Journal of Antimicrobial Chemotherapy (1976) 2, 293-298

The treatment of simple and complicated urinary tract infections with carfecillin; a new oral ester of carbenicillin

D. A. Leigh and K. Simmons

Sixty patients with urinary tract infections were treated with a 7-day course of carfecillin. The cure rate in simple infections was 91 % but in complicated infections it was considerably lower (67%). In 16 (69%) of 23 patients with Ps. aeruginosa infections, the organisms were eradicated but reinfection with Klebsiella species occurred in 9 patients. Side effects were only seen in 3 patients and a satisfactory clinical response was obtained in many patients with bacteriological failure. In volunteers, urine concentrations of carbenicillin were high with a mean peak level of 800 ng/ml, and 26-5% of the dose was recovered over a 6-h period. Serum concentrations were very low and were inadequate for the treatment of systemic infections. The indication for carfecillin therapy is the presence of urinary tract infection particularly those caused by Pseudomonas aeruginosa and the indole positive strains of Proteus spp. Introduction Carbenicillin was introduced in 1967 and was the first penicillin compound with marked activity against the resistant strains of Enterobacteriaciae, particularly Pseudomonas aeruginosa (Brumfitt, Percival & Leigh, 1967). It could only be given systemically as there was poor absorption after oral administration due to acid instability. Carfecillin (uticillin) is the a-phenyll ester of carbenicillin and this substitution greatly increases the oral absorption. The bacteriologically inactive ester is rapidly hydrolysed in the intestinal mucosa by non-specific esterases releasing active carbenicillin and phenol, the latter is rapidly detoxicated by conjugation and is not detectable in the blood (Wilkinson, Reeves, Wise & Allen, 1975). Carbenicillin is excreted mainly by the kidneys and high concentrations appear in the urine, allowing treatment of urinary tract infections due to non-pMactamase producing strains of the Enterobacteriaciae especially Pseudomonas aeruginosa and the indole positive strains of Proteus spp. which are resistant to the majority of urinary antibiotics. This study investigates the pharmacological properties of carfecillin and describes its use in the treatment of urinary tract infections in patients in hospital and general practice. 293

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Department of Microbiology, Wycombe and Amersham General Hospitals, High Wycombe, Bucks, England

294

D. A. Leigh and K. Simmons Patients and methods

Serum and urine concentrations Carfecillin was given to 11 fasting volunteers in a single dose of 500 mg equivalent to 397 mg carbenicillin pure free acid. Carbenicillin levels in the serum were assayed at 30 min., 1, 2, 4 and 6 h after the dose. Urine was collected over three 2-h periods up to 6 h after the dose. The concentration of carbenicillin was determined by a plate diffusion technique using Ps. aeruginosa (NCTC 10490) as the indicator strain. Serum concentrations were also determined at 1, 2, 4 and 6 h after the first dose in 8 patients receiving carfecillin, 500 mg qds for 7 days. Three of these patients had a moderate degree of renal failure with a blood urea of between 60 and 80 mg/100 ml.

Results

Serum concentrations The serum concentrations of carbenicillin in 11 fasting volunteers (see Figure 1) were low and showed considerable individual variation. The mean peak level (1-38 ug/ml) occurred at 2 h after the dose but after 6 h the level was not detectable. The serum concentrations were considerably higher in the presence of renal failure (Table I) and in patients with normal renal function the levels were slightly higher than those seen in the volunteers. Urine concentrations In the volunteers high concentrations of carbenicillin were present in the urine over the 6-h collection period (Table II). The mean peak level was 830 ug/ml and occurred between 2 and 4 h, but there was considerable variation between individual volunteers and concentrations of 1500 and 3000 ug/ml were observed. The mean total recovery of carbenicillin over 6 h represented 26-5 % of the dose.

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The patients Sixty patients with urinary tract infections were treated with carfecillin. Twenty-five were referred from their general practitioner, and 35 were inpatients on the geriatric wards of Amersham General Hospital. Urinary tract infection was defined as the presence of 105 or more bacteria per ml of urine in a single specimen. Confirmation of the infection was obtained by examining a second specimen where possible. Each patient received carfecillin (capsules) in a dose of 500 mg every 8 h for 7 days. Those with a history of penicillin hypersensitivity were not included and all infecting organisms were shown to be sensitive to carbenicillin by antibiotic disc (100 ug) sensitivity testing before the patient was accepted into the study. The minimal inhibitory concentration of all infecting organisms was determined by a standard tube dilution method. Follow up specimens of urine were examined 14 days after treatment in all cases and where possible 4 weeks later. A treatment cure was denned as the eradication of the original infecting strain and included cases where reinfection with a different strain or species occurred. Failure of treatment was due to the persistence of the initial infecting organism. The patients were divided into 2 groups, those with complicated infections where there was urinary tract disease or abnormality and an indwelling catheter was frequently present, and those with simple infections where the urinary tract was clinically normal.

