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Doxycycline in the Treatment of Infections of the Urinary Tract
V0L l.02, _-\.ug,
TE..Vi Jou.HKAL OF llB.01.01__·:ry
Printed
Copy righi.. (g) 1969 by The VVilliarns & \Vilkins
C
DOXYCYCLINE IN THE TREATMENT OF I:'\.FECTIONS OF THE URINARY TRACT WILLIAM J. HOLLOWAY, JOHN H. FURLONG
AND
E.G. SCOTT
From the Infectious Disease Research Laboratory, Pyelonephritis Clinic, lvlicrobiology Department, Wilmington Medical Center, Wilmington, Delaware
peated, when possible, at weekly intervals during therapy Cultures were obtained 6 weeks following cessation of therapy in all but 7 cases. In these instances, cultures were obtained at least 4 weeks after termination of therapy. Complete blood count, urinalysis, blood urea nitrogen and serum glutamic oxaloacetic transaminase determinations were obtained before and after treatment in all patients. Serurn antibiotic and antibacterial levels also were obtained in selected cases. The infecting organisms were tested for doxycycline susceptibility by the agar diffusion disk technique. Doxycycline was supplied as 50 mg. capsules for oral administration and was given by 2 dosr1ge schedules. In 36 courses of therapy 100 mg. 100 mg. once in every 12 hours was followed 24 hours. The duration of therapy varied with the organism but ranged from 7 to 45 Most patients received therapy for 14 clays or more. In addition, 11 patients in the pyelonephritis clinic of the Wilmington Medical Center were given long-term therapy with doxycycline. Fourteen courses of therapy, 100 mg. cline twice daily, were given to 5 women and 6 men (ages 23 to 82) for 10 to '730 days (median 150 days). The toxicity studies listed herein were obtained at intervals of at least 1 month.
Doxycycline* is a new tetracycline antibiotic prepared by the hydrogenation of methacycline. The antibiotic resembles demethylchlortetracycline in activity. Doxycycline has been reported to have several advantages over the older tetracyclines, including a relatively high plasma level with small dosage and a prolonged halflife.1 Apparently its absorption is not affected by food ingestion when given orally. Doxycycline has been used successfully in the treatment of urinary tract infections with minimal side effects. 2 Photosensitivity and gastrointestinal disturbances have been the most common undesirable effects. 2 •3 Our study was undertaken to evaluate further this new tetracycline in the treatment of selected cases of acute and cohronic infections of the urinary tract. MATERIAL AND METHODS
.Forty-two patients at the Wilmington Medical Center and Brandywine Medical Center were given 44 courses of therapy with doxycycline. The patients were grouped as follows: 10 cases of acute pyelonephritis, 16 cases of chronic pyelonephritis, 8 cases of acute cystitis, 2 cases of chronic cystitis, 1 case of prostatitis and 7 cases of asymptomatic bacteriuria. There were 33 women and 9 men, ranging in age from 20 to 81 years. Pre-treatment cultures were obtained catheter or clean-catch techniques and re-
RESULTS
Accepted for publication September 16, 1968. 1/ibramycin, Chas. Pfizer Laboratories, New New York. J.E., Barrett, J.E., Brodie, .J. L. and Kirby, W. of in vitro activitv and clinical of with other tetracyclines. Chemother., 6: 134, 1966. 'Colmore, J. P., Braden, B. and Wilkerson, R. · Effectiveness of doxycycline treatment in chronic urinary tract infections. Antimicrob. Agents Chemother., 6: 118, 1966. 3 Huang, N. N., Sheng, K. T. and Basavanand, N.: Doxycycline treatment of children with cystic fibrosis of the pancreas. Antimicrob. Agents Chemother., 6: 127, 196G.
