ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, June 1986, p. 1108-1109 Vol. 29, No.

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0066-4804/86/061108-02$02.00/0

Cephalosporin-Induced Hypoprothrombinemia: Is the

N-Methylthiotetrazole Side Chain the Culprit?
GIANCARLO AGNELLI,'* ALBANO DEL FAVERO,1 PASQUALE PARISE,2 ROBERTO GUERCIOLINI,1
BRUNA PASTICCI,3 GIUSEPPE G. NENCI,2 AND FRED OFOSU4
Institutes of Clinica Medica,' Semeiotica Medica?- and Malattie Infettive, University of Perugia, 06100 Perugia, Italy,
and Department of Pathology, McMaster University, Hamilton, Ontario, L8N 3Z5 Canada4
Received 26 June 1985/Accepted 20 December 1985

The reported high incidence of vitamin-K-reversible hypoprothrombinemia associated with the new
13-lactamase-stable cephalosporins prompted us to evaluate the effect on hemostasis of three cephalosporins

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(cefamandole, ceftriaxone, and ceftazidime) in 30 patients with serious infections. Cefamandole and ceftriax-
one, both containing a sulfhydryl group, induced a significant and similar prolongation of prothrombin time
and decrease in factor VII activity. Ceftazidime, in contrast, had no effect on these two parameters.

Cefamandole and other new P-lactamase-stable cephalo-
sporins, including moxalactam, cefoperazone, and
cefmetazole, have been associated with a high incidence of
vitamin-K-reversible hypoprothrombinemia (8). Whether
these cephalosporins induce hypoprothrombinemia through
a suppression of vitamin-K-producing bowel flora or through
a direct interference with vitamin-K-dependent clotting fac-
tor synthesis has been discussed (1, 9). All these antibiotics
contain a methylthiotetrazole (MTT) side chain at position 3
of the 13-lactam ring. MTT has been found to inhibit in vitro
the vitamin-K-dependent -y-carboxylation of glutamic acid, a
reaction necessary for the synthesis of the vitamin-K-
dependent clotting factors (6), but the relevance in vivo of
this observation has been questioned (10). More recently,
evidence has been presented that the in vitro inhibition of the
-y-carboxylation system by MTT may be related to its
sulfihydryl group (7).
To confirm these results in vivo, we compared the effects
of treatment with three structurally different cephalosporins:
cefamandole, which contains an MTT group at position 3 of
the P-lactam ring; ceftriaxone, which contains a thriazine
ring instead of the MTT side chain but still has a sulfhydryl
group at position 3 of the P-lactam ring; and ceftazidime,
which contains neither an MTT side chain nor a sulfhydryl
group at this position.
Thirty inpatients of both sexes with cefamandole-, ceftri-
axone-, and ceftazidime-susceptible serious infections and
normal hemostatic profiles were sequentially enrolled in the
study. The patients in the three groups were comparable for
sex, age, and severity of disease. All patients were taking
normal enteral diet, and people with nutritional diseases
were excluded. Any treatment known to affect hemostasis
was avoided, and patients with renal or liver disease were
excluded from the study. Furthermore, liver and renal
functions were monitored during treatment. Patients with
recent antibiotic treatment were also excluded. Ten patients
were treated with cefamandole (Mandokef; Eli Lilly & Co.),
1 g (9 patients) or 2 g (1 patient) every 6 h; 10 patients
received ceftriaxone (Rocephin; Roche Diagnostics, Div.
Hoffman-LaRoche Inc.), 1 g daily; and the remaining 10
*
Corresponding author.
1108
patients received ceftazidime (Glazidim; Glaxo Pharmaceu-
ticals, Ltd.), 1 g every 8 h.
The antibiotics were administered intravenously for 10
days. Any treatment known to affect hemostasis was
avoided. Determination of prothrombin time, activated par-
tial thromboplastin time, thrombin clotting time, and platelet
count and the assay of fibrinogen, fibrin monomers, fibrino-
gen-fibrin degradation products, and factor VII (one-stage
assay) were performed before the start of cephalosporin
treatment, daily during treatment, and 3 and 6 days after the
end of treatment. Factor VII was chosen for evaluation as a
representative vitamin-K-dependent clotting factor because
of its short half-life.
Wilcoxon's matched-pair signed-rank sum test was used
for the statistical evaluation of results.
Cefamandole, ceftriaxone, and ceftazidime controlled the
infection in all patients. No side effects, except for an
antabuse-like reaction in 1 of 10 patients treated with cefa-
mandole, were observed. In particular, no bleeding was
observed in any patient.
Cefamandole and ceftriaxone treatments were followed by
a prolongation of the prothrombin time and a reduction in
factor VII activity (Fig. 1). Both values became significantly
different from basal values 48 h after the initiation of
treatment (P < 0.05) with the two drugs. The prothrombin
time and factor VII activity returned to normal 6 days after
the termination of treatment. No significant difference be-
tween the effect of cefamandole and ceftriaxone on
prothrombin time and factor VII activity was observed.
Ceftazidime did not cause any change in prothrombin time
and factor VII activity. None of the other hemostatic param-
eters showed significant changes during treatment with the
three antibiotics.
The three structurally different cephalosporins exerted
different effects on vitamin-K-dependent clotting factor ac-
tivity. We found that treatment with ceftriaxone, which has
a free sulfhydryl group but does not contain the MTT side
chain, caused a hypoprothrombinemic state equivalent to
that induced by cefamandole. Therefore, our results suggest
that the MTT side chain should not be considered the only
factor responsible for hypoprothrombinemia induced by the
new cephalosporins. Glutathione was found to markedly
VOL. 29, 1986 NOTES 1109
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FIG. 1. Prothrombin time (squares) and factor VII activity (triangles) before treatment, during 10 days of treatment, and 3 and 6 days after
the end of treatment. l, A, Cefamandole; *, A, ceftriaxone; U, A, ceftazidime.

