Scandinavian Journal of Infectious Diseases
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Short-Term Treatment of Urinary Tract Infections with Trimethoprim/Sulphamethoxazole: A Clinical and Bacteriological Study Mogens Lykkegaard Nielsen, Helga Laursen & Ivan Strøyer To cite this article: Mogens Lykkegaard Nielsen, Helga Laursen & Ivan Strøyer (1970) ShortTerm Treatment of Urinary Tract Infections with Trimethoprim/Sulphamethoxazole: A Clinical and Bacteriological Study, Scandinavian Journal of Infectious Diseases, 2:3, 211-214 To link to this article: http://dx.doi.org/10.3109/inf.1970.2.issue-3.10
Published online: 02 Jan 2015.
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Date: 05 November 2015, At: 18:07
Scand J Infect Dis 2: 211-214, 1970
SHORT-TERM TREATMENT OF URINARY TRACT INFECTIONS WITH TRIMETHOPRIM/SULPHAMETHOXAZOLE A Clinical and Bacteriological Study Mogens Lykkegaard Nielsen, Helga Laursen and Ivan Streyer
Downloaded by [Deakin University Library] at 18:07 05 November 2015
From the Department K of Surgery, the Department E of Internal Medicine, and the Statens Seruminstitut's Laboratory of Clinical Microbiology, Fredriksberg Hospital, Copenhagen, Denmark
ABSTRACT. The clinical effects of treatment with a trimethoprim (TMP)-sulphamethoxazole (SM) combination were studied in 40 patients with urinary tract infection. The indication for treatment was symptoms of urinary tract infection with > HI5 colonies per ml of urine. The dosage was 160 mg of TMP and 800 mg of SM administered orally twice daily for 10 days. The bacteriological in vitro examination revealed synergic effect of the two agents on 30 out of 55 bacterial strains (55 %). Out of 32 strains which were resistant or slightly sensitive to SM, synergy was revealed in 14 instances (44%). Development of resistance to TMP was seen in one case. In 20 patients with non-complicated urinary tract infections, sterile urine was found 3 and 14 days after termination of treatment in 100% and 89%, respectively. In one case there was recurrence, and in one case reinfection occurred. In 20 patients with complicated urinary tract infections, sterile urine was found 3 and 14 days after termination of treatment in 80 % and 55 %, respectively. In 4 cases infection recurred, and in 5 cases the treatment had no effect. Side effects were seen in 3 patients; one case of exanthem, one of nausea, and one of leucopenia. In one case treatment had to be withdrawn because of exanthem, in another because of nausea.
The pharmacokinetic properties of trimethoprim (IMP) and the bacteriological aspects of combined treatment with TMP and sulphamethoxazole (SM) were described in a previously published survey (7). Here it will only be pointed out that the sensitivity in vitro of sulphonamide-resistant urinary tract pathogens to the SM /TMP combination is often very high (3, 6), and consequently, this combined treatment could be indicated in urinary tract infections. Several clinical studies on urinary tract infec-
tions treated with the SM /TMP combination have been published (1, 4, 5, 8, 9, 10). The purpose of the present study was to assess the clinical effect of the dosage currently recommended of TMP and SM in a group of patients with urinary tract infections, and to assess the bacteriological effect of the SM /TMP combination.
MATERIAL AND METHODS Patients The series comprised 40 patients with urinary tract infections, divided into 2 groups. Treatment and check-up were identical in the two groups. Group I comprised 20 patients with known disposition to urinary tract infection, and group II 20 patients without any disposition to urinary tract infection. The urological diagnoses are shown in Table I, the age and sex distribution are listed in Table II and III. Most of the patients were treated in a medical or surgical ward, a few patients were treated or followed up on an out-patient basis. Indication for treatment. Clinical symptoms of infection and significant bacteriuria (more than 100 000 colonies per rnl urine) were requested. None of the patients had received other chemotherapeutics during the last week immediately preceding treatment. Dosage and check-up. All patients were treated orally for 10 days with SMjTMP (Bactriumm) tablets (320 mg of TMP and 1 600 mg of SM per day, divided into 2 doses). The patients were checked before commencement of treatment, and 3, 7, and 14 days after termination of treatment. At each check-up, a bacteriological examination of the urine referred to below was carried out, as well as urine microscopy and leucocyte count. Furthermore, haemoglobin, WBC count, platelet count, serum creatinine clearance, thymol, alkaline phosphatases and glutamic oxaloacetic transaminases (GOT) were determined before and after treatment. Criterion of cure. Successful treatment was recorded Scand J Infect Dis 2
