Journal of Antimicrobial Chemotherapy (1980) 6, Suppl.

A, 79-82

Toxicology of cefotaxime in comparison to other cephalosporins

B. I. Doerr*, R. Glomotf, H. KiefJ, M. KramerJ and T. Sakagochi§

^Department of Toxicology of Roussel Uclaf, Paris, France,

*Hoechst-Roussel Pharmaceuticals Inc., SomervUle, NJ., U.S.A., §Hoechst Japan Ltd.,
Tokyo, Japan and Pharma Research Hoechst AG, Frankfurt/M., West Germany

Cefotaxime is very well tolerated in animals, the LD J0 in rats and mice

following intravenous administration is in the range of 9 to 10 g/kfr This >s unusual
for a chemotherapeutic agent Even the LD50 of penicillin G in the mouse is in the
range of 2 g/kg> which means its toxicity is about 5 times higher compared to that of
cefotaxime. Comparative nephrotoxicity studies revealed that cefotaxime is one of
the best tolerated cephalosporins. Its kidney tolerance in the rat is ten times better
than that of cephaloridine. Subacute and chronic toxicity studies in rats and dogs
showed an extremely high tolerance of the compound in both species. Reproduction
toxicological studies did not show any adverse effect, either on fertility or on fetal
development Cefotaxime is a highly effective antibacterial agent with unusually
high tolerance.

In acute toxicity studies attempts have been made to determine LD 5 0 values of

cefotaxime in mice and rats. The results compared with those for cephamandole and
cephalothin taken from the literature are given in Table I. According to these results
cefotaxime is one of the least toxic cephalosporins known. It shares its low toxicity
with cefuroxime. Penicillin G, for example, given intravenously to the mouse has a
LD 5 0 of about 2 g/kg, which underlines the excellent tolerance of cefotaxime.
In determining toxicological properties of a new cephalosporin serious consideration
has to be given to the kidney. The only serious toxic effect of cephalosporins known so
far is nephrotoxicity which is shared in animal experiments by all compounds of the
group but with distinct quantitative differences. According to results of experimental
studies the most nephrotoxic cephalosporin is cephaloridine and the least is cefuroxime.
Sack et al. (1978) made a comparison of the renal tolerance of several cephalosporins
by injecting intramuscularly 9 single doses at 12 h intervals in female Wistar rats and
measuring the urinary excretion of renal epithelial cells. Table II shows the threshold
doses of eleven cephalosporins taken from Sack et al. (1978). The doses necessary to
produce a significant increase of the excretion of epithelial cells according to the
criteria applied in this experimental procedure were ten times higher in the case of
cefotaxime than that of cephaloridine. This threshold dose of 5 g/kg is already half of
the LD 5 0 of cefotaxime and about the 125- to 250-fold of the recommended single dose of
cefotaxime for patients.
In our own studies of nephrotoxicity 10 male and 10 female rats received 20 mg/kg
of fnisemide intravenously and 15 min later one-half or one-quarter of the LD J 0 of
79
0305-7453/8O/A00O79 + 04 $01.00 © 1980 The British Society for Antimicrobial Chemotherapy
80 & I. Doerr, R. Glomot, H. Kief, M. Kramer and T. Sakagnchi

Table I. Comparative acute toxicity of cefotaxime sodium, cefamandole nafate and cephalothin
sodium in laboratory animals

LD 3 0 (mgAg)
Animal (route) Cefotaxime Cefamandole* Cephalothin*

Mouse (Lv.) cT '> 10400 3915 -5000

9 9100
Rat (i.v.) 10700 2562-3336
9 9860
Rabbit (i.v.) >2000
Dog (Lv.) * O "
O + *> 1500 >1000
Mouse (S.C.) * p 18700 -7000 -7500
Mouse (i-P) 9 12060
Rat (Lm.) cJ 9 > 7000
Rat (S.C.) -7500

• Data from J. S. Wold et al. Journal of Infectious Diseases 137 SuppL: 51 (1978).

cefotaxime. The animals were killed 48 h later and the kidneys histologically examined.
In both sexes no nephrotoxic effect could be detected. A similar experiment was con-
ducted in mice. One-third or one-sixth of the LD 50 of cefotaxime was injected intra-
peritoneally 15 min after 20 mg/kg of frusemide. Again, histological examination of the
kidneys removed 48 h later revealed no nephrotoxicity.
A single intravenous injection of 5 g/kg of cefotaxime given to rabbits produced
necrosis and atrophy of the tubules with calcification in 3 out of 6 animals. The same
dose in combination with 100 mg of gentamicin per kg produced necrosis of the tubules
in all of the animals. One hundred mg of gentamicin per kg alone was also nephrotoxic.
The nephrotoxic effect of both compounds was additive. The LD S0 of a combination of
cefotaxime and gentamicin (50:1) given by intravenous administration to rats was
slightly higher than that of cefotaxime alone, the difference not being statistically
significant Probenicid did not influence the toxicity of cefotaxime in rats.