249
WITH
SHORT-TERM
THERAPY
There were 42 patients who received 44 courses of therapy. In 32 instances there was good result characterized improvement in clinical symptoms with eradication of the pathogen from the urine and with urine for 4 to 6 weeks "'"''-'n"M''"· In instances the result was considered poor. Acute pyelonephritis. Ten patients with acute pyeloncphritis (diagnosis based on findings) physical findings and typical all responded to therapy with doxycycline. Of these, 8 patients were infected with Escherichia coli susceptible in vitro to low concentrations of the antibiotic and 2 patients were infected
'.250
HOLLOWAY, FURLONG AND SCOTT
with P,;euclomonas aeruginosa which required .SO rncg. per ml. cloxycycline for an in vitro bacteriostatic effect. These latter 2 patients had undergone renal operation (renal calculus removal in one and a plastic procedure on the renal pelvis in the other) 2 to 3 weeks before the onset of infection. The 8 patients with E. coli were treated for 7 to 20 clays. All but one received therapy for at least 10 clays. The 2 patients with Pseuclomonas organisms were trea tecl for 40 to 4.S clays, respectively. Chronic pyelonephritis. There were 16 patients with chronic pyelonephritis included in the study. In many, the chronic inflammatory process was complicated by inoperable renal ealculi or uncorrectable obstructive disease. Seven of these patients obtained a good result demonstrated by clinical improvement with eradication of the infecting organism for at least 6 weeks following treatment. Nine patients obtained a poor result: in 3 patients the infecting organism was eradicated but relapse due to another pathogen occurred, in 1 patient the infecting organism was eradicated but relapse due to the same organism occurred, in 2 patients there was only a temporary reduction in the colony count during therapy, in 3 patients there was no obvious effect upon the infecting organism. The pathogens in the 16 cases of chronic pyelonephritis were 10 E. coli, 3 enterococcus, 1 Klebsiella-Aerobacter, 1 Providence species and 1 Pseudomonas aeruginosa. Six of 7 patients with chronic pyelonephritis who benefited by doxycycline had 110 evidence of obstructive disease or anatomical abnormality. The seventh patient had a parenchymal renal c,1lculus complicating infection and he suffered relapse or re-infection 8 weeks following cessation of doxycycline. Noteworthy is the patient with chronic pyelonephritis clue to Ps. aeruginosa, a 32-yearold man with cerebral trauma who required an indwelling bladder catheter for several weeks. Ifocurrent bouts of chills, fever and flank pain responded temporarily to colistin therapy. The fourth episode was treated with doxycycline, 100 mg. every 12 hours for .S days and then .SO mg. every 12 hours for 23 additional days with an apparent cure based on a 10-month followup. Cystitis. Eight patients suffering their first episode of acute cystitis were all successfully treated with cloxycycline. In 6 patients E. coli was the infecting organism while in one an
anaerobic streptococcus was the pathogen . Ps. aeruginosa was the causative organism in a 66-year-old diabetic woman with minimal symptoms during her first attack of urinary infection. Ten days of doxycycline therapy resulted in permanent eradication of the organism (1-year followup). Two patients with recurrent or chronic cystitis (Ps. aeruginosa and E. coli respectively) were treated for 2 weeks with a good clinical and microbiologic result in each instance. Asymptomatic bacteriuria. Routine examination revealed pyuria and bacteriuria in 6 patients who were free of symptoms. Subsequent catheter or midstream culture revealed persistent bacteriuria. Doxycycline was given to these patients for 10 to 2.S days; in 3 patients the urine was rendered sterile for at least 4 weeks following therapy. In 1 patient E. coli was eradicated from the urine in 10 days of therapy but recurred 5 days following cessation of therapy. A second course of cloxycycline for 21 days resulted in prolonged urine sterilization. In 1 patient there was no reduction in the colony count of E. coli during therapy and in the 1 patient there was only a temporary reduction in the colony count. Chronic prostatitis. A 43-year-old man with chronic recurrent prostatitis manifested by chills, fever, perineal pain and E. coli isolated from the prostatic fluid was given doxycycline, 100 mg. per day for 3.S days. Prostatic fluid culture was negative 1 month following cessation of therapy and a 2-year clinical followup revealed no recurrence of ~ymptoms. RESUUrS
WITH
LO:',G-TERM
THERAPY
Eleven patients with chronic pyelonephritis were given 14 courses of long-term therapy with doxycycline. They had history, physical findings, x-ray changes and urinary abnormalities typical of chronic pyelonephritis. In addition, 2 patients had obstructive disease with renal calculi, 2 patients had obstructive disease alone, 1 patient had renal calculi without obstruction and 1 patient is a diabetic who previously suffered necrotizing papillitis. The offending organism was Ps. aeruginosa in 6 instances, E. coli in 3, Klebsiella-Aerobacter in one and Providence species in one. Based on clinical parameters, the results of long-term therapy were considered good in 7 instances, poor in 3 and indeterminate in 4. Evaluation on a microbiological basis was less
251
DOXYCYCLINE FOR URINARY TRACT TJ.;FECTI0:',;8
encouraging. Only ;3 ]Jatients treated with longterm doxycycline experienced uriue sterilization without relapse. Two patients have become abacteriuric bnt have had to be maintained on a dose of 50 mg. daily to achieve this result. One patient is infected with E. coli and the other with Ps. aeruginosa. Both patients have had a poor respmrne to other antimicrobial agents. In 4 patients the long-term therapy failed to im11rove the infected state, while in 3 patients the original mganism was temporarily erndicated but relapse follo,ved cessation of therapy. In the remaining 2 patients the colony count was reduced but there was no consistent bacteriologic im1iroveme11t.