212
M. Lykkegaard Nielsen et al.
Table I. Diagnoses in 40 patients treated with sulphamethoxazole/trimethoprim No. of patients
Downloaded by [Deakin University Library] at 18:07 05 November 2015
Diagnosis
Group I Prostatic hypertrophy Prostatic hypertrophy + incontinence of urine Prostatic hypertrophy + chronic pyelonephritis Prostatic hypertrophy + vesical calculus Prostatic hypertrophy + atony of the bladder Chronic pyelonephritis Chronic pyelonephritis + vesical calculus Recurrent pyelonephritis + bilateral renal calculi Nephropathy + bilateral renal calculi Recurrent cystitis + right renal calculus Chronic cystitis + sequels of prostatectomy Diverticulum + neoplasm of the urinary bladder
when the urine was sterile and no clinical symptoms were present at the third check-up 14 days after termination of treatment. Patients with sterile urine at the first check-up and with a bacteria isolated in significant amounts at the third check-up, which had not been found previously, were considered to be reinfected.
Bacteriological method 3 2 1
The samples of urine were colIected as midstream specimens or by means of sterile disposable catheter sets and were stored at 4°C. Quantitative and qualitative urine cultivation was carried out according to the principles previously described in a Danish paper (11) with determination of species using routine bacteriological methods. AlI strains were examined for sensitivity to SM, TMP and Bactrim using the same technic as described in another paper (6). The zones of inhibition were read in mrn. According to Bohni (2), strains with a zone of inhibition of 18 mm as sensitive to the agent tested. Synergy can be presumed to exist if the zone of inhibition for Bactrim is at least 5 mm larger than the larger of the zones of inhibition for the individual agents TMP and SM.
1
3
4 1 1 1 1 I 1
Group II Acute cystitis Haemorrhagic cystitis Recurrent cystitis Acute pyelonephritis
14
1 3
2
Table II. Age, sex, and bacteriological check-up of group I patients S ~ sensitivity to sulphamethoxazole in mm of zone of inhibition; T B = sensitivity to Bactrim in mm of zone of inhibition
~ sensitivity
to trimethoprim in mm of zone of inhibition;
First check-up
Third check-up
Before treatment Sex
Age Pat. (yrs.) no.
CS CS
88 72
1 2
CS
68
3
'i2 'i2 'i2
88 59 80 37
4 5 6 7
CS CS
'i2 'i2 CS CS CS CS CS CS CS
'i2 CS CS
Bacteria E. coli E. coli {Kl. pneumoniae Str. faecalis Ci. intermedius Pro morgani E. coli E. coli Staph. aureus
S
T
B
16 6 6 6 25 6 6 6 6
23 26 18 35 18 24 24 30 19
25 28 22 38 28 26 24 30 25
78 83 74 78 70 55 77 78
8 9 10 11 12 13 14 15
Kl. pneumoniae Kl. species E. coli Ale, faecalis Pro mirabilis E. coli Kl. ozoenae Kl. pneumoniae
6 22 25 6 25 6 6 6
22 20 25 6 20 19 14 6
23 32 38 18 29 27 19 12
70 67 83 80 79
16 17
Str. faecalis Str. faecalis Str. faecalis Pro mirabilis Str. faecalis
6 6 6 33 6
30 30 29 20 36
30 37 36 35 42
18 b
19 20
1000 col. per ml urine
B
1000 col. per ml urine 0 0
0
0
0 0 0 Staph. aureus 6 10-100 0 0 0 0 Pro mirabilis> 100 20 0 0 Kl. pneumoniae 6 10-100 0 0 Str, faecalis 10-100 6 0 0
Treatment discontinued on the 5th day because of side effects.
