Journal of Chemotherapy

ISSN: 1120-009X (Print) 1973-9478 (Online) Journal homepage: http://www.tandfonline.com/loi/yjoc20

Short vs. Long Cotrimoxazole Courses in Eradicating Bacteriuria in the Elderly A.S. Dontas, H. Giamarellou, M. Staszewska-Pistoni, G. Petrikkos, M. Iakovou & V. Tzias To cite this article: A.S. Dontas, H. Giamarellou, M. Staszewska-Pistoni, G. Petrikkos, M. Iakovou & V. Tzias (1992) Short vs. Long Cotrimoxazole Courses in Eradicating Bacteriuria in the Elderly, Journal of Chemotherapy, 4:2, 114-118, DOI: 10.1080/1120009X.1992.11739150 To link to this article: http://dx.doi.org/10.1080/1120009X.1992.11739150

Published online: 15 Jul 2016.

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Journal of Chemotherapy

Short vs. Long Cotrimoxazole Courses in Eradicating Bacteriuria in the Elderly A.S. DONTAS - H. GIAMARELLOU* M. STASZEWSKA-PISTONI G. PETRIKKOS* - M. IAKOVOU* V. TZIAS Summary - - - - - - - - - - - - - - - -

To test whether longer duration of treatment of asymptomatic bacteriuria in old age could improve the efficacy of cotrimoxazole therapy, three regimens were given to 75 ambulant bacteriuric residents of a retirement home, aged ~ 68 years. The groups and regimens were: A:23 subjects (160/800 mg b.i.d. orally X 3 days). 8:24 subjects (160/800 mg i.m. X 10 days); C:28 subjects (160/800 mg b.i.d. orally X 20 days). One week, one month and five months post-therapy urines were negative in 78.3% vs 52.9% vs 42.9% of group A, in 54.2% vs 56.5% vs 50% of group 8 and in 57.1% vs 60.7% vs 68% of group C subjects respectively. The data indicate that: 1) the efficacy of any schedule is only moderate irrespective of the presence of antibody-coated bacteria in urine; 2) a 3-day course appears more effective at one week post-therapy; 3) at one and five months ~ 50% of the subjects were infection-free, the 20 day treatment resulting in fewer failures; 4) subjects with long-term eradication had no mobility problem, low serum creatinine and a normal urinary tract as seen by ultrasound. Key words: Asymptomatic bacteriuria, old age, cotrimoxazole therapy, short-long duration.

Center of Studies of Age-Related Changes in Man, Athens.

Vol. 4 - n. 2 (114-118) - 1992

INTRODUCTION

The therapy of bacteriuria in elderly individuals with short courses of antibiotics is generally unsatisfactory 1 ' 2 ' 3 ' 4 • Following a 3-day course with three commonly used agents 70% of 71 subjects obtained negative urine at one week; at 6 months, however, only about 25% remained free of infection, these being individuals with adequate mobility and normal renal function 5 • Cotrimoxazole remains a widely used and fairly effective agent for urinary tract infections 20 years after its introduction 6 • 7 • Its effectiveness in a recent study on elderly bacteriuric subjects 5 was found to approximate that of norfloxacin. A high degree of relapses and reinfections, however, was observed with both agents at one month and 6 months of follow-up. Since susceptibilities of microorganisms isolated during follow-up were about equal to those of the initial isolates, it was suggested that longer periods of treatment may have been more effective. We decided to carry out three sequential therapeutic trials with cotrimoxazole to assess the effectiveness which progressively longer therapeutic regimens by intramuscular or oral route may have on the eradication/suppression of susceptible bacteria in urinary tract infection in elderly patients. SUBJECTS AND METHODS

* First Department of Propedeutic Medicine, Athens University School of Medicine, La'iko, General Hospital, Athens Greece. Corresponding author. H . Giamarellou M.D., 1st Dept of Propedeutic School Medicine, Athens· University School of Medicine, La'iko General Hospital, 11527 - Athens, Greece. © Edizioni Riviste Scientifiche - Firenze

Of 500 men and women who are long-term residents of the Athens Home for the Aged, some 90-100 subjects are permanently bacteriuric. Of these, about 30 have mobility probISSN 1120-009X