TABLE
Case No,
LABORATORY DATA
Blood for c111tibiotic scrum level was obtained flt the initial 100 mg. dose of number of at 4 hourn and effective levels were still present at 6 hours (table 1). Serum antibacterial levels were performed using paired sern against the patient's infecting organism. Significant inhibition was observed at dilutions of l :4 or more in all but a few instances.
+ Hrs.
2 Hrs.
6 Hrs.
1.57
1.12
5 (j
7 8
9 10 11
12 13
2.;3
3.79 2.54 1.30
1. 7(i
81DE EFFECTS
Fifty-three patienb were observed carefully and interviewed during 58 courses of therapy. Note was made of any significant side effects. Nausea was a complaint in 7 rmtients but required cessation of therapy in only one. Nausea persisted throughout the period of drug ingestion in ;3 patients and disappeared after the first few doses in 3 additional cases. Diarrhea occurred in rt 23-year-olcl woman, requiring ccssa tion of therapy in 5 A ,,ubsequent course of doxycycline was tolerntcd without gastrointestinal effect. Vulvovaginitis in a .52-year-old woman required cessation of therapy in 10 clays. She has experienced this side effect from other antibiotics. Photosensitivity was reported by :1 patients. The tingling, burning and itching were severe enough to cause them to avoid sun exposure, though cessation of therapy was not necessary. Eosinophilia (6 per cent or more) occurred in 4 patients, this being the only abnormality detected in the various laboratory parameters cxa.rni n eel,
L Blood levels following 100 mg. do.se
0.89
2.21
0 89 1.71
0 8fi
2 69 2.15 1.30
2.12
1.57 2.36 1. 22
1.92
5.70 1.12
3.12
14
2. Susceptib·ility testing of 25 strains of P.sewlomonas species by test tube technique
Ti,Bl,E
11inimal Inhibitory Concentration (mcg. per ml.) ----------~- - - - - - -
Tet,racyeline
0
Methacyeline Doxycycline
±
~-
10
1.56
6.25
to
8 10 5
25 to
100
or
12.5
so
> 10()
5
5 5 2
±
2 4
7 4
--·-
The bacteria isolated from patients were tested for susceptibility to doxycycline, using the disk agar diffu:;ion technique and the 2-folcl serial dilution technique. In ,idclition, a number of clinical isolate;; obtained from the Section of the Vvilmington :VIedical Center were to doxycycline thr: tested for techniques rm,ntioned herein. With a :30 mcg. doxycycfoie disk, a zone of inhibition of 14 mm. or more was obtained 80 ol' l 00 strain,, of K 30 of 70 otrains of Klebsiella-Aerobacter, 50 of 70 strains of Proteus and 20 of 25 strains of Pseudornona,s. There was good cmrelation between the results the test tube dilution obtained and the disk agar diffusion technique. The cffocti\'em,,s of doxycycline the 25 strainb of P:,eudomonas was compared to that of methacycline and tetracycline using the tes'G tube serial dilution method. Comparison indicates a slight advantage for doxycycline over the other 2 tetracyclines ( table 2).
