Current Medical Research and Opinion

ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20

The treatment of chronic pyelonephritis with carindacillin H. G. E. Michiels, F. M. J. Debruyne & W. A. Moonen To cite this article: H. G. E. Michiels, F. M. J. Debruyne & W. A. Moonen (1978) The treatment of chronic pyelonephritis with carindacillin, Current Medical Research and Opinion, 5:5, 394-400, DOI: 10.1185/03007997809111904 To link to this article: http://dx.doi.org/10.1185/03007997809111904

Published online: 11 Aug 2008.

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Date: 05 November 2015, At: 17:19

Current Medical Research and Opinion

Vol. 5, No. 5, 1978

The treatment of chronic pyelonephritis with carindacillin

H. G. E. Michiels,* M.D. F. M. J. Debruyne, M.D., and

W. A. Moonen, M.D.

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Department of Urology, University Clinic, Nijnegen, The Netherlorah

Curr. Med. Res. Opin., (1978), 5,394.

Received: 22nd November 1977

Summary Forty-two patients with a radiologically confirmed diagnosis of chronic pyelonephritis were treated with I g carindacillin every 6 hours over a period of 6 weeks. An underlying urologicaldisease was present in 84 % of the 38 patients for whom suficient data were available for evaluation. The results of carindacillin treatment, as judged by bacteriological evaluation I month post-treatment, were good in 12 (32%) and moderate in 9 of the patients. This success rate was remarkable in that all of the patients had been treated previously with one or more other antibiotics and chemotherapeutic agents with little or no response. The authors recommend that, because carindacillin has proved so valuable in treating chronic as well as acute urinary tract infections, its use should be limited to patients with serious disease who have not responded to other treatment. Key words: Carbenicillin - pyelonephritis - urinary tract infections

Introduction Chronic as well as acute pyelonephritis constitutes a problem in daily urological practice. The di5culties are partly bacteriological; often one has to deal with resistant micro-organisms against which many antibiotics have already been tried; on the other hand, underlying disease which cannot be cured is also encountered. The existence of concurrent diseases, for example renal insutliciency, precludes the use of a number of antibiotics. There is a need, therefore, for an antibiotic that is safe for this group of patients and active against the micro-organisms shown by the urine culture. It is well documented that carbenicillin is active against Pseudomonas aerug i r i ~ s a , * - a~ *micro-organism ~ often responsible for long-standing pyeIonephritis. Carindacillin is an indanyl ester of carbenicillin which is orally effective. It is stable in acid medium and is quickly absorbed from the intestinal tract.4 In vivo, carindacillin is rapidly hydrolyzed into carbenicillin and indanol.5 In experimental urinary infections in mice and rats, carindacillin gives the same therapeutic effect as parenteral carbenicillin.’ As is the case with the parent compound, carbenicillin, the indanyl ester is remarkably non-toxic.6 *Present address: De heilige Hart Kliniek, Leuven, Belgium 394

H. 0.E. Michiels, F. M. J. Debruyne and W.A. Mooneo

In view of these findings, it was decided to carry out an investigation into the effectiveness and tolerance of carindacillin in a number of patients with radiologically proven pyelonephritis in whom infection had persisted in spite of previous treatment.

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Patients and methods Forty-two patients with serious pyelonephritis, confirmed radiologically by intravenous pyelography, were selected for the study. Many of the patients had not been free from infection for years, and the majority had anatomical defects which could be held to be responsible for the chronic character of the urinary tract infection (Table I).Excluded from the trial were patients with liver or serious renal insufficiency and those with a history of allergy to penicillin. Table I. Data on patients whose results were analyzed Characteris tics

No. patients

Total no. patients Sex: Male Female Age (years): Mean Range

38 22 16 42

Underlying disease Neurogenic bladder Coral calculus Urinary retention Vesical tumour Prostate hypertrophy Stoma urinae (Bricker) Vesical fistula Prostatitis Renal insufficiency Renal tuberculosis