Treatment of urinary infections with carfecillin

295

Clinical trial

Thirty-six of the patients treated with carfecillin had complicated infections and 24 simple infections but 2 patients in the latter group were unable to complete the course of treatment. One patient developed a generalized skin rash and the other died on the fifth day of treatment from cerebral thrombosis. There were significant age differences between the two groups of patients, 30 with complicated infections being over 60 years of age as against only 7 with simple infections. The majority of patients with simple infections had acute urinary symptoms whilst in the complicated group the infection was frequently asymptomatic and only diagnosed on routine screening of the urine.

Time (h)

Figure 1. Serum concentrations of carbenicillin following an oral dose of 500 mg carfecillin (equivalent to 397 mg carbenicillin pure free acid). Lower limit of assay, 0-1 ug/ml. Table I. Serum concentrations of carfecillin in 8 patients Time (h) 1

No.

Normal renal function (blood urea less than 40mg/100ml) Range Abnormal renal function (blood urea over 40 mg/100 ml) Range

5

0-77 018-2-8

2

4

6

1-34 0-7- 3 0

2-5

11- 40

1 41 0 1 - 3-2

7-5

9-7

7-6

6-5

0-95-150

8-2-10-8

4-5-100

3-0-10-0

3

Table II. Urinary concentration of carbenicillin in 11 fasting volunteers after a single oral dose of 500 mg carfecillin

0-2

Mean concentration (ug/ml) Range (ug/ml)

Time (h) 2-4

4-6

550 830 230 50-1500 110-3000 50-580

Total % recovery of carbenicillin over 6 h 26-5% 4-5-61-5%

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30 451

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Fifty-eight patients were included in the study and the infecting organisms in the urine were Esch. coli (26 cases), Ps. aeruginosa (23), Proteus mirabilis (7), Proteus vulgaris (1) and Staph. albus (1). The overall cure rate was 74-5 % (Table III) but this was significantly higher (91 %) in simple infections than in complicated infections (67 %). All the Ps. aeruginosa infections were in the complicated group of patients and whilst the cure rate (69 %) was surprisingly Table HF. Results of carfecillin treatment in 58 patients with urinary tract infection Total

Reinfection

17 4 1 22

16 (94%) 3(75%) 1 20(91%)

1 (6%) 1 1 2 (9%)

1 — — 1 (5%)

23 9 3 1 36 58

16(69%) 5(55%) 2 1 24(67%) 44(74-5%)

7(31%) . 4 1 — 12(33%) 14(25-5%)

10(62%)* 1 — — 11 (42%) 12(27%)

•Nine cases by Klebsiella spp. (MIC carbenicillin>200 ng/ml). Table IV. Details of 14 patients in whom treatment failed Case

Infecting organism

MIC carbenicillin Hg/ml)

Sex

Age

6 13

F F

65 79

22 32 33

M M F

86 72 77

312 312 12-5

18

F

60 Ps. aeruginosa

50

37 44

F M

60 65

200 100

45

M

65

100

46

M

74

50

53 58

M M

37 75

50 50

11 40

F M

78 Proteus mirabilis 71

no. Esch. coli

>200 25

0-39 200

Contributory causes Catheter. Incontinence Catheter. Fractured femur — Bifid kidneys. Catheter Diabetic kidneys Catheter Multiple sclerosis Catheter Catheter Prostatic obstruction Catheter Prostatic obstruction Catheter Multiple sclerosis. Catheter Pyonephrosis Prostatic obstruction Catheter — Renal calculi. Catheter

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Simple infections Esch. coli Proteus mirabilis Staph. albus Total Complicated infections Ps. aeruginosa Esch. coli Proteus mirabilis Proteus vulgaris Total Overall total

Failure

Cure

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297

high, 10 patients became reinfected, 9 by carbenicillin resistant strains of Klebsiella species. The reinfection rate with other bacteria was very low. The details of the 14 patients who failed treatment are shown in Table IV. Thirteen patients were over the age of 60 years and in 12 there were significant contributory causes such as multiple sclerosis, prostatic obstruction, and indwelling catheter, to account for the failure of carfecillin therapy. However, 5 organisms, 3 strains of Ps. aeruginosa, 1 strain of Proteus mirabilis and Esch. coli had minimum inhibitory concentrations of 100 ug/ml or more and may not have been sensitive to the urinary levels of carfecillin present in these patients. Only 3 patients developed side effects attributable to the antibiotic. In one case a generalized skin rash precluded continuation of therapy and 2 patients developed mild diarrhoea, but the full course of treatment was completed. ~*