252
HOLLOWAY, FURLONG AND SCOT'l' COMMENT
As additional antibiotics become available for clinical use, it is necessary to evaluate their efficacy and to determine their proper place in the therapeutic armamentarium. A well-populated pyelonephritis clinic affords an opportunity to study antibiotics of potential value in urinary tract infections. Patients with acute, uncomplicated urinary infection are relatively easy to treat and evaluate. Patients who are chronically infected, with or without co-existing anatomical abnormalities are less amenable to treatment and evaluation'. With this in mind it appears that doxycycline is a satisfactory agent in the treatment of acute urinary tract infection and is as good as similar agents in the treatment of chronic infection. No attempt was made to compare doxycycline in vivo with other tetracyclines. However, our recent experience with another tetracycline derivative in a similar group of patients produced comparable results. 4 Pseudomonas organisms in the urinary tract are particularly refractory to treatment. In the limited number of patients suffering Pseudomonas infection in this study, doxycycline produced encouraging results. Further clinict1! experience 4 Holloway, W. J., Kahlbaugh, R. A. and Scott E. G.: Methacycline in the treatment of nrinar; tract infections. Delaware Med. J., 39: 245, 1967.·
with this antibiotic in Pseudomonas urinary tract infection is warranted. SUMMARY
Doxycycline is effective in the treatment of acute urinary tract infection. There were 110 failures in 18 such patients treated in our study. Therapy in patients with chronic infection was not as successful, with 9 failures in 16 cases of chronic pyclonephritis and 3 failures in 7 patients with asymptomatic bacteriuria. Eleven patients with refractory chronic pyelonephritis were given 14 courses of long-term therapy with doxycycline. Good results were obtained in 7 instances, while the results were poor in 3 instances and indeterminate in 4. In this study 7 patients with Pseudomonas urinary tract infection were cleared with doxycycline therapy. This prompted further investigation of the in vitro effectiveness of doxycyclinc against strains of Pseudomonas. This limited study showed a slight advantage for doxycycline when compared to tetracycline and methacycline. Since the agents commonly used to treat Pseudomonas organisms have considerable inherent toxicity, doxycycline should be further evaluated in the treatment of these infections. Doxycycline was well tolerated by mouth and appears to have a low order of toxicity. Doxycycline was supplied by Dr. Joseph Migliardi.
TE..Vi Jou.HKAL OF llB.01.01__·:ry
Printed
Copy righi.. (g) 1969 by The VVilliarns & \Vilkins
C
DOXYCYCLINE IN THE TREATMENT OF I:'\.FECTIONS OF THE URINARY TRACT WILLIAM J. HOLLOWAY, JOHN H. FURLONG
AND
E.G. SCOTT
From the Infectious Disease Research Laboratory, Pyelonephritis Clinic, lvlicrobiology Department, Wilmington Medical Center, Wilmington, Delaware
peated, when possible, at weekly intervals during therapy Cultures were obtained 6 weeks following cessation of therapy in all but 7 cases. In these instances, cultures were obtained at least 4 weeks after termination of therapy. Complete blood count, urinalysis, blood urea nitrogen and serum glutamic oxaloacetic transaminase determinations were obtained before and after treatment in all patients. Serurn antibiotic and antibacterial levels also were obtained in selected cases. The infecting organisms were tested for doxycycline susceptibility by the agar diffusion disk technique. Doxycycline was supplied as 50 mg. capsules for oral administration and was given by 2 dosr1ge schedules. In 36 courses of therapy 100 mg. 100 mg. once in every 12 hours was followed 24 hours. The duration of therapy varied with the organism but ranged from 7 to 45 Most patients received therapy for 14 clays or more. In addition, 11 patients in the pyelonephritis clinic of the Wilmington Medical Center were given long-term therapy with doxycycline. Fourteen courses of therapy, 100 mg. cline twice daily, were given to 5 women and 6 men (ages 23 to 82) for 10 to '730 days (median 150 days). The toxicity studies listed herein were obtained at intervals of at least 1 month.
