332
tion, important unwanted effects clearly occur in the first few hours after decanoate administration, and, to a greater extent, at up to two days after enanthate. While the frequency of unwanted effect reporting was undoubtedly increased by the design of the study, we feel that it is important to emphasise the occurrence of these early, reversible effects, since the possibility of such effects has not been previously reported. Emphasis in the past has been largely on long-term unwanted effects, especially tardive dyskinesia. In contrast with the above, there were no significant changes in blood-pressure, and the small increase in pulse-rate and small decrease in handwriting length were greatest at 48 h to 7 days after the dose and occurred after the decanoate only.
Department of Pharmacology and Therapeutics, London Hospital Medical College, London E1 2AD
Preston Hall Hospital,
Maidstone, Kent
S. H. CURRY A. C. ALTAMURA S. MONTGOMERY
CEFOTAXIME (HR 756) AND NEPHROTOXICITY SIR,-Cephalosporins are potentially nephrotoxic. The kidney damage is dose related and due either to a direct toxic effect on tubular cells or to delayed hypersensitivity. This side-effect is usually recognised late when the serum-creatinine rises and when casts appear in the urinary sediment. Earlier detection may be possible by measurement of the urinary excretion
ofN-acetyl--D-glucosaminidase (N.A.G.)2 and alanine
aminopeptidase (A.A.P.) after gentamicin;3 increases are found early after a gentamicin administration45and they also provide the first warning of renal-transplant rejection.6
We have monitored the excretion of these two enzymes in three patients treated with a new cephalosporin cefotaxime (HR756), which has unusually broad-spectrum activity in vitro7 and is thus likely to have widespread clinical use. Case .—An 18-year-old male (weight 62 kg), operated on for acute small-intestinal obstruction, had peritonitis and septicwmia due to Escherichia coli. He was treated without success by a combination of cephalothin and gentamicin. Serum-creatinine was normal but urinary values of N.A.G. and A.A.P. were a hundred times the normal. The M.i.c. of cefotaxime for E. coli isolated from blood was 0-125mg/1. Chemotherapy was thus changed to cefotaxime given intravenously, 1 g four times daily for 7 days. At the end of this treatment the patient was clinically much improved; serum-creatinine remained normal and enzyme excretion fell. Case 2.-A 73-year-old diabetic female (weight 59 kg) had bilateral renal papillary necrosis and urinary infection and septicaemia, both due, to E. coli. Serum-creatinine was 380 p.mol/1 and urea nitrogen 35 mmol/l (upper limit of normal values respectively 100 and 10). Urinary excretion of N.A.G. and A.A.P. were 15 times normal. Cefotaxime was administered i.v. 4 g/day the first day, 3 g on the second day and then 2 g/day for 7 days. At the end of treatment, the patient was clinically improved and signs of infection had disappeared; serumcreatinine had fallen to 106 mol/1 and excretion of N.A.G. and A.A.P. were almost normal. Case 3.-A 10-year-old girl (weight 31 kg), treated as an outpatient with lincomycin and amoxycillin for pulmonary infection, was admitted to hospital for high fever and dyspnoea; X-rays revealed bilateral bronchopneumonia. She was given ,
1. Barza, N. J. infect. Dis. 1978, 137, suppl. 60. 2. Dance, N., Price, R. G., Robinson, D., Stirling,
J. L. Clin. chim. Acta, 1969. 24,189. 3. Peters, J. E., Mampel, E., Schneider, I., Burchardt, U., Fukala, E., Ahrens, I., Haschen, R. J. ibid. 1972, 37, 213. 4. Wellwood, J. M., Lovell, D., Thompson, A. E., Tighe, J. R. J. Path. 1976, 118, 171. 5. Mondorf, A. W., Zegelman, M., Klose, J., Hendus, J., Breier, J. J. antimicrob. Chemother. 1978, 4, suppl. 4, p.53. 6. Tucker, S. M., Boyd, P. J. R., Thompson, A. E., Price, R. G. Clin. chim. Acta, 1975, 62, 333.
