Journal of Antimicrobial Chemotherapy (1975) 1 (Suppi), 119-133
Cephaloridine, cephalothin and the kidney
R. D. Foord
An analysis of cases of possible nephrotoxicity from cephaloridine (96) and cephalothin (63) reported over the last 10 years shows that in the majority of cases the toxicity was associated with either excessive dosage or previous renal functional impairment without appropriate dosage reduction. Other factors found frequently and thought to predispose towards toxicity are: the concurrent use of other potentially nephrotoxic antibiotics, especially gentamicin or the diuretic frusemide; the presence of intercurrent severe drug allergy and factors leading to temporary reductions in renal clearance such as surgical operations, dehydration and shock. Introduction
Cephaloridine and cephalothin have been used extensively and with notable safety throughout the world in the treatment of bacterial infections since 1964. Some 20 million people have been treated with cephaloridine for example. In the literature over this time cases have been reported of suspected nephrotoxic reactions (oligo-anuria or renal failure with maintained diuresis) to these cephalosporins on 71 occasions for cephaloridine and on 61 for cephalothin. Twenty-five other cases with cephaloridine and two with cephalothin are known through personal communication. The case reports of these patients have been examined to identify any common or predisposing factors. By 1969, just over 4 years after the introduction of cephaloridine, 36 cases of possible nephrotoxicity from it had been reported. An analysis then of these cases led to the suggestion that potent diuretics, especially frusemide, might enhance the nephrotoxicity of cephaloridine (Foord, 1969). This was then confirmed in laboratory animals (Dodds & Foord, 1970; Lawson, Macadam, Singh, Gavras & Linton, 1970). These first 36 cases have been included in the present analysis. Animal toxicity
Both cephalosporins are drugs of very low toxicity. However, some species of laboratory animals can show one toxic effect if given doses which are much above those required clinically—damage to the proximal cells of the kidney tubules (Atkinson, Currie, Davis, Pratt, Sharpe & Tomich, 1966; Welles, Gibson, Harris, Small & Anderson, 1966; Perkins, Apicella, Lee, Cuppage & Saslaw, 1968; Ueda, Matsumoto, Nakamura, Noda, Kobayashi & Omori, 1970). The degree of damage, up to tubular cell necrosis, and the 119
Downloaded from http://jac.oxfordjournals.org/ at East Carolina University on July 14, 2015
Clinical Pharmacology Department, Glaxo Research Ltd, Greenford, Middlesex, England
120
R. D. Foord
Human pharmacology and toxicity
Both antibiotics are excreted in high concentration through the kidney. Renal clearances are about 125 and 275 ml/min/1-73 m* for cephaloridine and cephalothin, respectively.
Downloaded from http://jac.oxfordjournals.org/ at East Carolina University on July 14, 2015
dose necessary to produce a damaging effect vary with the species of animal tested and also differ with the two cephalosporins. The single subcutaneous doses producing some damaging effect in rats are 1000 and 2000 mg/kg for cephaloridine and cephalothin respectively. The corresponding subacute intramuscular doses in rats are 400 and 800 mg/kg/day for 21 days (Ueda et al., 1970). In rabbits (N.Z. white strain), the most sensitive of the species tested for this effect, the single intramuscular doses required are 100 to 200 and 500 to 1000 mg/kg for cephaloridine and cephalothin, respectively (Atkinson et al., 1966; Fleming & Jaffe, 1967; Perkins et al., 1968; Luscombe & Nicholls, 1975). However, Venuto, Stein & Ferris (1972) were unable to demonstrate nephrotoxicity of cephalothin in rabbits with reduced renal function. In general, the dose of cephalothin required to produce a damaging effect if one is seen at all, is 2 to 6 times higher than that of cephaloridine. The kidney tissue concentrations of these cephalosporins which are associated with this nephrotoxicity are not known. It is known that these cephalosporins can be cytotoxic to cells in tissue culture: cephaloridine at 500 to 1000 jig/ml to embryo rabbit and monkey kidney cells and at 270 ug/ml to human amnion cells and cephalothin at 20 ug/ml to human amnion cells and at 25 to 42 ug/ml to cultures of McCoy cells (Stewart & Holt, 1964; Chang & Weinstein, 1967; Pain, Nickell & Jarman, 1967). It is known also from work in dogs and rabbits that cephaloridine concentrates in the proximal part of the renal tubule within an hour of administration (Currie, Little & McDonald, 1966; Silverblatt, Turck & Bulger, 1970). There is evidence from other work in dogs that the renal tubular wall has a physico-chemical inner or luminal cell membrane which limits to a varying degree the amount of cephalosporin passing from the tubular cell into the luminal fluid. It seems likely that cephaloridine is transported into the proximal tubular cell from the blood stream at the peritubular cell membrane, but does not move readily across the luminal cell into the tubular fluid. The high intracellular cephaloridine concentration which may result from this process may be partly responsible for the drug's toxicity to proximal tubular cells (Tune, 1972; Tune & Fernholt, 1973; Tune, Femholt & Schwartz, 1974). With cephalothin there appears to be a greater facility in crossing the luminal cell membrane, with consequently a greater proportion of the excreted antibiotic being secreted through the tubules and a lesser tendency for accumulation to possible toxic concentrations inside the proximal tubular cells. Further support for the belief that tubular transport mechanisms are involved in this type of nephrotoxicity are the observations that the acute tubular necrosis which results in rabbits from toxic doses of cephaloridine can be prevented by the prior administration of high dosage probenecid (Child & Dodds, 1967; Fleming & Jaffe, 1967) or the simultaneous administration of high dosage cephalothin (Tune & Kempson, 1973). The blood level of cephalosporin associated with nephrotoxicity is known in rabbits. Doses of cephaloridine producing plasma levels of less than 150 ug/ml are not nephrotoxic whereas those producing levels of 180 to 600 ug/ml are, or can be, toxic (Welles et al, 1966; Fleming & Jaffe, 1967; Perkins et al., 1968; Matthew & Ryan, 1973). With cephalothin doses of 500 mg/kg/day produce mean plasma levels of 188 ng/ ml at 2 h on the fourth day of administration and this dose is marginally toxic to the tubules (Perkins et al., 1968).