Doxycycline* is a new tetracycline antibiotic prepared by the hydrogenation of methacycline. The antibiotic resembles demethylchlortetracycline in activity. Doxycycline has been reported to have several advantages over the older tetracyclines, including a relatively high plasma level with small dosage and a prolonged halflife.1 Apparently its absorption is not affected by food ingestion when given orally. Doxycycline has been used successfully in the treatment of urinary tract infections with minimal side effects. 2 Photosensitivity and gastrointestinal disturbances have been the most common undesirable effects. 2 •3 Our study was undertaken to evaluate further this new tetracycline in the treatment of selected cases of acute and cohronic infections of the urinary tract. MATERIAL AND METHODS
.Forty-two patients at the Wilmington Medical Center and Brandywine Medical Center were given 44 courses of therapy with doxycycline. The patients were grouped as follows: 10 cases of acute pyelonephritis, 16 cases of chronic pyelonephritis, 8 cases of acute cystitis, 2 cases of chronic cystitis, 1 case of prostatitis and 7 cases of asymptomatic bacteriuria. There were 33 women and 9 men, ranging in age from 20 to 81 years. Pre-treatment cultures were obtained catheter or clean-catch techniques and re-
RESULTS
Accepted for publication September 16, 1968. 1/ibramycin, Chas. Pfizer Laboratories, New New York. J.E., Barrett, J.E., Brodie, .J. L. and Kirby, W. of in vitro activitv and clinical of with other tetracyclines. Chemother., 6: 134, 1966. 'Colmore, J. P., Braden, B. and Wilkerson, R. · Effectiveness of doxycycline treatment in chronic urinary tract infections. Antimicrob. Agents Chemother., 6: 118, 1966. 3 Huang, N. N., Sheng, K. T. and Basavanand, N.: Doxycycline treatment of children with cystic fibrosis of the pancreas. Antimicrob. Agents Chemother., 6: 127, 196G.
249
WITH
SHORT-TERM
THERAPY
There were 42 patients who received 44 courses of therapy. In 32 instances there was good result characterized improvement in clinical symptoms with eradication of the pathogen from the urine and with urine for 4 to 6 weeks "'"''-'n"M''"· In instances the result was considered poor. Acute pyelonephritis. Ten patients with acute pyeloncphritis (diagnosis based on findings) physical findings and typical all responded to therapy with doxycycline. Of these, 8 patients were infected with Escherichia coli susceptible in vitro to low concentrations of the antibiotic and 2 patients were infected
'.250
HOLLOWAY, FURLONG AND SCOTT
with P,;euclomonas aeruginosa which required .SO rncg. per ml. cloxycycline for an in vitro bacteriostatic effect. These latter 2 patients had undergone renal operation (renal calculus removal in one and a plastic procedure on the renal pelvis in the other) 2 to 3 weeks before the onset of infection. The 8 patients with E. coli were treated for 7 to 20 clays. All but one received therapy for at least 10 clays. The 2 patients with Pseuclomonas organisms were trea tecl for 40 to 4.S clays, respectively. Chronic pyelonephritis. There were 16 patients with chronic pyelonephritis included in the study. In many, the chronic inflammatory process was complicated by inoperable renal ealculi or uncorrectable obstructive disease. Seven of these patients obtained a good result demonstrated by clinical improvement with eradication of the infecting organism for at least 6 weeks following treatment. Nine patients obtained a poor result: in 3 patients the infecting organism was eradicated but relapse due to another pathogen occurred, in 1 patient the infecting organism was eradicated but relapse due to the same organism occurred, in 2 patients there was only a temporary reduction in the colony count during therapy, in 3 patients there was no obvious effect upon the infecting organism. The pathogens in the 16 cases of chronic pyelonephritis were 10 E. coli, 3 enterococcus, 1 Klebsiella-Aerobacter, 1 Providence species and 1 Pseudomonas aeruginosa. Six of 7 patients with chronic pyelonephritis who benefited by doxycycline had 110 evidence of obstructive disease or anatomical abnormality. The seventh patient had a parenchymal renal c,1lculus