11 to 80

No. patients

3 3 2 2 2 1 ~~

Duration of illness Less than 1 year 1 year 2 Y3 years

Underlying disease No. patients Extrophia vesicae 1 Hypoplasia (right kidney) 1 Idiopathic retroperitoneal fibrosis 1 Infected renal cysts 1 Ureter carcinoma (1) 1 Bladderneck stenosis 1 Bladder stones 1 Urethral stenosis 1 Hypertension 1

11 6 5 3

3 2 5

3

~~

~~

Duration of illness 4 years 5 Years 6 years and over Not known

8 4 4 9

Three days before the start of carindacillin treatment all other antibiotic therapy was stopped. Patients were then treated with 1 g carindacillin every 6 hours over a period of 6 weeks. No other antibiotics were used concurrently. The patients were seen before treatment started, 1, 3 and 6 weeks after the start, and finally 1 month after antibiotic treatment was terminated. Included in the medical checks were bacteriological, haematological and urine examinations. A record was kept of symptoms, signs and side-effects. 395

The treatment of chronic pyelonephritis with carindacillin

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Results Inadequate data were available from 4 of the 42 patients originally entered in the study. The results, therefore, were evaluated only for 38 patients. Table I summarizes the age, sex, and clinical data. An underlying disease was diagnosed in 32 patients. The urinary tract infection was in the chronic phase in 26 patients, and in an acute phase in 7 patients. I n 5 patients no data in this respect were given. The duration of the illness varied from less than 1 year to more than 6 years. All patients had previously received chemotherapy, some with more than one agent, and in all cases with unsatisfactory results (Table 11). Table 11. Previous therapy received by patients

Drug treatment

No. patients

Nalidixic acid Nitrofurantoin Co-trimoxazole Doxycycline Ampicillin Cephalexin Gentamicin Amoxycillin

13 6

Drug treatment

No. patients 2 2

Colistin Hydroxymethylnitrofurantoin Sulphafurazole Chloramphenicol Pivampicillin Rifampicin Carbenicillin (i.v.)

5 5 5

3 3 2

2 1

I 1 1

Bacteriology Table IIII shows the number and type of micro-organisms isolated from the urine at the pre-treatment stage, after 1 week, 3 weeks and 6 weeks of treatment, and 1 month after the antibiotic treatment was stopped. In all cases the concentration of bacteria was more than 100,000/ml.Details of mixed flora of less than 1000bacteria/ml and samples containing non-pathogens are not given. During the course of treatment, a change of infecting organism was demonstrated in a number of the patients (Table IV). TableV shows the sensitivity of the isolated bacteria to various antibiotics including carbenicillin. Table IU. Bacteria isolated from urine of 38 patients Bacteria

Pseudomonas Proteus E. roli Klebsiella Mixed flora with Pseumonas Mixed flora with Proteus

3 96

Pretreatment 16

After treatment 1 week

3 weeks

6 weeks

3

1 2 5

1 3 3 6

1 1 3

1

1

4

4

2 6 1

1 month after end of treatment

3 2

5

1

H. G. E. Michiels, F. M. J. Debruyne and W. A. Moonen

Table 1V. Changes from pre-treatment findings in bacterial flora in individual patients during and after end of treatment Bacteria pre-treatment/ Patient no.

After treatment 1 week

3 weeks

6 weeks

1 month after end of treatment

E. coli

Klebsiella

Mixed flora

Klebsiella

Klebsiella

Pseudomonas

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2 6 Mixed flora Pseudomonas Mixed flora

11 12 16 18 22 23 26 32

Gram neg. rods E. coli

33 34 36 37

Mixed flora

E. coli Klebsiella

Proteus Klebsiella E. coli Proteus

Proteus

Protzus+ Klebsiella

Proterrs 13 15 19 25

Mixed flora

Mixed flora

Mixed flora Proteus

Proteus

E. coli 1 3

E. coli

E. coli

14

E. coli E. coli

30 Klebsiella 8 41

E. coli E. coli

Mixed flora

Mixed flora E. coli

Mixed flora

E. coli Klebsiella

Mixed flora

Table V. Sensitivity of isolated bacteria to carbenicillin and other agents: number of sensitive/resistantstrains ~~