Cephaloridine, cephalothln and the kidney
121
Table I. Prc-treatment renal function, age and cephaloridine dosage More than 6 g/day Pre- treatment renal function Impaired Very doubtful Doubtful Apparently normal Totals
Less than 6 g/day
6 g/day 50 or more yr
Less than 50 yr
50 or more yr
Less than 50 yr
1
4 3 2
2 2 2
20 5 4
3 1 1
4
7
4
2
11
1
12
11 24
13 21
8
40
6 49
50 or more yr
Less than 50 yr
6 2
3
Age unknown 1
1
Total cases Age unknown 1 1 1
40 14 11 31*
3 96*
* Including two patients with apparently normal renal function but with the dosage unknown Analysis of case reports Pre-treatment renal function, age and dosage
In the 96 cephaloridine (CER) cases the renal function before treatment was normal in only 31, and in the 63 cephalothin (CET) cases only 28 were normal. In 10 CET cases the pre-treatment renal function was not reported (Tables I and II). All patients in both series with one exception, a neonate treated with cephaloridine and high dosage gentamicin, were adults. Of the 91 cephaloridine patients in whom the age was reported 66 (73 %) were aged 50 or more years. Forty out of 46 (87 %) receiving less than 6 g/day and 26 out of 45 (57 %) receiving 6 g or more/day were aged 50 or more years (i >
Cephaloridine, cephalothin and the kidney
R. D. Foord
An analysis of cases of possible nephrotoxicity from cephaloridine (96) and cephalothin (63) reported over the last 10 years shows that in the majority of cases the toxicity was associated with either excessive dosage or previous renal functional impairment without appropriate dosage reduction. Other factors found frequently and thought to predispose towards toxicity are: the concurrent use of other potentially nephrotoxic antibiotics, especially gentamicin or the diuretic frusemide; the presence of intercurrent severe drug allergy and factors leading to temporary reductions in renal clearance such as surgical operations, dehydration and shock. Introduction
Cephaloridine and cephalothin have been used extensively and with notable safety throughout the world in the treatment of bacterial infections since 1964. Some 20 million people have been treated with cephaloridine for example. In the literature over this time cases have been reported of suspected nephrotoxic reactions (oligo-anuria or renal failure with maintained diuresis) to these cephalosporins on 71 occasions for cephaloridine and on 61 for cephalothin. Twenty-five other cases with cephaloridine and two with cephalothin are known through personal communication. The case reports of these patients have been examined to identify any common or predisposing factors. By 1969, just over 4 years after the introduction of cephaloridine, 36 cases of possible nephrotoxicity from it had been reported. An analysis then of these cases led to the suggestion that potent diuretics, especially frusemide, might enhance the nephrotoxicity of cephaloridine (Foord, 1969). This was then confirmed in laboratory animals (Dodds & Foord, 1970; Lawson, Macadam, Singh, Gavras & Linton, 1970). These first 36 cases have been included in the present analysis. Animal toxicity
Both cephalosporins are drugs of very low toxicity. However, some species of laboratory animals can show one toxic effect if given doses which are much above those required clinically—damage to the proximal cells of the kidney tubules (Atkinson, Currie, Davis, Pratt, Sharpe & Tomich, 1966; Welles, Gibson, Harris, Small & Anderson, 1966; Perkins, Apicella, Lee, Cuppage & Saslaw, 1968; Ueda, Matsumoto, Nakamura, Noda, Kobayashi & Omori, 1970). The degree of damage, up to tubular cell necrosis, and the 119
Downloaded from http://jac.oxfordjournals.org/ at East Carolina University on July 14, 2015
Clinical Pharmacology Department, Glaxo Research Ltd, Greenford, Middlesex, England
120
R. D. Foord
Human pharmacology and toxicity
Both antibiotics are excreted in high concentration through the kidney. Renal clearances are about 125 and 275 ml/min/1-73 m* for cephaloridine and cephalothin, respectively.
