Cephradine-a new cephalosporin in recurrent urinary tract infectionVidya N Acharya, Kamini J Shroff, Neela H Mehta, KC Patel, Surangi K Jadav
Artificial Kidney Division Department of Medicine, Seth G. S. Medical College & K.E.M. Hospital, Parel, Bombay-400 012., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 615262
Source of Support: None, Conflict of Interest: None
Out of 866 bacterial isolates grown in significant colony counts from 3 consecutive mid-stream urine samples or from a single sample of urine obtained by suprapubic bladder puncture, 305 isolates (35.22%) were found to be sensitive to Cephradine. It was noted that Gram positive organisms (63.44%) manifested highest sensitivity to this antibiotic. Next in order was E. coli with a sensitivity of 60.54%. The clinical trial revealed a good response in 59.37% and 81.81; of patients with oral and injectable group respectively. The maximum response was seen in E. coli infections (89.47%) and Gram positive organisms coming next with 80% response. No major untoward reactions were noted in patients with or without azotaemia and the antibiotic could be used safely even in presence of renal failure.
Cephradine is a new, acid stable, unique, broad spectrum, semisynthetic derivative of cephalosporine. It was synthesized in 1969 at the Squibb Institute for Medical Research .  The structure of Cephradine is shown in [Figure 1].
The previous bacteriological studies have demonstrated its antibacterial activity against a wide range of micro-organisms including both Gram positive and Gram negative bacteria. It has been reported that cephradine is not acted upon by staphylococcal penicillinase. ,, It has also been proved by several investigators that cephalosporins are important agents for antimicrobial therapy of urinary tract infection. , Cephradine has an advantage over other cephalosporins in that it is the only one of this group effective by both oral and injectable route. Various reports on the evaluation of cephradine in clinical situations have been published and these have confirmed that orally and parenterally it is highly effective in the treatment of infections of urinary tract. ,,,,,,,
It has been shown that most of the cephradine is excreted unchanged in the urine within 6 hours. , However, in studies of mice, rats, dogs and monkeys, cephradine has been shown to possess a low order of acute, sub-acute and chronic toxicity after its administration by either route and does not induce any teratogenic changes in the offsprings of mice and rats. 
The study reported here was initiated to determine the effectiveness of cephradine by oral as well as parenteral route ix: treating recurrent urinary tract infection with micro-organisms susceptible to cephradine and to record the incidences of side effects if any.
Urine cultures were done from 829 suspected cases of recurrent urinary tract infection by 3 consecutive mid-stream urine samples or by a single urine sample drawn by suprapubic bladder aspiration technique. The mid-stream samples were studied for significant bacteriuria (colony count of more than 10 5 organisms/ml.) by Dip Slide Inoculum Method as reported earlier.  The sensitivity test was performed by impregnated disc method as described by Bauer and Kirby  by using 30 meg. sensitivity discs of cephradine. Depending upon the zone of inhibition that developed round the disc, the organisms were labelled as highly sensitive (10-20 mm diameter), mildly sensitive (5-10 mm diameter) and resistant (less than 5 mm diameter).
Patient Selection: Patients taken up for the study were found to be suffering from an infection of urinary tract confirmed by the presence of micro-organism's in the urine in a concentration of >10 5 organisms/ml. as described above. Cephradine was administered to a total of 54 patients having recurrent urinary tract infection due to various causes. The underlying etiological factors for recurrent urinary tract infections were diabetes mellitus, calculus disease, prostatic enlargement, chronic pyelonephritis with varying grades of renal failure and congenital abnormalities of urinary tract.
Trial Design: The treatment was started on receipt of positive urine culture. Out of 54 patients, 32 were treated with oral cephradine in a dose of 1 gm. (2 capsules of 500 mgs. each) 4 times a day for 14 days. The remaining 22 patients were administered cephradine parenterally in the dosage of 500 mgs. twice a day by intramuscular route for 14 days. Urine was cultured at the beginning of the trial and after 2, 7 and 14 days of the treatment. The same was repeated one month after stopping the treatment. The laboratory investigations including complete blood count with a differential smear, BUN, Creatinine and liver function tests were carried out before and after starting the treatment.
Criteria for assessing efficacy: The response as obtained was graded as follows:
Good response: Symptomatic improvement plus urine becoming sterile at 2 days after starting therapy and remaining sterile thereafter.
Partial response: Symptomatic improvement plus urine becoming sterile at 2 days and remaining sterile at 7 days and/or 14 days, but not one month after stopping therapy.
Poor response: No symptomatic improvement, urine not becoming sterile at 2, 7 or 14 days.