complicating infection and he suffered relapse or re-infection 8 weeks following cessation of doxycycline. Noteworthy is the patient with chronic pyelonephritis clue to Ps. aeruginosa, a 32-yearold man with cerebral trauma who required an indwelling bladder catheter for several weeks. Ifocurrent bouts of chills, fever and flank pain responded temporarily to colistin therapy. The fourth episode was treated with doxycycline, 100 mg. every 12 hours for .S days and then .SO mg. every 12 hours for 23 additional days with an apparent cure based on a 10-month followup. Cystitis. Eight patients suffering their first episode of acute cystitis were all successfully treated with cloxycycline. In 6 patients E. coli was the infecting organism while in one an
anaerobic streptococcus was the pathogen . Ps. aeruginosa was the causative organism in a 66-year-old diabetic woman with minimal symptoms during her first attack of urinary infection. Ten days of doxycycline therapy resulted in permanent eradication of the organism (1-year followup). Two patients with recurrent or chronic cystitis (Ps. aeruginosa and E. coli respectively) were treated for 2 weeks with a good clinical and microbiologic result in each instance. Asymptomatic bacteriuria. Routine examination revealed pyuria and bacteriuria in 6 patients who were free of symptoms. Subsequent catheter or midstream culture revealed persistent bacteriuria. Doxycycline was given to these patients for 10 to 2.S days; in 3 patients the urine was rendered sterile for at least 4 weeks following therapy. In 1 patient E. coli was eradicated from the urine in 10 days of therapy but recurred 5 days following cessation of therapy. A second course of cloxycycline for 21 days resulted in prolonged urine sterilization. In 1 patient there was no reduction in the colony count of E. coli during therapy and in the 1 patient there was only a temporary reduction in the colony count. Chronic prostatitis. A 43-year-old man with chronic recurrent prostatitis manifested by chills, fever, perineal pain and E. coli isolated from the prostatic fluid was given doxycycline, 100 mg. per day for 3.S days. Prostatic fluid culture was negative 1 month following cessation of therapy and a 2-year clinical followup revealed no recurrence of ~ymptoms. RESUUrS
WITH
LO:',G-TERM
THERAPY
Eleven patients with chronic pyelonephritis were given 14 courses of long-term therapy with doxycycline. They had history, physical findings, x-ray changes and urinary abnormalities typical of chronic pyelonephritis. In addition, 2 patients had obstructive disease with renal calculi, 2 patients had obstructive disease alone, 1 patient had renal calculi without obstruction and 1 patient is a diabetic who previously suffered necrotizing papillitis. The offending organism was Ps. aeruginosa in 6 instances, E. coli in 3, Klebsiella-Aerobacter in one and Providence species in one. Based on clinical parameters, the results of long-term therapy were considered good in 7 instances, poor in 3 and indeterminate in 4. Evaluation on a microbiological basis was less
251
DOXYCYCLINE FOR URINARY TRACT TJ.;FECTI0:',;8
encouraging. Only ;3 ]Jatients treated with longterm doxycycline experienced uriue sterilization without relapse. Two patients have become abacteriuric bnt have had to be maintained on a dose of 50 mg. daily to achieve this result. One patient is infected with E. coli and the other with Ps. aeruginosa. Both patients have had a poor respmrne to other antimicrobial agents. In 4 patients the long-term therapy failed to im11rove the infected state, while in 3 patients the original mganism was temporarily erndicated but relapse follo,ved cessation of therapy. In the remaining 2 patients the colony count was reduced but there was no consistent bacteriologic im1iroveme11t.
TABLE
Case No,
LABORATORY DATA
Blood for c111tibiotic scrum level was obtained flt the initial 100 mg. dose of number of at 4 hourn and effective levels were still present at 6 hours (table 1). Serum antibacterial levels were performed using paired sern against the patient's infecting organism. Significant inhibition was observed at dilutions of l :4 or more in all but a few instances.
+ Hrs.
