THE ADMINISTRATION OF CEPHRADINE TO PATIENTS IN RENAL FAILURE

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1 Br. J. clin. Pharmac. (1975), 2, 3-8 THE ADINISTRATION O CEPHRADINE TO PATIENTS IN RENAL AILURE ANNE E. SOLOON & J.D. BRIGGS Renal Unit, Western Infirmary, Glasgow Gl1 6NT R. cgeachy & J.D. SLEIGH Department of Bacteriology and Immunology, Western Infirmary, Glasgow G11 6NT 1 Cephradine was given to two control and twenty subjects with varying degrees of renal failure. Serum levels at various times were recorded and side-effects noted. Recommendations for dosage schedules for subjects with renal failure have been made. Introduction Cephradine is a new semi-synthetic cephalosporin antibiotic with the chemical formula 7 - [D(-) amino (1, - cyclohexadien yl) - acetamidol] methyl oxo thia aza - bicyclo - [.2.] oct-2-ene-2 carboxylic acid (igure 1). Like other cephalosporins, cephradine is bactericidal for a wide range of Gram-positive and Gram-negative organisms. The Gram-positive organisms include Staphylococcus aureus (penicillinase and non-penicillinase producers), Streptococcus pyogenes, Streptococcus pneumoniae and Streptococcus viridans. The Gram-negative organisms include most strains of Escherichia coli, Klebsiella species, Proteus mirabilis, salmonellae and shigellae, many strains of Haemophilus influenzae and Neisseria gonorrhoeae. It is inactive against ycobacterium tuberculosis and Pseudomonas aeruginosa and only mildly active against Proteus morganii, Proteus vulgaris, Proteus rettgeri and Streptococcus faecalis. Cephradine and cephalexin are the only two cephalosporin antibiotics which are effectively absorbed orally. There has been considerable documentation of the pharmacokinetics of cepha- igure 1 Cephradine NH2 N H COOH The structural formula of cephradine. lexin in normal and uraemic subjects (Yamasaku, Tsuchida & Usada, 197; Bailey, Gower & Dash, 197; Kabins, Kelner, Walton & Goldstein, 197; Linquist, Siddiqui & Smith, 197; Regamey & Humair, 1971). Studies of the absorption, blood levels, excretion and clinical effectiveness of cephradine in individuals with normal renal function have shown that the drug is rapidly absorbed when administered orally with peak levels reached 1 h after ingestion, (Rampazzo, 1972; Zaki, Schreiber, Weliky, Knill & Hubsher, 197; Weliky & Zaki, 1973; Harvengt, De Schepper, Lamy & Hansen, 1973). The drug is excreted unchanged in the urine and is almost completely cleared from the plasma within 6 h (Neiss, 1973). It is effective in treating recurrent urinary tract infections (Lotti & uzzonigro, 1972), chest infections (ogabgab, 1973) and various soft tissue infections (artin, 1973) with few side-effects. There are, however, few published studies of the pharmacokinetics of cephradine in patients with renal failure. The only available information at the present time is based on a study using capsules of cephradine (5 mg) administered 8-hourly (Vukovich, artinez- & Neiss, 1973). This produced very high serum concentrations of the order of 6-12 jg/ml when the steady state was reached. rom this a varying time schedule for dosage with 5 mg capsules was calculated. The dose interval to maintain therapeutic serum concentrations in patients with creatinine clearance values of less than 5 ml/min was from 5 to 7 hours. The present study provides further information on the pharmacokinetics of cephradine in patients with renal failure and evaluates the use of a lower dose (25 mg) capsule in such patients.