decrease the MTT inhibitory effect (7), indicating that the
sulihydryl group of MTT may play an important role. In
support of this was our observation that ceftazidime, which
does not contain a free sulfhydryl group, did not induce
hypoprothrombinemia.
Moreover, as suppression of bowel flora by antibiotics has
been shown to lower vitamin-K-dependent clotting factors
after 3 to 4 weeks (4), our findings of the early onset of
cefamandole- and ceftriaxone-induced hypoprothrom-
binemia support a direct 'interference with the synthesis of
vitamin-K-dependent clotting factors.
It must be stressed, however, that the degree of cefaman-
dole- and ceftriaxone-indticed hypoprothrombinemia we ob-
served is unlikely to be clinically relevant. Therefore, the
hemorrhagic complications' observed in patients treated with
cefamandole (8) and ceftriaxone (5) must have been due to
additional factors., Cefamandole-induced hypoprothrom-
binemia and hemorrhagic'complications have been observed
mainly in patients with renal failure (2). The impaired
synthesis of vitamin-K-dependent clotting factors (3) and the
pharmacokinetic changes found in patients with renal failure
may concur as causative factors for the high incidence of
hypoprothrombinemia and hemorrhagic complications in-
duced by cephalosporins in these subjects.
We thank Mary Alpini for technical assistance and Katherine
Ton4to for assistance in the preparation of the manuscript.
LITERATURE CITED
1. Bruch, K. 1983. Hypoprothrombinaemia and cephalosporins.
Lancet i:535-536.
2. Chang, J. C. 1983. Acquired coagulopathy owing to parenteral
cefamandole: renal failure as a predisposing factor. Ann. Clin.
Lab. Sci. 13:418-424.
3. Cheney, K., and J. A. Bonnin. 1962. Haemorrhage, platelet
dysfunction and other coagulation defects in uraemia. Br. J.
Haematol. 8:215-221.
4. Frick, P. G., G. Riedler, and H. Brogli. 1967. Dose response and
minimal daily requirement for vitamin K in man. J. Appl.
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5. Haubenstock, A., P. Schmidt, J. Zazgornik, P. Baicke, and H.
Kopsa. 1983. Hypoprothrombinaemic bleeding associated with
ceftriaxone. Lancet i:1215-1216.
6. Lipsky, J. J. 1983. N-methyl-thio-tetrazole inhibition of the
gamma carboxylation of glutamic acid: possible mechanism for
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193.
7. Lipsky, J. J. 1984. Mechanism of the inhibition of the y-
carboxylation of glutamic acid by N-methylthiotetrazole-
containing antibiotics. Proc. Natl. Acad. Sci. USA 81:2893-
2897.
8. Neu, H. C. 1982. The new beta-lactamase-stable cephalospo-
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10. Wold, J. S., M. K. Buening, and G. K. fIanasono. 1983.
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