Table n. Tubulotoxic threshold doses of 11 cephalosporins

in rats*
Threshold dose
Cephalosporin (mg/kg/day)

Cephaloridine 500
Cephradine 1000
Cefazolin 2000
Cefazedon 2000
Cefoxitin 2000
Cephalothin 3000
Cephacetrile 3000
Cefamandole 3000
Cephapirin 5000
Cefuroxime 5000
Cefotaxime 5000

Female Wutar rats, criterion of toxicity: urinary excretion of

kidney epithelial cells (9 single doses in a 12-h intervals)
• According to Sack et aL, Medizinische Well 29: 1233 (1978).
 Toxicology of cefotaxime 81

Sub-occipital injection of cefotaxime was better tolerated by rats than that of

cephaloridine. Anaesthetized beagle dogs given 50 mg of cefotaxime by the sub-occipital
route had slight tetanic convulsions for about 1 h during recovery from anaesthesia.
The animal receiving saline did not show similar symptoms.

Table III. Repeated dose toxicity studies with cefotaxime sodium

Animal Duration Doses (mg/kg) No. per group Findings

Rat 30 days i.v. 0/33-5/100/300 15 6715 9 NSF* .

30 days s.c. 0/40/99/238 10 6710 9 NSF

+o
13 weeks s.c. 0/400/800/1600 15 6715 Haemosiderosis
6 months s.c. 0/40/100/250 25 6725 9 NSF
Dog 30 days Lm. 0/29/72/179 3 67 3 9 NSF
3 67 3 NSF

-to •to
30 days i.v. O/33-5/1OO/3OO
(juvenile) 30 days s.c. 0/5O0/1OO0/150O 4 67 4 pain at inj. sites
13 weeks Lv. 0/5O0/1OO0/15OO 3 61 3 9 very slight lesions prox
tub (post mortem?)
6 months i.m. 0/40/100/250 4 61 9 NSF

* NSF: no significant findings.

Subacute and chronic toxicity studies conducted with cefotaxime in rats and dogs
are listed in Table HI. Some slight changes in the proximal tubules of the dogs in the
90-day study with necrosis of single cells were of doubtful significance. Where cefo-
taxime was injected subcutaneously or intramuscularly haemosiderosis occasionally
occurred due to local intolerance of the compound. No other signs of toxicity whatso-
ever could be detected in haematology, clinical chemistry, or histology.
Reproduction toxicological studies are reported in Table IV. There was no influence
on fetal development or litter size, postnatal mortality, fertility, or postnatal develop-
ment in the experiments conducted in rats and rabbits.

Table FV. Reproduction toxicity studies with cefotaxime sodium

Type of study Animal No. per group Period of administration Doses (mg/kg)

Embryotoxicity Mouse Lv. 24 6.-17. 0/40/100/250

Rat Lm. 24 6.-18. 0/40/95/210
15 6.-12. 25/50
15 11-18. 25/50
15 6.-9. day of pregnancy 90
Rabbit Lm. 20 9.-12. 90
15 11-15. 90
15 15.-18. 90
15 6.-18. controls (solv.)
Fertility Rat s.c. 20 cf cJ 9 weeks prior to mating 0/40/100/250
25 $ 9 2 weeks before, during,
and after pregnancy till
weaning
Peri- post-natal Rat i.m. 24 15. day of pregnancy till 0/40/100/250
development 21. day post partum
82 B. I. Doerr, R. Glomot, H. Kief, M. Kramer and T. Sakagucfai

Mutagenicity studies were conducted in vivo as the micronucleus test in the mouse.
The test was negative at doses as high as 9 gAg-
In antigenicity studies cefotaxime alone produced no systemic anaphylaxis, passive
cutaneous anaphylaxis, or Arthus reaction. A cefotaxime protein conjugate, however,
showed some antigenicity as did protein conjugates of other /Mactam antibiotics.
Further studies are necessary to show whether the formation of protein conjugates
plays a significant role in humans.

References
Sack, K.., Lepcre, A. & Schwider, G. Renal tolerance of cephalosporin antibiotics, cefoxitin and
HR 756. Medizinische Welt 29: 1233-7 (1978).
Wold, J. S., Welles, J. S., Owen, N. V., Gibson, W. R. & Morton, D. N. Toxicologic evaluation
of cefamandole nafate in laboratory animals. Journal of Infectious Diseases 137 Suppl.: 51-4
(1978).