Although urinary tract infections caused by Ps. aeruginosa and the indole positive strains of Proteus species are not usually associated with severe clinical illness, they frequently accompany prolonged catheterization and can cause a marked inflammation with the accumulation of mucus and debris in the bladder. This may lead to obstruction of the catheter and antibiotic treatment may be indicated to prevent this complication. Before the introduction of carfecillin it was only possible to treat these patients with systemic therapy with carbenicillin or gentamicin or to give intravesical washouts, both procedures necessitating hospital admission. Carfecillin is hydrolysed in the intestinal mucosa to carbenicillin which is excreted in very high concentrations in the urine, and mean levels of over 800 ug/ml were found in volunteer studies. On the other hand serum concentrations are inadequate to treat systemic infections and the lower levels are probably caused by incomplete absorption as only about 25 % of the drug is recovered in the urine. The mean peak level (1-38 ug/ml) found here is considerably lower than that reported by Knudsen (1974) and is slightly lower than the level found by Wilkinson, Reeves, Wise & Allen (1975) in volunteers on a 4-day course of Carfecillin. In the presence of impaired renal function the serum concentrations are higher and might be sufficient for highly sensitive strains of Esch. coli and Proteus mirabilis but more effective alternative treatments are available. The main clinical indication for carfecillin is in the treatment of urinary tract infection, especially those caused by Ps. aeruginosa and certain strains of Proteus spp. The cure rates obtained with this antibiotic in both simple and complicated infections compares favourably with any available urinary antibiotic. In simple infections a cure rate of 91 % was found and there was no obvious explanation for the two treatment failures where the MIC's of the infecting organisms were 0-39 and 312 ug/ml. Although the cure rate in complicated infections was satisfactory (67 %) reinfection with carbenicillin resistent strains of Klebsiella species occurred rapidly in 9 of the 23 patients with Ps. aeruginosa infections. However, the patients with complicated infections had a high incidence of urinary tract abnormalities and represent a very difficult therapeutic problem. In many patients where there was failure to eradicate the infecting organism, considerable relief of symptoms followed the course of carfecillin therapy. The incidence of side effects was low, confirming the findings of Wilkinson et al. (1975) and compares favourably with the indanyl ester of carbenicillin (Berrill, Maskell, Pead & Polak, 1973). Diarrhoea was only observed in 2 patients (3-3%) in this study and this is

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Discussion

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considerably lower than that found by Lees & Harding (1974) who also used a capsule formulation. However these authors reported a significant reduction in this side effect using tablets of carfecillin. There have been difficulties associated with the proprietary name of carfecillin, but it should be clear that the name Uticillin is used to suggest that its sole indication is in urinary tract infections and not to infer a superior therapeutic activity (Knudsen, 1974). The availability of a well tolerated oral antibiotic for the treatment of urinary tract infections, especially caused by Ps. aeruginosa is a valuable addition to the range of urinary antibiotics. However, the presence of renal parenchymal infection will require the use of systemic therapy with carbenicillin. Acknowledgements

References Berrill, W. T., Maskell, R., Pead, L. & Polak, A. Treatment of pseudomonas urinary infections with oral carbenicillin. British Journal of Urology 45: 563 (1973). Brumfitt, W., Percival, A. & Leigh, D. A. Clinical and laboratory studies with carbenicillin: a new penicillin active against pseudomonas pyocyanea. Lancet i: 1289 (1967). Knudsen, E. T. Uticillin. British Medical Journal iv: 530 (1974). Lees, L. J. & Harding, J. W. Urinary tract infections in general practice, a preliminary trial of carfecillin. British Journal of Clinical Practioner 28: 349 (1974). Wilkinson, P. J., Reeves, D. S., Wise, R. & Allen, J. T. Volunteer and clinical studies with carfecillin ; a new orally administered ester of carbenicillin. British Medical Journal ii: 250 (1975). (Manuscript accepted 10 March 1976)

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We would like to thank Dr A. T. Sinniah, Consultant Geriatrician and Dr R. G. Finch at Amersham General Hospital, Drs Fabre, Heywood, Harley, King and McMullan, general practitioners in Chesham, for allowing their patients to be treated, and Dr E. A. P. Croydon and Beechams Pharmaceuticals for providing the carfecillin and for helpful advice. One of us (K.S.) is in receipt of a research grant from Beechams Research Laboratories.

The treatment of simple and complicated urinary tract infections with carfecillin; a new oral ester of carbenicillin.

Journal of Antimicrobial Chemotherapy (1976) 2, 293-298 The treatment of simple and complicated urinary tract infections with carfecillin; a new oral...
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