Scand J Infect Dis 2
T
0 0
a No examination made. b
S
22
22
12
15
Pro mirabilis > 100 0 0 26 Staph. aureus 10-100 Kl. ozoenae > 100 0 0 Str. faecalis > 100 28 Pro mirabilis > 100 E. coli> 100 0 18 Kl. pneumoniae > 100 0 Str. faecalis > 100 15 Str. faecalis >100 0 0
S
T
B
6
21
24
6
22
26
6
- a
- a
6 20 6
18 20 18
22 32 25
6
12
17
6 6
28 6
35 10
Treatment of urinary tract infections with trimethoprim / sulphamethoxazole
213
Table III. Age, sex, and bacteriological check-up of group II patients S = sensitivity to sulphamethoxazole in mm of zone of inhibition; T ~ sensitivity to trimethoprim in mm of zone of inhibition; B = sensitivity to Bactrim in mm of zone of inhibition. First check-up
Third check-up
Before treatment Sex
(yrs.) no.
Bacteria
S
T
B
1 000 col. per ml urine S
~ ~ ~ ~ ~ ~ ~ ~
69 76 42 68 46 52 83 82
5 6 7 8
Str. faecalis E. coli Staph. albus Ci. freundii E. coli E. coli E. coli E. coli
20 22 6 6 32 6 6 22
17 22 18 23 26 22 20 12
25 35 30 23 34 26 24 38
0 0 0 0 0 0 0 0
~
68
9
Kl. pneumoniae
14
14
26
0
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
64 74 68 86 65 90 76 88 66 47 53
10
Kl. pneumoniae 20 E. coli 30 E. coli 23 E. coli 20 Ci. freundii 30 Kl. oxytoca 21 Cl. Welchii > 18 Staph. albus 33 E. coli 22 Staph. aureus 30 E. coli 20
20 20 24 24 24 15 > 18 6 18 19 29
26 38 30 30 34 32
0 0 0 0 0 0 0 0 0 0 0
Downloaded by [Deakin University Library] at 18:07 05 November 2015
Age
Pat.
I
2 3
4a
II
12 13 14 15 16 17 18 19 20
-
b
33 36 32 34
T
1000 col. per ml urine S
B
0 0 0 0 0 0 0 E. coli 20 > 100 Ent. cloacae 20 >100 0 0 0 -
T
B
6
30
18
32
b
0 0 0 0 0 0 0
a Treatment discontinued on the 5th day because of side effects. b
No examination made.
RESULTS The course and results of the treatment are shown in Table II and III. Only the first and the third bacteriological check-ups, 3 and 14 days after termination of treatment, respectively, are included in the tables. As regards group I, Table II shows that 16 patients (80 %) had sterile urine 3 days after termination of treatment, whereas only 11 patients (55 %) had sterile urine 14 days after termination of treatment. In 4 cases reinfection occurred, in 4 cases the treatment had no effect, and in one case (no. 18) the treatment had to be withdrawn on the fifth day. Regarding group II, Table III shows that all the patients presented sterile urine 3 days after termination of treatment, whereas 17 out of 19 (89 %) had sterile urine 14 days after termination of treatment. As regards patient no. 13, the third check-up was not carried out because of transfer to another ward. In one case (no. 8), the treatment had no effect, and in another case reinfection
occurred. In one case (no. 4), the treatment was discontinued on the fifth day because of side effects. Reviewing group I and II collectively, it appears that 36 out of 40 patients (90 %) had sterile urine 3 days after termination of treatment, whereas 28 out of 39 patients (72 %) had sterile urine 14 days after termination of treatment. Taking into consideration that the patients were hospitalized, the distribution into species is not of particular interest except for case no. 16 in group II. This patient presented severe symptoms of cystitis and Clostridium Welchii was isolated in 2 consecutive' samples before treatment was started. The clinical symptoms disappeared within 4 days by which time the urine became sterile. In the complicated urinary tract infections 17 out of 22 strains (77 %) were found to be resistant or only slightly sensitive to SM before treatment, whereas 5 strains were found to be resistant or slightly sensitive to TMP (23 %). In group II (non-complicated cases), 5 and 7 strains, Scand J Inject Dis 2