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SHORT VS. LONG COTRIMOXAZOLE COURSES IN ERADICATING BACTERIURIA IN THE ELDERLY

lems and remain in bed or in easy chairs for several hours a day. The remaining 60-70 subjects, having no major physical disabilities, and performing all activities of daily life unaided, comprised the subjects of the present study. Because adequate numbers of subjects for a parallel group study and a long enough period of follow-up were not available the treatment scheme adopted was sequential. Thus, 23 subjects were treated in 1986 (Group A), 24 in 1988 (Group B), and 28 in 1990 (Group C) for a total of 75 subjects (11 men, 64 women). The only prerequisite for admission to the study was that the subjects had to have urine bacteTia sensitive to cotrimoxazole. Of the 75 subjects, 4 entered trials A and B, and an additional4 were in trials A and C, thus the real number of treated subjects was 6 7. These 8 subjects were included in more than one trial, because they reverted back to steady bacteriuria at some point after each trial and because of the long interval between the successive trials. Ultrasound examination was performed on all subjects; inadequate cooperation, however, prevented the detection of functioning bladder and only structural defects were identified. Of the 64 women, 27 had structural abnormalities, : and of the 11 men, 8 had a previous prostatec1 tomy, prostatic enlargement or other abnormality. The mean ages of the three groups were 83.9 years for group A (range 70-102 years), 84.6 years for group B (range 70-103) and 82.4 years for group C {range 68-100) respectively. The cotrimoxazole doses given, the route of administration and the duration of treatment for the three groups were as follows: Group A: 160/800 mg twice daily orally for 3 days; group B: 160/800 mg once daily i.m . for 10 days; group C: 160/800 mg twice daily orally for 20 days . All subjects had serum creatinine levels determined before, and weekly during and follow ing the treatment period. Morning urine samples were cultured one week, one month and five months post therapy; subjects of group A were re-examined at one month only if they had negative urines at one week. As no cultures were obtained during therapy, the reisolation of the same agent at one week post therapy could not differentiate between persistence and relapse.

Microscopic urine examination was carried out on all subjects. Pyuria without bacteriuria, however, in women with atrophic vaginitis and low personal hygiene, and the lack of pyuria in several subjects with proven bacteriuria led us to the decision not to use pyuria as a sign of infection in this study. Antibody-coated bacteria (ACB) testing was performed on all isolates. In contrast to classic criteria 8 , considered to be rather weak, the test was interpreted as positive when at least 25% of organisms showed 3 + or 4 + fluorescence intensity, or if all bacteria demonstrated a 1 + or 2 + reaction. All readings were performed by · one person without knowledge of patients' other data. Seven of the 11 men, and 38 of the 64 women had ACB ( +) in the urine. The subjects were informed about the therapeutic trials and eagerly consented to take part in the study. They were not given additional antibiotics following each trial, irrespective of its outcome, but as many as 5 subjects could have obtained over-the-counter usual doses of ampicillin for intercurrent respiratory infections, one month or more after the end of treatment. A ''/} test without Yates correction was employed to detect significance of differences . The study was approved by the ethical committee of the Home. RESULTS

The isolated bacterial species in the three trials appear in Table 1. The predominance of Escherichia coli strains is evident in this nonrestrained group of subjects, as is the increasing frequency of other uropathogens in the subsequent trials.

TABLE

1 · Distribution of isolates in groups A, B, C.

Group (N. of subjects) Escherichia coli Proteus sp. Klebsiella sp. Enterobacter sp. Pseudomonas fluorescens Streptococcos sp.

A (23) 20 = 87% 3 = 13%

B (24) 19 = 1= 2= 2=

79.2% 4.2% 8.3% 8.3%

c

(28)

17 = 60.7% 4 = 14.3% 3 = 10.7% 2 = 7.1% 1 = 3.6% 1 = 3.6%

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TABLE 2 - Negative urine cultures and elimination of Escherichia coli at one week post therapy. Negative urine cultures at one week post-therapy Group (N. of subjects)

A (23)

B (24)

c

Women Men

14 (18) 4 (5)

11 (21) 2 (3)

13 (25) 3 (3)

18 = 78.3%

13 = 54.2%

16 = 57.1%

Total

(28)

Elimination of Escherichia coli at one week post-therapy

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et alii

A.S. DONTAS - H. GIAMARELLOU - M. STASZEWSKA·PISTONI, , .... -·

Group

A (20)

B (19)

Women Men

12 3

11 2

Total

15 = 75%

13 = 68.4%

c

(17)

7 2 9 = 52.9%

One week after therapy negative urine was obtained at rates of 78.3%, 54.2% and 57.1% respectively in trials A, B, C. Lower rates were obtained with the longer B and C trials (A vs. B p = 0.08; A vs. C p = 0.8; A vs B + C p = 0.06). (Table 2, upper half). Elimination of E. coli strains was not more successful than that of other pathogens (Table 2, lower half). Furthermore the success of treatment was unrelated to the presence of ACB (+)or ACB ( - )bacteria; in group B those subjects with ACB ( - ) bacteria appeared to respond better than those with ACB ( +) (N.S .) (Table 3). At one month, negative urines were present in 52.9%, 56.5% and 60.7% of subjects of groups A, B, and C respectively (N.S .) (Table 4). There were 28 total failures at one week, 29 one month and 31 at 5 months after treatment with all three trials. At one week, 50% of the failures were due to reisolation of the original organisms and 50% to reinfection; at one month, 22 (76%) of the failures were due to persistence or relapse and 7 (24%) to reinfection; at 5 months 19 (61%) of the failures were due to relapse or persistence and 12 (39%) to reinfection (Table 5). Five months after treatment 9 (7 women) of 21 subjects of group A (42.9%), 11 of 22 women of group B (50%) and 17 (14 women) of 25 subjects of Group C (68%) had negative urines, for a total of 37 (54.4%) of 68 subjects. Of