2 ANNE E. SOLOON, J.D. BRIGGS, R. cgeachy & J.D. SLEIGH ethods Twenty patients with varying degrees of renal failure and two control subjects were studied. The two control subjects each had creatinine clearances of more than 11 ml/minute. Clinical details of the patients are shown in Table 1. ourteen patients with some renal function were not on regular haemodialysis and they were divided into three groups on the basis of the severity of their renal failure (Table 2). The four patients in group 1A had creatinine clearance values of between 23 and 31 ml/minute. In group 1 B were seven patients whose creatinine clearances were between 6 and 19 ml/minute. Patients in both these groups were given cephradine orally in a dose of 5 mg on day 1 and 5 mg 6-hourly for days 2-5 with a final dose on the morning of the sixth day. Group 1 C consisted of three patients with creatinine clearance values of less than 6 ml/minute. They received cephradine in a dose of 25 mg on day 1 and 25 mg 6-hourly for day 2-5 with a final dose on the morning of day 6. Blood samples for cephradine assay were taken on day 1 at 1, 2, 3, 6 and 1 h after the first dose and on day 6 at, 1, 2, 3, 6, 1 and 2 h after the final dose. In these three groups, the second dose on day one was delayed till 1 h after the initial dose to allow measurement of the serum levels during this period. Six patients were either anephric or had negligible renal function and were receiving twice weekly haemodialysis. our of them (group 2A) were given cephradine orally in a dose of 25 mg at the beginning of a 1 h dialysis and blood samples were taken at 1, 2, 3, 6 and 9 hours. On a Table 1 Clinical details of the patients. Number Age (years) Sex Diagnosis Creatinine clearance (mil/min) Analgesic nephropathy Analgesic nephropathy Chronic glomerulonephfitis alignant hypertension Analgesic nephropathy alignant hypertension Polycystic kidneys Table 2 Analysis of the groups of patients studied based on the severity of their renal failure Creatinine Group Number of Patients clarance (mi/mini 1A lb ic 7 3 2A 2B 2 Cephradine dose mg day 1, 5 mg 6-hourly for days mg day 1, 5 mg 6-hourly for days mg day 1, 25 mg 6-hourly for days 2-6 Post-dialysis 125 mg single dose 25 mg at end of dialysis 25 mg at start of next dialysis 25 mg at end of next dialysis

3 CEPHRADINE IN RENAL AILURE 5 Day 1 Day 6 ~~~~~~k_~~~.-. E~~~~ ~ ~ ~~~ ~~~~~~~~~~~~~~~~~~ E O~' E7 <) cn igure 2 Serum cephradine concentrations in four patients (- patient 1, * patient 2, A patient 3 and patient, Table 1), group 1 A with a creatinine clearance of ml/min, on day 1 and day 6 after cephradine (5 mg) on day 1 and cephradine (5 mg, 6-hourly) on days 2-5 with a final dose on the morning of the sixth day. separate occasion, they were given a 25 mg dose immediately after a dialysis and blood samples were taken at, 1, 2, 3, 6, 9 and 2 hours. The other two patients (group 2B) were given cephradine (25 mg) orally immediately after a 1 h haemodialysis and blood samples were taken at, 1, 2, 3, 12, 2, 36, 8, 6,.72 and 8 h, that is,until the start of the next dialysis. At this time a further 25 mg capsule was given and blood samples were taken during the dialysis. At the end of the dialysis, (at 9.5 h in one patient and 6 h in the other), a further dose of cephradine (25 mg) was given and blood samples were taken up to 6 hours. Informed consent was obtained from all patients. None were fasted at the time of taking the cephradine and none had an infective illness. Creatinine clearance and blood urea estimations were performed before, during and after the test period. The assays were performed on large plates by the' diffusion method employing Sarcina lutea strain No. 931A in Oxoid antibiotic assay medium No. 1. The tests were compared with cephradine standards ranging from 16 g-1,g/ml. When the serum levels were greater than 16 ig/ml, suitable dilutions were made and the samples reassayed so that a value was recorded within the range covered by the assay. Zones were measured to the nearest.5 mm, and the results extrapolated from a graph on semi-log paper. Creatinine estimations were done by a modification of the Technicon method NIIB. Results The results in the two normal subjects correlate well with previous findings with peak serum levels between 1 and 15,ug/ml at 1 h, rapid excretion 29 mainly during the first 3 h and no accumulation of the drug by day 6. In group 1A patients (igure 2), there was a rapid rise in serum levels to a peak at 1-2 h which ranged from 17- g/ml. By 1 h no patient had a level greater than 1 gg/ml. After 5 days there was some accumulation of the drug in two patients (Cases 3 and ), with pre-dose levels of 12 and 28,g/ml, and persistance of a level of 9 mg/ml at 2 h after the last dose in one patient (Case ). The patients in group lb showed a higher peak at 1-2 h with a range of 1-51,ug/ml (igure 3). Significant amounts of cephradine were still present at 1 h in six of the seven patients, ranging from 5-31,g/ml. Case 6 had only 2,ug/ml at 1 hours. By day 6, considerable accumulation of the drug had occurred apart from in Case 6. Pre-dose levels were g/ml and after the final dose the peak level reached 12,ug/ml in one patient (Case 9). Twenty-four hours after the last dose, serum levels of 6-3,mg/ml were still present. Case 6 showed no accumulation by day 6 and no retention of the drug at 2 hours. Within groups 1A and 1B, the higher serum cephradine levels were usually associated with lower creatinine clearance values, the obvious exception being Case 6. The serum levels in the three patients in group 1 C showed a slower rise to a peak of 5-15,g/ml at 1-3 h after a 25 mg dose (igure ). Thereafter the levels fell slowly, if at all, over 1 hours. By day 6, accumulation of the drug had occurred with pre-dose levels of mg/ml. Twenty-four hours after the last dose there was persistence of the drug at levels between 5 and 12 mg/ml. When the four regular dialysis patients were given a single dose of cephradine (25 mg) at the start of dialysis, peak serum levels of 1-2 mg/ml were reached at between 1 and 3 h (igure 5). After a 9 h dialysis, the levels lay between 5 and