Downloaded by [Deakin University Library] at 18:07 05 November 2015
214
M. Lykkegaard Nielsen et al.
respectively, out of 20 strains were found to be resistant or slightly sensitive to SM and TMP before treatment. Definite synergy (Tables II and III) could be demonstrated in 30 out of 55 bacterial strains (55 %). Of the 32 strains presenting resistance Of only slight sensitivity to SM, definite synergy was demonstrated in 14 instances (44%). In 12 bacterial strains resistance or slight sensitivity to both SM and TMP was found; in 8 of these a definite synergic effect was seen. In 2 cases the treatment had to be discontinued because of side effects, nausea and rash, respectively (Tables II and III). By checking the peripheral blood before and after treatment, development of leucopenia, defined as < 3 000 leucocytes / mrn'' of blood, was revealed in one case only, the leucocyte count decreasing from 6 250 to 2 000/ mm". Spontaneous normalization occurred after termination of treatment. Clinical symptoms of leucopenia were not seen. Thrombocytopenia did not occur, and no damage to the liver or kidneys was seen. DISCUSSION From a bacteriological point of view, the combination of SM and TMP should be promising, partly because, during in vitro studies, TMP presents a higher activity than sulphonamides, partly because the synergic effect of the two agents makes the combination bactericidal (l, 3). Our results confirm both the higher activity of TMP as compared with SM, and the synergic effect of the two agents (Tables II and III). From a theoretical point of view, the bactericidal effect of the SM /TMP combination should impede the development of resistant strains of bacteria. Our studies confirm this theory since resistance to TMP developed in one single case only. This corresponds to the findings of other workers (3). After treatment of 41 patients for 7 days, Reeves et al. (9) found sterile urine 1 week after termination of treatment in 85 % of the cases and, after treatment of 27 patients, sterile urine in 67 % of the cases 4-5 weeks after termination of treatment. As regards the distribution of bacteria, this series compares well with our series, and the success rates stated correspond to those found in our series. By treating 39 patients for 5 days. Griineberg Scand J Infect Dis 2
and Kolbe (4) found sterile urine in 36 cases (92 %) 10 days after termination of treatment. This success rate corresponds to that found by us 3 days after termination of treatment (90 %), and the two series are comparable both as regards distribution of bacteria and the ratio of complicated to non-complicated cases. If it is borne in mind that the patients were hospitalized, that half of the cases had complicated urinary tract infections, and that more than one half were infected with sulphonamide-resistant bacteria, the results of the treatment must be considered to be favourable. Side effects were experienced in a total of 3 out of 40 patients; in only 2 cases, however, treatment had to be discontinued. REFERENCES 1. Bohni, E.: Sensitivity testing and outcome of therapy with the combination trimethoprim/sulphamethoxazole in patients with urinary tract infection. 6th International Congress of Chemotherapy, Tokyo 1969. 2. - Personal communication. 3. Darrell, J. H., Garrod, L. P. & Waterworth, P. M.: Trimethoprim: laboratory and clinical studies. J Clin Path 21: 202, 1968. 4. Gruneberg, R. N. & Kolbe, R.: Trimethoprim in the treatment of urinary infections in hospital. Brit Med J 1: 545, 1969. 5. Hoigne, R., MUller, U. & Schneider, R. H.: Bactrim Roche, ein Kombinationspraparat von Sulfamethoxazol und Trimethoprim. Schweiz Med Wschr 99: 1511, 1969. 6. Laursen, H. & Lykkegaard Nielsen, M.: Urinary tract pathogens-sensitivity to trimethoprimjsulphamethoxazole. Scand J Infect Dis 2: 205, 1970. 7. Lykkegaard Nielsen, M. & Laursen, H.: Trimethoprim. Nord Med 84: 1070, 1970. 8. Pechere, J. C.: Combination of trimethoprim with sulphamethoxazole. A study of antibacterial activity in vivo and comparison with gentamycin in the treatment of urinary tract infections. 6th International Congress of Chemotherapy, Tokyo 1969. 9. Reeves, D. S., Faiers, M. C., Pursell, R. E. & Brumfitt, W.: Trimethoprim-sulphamethoxazole: comparative study in urinary infections in hospital. Brit Med J 1: 541, 1969. 10. Sourander, L. B. & Werner, G. E.: Efficacy and tolerance of sulphonamide-trimethoprim combinations in geriatric patients with bacteriuria. 5th International Congress of Chemotherapy, Vienna 1967. 11. Vejlsgaard, R.: Urinundersegelse. Ugeskr Laeg 131: 545, 1969. H. Laursen, M.D., Iunggreensvej 9, 2000 Kebenhavn F, Denmark
ISSN: 0036-5548 (Print) 1651-1980 (Online) Journal homepage: http://www.tandfonline.com/loi/infd19
Short-Term Treatment of Urinary Tract Infections with Trimethoprim/Sulphamethoxazole: A Clinical and Bacteriological Study Mogens Lykkegaard Nielsen, Helga Laursen & Ivan Strøyer To cite this article: Mogens Lykkegaard Nielsen, Helga Laursen & Ivan Strøyer (1970) ShortTerm Treatment of Urinary Tract Infections with Trimethoprim/Sulphamethoxazole: A Clinical and Bacteriological Study, Scandinavian Journal of Infectious Diseases, 2:3, 211-214 To link to this article: http://dx.doi.org/10.3109/inf.1970.2.issue-3.10
Published online: 02 Jan 2015.