~

Agent

Pseudomonas

Carbenicillin Penicillin Ampicillin Colistin Chlorarnphenicol Tetracycline Kanarnycin Gentamicin Nitrofurantoin Nalidixic acid Nitronoline

2410

~

Proteus

E. coli

515

11/0 2/0 3/8 6/4 1012

Klebsiella Mixed flora : Pseudomonas Pseudomoms

Klebsiella -t Proteus

00

715

214 5/6 115 7/3

Klcbsiella Pseudo- Gram monos neg. i Groin rods ncg. rods

o/ 1

5/10

1212 12/3 l6/0 I6/0 l0/5 1510

3/14 210

813

816 1411 2/0 8/4 1115

8/7

391

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The treatment of chronic pyelonephritiswith carindacillin

Final evaluation of the effectiveness of carindacillin treatment was carried out on the basis of the concentration of micro-organisms in urine. The results were assessed as ‘good’ when this concentration amounted to less than lo00 bacteria/ml urine, as ‘moderate’ when the concentration was lo4 to 105 bacteria/ml, and ‘poor’ when it was over lo5 bacteria/ml. As will be seen from Table VI, 12 (32%) of the patients were classified as showing a good response to treatment at the 1-month post-treatment visit. Response was assessed as moderate in a further 9 patients and poor in only 3 patients. Insufficient data were available for the remaining 14 of the 38 patients for an assessment to be made on this basis. Table VI. Assessment of response to treatment: 38 patients Assessment

Good Moderate Poor No data

After treatment 1 week

3 weeks

6 weeks

13 9 4 12

12 I 6 13

9 8 7 14

1 month posttreatment

12 9 3 14

Symptomatology Details of the symptoms recorded for patients before, during and after treatment are given in Table VII. The number of patients with symptoms decreased during treatment. Table W. Number of patients with symptoms Symptom

Pre-

After treatment

treatment lweek Pyrexia Shivering Urgency Frequency of micturition Dysuria Malaise Abdominal pain Flank pain

2 1 8 10

Total no. symptoms No. patients with symptoms

6

2 3

3weeks

6weeks

1 month post-. treatment

1 2

1 2 3

2

2

2 2 3 2

21 9

10 7

5 2

5 2

2

3 6

6 3 38 16

5

Side-effects A total of 16 side-effects were recorded during the 6-week treatment period with carindacillin. In 3 patients, side-effects were severe enough to necessitate treatment being stopped (2 patients with upper and lower abdominal complaints during Week 1, and 1 patient with a rash during Week 3). Four other patients complained 398

H. G. E. Michiels, F. M. J. Debruyne and W. A. Moonen

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of side-effects during Week 1 (3 reports of moderate and 2 of severe abdominal complaints, 1 report of severe giddiness), 2 during Week 3 (1 report each of moderate abdominal complaint and pruritus), and 2 patients reported 3 side-effects (2 severe and 1 moderate gastro-intestinal complaints) at the Week 6 visit. Urinalysis The urine was examined for casts, protein, glucose, erythrocytes, leucocytes and bacteria (Table VIII). The specific gravity was determined in 20 patients. The average value was 1.015 (1.009 to 1.020). The pH was also determined; it averaged between 5 and 6. In 12 cases of Proteus infection the pH was 8 or more. Table VIII. Urinalysis: number of patients positive for each item Item

Pretreatment

Casts Protein Glucose Erythrocytes Leucocytes Bacteria

0 8 0 16 28 21

After treatment 1 week

3weeks

0 5

0 4

1

1

11 16

8 15

1

11

6weeks 0 2 1 4 14 11

1 month posttreatment 0

3 1

I 12 1

Haematology Determinations were made of haemoglobin, erythrocyte sedimentation rate, leucocytes, neutrophils, eosinophils, basophils, lymphocytes, monocytes, erythrocytes, alkalinephosphatase, SGOT and SGPT in serum, blood urea nitrogen and creatinine. Table IX gives the number of patients with above normal values. Table IX. Results of blood analysis: number of patients with above normal values Measurement