4 6 ANNE E. SOLOON, J.D. BRIGGS, R. cgeachy & J.D. SLEIGH =1 vay I / < va ) igure 3 Serum cephradine concentrations in seven patients (- patient 5, * patient 6, * patient 7, o patient 8, o patient 9, A patient 1 and o patient 11, Table 1), group 1 B with a creatinine clearance of 6-19 ml/min, on day 1 and day 6 after cephradine (5 mg) on day 1 and cephradine (5 mg, 6-hourly) on days 2-5 with a final dose on the morning of the sixth day. 8 Dayl Day6 E 6 *o 8 co -C ) 6- :- E -.. a igure Serum cephradine concentrations in three patients (- patient 12, * patient 13 and A patient 1, Table 1), group 1 C with a creatinine clearance of < 6ml/min, on day 1 and day 6 after cephradine (25 mg) on day 1 and cephradine (25 mg, 6-hourly) on days 2-5 with a final dose on the morning of the sixth day. 2 1 ṯ 6C U -S (a : 2 - During dialysis Post dialysis E o cn 'I I a a I I a a.1 I II I I I. -1- a a A igure 5 Serum cephradine concentrations in four patients (- patient 15, * patient 16,A patient 17 and o patient 18, Table 1),group 2A with a creatinine clearance of ml/min on dialysis, after cephradine (25 mg) at the beginning of dialysis and, on a separate occasion, cephradine (25 mg) immediately post-dialysis. 2

CEPHRADINE IN RENAL AILURE 7 6r.--.E 2 Second Dia"is Start I End 11 t I 1 A. Dose 1. a a I a. a I - 3 5 7 9 Dose 2 t.

5 CEPHRADINE IN RENAL AILURE 7 6r.--.E 2 Second Dia"is Start I End 11 t I 1 A. Dose 1. a a I a. a I Dose 2 t.ldose 3 Time after first dialysis (h) igure 6 Serum cephradine concentrations in two patients (. patient 19 and * patient 2, Table 1), group 2B with a creatinine clearance of ml/min and on dialysis, after cephradine (25 mg) at end of first dialysis, at the start of the second dialysis and at the end of the second dialysis. - A 1 g/ml. When the same dose was repeated without dialysis, the peak levels were higher at jg/ml. At 9 h, a slight fall had occurred to 15-2,ug/ml and the levels at 2 h ranged from 1-18 ug/ml. In the two anephric patients whose serum levels were measured for 8 h, peaks of 2-3 g/ml respectively were reached at 2 hours. The levels then fell to 2 and pg/ml at 36 h, then remained between 1 and 2 ;g/ml over the next 2 days. A further 25 mg dose at the start of dialysis produced peak levels of 12 and 18jug/ml, with a fall at the end of dialysis to and 7 jig/ml. A third dose at this time resulted in peak levels of 2 and,g/ml with a steady fall to 2 Ag/ml 8 h after this dose (igure 6). Three of the twenty patients developed side-effects which did not necessitate withdrawal of the drug during the 5 days, but would have prevented further dosage. Case 11, who was known to be allergic to penicillin, developed an itchy erythematous rash. His peak serum cephradine level was the highest recorded at 12 Ag/ml. Case 1 developed diarrhoea which persisted for a week. Case 19 developed an exacerbation of abdominal pain which had been present for some time and was thought to be due to adhesions. In none of the patients was there any deterioration in renal function after the course of cephradine. Discussion We agree with other workers that this is a safe antibiotic which can be recommended for use in subjects with renal failure. There are few side-effects, although the possible cross-sensitivity with penicillin should be noted, and there is no adverse effect on renal function. It is well absorbed when given orally, although when the creatinine clearance is less than 2 ml/min, the peak serum level tends to occur at 1 or 2 h later in the normal subject. As expected, accumulation of cephradine will occur if 5 mg 6-hourly is given to patients with creatinine clearances of below 2 ml/minute. The exception of case 6 may well be due to the creatinine clearance estimation being too low. Accumulation also occurs if 25 mg is given 6-hourly in patients with creatinine clearances below 5 ml/minute. We suggest the following dosage schedules: Creatinine clearance > 2 ml/min < 2 ml/min, > 5 ml/min < 5 ml/min 5 mg 6-hourly 25 mg 6-hourly 25 mg 12-hourly or patients on chronic intermittent haemodialysis: 25 mg at start of haemodialysis 25 mg at 12 h after start of haemodialysis 25 mg at 2 h after start of haemodialysis 25 mg at start of next haemodialysis, if this is 3 h or more after previous dose. We should like to thank E.R. Squibb & Sons Ltd, for providing ample supplies of cephradine (Velosef), and the biochemistry department of the Western Infirmary, Glasgow for the measurement of creatinine clearances. Reprint requests should be addressed to Dr. Anne Solomon.