Downloaded from http://jac.oxfordjournals.org/ at East Carolina University on July 14, 2015
dose necessary to produce a damaging effect vary with the species of animal tested and also differ with the two cephalosporins. The single subcutaneous doses producing some damaging effect in rats are 1000 and 2000 mg/kg for cephaloridine and cephalothin respectively. The corresponding subacute intramuscular doses in rats are 400 and 800 mg/kg/day for 21 days (Ueda et al., 1970). In rabbits (N.Z. white strain), the most sensitive of the species tested for this effect, the single intramuscular doses required are 100 to 200 and 500 to 1000 mg/kg for cephaloridine and cephalothin, respectively (Atkinson et al., 1966; Fleming & Jaffe, 1967; Perkins et al., 1968; Luscombe & Nicholls, 1975). However, Venuto, Stein & Ferris (1972) were unable to demonstrate nephrotoxicity of cephalothin in rabbits with reduced renal function. In general, the dose of cephalothin required to produce a damaging effect if one is seen at all, is 2 to 6 times higher than that of cephaloridine. The kidney tissue concentrations of these cephalosporins which are associated with this nephrotoxicity are not known. It is known that these cephalosporins can be cytotoxic to cells in tissue culture: cephaloridine at 500 to 1000 jig/ml to embryo rabbit and monkey kidney cells and at 270 ug/ml to human amnion cells and cephalothin at 20 ug/ml to human amnion cells and at 25 to 42 ug/ml to cultures of McCoy cells (Stewart & Holt, 1964; Chang & Weinstein, 1967; Pain, Nickell & Jarman, 1967). It is known also from work in dogs and rabbits that cephaloridine concentrates in the proximal part of the renal tubule within an hour of administration (Currie, Little & McDonald, 1966; Silverblatt, Turck & Bulger, 1970). There is evidence from other work in dogs that the renal tubular wall has a physico-chemical inner or luminal cell membrane which limits to a varying degree the amount of cephalosporin passing from the tubular cell into the luminal fluid. It seems likely that cephaloridine is transported into the proximal tubular cell from the blood stream at the peritubular cell membrane, but does not move readily across the luminal cell into the tubular fluid. The high intracellular cephaloridine concentration which may result from this process may be partly responsible for the drug's toxicity to proximal tubular cells (Tune, 1972; Tune & Fernholt, 1973; Tune, Femholt & Schwartz, 1974). With cephalothin there appears to be a greater facility in crossing the luminal cell membrane, with consequently a greater proportion of the excreted antibiotic being secreted through the tubules and a lesser tendency for accumulation to possible toxic concentrations inside the proximal tubular cells. Further support for the belief that tubular transport mechanisms are involved in this type of nephrotoxicity are the observations that the acute tubular necrosis which results in rabbits from toxic doses of cephaloridine can be prevented by the prior administration of high dosage probenecid (Child & Dodds, 1967; Fleming & Jaffe, 1967) or the simultaneous administration of high dosage cephalothin (Tune & Kempson, 1973). The blood level of cephalosporin associated with nephrotoxicity is known in rabbits. Doses of cephaloridine producing plasma levels of less than 150 ug/ml are not nephrotoxic whereas those producing levels of 180 to 600 ug/ml are, or can be, toxic (Welles et al, 1966; Fleming & Jaffe, 1967; Perkins et al., 1968; Matthew & Ryan, 1973). With cephalothin doses of 500 mg/kg/day produce mean plasma levels of 188 ng/ ml at 2 h on the fourth day of administration and this dose is marginally toxic to the tubules (Perkins et al., 1968).
Cephaloridine, cephalothln and the kidney
121
Table I. Prc-treatment renal function, age and cephaloridine dosage More than 6 g/day Pre- treatment renal function Impaired Very doubtful Doubtful Apparently normal Totals
Less than 6 g/day
6 g/day 50 or more yr
Less than 50 yr
50 or more yr
Less than 50 yr
1
4 3 2
2 2 2
20 5 4
3 1 1
4
7
4
2
11
1
12
11 24
13 21
8
40
6 49
50 or more yr
Less than 50 yr
6 2
3
Age unknown 1
1
Total cases Age unknown 1 1 1
40 14 11 31*
3 96*
* Including two patients with apparently normal renal function but with the dosage unknown Analysis of case reports Pre-treatment renal function, age and dosage
In the 96 cephaloridine (CER) cases the renal function before treatment was normal in only 31, and in the 63 cephalothin (CET) cases only 28 were normal. In 10 CET cases the pre-treatment renal function was not reported (Tables I and II). All patients in both series with one exception, a neonate treated with cephaloridine and high dosage gentamicin, were adults. Of the 91 cephaloridine patients in whom the age was reported 66 (73 %) were aged 50 or more years. Forty out of 46 (87 %) receiving less than 6 g/day and 26 out of 45 (57 %) receiving 6 g or more/day were aged 50 or more years (i >
