patients would be poor. All organisms isolated were tested for sensitivity against cephalexin and the other cephalosporin derivatives: cephaloglycin, cephaloridine and cephalothin, as well as against most commonly used antibiotics using disk sensitivity testing. A 30 µg. disk was used for cephalexin and an inhibition zone size of 16 mm. following overnight incubation was considered as the dividing point between sensitivity and resistance of the micro-organism. 1• 4 • 5- 9 Bio-assays of cephalexin in blood and urine were carried out by a cup-plate method using Sarcina lutea as test organism. Various laboratory analyses were done 8 Clark, H. and Turck, M.: In vitro and in vivo evaluation of cephalexin. Antimicrob. Agents Chemother., 8: 296, 1968. 9 Levison, M. E., Johnson, W. D., Thornhill, T. S. and Kaye, D.: Clinical and in vitro eval nation of cephalexin. J.A.M.A., 209: 1331, 1969.
757
758
MOHRING, GENSTER AND MADSEN
·,
NO TREATMENT
40 Patients
100
- . 36 Patients
TREATMENT WITH CEPHALEXIN ORALLY 14 OAYS
33 Patients 750mg/Day' 0
50
50Patient1' -
"
___.j
======·.-:.,.,-~
~ 4 1 Patients
1500mg/Ooy - • 45Patients
0 DAY OF CULTURE.
7th
ISi
14th
I0-45th
Fm. 1. Course of urinary tract infection in untreated control group and in 2 comparable patient groups with normal renal function treated with 250 mg. cephalexin 3 times daily or 500 mg. 3 times daily for 2 weeks. before and immediately following completion of the treatment with cephalexin: urinalysis, complete blood count, blood urea nitrogen, serum creatinine, alkaline phosphatase and serum glutamic oxaloacetic transaminase.
1. Diagnoses in 121 patients with urinary
tract infection
Prostatic hypertrophy Cancer of prostate Cancer of bladder Epididymitis, prostatitis Hydronephrosis, pyelonephritis N eurogenic bladder Bladder calculi Bladder diverticulum Urethral stricture
20 "j
.,ui
~ "':I. ~
TABLE
15
lo: a::
!z
i ~
Totals
Normal Renal Function
Impaired Renal Function
51
7
10 3 3 0 6
1 3 1 3
0 0 0
95
26
14 7
8
4
10
~
RESULTS
z
The in vitro sensitivity and the bacteriological response to treatment in 95 patients with normal renal function were noted (table 2). We found no statistically significant difference between results from treatment with 750 mg. daily and 1,500 mg. daily. Another measure of the efficacy of cephalexin in the treatment of chronic urinary tract infection was the percentage of patients infected during and following cephalexin treatment as compared to an untreated control group of 40 patients undergoing transurethral resection of the prostate, all infected at the time of the operation (fig. 1). This group of patients had been followed 1 to 2 years prior to the cephalexin study but since the 2 groups represent the same type of patients they were considered comparable.10
§
iw
5
i ,_l DAY OF TREATMENT
I 7 14
-½l-½7'°'14-!-----'-l,',7:'-l,..f4---{
I 7 14
I 7 14
700
700
700
1500
1000
CREATINNE CLEARANCE 75.9 ±S.E. ml/min :t.5.0
53.3 t6.0
260
74.1
22.1
CEPHALEXIN
ffiQ/DAY
NUMBER OF PATIENTS
6
:!-3.8
tB.6
±50
9
Fm. 2. Cephalexin serum concentrations in patients with normal renal function, slightly impaired renal function and poor renal function as expressed by creatinine clearance. Cephalexin doses were 250 mg. 3 times daily for 14 days or 500 mg. 3 times daily for 14 days. All blood samples were obtained 2 hours following administration of medication at 9 a.m. Slight accumulation of cephalexin in blood is seen in patients with poor renal function treated for 14 days with 1,500 mg. daily.