Submit your article to this journal
Article views: 4
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=infd19 Download by: [Deakin University Library]
Date: 05 November 2015, At: 18:07
Scand J Infect Dis 2: 211-214, 1970
SHORT-TERM TREATMENT OF URINARY TRACT INFECTIONS WITH TRIMETHOPRIM/SULPHAMETHOXAZOLE A Clinical and Bacteriological Study Mogens Lykkegaard Nielsen, Helga Laursen and Ivan Streyer
Downloaded by [Deakin University Library] at 18:07 05 November 2015
From the Department K of Surgery, the Department E of Internal Medicine, and the Statens Seruminstitut's Laboratory of Clinical Microbiology, Fredriksberg Hospital, Copenhagen, Denmark
ABSTRACT. The clinical effects of treatment with a trimethoprim (TMP)-sulphamethoxazole (SM) combination were studied in 40 patients with urinary tract infection. The indication for treatment was symptoms of urinary tract infection with > HI5 colonies per ml of urine. The dosage was 160 mg of TMP and 800 mg of SM administered orally twice daily for 10 days. The bacteriological in vitro examination revealed synergic effect of the two agents on 30 out of 55 bacterial strains (55 %). Out of 32 strains which were resistant or slightly sensitive to SM, synergy was revealed in 14 instances (44%). Development of resistance to TMP was seen in one case. In 20 patients with non-complicated urinary tract infections, sterile urine was found 3 and 14 days after termination of treatment in 100% and 89%, respectively. In one case there was recurrence, and in one case reinfection occurred. In 20 patients with complicated urinary tract infections, sterile urine was found 3 and 14 days after termination of treatment in 80 % and 55 %, respectively. In 4 cases infection recurred, and in 5 cases the treatment had no effect. Side effects were seen in 3 patients; one case of exanthem, one of nausea, and one of leucopenia. In one case treatment had to be withdrawn because of exanthem, in another because of nausea.
The pharmacokinetic properties of trimethoprim (IMP) and the bacteriological aspects of combined treatment with TMP and sulphamethoxazole (SM) were described in a previously published survey (7). Here it will only be pointed out that the sensitivity in vitro of sulphonamide-resistant urinary tract pathogens to the SM /TMP combination is often very high (3, 6), and consequently, this combined treatment could be indicated in urinary tract infections. Several clinical studies on urinary tract infec-
tions treated with the SM /TMP combination have been published (1, 4, 5, 8, 9, 10). The purpose of the present study was to assess the clinical effect of the dosage currently recommended of TMP and SM in a group of patients with urinary tract infections, and to assess the bacteriological effect of the SM /TMP combination.
MATERIAL AND METHODS Patients The series comprised 40 patients with urinary tract infections, divided into 2 groups. Treatment and check-up were identical in the two groups. Group I comprised 20 patients with known disposition to urinary tract infection, and group II 20 patients without any disposition to urinary tract infection. The urological diagnoses are shown in Table I, the age and sex distribution are listed in Table II and III. Most of the patients were treated in a medical or surgical ward, a few patients were treated or followed up on an out-patient basis. Indication for treatment. Clinical symptoms of infection and significant bacteriuria (more than 100 000 colonies per rnl urine) were requested. None of the patients had received other chemotherapeutics during the last week immediately preceding treatment. Dosage and check-up. All patients were treated orally for 10 days with SMjTMP (Bactriumm) tablets (320 mg of TMP and 1 600 mg of SM per day, divided into 2 doses). The patients were checked before commencement of treatment, and 3, 7, and 14 days after termination of treatment. At each check-up, a bacteriological examination of the urine referred to below was carried out, as well as urine microscopy and leucocyte count. Furthermore, haemoglobin, WBC count, platelet count, serum creatinine clearance, thymol, alkaline phosphatases and glutamic oxaloacetic transaminases (GOT) were determined before and after treatment. Criterion of cure. Successful treatment was recorded Scand J Infect Dis 2