N.A.G. excretion in morning urine in three treatment with cefotaxime (HR756). N.A.G.
expressed
as
mmol
patients during
4-methylumbelliferone released/h/mg
creatinine.
cefotaxime i.v. 1 g two times daily for 7 days. No microorganism were isolated from blood cultures done on admission. She was discharged with a normal chest X-ray. Serum-creatinine remained normal and urinary N.A.G. and A.A.P. which were moderately high at the beginning of treatment, fell to normal. N.A.G. excretion patterns are shown in the figure; values of A.A.P. followed a similar course. The high excretion-rates of enzymes at the beginning of treatment may be explained either by the nephrotoxicity of cephalothin/gentamicin’ or by injury to the renal parenchyma during the infection or by a severe infectious state which may by itself impair proximal tubular function. Whatever the mechanism, enzyme excretion fell toward normal during cefotaxime treatment. In these three patients there was no evidence for direct tubular toxicity of cefotaxime, despite doses of the drug which seem high when set beside regimens extrapolated from recent invitro studies.8 If a lower cefotaxime dosage were adopted nephrotoxicity would seem unlikely. HR756 was given by Dr G. Dewaersegger (Roussel, Belgium). I thank Dr J. Young and Dr R. Wise for their advice and editorial assistance.
Hôpital de Jolimont, Haine-Saint-Paul,
G. NINANE
Belgium
URINARY INFECTION AFTER MICTURATING CYSTOGRAM
SIR,-Dr Maskell and her colleagues9 report
a
surprisingly
incidence of urinary infection after cystography. In our series of 180 children, investigated following urinary-tract infection, only 2 had a urinary infection after the cystogram. Our policy is to wait, if possible, until the child has been free from infection for 3-4 weeks before carrying out such an investigation. We cover the child with prophylactic antibiotics, if he is not already on maintenance therapy, and we check the urine within a month of the X-ray.
high
7. 8.
Vanhoof, R., Butzler, J. P., Yourassowsky, E. Lancet, 1978, ii, 209. Hamilton-Miller, J. M. T., Brumfitt, W., Reynolds, A. V. J. antimicrob. Chemother. 1978, 4, 437. 9. Maskell, R., Pead, L., Vinnicombe, J. Lancet, 1978, ii, 1191.
tion, important unwanted effects clearly occur in the first few hours after decanoate administration, and, to a greater extent, at up to two days after enanthate. While the frequency of unwanted effect reporting was undoubtedly increased by the design of the study, we feel that it is important to emphasise the occurrence of these early, reversible effects, since the possibility of such effects has not been previously reported. Emphasis in the past has been largely on long-term unwanted effects, especially tardive dyskinesia. In contrast with the above, there were no significant changes in blood-pressure, and the small increase in pulse-rate and small decrease in handwriting length were greatest at 48 h to 7 days after the dose and occurred after the decanoate only.
Department of Pharmacology and Therapeutics, London Hospital Medical College, London E1 2AD
Preston Hall Hospital,
Maidstone, Kent
S. H. CURRY A. C. ALTAMURA S. MONTGOMERY
CEFOTAXIME (HR 756) AND NEPHROTOXICITY SIR,-Cephalosporins are potentially nephrotoxic. The kidney damage is dose related and due either to a direct toxic effect on tubular cells or to delayed hypersensitivity. This side-effect is usually recognised late when the serum-creatinine rises and when casts appear in the urinary sediment. Earlier detection may be possible by measurement of the urinary excretion
ofN-acetyl--D-glucosaminidase (N.A.G.)2 and alanine
aminopeptidase (A.A.P.) after gentamicin;3 increases are found early after a gentamicin administration45and they also provide the first warning of renal-transplant rejection.6