A total of 866 bacterial isolates were obtained from 829 patients. Out of these, 305 isolates (35.22%) were found to be sensitive to cephradine. Bacteriological data on these 305 cultures is presented in [Table 1]. It can be seen that E. colt and Gram positive organisms showed higher sensitivity to cephradine while Pseudornonas aeruginosa and Proteus group were highly resistant to cephradine.
The results of oral and parenteral therapy have been evaluated separately as shown in [Table 2].
Although 59.37% and 81.81; 0 of the patients in oral and parenteral group respectively showed a good response, there is no statistically significant difference in the response in relation to the type of therapy (x 2 = 3.148, df = 2, N.S.). It was noted that 8 of these 54 patients had recurrent urinary tract infection due to other microorganisms after 14 days of therapy or one month after stopping treatment. These patients were considered to have partial response, though the original infection cleared.
It can be noted from [Table 3] that maximum response was seen in E. colt infections (89.47%), in Gram positive organisms (80%) and in infections with other Gram negative organisms (77.77%) which include Providence group, Enterobacter group and Alcaligenes f aecalis.
Out of 54 cases on trial, 11 showed azotaemia of varying degree with serum creatinine of 4.5 mg% to 15.3 mg%. There were 7 subjects with azotaemia in oral group and 4 in injectable group. Out of the patients in oral group group, 3 subjects became non-azotaemic with the control of infection at the end of trial, 2 died due to septicaemia and had exhibited poor response and-2 showed good response, but still remained azotaemic. Out of 4 azotaemic patients in the injectable group, 2 responded with good outcome, 1 had partial response and 1 died due to end stage renal failure.
There was no significant difference in the renal function tests and liver function tests in both the azotaemic and non-azotaemic groups except that there was a significant reduction in BUN (p<0.01) and Creatinine (p<0.05) in patients with azotaemia [Table 4] at the end of the therapy. [Table 4] shows the laboratory investigations to include renal function tests and liver function tests before and after the trial in azotaemic and non-azotaemic trial patients.
Side effects: No gastro-intestinal symptoms were noted in both azotaemic and non-azotaemic patients. Transient skin rash was noted in one azotaemic patient which disappeared with anti-histaminics inspite of continuing the antibiotic with good outcome.
Many reports are available on the clinical trials of cephradine in acute urinary tract infection. However, there are only two such reports available in literature for its utility in recurrent urinary tract infection. , The studies reported here were initiated to determine the effectiveness of a new antibiotic- cephradine by oral and parenteral route in treating recurrent urinary tract infection with organisms susceptible to cephradine and to record the incidence of side effects.
The previous bacteriological studies of cephradine have demonstrated its bactericidal activity, against a wide range of pathogens like staphylococcus, streptococcus, Neisseria More Detailse, Escherichia More Details, klebsiella, aerobacter and proteus group specially indole positive strains. , The present study has shown that E. coli and Gram positive organisms were more sensitive to cephradine. Clinical trials at various centres have confirmed that orally and parenterally, cephradine is effective in the treatment of infections of the urinary tract caused by susceptible organisms. ,,,,, Published data of multicentric trials of cephradine in urinary tract infections has indicated that an average of 76% of patients showed satisfactory outcome.  Klastersky et al,  in their trials of cephradine in urinary tract infection, observed excellent response in 42% whereas the response was graded as only favourable in 21% cases. In the present study, good response was noted in 59.37% and 81.815 of the patients treated by oral and parenteral route respectively. A maximum and satisfactory bacteriological response was noted in E. coli and in infections with other Gram negative organisms like Enterobacter group, Providence group and Alcaligenes faecalis. Gulati et al  have also reported a satisfactory bacteriological suppression in majority of E. coli and Klebsiella infection.
The side effects noted were hardly any except in one azotaemic patient who developed a hypersensitivity rash. There appeared to be no deterioration in renal functions as well as in liver functions at the end of the study period. It has been stated that some of the patients of renal failure by the nature of their illness sometimes have some degree of renal damage, however, cephradine does not lead to any deterioration. , The same was confirmed by the present work too. Thus the study confirms the efficacy of cephradine in both azotaemic and non-azotaemic patients with recurrent urinary tract infection.
This clinical trial was made possible by the financial support given by Messrs. Sarabhai Chemicals Ltd. We sincerely thank them for their supply of oral and parenteral cephradine for this work. Our thanks are also due to Dr. C. K. Deshpande-President, K. E. M. Hospital and Seth G. S. Medical College Research Society for having given us facilities to carry out the project. For statistical analysis of the results we are grateful to Mrs. K. D. Lotlikar. The Laboratory Staff of No. 44-Department of Medicine carried out the biochemical and haematological data for this project-our sincere gratitude to them.
[Table 1], [Table 2], [Table 3], [Table 4]