these, however, 4 subjects of groups A and B had a positive urine culture at one week or one month. Furthermore, 2 subjects of group C, with negative urine cultures at 5 months, had positive cultures at one week and one month TABLE 3 - Success of treatment at one week versus presence of ACB ( +) or ACB (- ) bacteria at entry. Group

ACB(-) negative/ treated

ACB(+) positive/ treated Total

c

A (23)

B (24)

5/7 (71.4 % )

6/9 (66.7%)

6/ 12 (50%)

17/28 (60.7 %)

13/1 6 (81.3%)

7/15 (46.7% )

8/ 13 (61.5%)

28/44 (63 .6%)

18/23 (78.3 % )

13/24 (54.2%)

14/25 (56% )

45/72 (62 .5%)

(25)

All

TABLE 4 - Negative urine cultures at one month. Group

A (17)*

Women Men

8 1

12 1

9 =52.9%

Total

B (23)

13 =56.5%

c

(28)

14 3 17 =60.7%

* Only subjects with negative urines at one week have been tested at one month in group A.

TABLE 5 - Treatment failures at one week and one month after therapy. Treatment failures at one week after therapy Group (N. of Failures)

A (5)

B (11)

c

(12)

Re-isolation of original species

4 (80%)

3 (27.3%)

7 (53.8%)

Reinfection

1 (20%)

8 (72.7%)

(41.7%)

5

Treatment failures at one month after therapy Group (N. of Failures)

A (8)

B (10)

5

(11)

(50%)

8 (72.7%)

5

Persistence

c

Relapse

(62.5%)

3 (30%)

1 (9.1%)

Reinfection

3 (37.5 %)

2 (20%)

2 (1 8.2%)

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SHORT VS. LONG COTRIMOXAZOLE COURSES IN ERADICATING BACTERIURIA IN THE ELDERLY

post therapy. Overall, of the original 4 7 subjects with sterile urines at one week, 29 (61.7%) i.e. 38 .7% of all treated, remained continuously free of infection for 5 months. These latter subjects were physically quite active, 23 (79%) had no anatomical urinary abnormality or at most small single cysts in either of the kidneys, while the remaining 6 (21%) had small pyelocalyceal dilatations as the sole defect. Of the 28 subjects whose therapy was unsuccessful and the 18 with only short-term results, 18 (39%) had various structural abnormalities of their urinary tract, while 28 had no abnormalities. Serum creatinine levels indicated no change after therapy with any one of the three trials. The mean pre-treatment value (±S.D.) was 1.08 (±0.3) mg% for all groups and post-treatment value was 1.15 (±0.3) mg%. The mean entry serum creatinine of subjects whose infection was permanently eradicated, i.e. had negative urines throughout the follow-up, was 1.07 mg%. Serum creatinine of subjects whose infection cleared but relapsed during follow-up was 1.08 mg%, and of those not responding to therapy was 1.09 mg% (N.S.). Furthermore, an equal number of subjects with ACB ( +) and ACB (-) bacteria, once treated successfully at one week retained negative urines at 5 months. No adverse reaction was noted with any of the treatment modalities and no patient discontinued treatment. DISCUSSION

Cotrimoxazole, 20 years after its introduction, continues to be an effective agent against most types of urinary tract infection, its efficacy being comparable to that of several of the recently introduced fluoroquinolones 7 • 9 • 10 • 11 • We therefore felt justified in administering it to patients without chronic exposure to other antimicrobials and in whom financial considerations may be of consequence. Our results proved surprisingly that a 3-day treatment had a somewhat greater efficacy at one week post-treatment than had longer courses, the difference being of borderline significance. It is important to note that the majority of bacteriologic failures with all three regimens were due to the original microorganisms with susceptibilities approximately equal to the

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original ones. This likely indicates an inefficient drug concentration at the infected sites, even with the long duration of 20 days. Thus a higher dose, perhaps double that employed, or much longer courses, might have been more effective. Negative urines in subjects given a 3-day or a 10-day course were more numerous at one month than at 5 months of follow-up. Thus a cost-effective treatment modality might be the administration of appropriate doses as a shortterm schedule, i.e. three-days, or even shorter courses of one to two days, and their repetition, if necessary, at monthly intervals. The somewhat better results of the 20-day treatment at 5 months, or borderline significance, compared to the shorter trials of 3 and 10 days (68% vs. 42.9% and 50%, P