212
M. Lykkegaard Nielsen et al.
Table I. Diagnoses in 40 patients treated with sulphamethoxazole/trimethoprim No. of patients
Downloaded by [Deakin University Library] at 18:07 05 November 2015
Diagnosis
Group I Prostatic hypertrophy Prostatic hypertrophy + incontinence of urine Prostatic hypertrophy + chronic pyelonephritis Prostatic hypertrophy + vesical calculus Prostatic hypertrophy + atony of the bladder Chronic pyelonephritis Chronic pyelonephritis + vesical calculus Recurrent pyelonephritis + bilateral renal calculi Nephropathy + bilateral renal calculi Recurrent cystitis + right renal calculus Chronic cystitis + sequels of prostatectomy Diverticulum + neoplasm of the urinary bladder
when the urine was sterile and no clinical symptoms were present at the third check-up 14 days after termination of treatment. Patients with sterile urine at the first check-up and with a bacteria isolated in significant amounts at the third check-up, which had not been found previously, were considered to be reinfected.
Bacteriological method 3 2 1
The samples of urine were colIected as midstream specimens or by means of sterile disposable catheter sets and were stored at 4°C. Quantitative and qualitative urine cultivation was carried out according to the principles previously described in a Danish paper (11) with determination of species using routine bacteriological methods. AlI strains were examined for sensitivity to SM, TMP and Bactrim using the same technic as described in another paper (6). The zones of inhibition were read in mrn. According to Bohni (2), strains with a zone of inhibition of 18 mm as sensitive to the agent tested. Synergy can be presumed to exist if the zone of inhibition for Bactrim is at least 5 mm larger than the larger of the zones of inhibition for the individual agents TMP and SM.
1
3
4 1 1 1 1 I 1
Group II Acute cystitis Haemorrhagic cystitis Recurrent cystitis Acute pyelonephritis
14
1 3
2
Table II. Age, sex, and bacteriological check-up of group I patients S ~ sensitivity to sulphamethoxazole in mm of zone of inhibition; T B = sensitivity to Bactrim in mm of zone of inhibition
~ sensitivity
to trimethoprim in mm of zone of inhibition;
First check-up
Third check-up
Before treatment Sex
Age Pat. (yrs.) no.
CS CS
88 72
1 2
CS
68
3
'i2 'i2 'i2
88 59 80 37
4 5 6 7
CS CS
'i2 'i2 CS CS CS CS CS CS CS
'i2 CS CS
Bacteria E. coli E. coli {Kl. pneumoniae Str. faecalis Ci. intermedius Pro morgani E. coli E. coli Staph. aureus
S
T
B
16 6 6 6 25 6 6 6 6
23 26 18 35 18 24 24 30 19
25 28 22 38 28 26 24 30 25
78 83 74 78 70 55 77 78
8 9 10 11 12 13 14 15
Kl. pneumoniae Kl. species E. coli Ale, faecalis Pro mirabilis E. coli Kl. ozoenae Kl. pneumoniae
6 22 25 6 25 6 6 6
22 20 25 6 20 19 14 6
23 32 38 18 29 27 19 12
70 67 83 80 79
16 17
Str. faecalis Str. faecalis Str. faecalis Pro mirabilis Str. faecalis
6 6 6 33 6
30 30 29 20 36
30 37 36 35 42
18 b
19 20
1000 col. per ml urine
B
1000 col. per ml urine 0 0
0
0
0 0 0 Staph. aureus 6 10-100 0 0 0 0 Pro mirabilis> 100 20 0 0 Kl. pneumoniae 6 10-100 0 0 Str, faecalis 10-100 6 0 0
Treatment discontinued on the 5th day because of side effects.