Pn-

Normal value

treatment

11-18 g/100ml 6 mm/hr

0 8

After treatment 1 week

Haemoglobin Erythrocyte sedimentation rate Leucocytes Neutrophils Eosinophils Lymphocytes Monocytes Basophils Erythrocytes Alkaline phosphatase

SGOT SGPT Blood urea nitrogen Creatinine

0 10

3 0 0 2 1 0

3-lox 109/1

40-70% O-S% 2045%

243% 0-1yo

0

2.54~ 1012/1 120-160 KA units/l

3

3 weeks

6 weeks

1 month posttreatment

0 9

0 8

0 3

1 1

0 I 0 1 0 3

6-20 unitsll 6-20 units/l 1-8 mmol/l

0 0 8

0 0 7

0

1

0

0

1

0

7

6

6

40-180 umol/l

6

6

6

6

6

399

The treatment of chronic pyelonephritis with carindacillin

The abnormal values of alkaline phosphatase returned to normal after treatment. The increase in the SGOT and SGPT values were only slight (21 and 23 U/I) and returned to normal after treatment. Six patients had impaired renal function, as is apparent from the raised blood urea nitrogen and creatinine levels.

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Discussion The patients included in this study all suffered from pyelonephritis, proven by radiology. Intravenous pyelography showed clubbing of the calices and scarring of the renal cortex. In the majority of the 38 (84 %) patients evaluated, an irreversible underlying urological disease was present. The urinary tract infection in most of them (68 %)was in the chronic phase at the start of carindacillin treatment, and all patients had already teen treated with maintenance doses of other antibiotics, without success, and this had resulted in the development of strains very resistant to treatment. In view of the above, it is considered quite remarkable that 32 % of our patients responded so well to carindacillin, judged on the basis of the bacteriological findings at the control visit 1 month after the end of treatment. Because of this success rate, we are of the opinion that carindacillin merits a place in the treatment of upper urinary tract infections in the chronic as well as in the acute phase. We recommend, however, that usage of carindacillin should be limited to infections resistant to other treatment, as was the case with our patients. By limiting its use, the risk of resistant strains developing will be minimized and the antibiotic will retain its usefulness in serious disease.

References 1. Butler, K., English, A. R., Briggs, B., Gralla, E., Stebbins, R. B., and Hobbs, D. C., (1973). Indanyl carbenicillin : chemistry and laboratory studies with a new semisynthetic penicillin. J . Infect. Dis., 127, Suppl., S97. 2. Duncan, J. B. R., (1975). Susceptibility of 1500 isolates of Pseurlomoms aeruginosn to gentamicin, carbenicillin, colistin, and polymyxin B. Antimicrob. Agents Chernother., 5,9. 3. English, A. E., Retsema, J. A., Ray, V. A., and Lynch, J. E., (1972). Carbenicillin indanyl sodium, an orally active derivative of carbenicillin. Anrimicrob. Agents Chemorher., 1, 185. 4. Fabre, J., Burgy, C., Rudhardt, M., and Herrema, A., (1972). The behaviour in man of CP 15,464, a carbenicillin absorbed following oral administration. Chemotherapy, 17, 334. 5. Hobbs, D. C., (1972). Metabolism of indanyl carbenicillin by dogs, rats and humans. Anrirnicrob. Agenrs Chernother., 2, 272. 6. Knirsch, A. K., Hobbs, D. C., and Korst, J. J., (1973). Pharmacokinetics, toleration, and safety of indanyl carbenicillin in man. J. Infect. Dis., 127, Suppl., S105. 7. Rosdahl, V. T., and Rosdahl, N., (1971). Minimum inhibitory concentrations of carbenicillin against Pseudomonas aeruginosa. Chemotherapy, 16, 18.

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The treatment of chronic pyelonephritis with carindacillin.

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