2 Hrs.
6 Hrs.
1.57
1.12
5 (j
7 8
9 10 11
12 13
2.;3
3.79 2.54 1.30
1. 7(i
81DE EFFECTS
Fifty-three patienb were observed carefully and interviewed during 58 courses of therapy. Note was made of any significant side effects. Nausea was a complaint in 7 rmtients but required cessation of therapy in only one. Nausea persisted throughout the period of drug ingestion in ;3 patients and disappeared after the first few doses in 3 additional cases. Diarrhea occurred in rt 23-year-olcl woman, requiring ccssa tion of therapy in 5 A ,,ubsequent course of doxycycline was tolerntcd without gastrointestinal effect. Vulvovaginitis in a .52-year-old woman required cessation of therapy in 10 clays. She has experienced this side effect from other antibiotics. Photosensitivity was reported by :1 patients. The tingling, burning and itching were severe enough to cause them to avoid sun exposure, though cessation of therapy was not necessary. Eosinophilia (6 per cent or more) occurred in 4 patients, this being the only abnormality detected in the various laboratory parameters cxa.rni n eel,
L Blood levels following 100 mg. do.se
0.89
2.21
0 89 1.71
0 8fi
2 69 2.15 1.30
2.12
1.57 2.36 1. 22
1.92
5.70 1.12
3.12
14
2. Susceptib·ility testing of 25 strains of P.sewlomonas species by test tube technique
Ti,Bl,E
11inimal Inhibitory Concentration (mcg. per ml.) ----------~- - - - - - -
Tet,racyeline
0
Methacyeline Doxycycline
±
~-
10
1.56
6.25
to
8 10 5
25 to
100
or
12.5
so
> 10()
5
5 5 2
±
2 4
7 4
--·-
The bacteria isolated from patients were tested for susceptibility to doxycycline, using the disk agar diffu:;ion technique and the 2-folcl serial dilution technique. In ,idclition, a number of clinical isolate;; obtained from the Section of the Vvilmington :VIedical Center were to doxycycline thr: tested for techniques rm,ntioned herein. With a :30 mcg. doxycycfoie disk, a zone of inhibition of 14 mm. or more was obtained 80 ol' l 00 strain,, of K 30 of 70 otrains of Klebsiella-Aerobacter, 50 of 70 strains of Proteus and 20 of 25 strains of Pseudornona,s. There was good cmrelation between the results the test tube dilution obtained and the disk agar diffusion technique. The cffocti\'em,,s of doxycycline the 25 strainb of P:,eudomonas was compared to that of methacycline and tetracycline using the tes'G tube serial dilution method. Comparison indicates a slight advantage for doxycycline over the other 2 tetracyclines ( table 2).
252
HOLLOWAY, FURLONG AND SCOT'l' COMMENT
As additional antibiotics become available for clinical use, it is necessary to evaluate their efficacy and to determine their proper place in the therapeutic armamentarium. A well-populated pyelonephritis clinic affords an opportunity to study antibiotics of potential value in urinary tract infections. Patients with acute, uncomplicated urinary infection are relatively easy to treat and evaluate. Patients who are chronically infected, with or without co-existing anatomical abnormalities are less amenable to treatment and evaluation'. With this in mind it appears that doxycycline is a satisfactory agent in the treatment of acute urinary tract infection and is as good as similar agents in the treatment of chronic infection. No attempt was made to compare doxycycline in vivo with other tetracyclines. However, our recent experience with another tetracycline derivative in a similar group of patients produced comparable results. 4 Pseudomonas organisms in the urinary tract are particularly refractory to treatment. In the limited number of patients suffering Pseudomonas infection in this study, doxycycline produced encouraging results. Further clinict1! experience 4 Holloway, W. J., Kahlbaugh, R. A. and Scott E. G.: Methacycline in the treatment of nrinar; tract infections. Delaware Med. J., 39: 245, 1967.·
with this antibiotic in Pseudomonas urinary tract infection is warranted. SUMMARY
Doxycycline is effective in the treatment of acute urinary tract infection. There were 110 failures in 18 such patients treated in our study. Therapy in patients with chronic infection was not as successful, with 9 failures in 16 cases of chronic pyclonephritis and 3 failures in 7 patients with asymptomatic bacteriuria. Eleven patients with refractory chronic pyelonephritis were given 14 courses of long-term therapy with doxycycline. Good results were obtained in 7 instances, while the results were poor in 3 instances and indeterminate in 4. In this study 7 patients with Pseudomonas urinary tract infection were cleared with doxycycline therapy. This prompted further investigation of the in vitro effectiveness of doxycyclinc against strains of Pseudomonas. This limited study showed a slight advantage for doxycycline when compared to tetracycline and methacycline. Since the agents commonly used to treat Pseudomonas organisms have considerable inherent toxicity, doxycycline should be further evaluated in the treatment of these infections. Doxycycline was well tolerated by mouth and appears to have a low order of toxicity. Doxycycline was supplied by Dr. Joseph Migliardi.