We have monitored the excretion of these two enzymes in three patients treated with a new cephalosporin cefotaxime (HR756), which has unusually broad-spectrum activity in vitro7 and is thus likely to have widespread clinical use. Case .—An 18-year-old male (weight 62 kg), operated on for acute small-intestinal obstruction, had peritonitis and septicwmia due to Escherichia coli. He was treated without success by a combination of cephalothin and gentamicin. Serum-creatinine was normal but urinary values of N.A.G. and A.A.P. were a hundred times the normal. The M.i.c. of cefotaxime for E. coli isolated from blood was 0-125mg/1. Chemotherapy was thus changed to cefotaxime given intravenously, 1 g four times daily for 7 days. At the end of this treatment the patient was clinically much improved; serum-creatinine remained normal and enzyme excretion fell. Case 2.-A 73-year-old diabetic female (weight 59 kg) had bilateral renal papillary necrosis and urinary infection and septicaemia, both due, to E. coli. Serum-creatinine was 380 p.mol/1 and urea nitrogen 35 mmol/l (upper limit of normal values respectively 100 and 10). Urinary excretion of N.A.G. and A.A.P. were 15 times normal. Cefotaxime was administered i.v. 4 g/day the first day, 3 g on the second day and then 2 g/day for 7 days. At the end of treatment, the patient was clinically improved and signs of infection had disappeared; serumcreatinine had fallen to 106 mol/1 and excretion of N.A.G. and A.A.P. were almost normal. Case 3.-A 10-year-old girl (weight 31 kg), treated as an outpatient with lincomycin and amoxycillin for pulmonary infection, was admitted to hospital for high fever and dyspnoea; X-rays revealed bilateral bronchopneumonia. She was given ,
1. Barza, N. J. infect. Dis. 1978, 137, suppl. 60. 2. Dance, N., Price, R. G., Robinson, D., Stirling,
J. L. Clin. chim. Acta, 1969. 24,189. 3. Peters, J. E., Mampel, E., Schneider, I., Burchardt, U., Fukala, E., Ahrens, I., Haschen, R. J. ibid. 1972, 37, 213. 4. Wellwood, J. M., Lovell, D., Thompson, A. E., Tighe, J. R. J. Path. 1976, 118, 171. 5. Mondorf, A. W., Zegelman, M., Klose, J., Hendus, J., Breier, J. J. antimicrob. Chemother. 1978, 4, suppl. 4, p.53. 6. Tucker, S. M., Boyd, P. J. R., Thompson, A. E., Price, R. G. Clin. chim. Acta, 1975, 62, 333.
N.A.G. excretion in morning urine in three treatment with cefotaxime (HR756). N.A.G.
expressed
as
mmol
patients during
4-methylumbelliferone released/h/mg
creatinine.
cefotaxime i.v. 1 g two times daily for 7 days. No microorganism were isolated from blood cultures done on admission. She was discharged with a normal chest X-ray. Serum-creatinine remained normal and urinary N.A.G. and A.A.P. which were moderately high at the beginning of treatment, fell to normal. N.A.G. excretion patterns are shown in the figure; values of A.A.P. followed a similar course. The high excretion-rates of enzymes at the beginning of treatment may be explained either by the nephrotoxicity of cephalothin/gentamicin’ or by injury to the renal parenchyma during the infection or by a severe infectious state which may by itself impair proximal tubular function. Whatever the mechanism, enzyme excretion fell toward normal during cefotaxime treatment. In these three patients there was no evidence for direct tubular toxicity of cefotaxime, despite doses of the drug which seem high when set beside regimens extrapolated from recent invitro studies.8 If a lower cefotaxime dosage were adopted nephrotoxicity would seem unlikely. HR756 was given by Dr G. Dewaersegger (Roussel, Belgium). I thank Dr J. Young and Dr R. Wise for their advice and editorial assistance.
Hôpital de Jolimont, Haine-Saint-Paul,
G. NINANE
Belgium
URINARY INFECTION AFTER MICTURATING CYSTOGRAM
SIR,-Dr Maskell and her colleagues9 report
a
surprisingly
incidence of urinary infection after cystography. In our series of 180 children, investigated following urinary-tract infection, only 2 had a urinary infection after the cystogram. Our policy is to wait, if possible, until the child has been free from infection for 3-4 weeks before carrying out such an investigation. We cover the child with prophylactic antibiotics, if he is not already on maintenance therapy, and we check the urine within a month of the X-ray.
high
7. 8.
Vanhoof, R., Butzler, J. P., Yourassowsky, E. Lancet, 1978, ii, 209. Hamilton-Miller, J. M. T., Brumfitt, W., Reynolds, A. V. J. antimicrob. Chemother. 1978, 4, 437. 9. Maskell, R., Pead, L., Vinnicombe, J. Lancet, 1978, ii, 1191.