10 Genster, H. G. and Madsen, P. 0.: Urinary tract infections following transurethral prostatec-
759
TREATMENT OF URINARY TRACT INFECTIONS WITH CEPHALEXIN
The results from bio-assays of urine and blood in patients with normal and impaired renal function at 2 dose levels are seen in figure 2. Some accumulation of the drug in patients with impaired renal function is noted when the creatinine clearance is less than 50 ml. per minute.11 Cephalexin in doses of 750 mg. a day has considerable clinical effect in the treatment of urinary tract infections. Au increase in dosage does not seem to improve the clinical results. The 750 mg. dose was divided into 3, 250 mg. doses and during this regimen urine concentrations of cephalexin in all 24-hour urine portions were higher than 100 µg. per ml. in patients with normal renal function (a veragc 325 µg. per ml.) and higher than 65 µg. per ml. in all patients with impaired renal function (average 198 µg. per ml.). Therefore, this urine concentration should easily be bactericidal to any organism showing sensitivity to the 30 µg. test disk. 1 • 4 · 6 - 9 , 12 This explains the good correlation between the bacteriological results and the in vitro testing. The results of in vitro cephalexin testing corresponded well to similar results for cephaloglycin, cephalothin and cephaloridine. In a few cases discrepancies between the sensitivity pattern of the 4 antibiotics were found but for practical purposes sensitivity testing to only one of these antibiotics would be sufficient. The relatively unsatisfactory clinical response is explained by the chronic and recunent nature of the infections. Approximately 25 per cent of patients with normal renal function and 50 per cent of patients with impaired renal function had more than 1 infecting micro-organism at some time during treatment. This explains why satisfactory bacteriological results in azotemic patients were only obtained in 6 of 13 strains considered sensitive to cephalexin and in only 2 of 15 strains considered resistant. In only 1 of 26 patients with impaired renal function was a completely sterile urine obtained and a total of 21 new micro-organisms, all resistant to cephalexin, appeared in the urine of these patients during treatment. Side effects. Cephalexin was well tolerated. In 1 patient the treatment had to be discontinued tomy: with special reference to the use of antimicrobials. J. Urol., 104: 163, 1970. 11 Kabins, S. A., Kelner, B., Walton, E. and Goldstein, E.: Cephalcxin therapy as related to renal function. Amer. J. l\led. Sci., 259: 133, 1970. 12 Griffith, IL S. and Black, H. R.: Cephalexin: a new antibiotic. Clin. Med., 75: 14, 1968.
2. Bacteriological response to cephalexin treatment in 95 patients with normal renal function (119 micro-organisms isolated)
TABU~
No. Strains Eradi·· cated or Reduced During Treatment*
E.coli Proteus mirabilis Klebsiella-Aerobacter Pseudomonas Proteus morganii Streptococcus faecalis Staphylococcus
Totals
f,,
31 19
9 0 13 8
80
26 17
0
g 0
0 13 8
73 (91%)
15 7 0
39
15 (38%)
Less than .5,000 colonies per milliliter.
because of a generalized skin rash probably caused by the drug. In 1 patient there was a slight transient increase in the serum glutamic oxaloacetic transaminase value. Ko other toxic effects on renal function, hepatic function and bone marrow activity as estimated by the previously mentioned tests were noted. No noticeable side effects were seen in any patients with impaired renal function despite the described accumulation. Development of resistance. Only 4 micro-organisms (3.4 per cent) considered sensitive to cephalexin before treatment developed resistance during the treatment (2 Proteus strains and 2 Escherichia coli strains). DISCUSSION
In our study the total amount of excreted cephalexin was only 50 to 60 per cent of the administered dose. The reason for this could be that the patients were not fasting, resulting in a recovery loss of approximately 10 per cent, and that almost all our patients were old. These old patients may have lowered gastrointestinal absorption. The relatively low blood values of cephalexin 2 hours following administration support this assumption. Since our were carried out almost 1 month after the samples had been taken we also may have a potency loss of an additional 10 per cent despite deep freezing of the specimens. 1 • 6 • 12 • 13 In 4 normal, young, 13 Thornhill, T. S., Levison, M. E., Johnson, W. D. and Kaye, D.: In vitro antimicrobial activity and human pharmacology of cephalexin, a
760
MOHRING, GENSTER AND MADSEN
non-fasting volunteers in whom the bio-assays were carried out immediately after obtaining the urine samples we were able to recover from 90 to 100 per cent of the ingested cephalexin, confirming the results of other investigators. 1- 3 , 12 SUMMARY
There were 121 male patients with chronic lower urinary tract infection treated with oral new orally absorbed cephalosporin C antibiotic. Appl. Microbiol., 17: 457, 1969.
cephalexin (750 mg. or 1,500 mg. per day for 12 days). Cephalexin was of considerable value in the treatment of urinary tract infections. An increase in dose from 750 to 1,500 mg. cephalexin daily did not influence clinical results. Cephalexin was tolerated well in patients with normal as well as in patients with impaired renal function with minimal side effects, although some accumulation of cephalexin in the serum of the latter was noted.