Scand J Infect Dis 2
T
0 0
a No examination made. b
S
22
22
12
15
Pro mirabilis > 100 0 0 26 Staph. aureus 10-100 Kl. ozoenae > 100 0 0 Str. faecalis > 100 28 Pro mirabilis > 100 E. coli> 100 0 18 Kl. pneumoniae > 100 0 Str. faecalis > 100 15 Str. faecalis >100 0 0
S
T
B
6
21
24
6
22
26
6
- a
- a
6 20 6
18 20 18
22 32 25
6
12
17
6 6
28 6
35 10
Treatment of urinary tract infections with trimethoprim / sulphamethoxazole
213
Table III. Age, sex, and bacteriological check-up of group II patients S = sensitivity to sulphamethoxazole in mm of zone of inhibition; T ~ sensitivity to trimethoprim in mm of zone of inhibition; B = sensitivity to Bactrim in mm of zone of inhibition. First check-up
Third check-up
Before treatment Sex
(yrs.) no.
Bacteria
S
T
B
1 000 col. per ml urine S
~ ~ ~ ~ ~ ~ ~ ~
69 76 42 68 46 52 83 82
5 6 7 8
Str. faecalis E. coli Staph. albus Ci. freundii E. coli E. coli E. coli E. coli
20 22 6 6 32 6 6 22
17 22 18 23 26 22 20 12
25 35 30 23 34 26 24 38
0 0 0 0 0 0 0 0
~
68
9
Kl. pneumoniae
14
14
26
0
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
64 74 68 86 65 90 76 88 66 47 53
10
Kl. pneumoniae 20 E. coli 30 E. coli 23 E. coli 20 Ci. freundii 30 Kl. oxytoca 21 Cl. Welchii > 18 Staph. albus 33 E. coli 22 Staph. aureus 30 E. coli 20
20 20 24 24 24 15 > 18 6 18 19 29
26 38 30 30 34 32
0 0 0 0 0 0 0 0 0 0 0
Downloaded by [Deakin University Library] at 18:07 05 November 2015
Age
Pat.
I
2 3
4a
II
12 13 14 15 16 17 18 19 20
-
b
33 36 32 34
T
1000 col. per ml urine S
B
0 0 0 0 0 0 0 E. coli 20 > 100 Ent. cloacae 20 >100 0 0 0 -
T
B
6
30
18
32
b
0 0 0 0 0 0 0
a Treatment discontinued on the 5th day because of side effects. b
No examination made.
RESULTS The course and results of the treatment are shown in Table II and III. Only the first and the third bacteriological check-ups, 3 and 14 days after termination of treatment, respectively, are included in the tables. As regards group I, Table II shows that 16 patients (80 %) had sterile urine 3 days after termination of treatment, whereas only 11 patients (55 %) had sterile urine 14 days after termination of treatment. In 4 cases reinfection occurred, in 4 cases the treatment had no effect, and in one case (no. 18) the treatment had to be withdrawn on the fifth day. Regarding group II, Table III shows that all the patients presented sterile urine 3 days after termination of treatment, whereas 17 out of 19 (89 %) had sterile urine 14 days after termination of treatment. As regards patient no. 13, the third check-up was not carried out because of transfer to another ward. In one case (no. 8), the treatment had no effect, and in another case reinfection
occurred. In one case (no. 4), the treatment was discontinued on the fifth day because of side effects. Reviewing group I and II collectively, it appears that 36 out of 40 patients (90 %) had sterile urine 3 days after termination of treatment, whereas 28 out of 39 patients (72 %) had sterile urine 14 days after termination of treatment. Taking into consideration that the patients were hospitalized, the distribution into species is not of particular interest except for case no. 16 in group II. This patient presented severe symptoms of cystitis and Clostridium Welchii was isolated in 2 consecutive' samples before treatment was started. The clinical symptoms disappeared within 4 days by which time the urine became sterile. In the complicated urinary tract infections 17 out of 22 strains (77 %) were found to be resistant or only slightly sensitive to SM before treatment, whereas 5 strains were found to be resistant or slightly sensitive to TMP (23 %). In group II (non-complicated cases), 5 and 7 strains, Scand J Inject Dis 2