8 ANNE E. SOLOON, J.D. BRIGGS, R. cgeachy & J.D. SLEIG1H References BAILEY, R.R., GOWER, P. & DASH, C.H. (197). The effect of renal function and haemodialysis on serum and urine levels of cephalexin.

6 8 ANNE E. SOLOON, J.D. BRIGGS, R. cgeachy & J.D. SLEIG1H References BAILEY, R.R., GOWER, P. & DASH, C.H. (197). The effect of renal function and haemodialysis on serum and urine levels of cephalexin. Postgrad. med. J., 6, Suppl., 6-6. HARVENGT, C., DE SCHEPPER, P., LAY,. & HANSEN, J. (1973). Cephradine absorption and excretion in fasting and nonfasting volunteers. J. clin. Pharmac., 13, 36. KABINS, S.A., KELNER, B., WALTON, E. & GOLDSTEIN, E. (197). Cephalexin therapy as related to renal function. Am. J. ed. Sci, 259, LINQUIST, A.A., SIDDIQUI, J. & SITH, I.. (197). Cephalexin in patients with renal disease. New Eng. J. ed., 283, LOTTI, T. & UZZONIGRO, G. (1972). Clinico - experimental research on the therapeutic activity of a new semisynthetic cephalosporin - cephradine. Quaderni diantibiotica, arch (translation) ARTIN, R.R. (1973). Clinical experience with oral cephradine. J. Irish ed. Ass. (Suppl.), 66, (6), OGABGAB, W.J. (1973). Use of cephradine in respiratory tract infections. J. Irish ed. Ass. (Suppl.), 66, (6), NEISS, E.S. (1973). Cephradine. A summary of preclinical studies and clinical pharmacology. J. Irish ed. Ass. (Suppl.), 66, (6), RAPAZZO,. (1972). Clinical research on a new semisynthetic cephalosporin: Cephradine. (Translation). Gazetta edica Italiana, 132, (8), REGAEY, C. & HUAIR, L. (1971). Pharmacokinetics of cephalexin in renal insufficiency. Postgrad. ed. J., 7, Suppl., VUKOVICH, R., ARTINEZ-.,. & NEISS, E.S. (1973). The safety and pharmacodynamics of cephradine in patients with renal impairment. 8th International Congress of Chemotherapy, Athens. WELIKY, I. & ZAKI, A. (1973). Absorption, distribution and elimination of cephradine after oral and parenteral administration to humans. 8th International Congress of Chemotherapy, Athens. YAASAKU,., TSUCHIDA, R. & USUDA, Y. (197). A study of the kinetics of cephalosporins in renal impairment. Postgrad. med. J., 6, Suppl., ZAKI, A., SCHREIBER, E.C., WELIKY, I., KNILL, J.R. & HUBSHER, J.A. (197). Clinical pharmacology of oral cephradine. J. clin. Pharmac., 1, (Revised arch 6, 1975)

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AXITAB-CV TAB. COMPOSITION : Each film coated tablet contains: Cefuroxime Axetil I.P. Eq. to Anhydrous 500mg. Potassium Clavulanate Diluted I.P. Eq. to Clavulanic Acid 125mg DESCRIPTION : Cefuroxime Axetil