Intracerebral haemorrhage caused by cefazoline-induced hypoprothrombinaemia in a renal transplant recipient

Dirk R. J. Kuypers and Kathleen Claes

Department of Nephrology and Renal Transplantation University Hospitals Leuven, Belgium

Sir,

Hypoprothrombinaemia is a rare but well-known serious side effect of antimicrobial therapy with cephalosporins [1].

We report a patient who became hemiplegic 5 days after a first cadaveric renal transplantation due to multiple intracerebral haemorrhages caused by an acute severe prolongation of the prothrombin time. The latter was induced by intoxication with cefazoline (Kefzol®, Eli Lilly) in the immediate postoperative period, possibly superimposed on a pre-existing low vitamin K status due to poor dietary intake.

Case. A 45-year-old female received her first cadaveric renal allograft after 1 year of intermittent haemodialysis treatment for a chronic renal insufficiency of unknown origin. Immunosuppressive treatment consisted of methylprednisolone (Medrol®, Upjohn), tacrolimus (Prograf®, Fujisawa) in an initial dose of 0.2 mg/kg/day and mycophenolate mofetil (Cellcept®, Roche) 1 g/day. The transplantation was complicated by delayed graft function with a glomerular filtration rate that slowly increased to 12 ml/min on the ninth day post-transplantation; intermittent haemodialysis was not necessary during the postoperative period. This patient received perioperatively three times a dose of 2 g of cefazolin as standard antibiotic prophylaxis. Due to the large transplant kidney size a Goretex® mesh was used for closure of the abdominal surgical wound. Because of the foreign material employed and the patient being immune-compromised, it was decided to extend the antibiotic prophylaxis to another 4 days. However, during the following days the dose of intravenous cefazolin was not adjusted to the degree of renal allograft function and 6 g were administered daily. On the fifth day after transplantation the patient suddenly became hemiplegic with complete paralysis of the right arm and severe paresis of the right leg. Computer tomography of the brain showed multiple bilateral foci of subependymal bleeding located near the lateral ventricles. A nuclear magnetic imaging scanner confirmed this finding and revealed some additional bleeding lesions in the periventricular white matter and the basal ganglia. Laboratory tests surprisingly revealed a severe prolongation of the prothrombin time to 74.6 s (normal range 9.5–14 s) or a value of <10% (normal range 70–100%) in comparison with a normal prothrombin time at the time of transplantation (11.5 s or 93.5%). The patient had never received coumarin treatment or any other known drugs with vitamin K antagonistic properties. There was no evidence of diffuse intravascular coagulation, liver disease or malabsorption and no blood transfusions had been given. The activated partial thromboplastin time was normal before transplantation (34.5 s (normal range 24–38 s)) and slightly prolonged to 49.7 s at the time of bleeding. The levels of the clotting factors II, VII and X were all very low (at 19%, 3% and 10%, respectively, normal range from 70 to 130%) while factor V was only moderately decreased (62%). There was no evidence of fibrinogen deficiency (4.49 g/l, normal range 1.8–3.6 g/l); thrombin time was normal (23.1 s, normal range 18–26 s) and both lupus anticoagulant and anticardiolipin antibodies were negative. Platelet count was above 100x10-9/l while protein C level was low at 29% (normal range 70–150%).

Double-checking the medications administered before and after transplantation for possible causes of bleeding, enoxaparin (Clexane® Rhône-Poulenc Rorer) prophylaxis in a dose of 20 mg/day subcutaneously was identified. However, the deficiencies of clotting factors II, VII and V were not indicative of enoxaparin overdose even when taking into account the marked degree of renal insufficiency. The extended prophylactic antibiotic treatment with an unadjusted high dosage of cefazolin was the only exceptional deviation from the standard postoperative care. It was considered as the most likely cause of this acute and severe hypoprothrombinaemia and unfortunate complication of intracerebral bleeding.

After prompt treatment with intravenous vitamin K1 (Konakion® Roche) 10 mg/day, the prothrombin time returned to normal after 2 days as did the clotting factors II, V, VII and X (77, 82, 95 and 115%, respectively; normal range 70–130%). The prothrombin time remained normal after stopping vitamin K1 therapy given over 6 days. The paresis of the right leg improved progressively although the severe paralysis of the right arm persisted.

Comment. Several mechanisms have been proposed to explain the vitamin K deficient state caused by cephalosporins. Usually a pre-existing vitamin K1 deficiency is required in order to induce a clinically relevant prolongation of the prothrombin time by cephalosporin antibiotics, such as for example in patients on total parenteral nutrition [1] or with malabsorption. However, due to adequate vitamin supplementation in present day parenteral nutrition, this complication has become extremely rare. Based on clinical grounds as well as on the measurements of other lipid-soluble vitamins in this patient (vitamin A and E) there was no evidence in favour of pre-existing malabsorption. However, a relative vitamin K deficiency due to poor dietary intake could not be ruled out in this patient with mild mental retardation.

Although we did not measure the actual cefazolin serum concentration, we think that the serum levels must have been extremely high, based on an earlier personal study. In this study we demonstrated that the intravenous administration of 2 g cefazolin three times a week in chronic haemodialysis patients was sufficient to achieve serum cefazolin 44-h trough levels of up to 145 µg/ml [2]. Therefore, in the present patient with severe renal failure secondary to delayed graft function, the daily administration of 6 g cefazolin for a total of 5 days must have resulted in toxic serum cefazolin levels. In our opinion, such a high concentration per se can be responsible for developing acute vitamin K1 deficiency, possibly through the mechanism explained below.

Certain cephalosporins may inhibit the vitamin K-dependent clotting factors through a specific N-metylthiotetrazole (MTT) side-chain [3]. Alterations in the hepatic glutathione redox state can be induced by the administration of MTT-containing cephalosporins, causing a dose-related increase of oxidized glutathione (GSSG) which is responsible for the inhibition of microsomal reduction of vitamin K epoxide [4]. Thus when administering different cephalosporins containing this side-chain to hospitalized patients, an accumulation of vitamin K1 2,3-epoxide occurred that was qualitatively similar, although quantitatively less marked than that produced by oral coumarins [1].

We conclude that although cephalosporin-induced hypoprothrombinaemia has become a rare complication in an era of adequate vitamin supplementation with both parenteral and oral nutrition, attention is still warranted when dosing these drugs in patients with severe renal insufficiency. Monitoring the prothrombin time is a cheap and easy method, allowing early detection of cephalosporin-induced hypoprothrombinaemia in such patients.

Notes

Email: Dirk.Kuypers{at}uz.kuleuven.ac.be Back

References

  1. Shearer MJ, Bechtold H, Andrassy K et al. Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism and vitamin K status. J Clin Pharmacol1988; 28: 88–95[Abstract/Free Full Text]
  2. Kuypers D, Vanwalleghem J, Maes B et al. Cefazolin serum concentrations with fixed intravenous dosing in patients on chronic hemodialysis treatment (letter). Nephrol Dial Transplant1999; 14: 2051[Free Full Text]
  3. Agnelli G, Del Favero A, Parise P et al. Cephalosporin-induced hypoprothrombinemia: is the N-metylthiotetrazole side chain the culprit? Antimicrob Agents Chemother 29: 1108–1109
  4. Mitchell MC, Mallat A, Lipsky JJ. Cephalosporin-induced alteration in hepatic glutathione redox state. A potential mechanism for inhibition of hepatic reduction of vitamin K1 2,3-epoxide in the rat. J Clin Invest1990; 86: 1589–1594[ISI][Medline]




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