Downloaded by [Deakin University Library] at 18:07 05 November 2015
214
M. Lykkegaard Nielsen et al.
respectively, out of 20 strains were found to be resistant or slightly sensitive to SM and TMP before treatment. Definite synergy (Tables II and III) could be demonstrated in 30 out of 55 bacterial strains (55 %). Of the 32 strains presenting resistance Of only slight sensitivity to SM, definite synergy was demonstrated in 14 instances (44%). In 12 bacterial strains resistance or slight sensitivity to both SM and TMP was found; in 8 of these a definite synergic effect was seen. In 2 cases the treatment had to be discontinued because of side effects, nausea and rash, respectively (Tables II and III). By checking the peripheral blood before and after treatment, development of leucopenia, defined as < 3 000 leucocytes / mrn'' of blood, was revealed in one case only, the leucocyte count decreasing from 6 250 to 2 000/ mm". Spontaneous normalization occurred after termination of treatment. Clinical symptoms of leucopenia were not seen. Thrombocytopenia did not occur, and no damage to the liver or kidneys was seen. DISCUSSION From a bacteriological point of view, the combination of SM and TMP should be promising, partly because, during in vitro studies, TMP presents a higher activity than sulphonamides, partly because the synergic effect of the two agents makes the combination bactericidal (l, 3). Our results confirm both the higher activity of TMP as compared with SM, and the synergic effect of the two agents (Tables II and III). From a theoretical point of view, the bactericidal effect of the SM /TMP combination should impede the development of resistant strains of bacteria. Our studies confirm this theory since resistance to TMP developed in one single case only. This corresponds to the findings of other workers (3). After treatment of 41 patients for 7 days, Reeves et al. (9) found sterile urine 1 week after termination of treatment in 85 % of the cases and, after treatment of 27 patients, sterile urine in 67 % of the cases 4-5 weeks after termination of treatment. As regards the distribution of bacteria, this series compares well with our series, and the success rates stated correspond to those found in our series. By treating 39 patients for 5 days. Griineberg Scand J Infect Dis 2
and Kolbe (4) found sterile urine in 36 cases (92 %) 10 days after termination of treatment. This success rate corresponds to that found by us 3 days after termination of treatment (90 %), and the two series are comparable both as regards distribution of bacteria and the ratio of complicated to non-complicated cases. If it is borne in mind that the patients were hospitalized, that half of the cases had complicated urinary tract infections, and that more than one half were infected with sulphonamide-resistant bacteria, the results of the treatment must be considered to be favourable. Side effects were experienced in a total of 3 out of 40 patients; in only 2 cases, however, treatment had to be discontinued. REFERENCES 1. Bohni, E.: Sensitivity testing and outcome of therapy with the combination trimethoprim/sulphamethoxazole in patients with urinary tract infection. 6th International Congress of Chemotherapy, Tokyo 1969. 2. - Personal communication. 3. Darrell, J. H., Garrod, L. P. & Waterworth, P. M.: Trimethoprim: laboratory and clinical studies. J Clin Path 21: 202, 1968. 4. Gruneberg, R. N. & Kolbe, R.: Trimethoprim in the treatment of urinary infections in hospital. Brit Med J 1: 545, 1969. 5. Hoigne, R., MUller, U. & Schneider, R. H.: Bactrim Roche, ein Kombinationspraparat von Sulfamethoxazol und Trimethoprim. Schweiz Med Wschr 99: 1511, 1969. 6. Laursen, H. & Lykkegaard Nielsen, M.: Urinary tract pathogens-sensitivity to trimethoprimjsulphamethoxazole. Scand J Infect Dis 2: 205, 1970. 7. Lykkegaard Nielsen, M. & Laursen, H.: Trimethoprim. Nord Med 84: 1070, 1970. 8. Pechere, J. C.: Combination of trimethoprim with sulphamethoxazole. A study of antibacterial activity in vivo and comparison with gentamycin in the treatment of urinary tract infections. 6th International Congress of Chemotherapy, Tokyo 1969. 9. Reeves, D. S., Faiers, M. C., Pursell, R. E. & Brumfitt, W.: Trimethoprim-sulphamethoxazole: comparative study in urinary infections in hospital. Brit Med J 1: 541, 1969. 10. Sourander, L. B. & Werner, G. E.: Efficacy and tolerance of sulphonamide-trimethoprim combinations in geriatric patients with bacteriuria. 5th International Congress of Chemotherapy, Vienna 1967. 11. Vejlsgaard, R.: Urinundersegelse. Ugeskr Laeg 131: 545, 1969. H. Laursen, M.D., Iunggreensvej 9, 2000 Kebenhavn F, Denmark
