Acquired Coagulopathy Owing to Parenteral Cefamandole: Renal Failure as a Predisposing Factor*

ANNALS OF CLINICAL AND LABORATORY SCIENCE, Vol. 13, No. 5 Copyright 1983, Institute for Clinical Science, Inc. Acquired Coagulopathy Owing to Parenteral Cefamandole: Renal Failure as a Predisposing Factor* JAE C. CHANG, M.D. Department of Medicine, Wright State University School of Medicine, and Hematology and Oncology Section, Good Samaritan Hospital and Health Center, Dayton, OH 45406 ABSTRACT W ithin a span of four m onths at a 550 bed community hospital, four elderly patients who had been taking cefamandole for various infections developed a severe coagulopathy within 10 days after initiation of cefamandole. All patients had a prolonged prothrom bin tim e and activated partial thromboplastin time with a marked decrease of the vitamin K dependent clotting factors II, VII, IX, X, and also were found to have mild to m oderate renal function im pairm ent. The coagulopathy was prom ptly corrected to normal with or without treatm ent of vitamin K and/or fresh frozen plasma when the drug was discontinued. Treatm ent with vitamin K while on cefamandole also corrected the coagulation abnormalities and in vitro cefamandole had no direct effect on prothrombin time and activated partial throm boplastin tim e in therapeutic concentrations. These clinical and laboratory observations and the nature of high excretion rate of cefamandole in bile suggest cefamandole induced coagulopathy is caused by decreased vitamin K synthesis, probably secondary to rapid depletion of vitamin K producing intestinal organisms. Introduction Bleeding diathesis associated with low levels of clotting factors dependent upon vitamin K for their biosynthesis has been reported to occur occasionally in debilitated and undern o u rish ed patients re ceiving broad-spectrum antibiotics.2 3'5,8'9 n, is. is, I? The pathogenesis of bleeding has been thought to be caused by decreased synthesis of factors II, VII, IX, X secondary to elimination of vitamin K producing intestinal organism s. However, the possibility that suppression of the vitam in K d e p e n d e n t clo ttin g factors is caused by a direct inhibitory effect on the biosynthesis of the vitamin K dependent clotting factors by the antibiotic in question has not been excluded. At the Good Samaritan Hospital and * Requests for reprints should be addressed to the author at Hematology and Oncology Section, Good Samaritan Hospital and Health Center, Dayton, OH 45406. 418 0091-7370/83/0900-0418 $01.20 Institute for Clinical Science, Inc.

Health Center which has a 550 bed capacity, four cases have b een observed with an acquired coagulopathy following an adm inistration of cefamandole within a span of four months. This syndrom e occurred in less than ten days of treatm ent w ith th e drug. B leeding tendency and abnormal clotting tests quickly reversed to norm al w hen the antibiotic was discontinued. It is of interest to note that coagulopathy seems to occur m ore often after cefamandole than with other antibiotics. If this phenomenon is true, clinical implication of cefamandole induced coagulopathy is thought to be very im portant. Described are clinical data and coagulation studies in these patients and in vitro study of the effects of cefamandole on prothrom bin tim e and activated partial thromboplastin time. These clinical and laboratory data suggest that cefamandole is a very potent inhibitor of vitam in K d ep en d en t factor synthesis, C E F A M A N D O L E A N D C O A G U LO PA TH Y 4 1 9 probably owing to an increased excretion of the drug in bile resulting in depletion of the vitamin K producing intestinal organism s, especially in p a tien ts w ith a compromised renal function. Case Histories Four patients (table I) who received cefamandole for various infections were found initially to have an acquired coagulopathy characterized by a markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (PIT). Three patients had clinical bleeding and one had no bleeding problem. All patients recovered from the acquired coagulopathy with or without treatments of vitamin K and/or fresh frozen plasma when cefamandole was discontinued. Case I (HX). This 58 year old white male with a long-standing history of rheumatoid arthritis, receiving acetyl salicylic acid, three to five g per day, was admitted because of sudden onset of severe chest pain. On admission, an electrocardiogram showed acute anterior myocardial infarction. The diagnosis was confirmed by cardiac enzyme studies. In the coronary care unit he was stable without any unusual complication except for bilateral pneumonitis, for which he was started on cefamandole one week after TABLE I C lin ic a l C h a r a c te r is tic s o f P a tie n ts Case I (HX) Case I I (SM) Case I I I (FX) Case IV (BX) Age 58 71 76 86 Race/Sex White male White male White male White female Reason for Admission Acute myocardial Perforated duo Abdominal Fever and infarction denal ulcer lymphoma dehydration Nutritional status Normal Normal Normal Undernourished History of alcoholism No No No No Reason for cefamandole Pneumonitis Peritonitis Pneumonia Sepsis therapy Bleeding Bpistaxis Abdominal wall None Extensive purpura hematemesis hematoma in extremities Clotting studies PT (sec.) 115 94 31 28 (normal: 12-14) PTT (sec.) 68 72 39 39.5 (normal: 19-33) Hemogram Hemoglobin (g per dl) 11.6 9.4 11.5 12.0 Hematocrit (%) 34.9 27.8 33.1 36.8 WBC (per mm3) 13,000 19,000 9,400 14,300 Platelet (per mm3) 685,000 502,000 360,000 137,000 Hepatic function Normal Normal Normal Normal BUN/Creatinine normal: 5-19 mg per 41/2.7 44/6.2 19/1.6 61/2.2 dl/q.6-1.3 mg per dl) P T : PIT: Prothrombin time Activated partial thromboplastin time

4 2 0 C H A N G admission. Nine days after cefamandole was begun, he began to have recurrent epistaxis and developed massive hematemesis. Also noticed was excessive bleeding at the sites of the intravenous catheter and venipuncture. Acetyl salicylic acid had been withheld since his admission and chest pain was controlled initially with morphine sulfate and later with acetaminophen. Liver function tests were normal. Because of unexpected bleeding diathesis, coagulation studies were performed. Case 11 (SM). This 71 year old white male was admitted because of severe abdominal pain and recurrent vomiting for about three weeks. The symptoms became worse a few hours prior to admission. About two years previously, he had been treated with antacid for duodenal ulcer with an improvement of symptoms. On admission, an intestinal perforation was suspected and the patient underw ent laparotomy. A perforated duodenal ulcer was encountered and subtotal gastrectomy was performed along with truncal vagotomy and Billorth I anastomosis. Two days after surgery, he was given cefamandole. Five days after the cefamandole was started, a painful swelling developed in the right lower quadrant of the abdomen along with easy bruisability. Liver function tests were normal. Markedly prolonged PT and PTT were noted at 94 and 72 seconds, respectively. The patient received three units of fresh frozen plasma and underwent abdominal wall exploration. A huge abdominal wall hematoma was removed. Case 111 (FX). This 76 year old white male with a history of mild hypertension for several years was admitted because of progressive abdominal swelling and discomfort associated with edema on both feet for about two months. Prior to this admission, an abdominal com puterized axial tomography scan showed a large retroperitoneal mass. Abdominal lymphoma was suspected. Physical examination was unremarkable other than fullness in the left side of the abdomen. No lymphadenopathy was present. Evaluation including chest roentgenogram and bone marrow biopsy was normal. The patient underwent exploratory laparotomy and extensive retroperitoneal tumors were found. The pathology of biopsies revealed non-hodgkin s lymphoma, poorly differentiated lymphocytic, diffuse type. One day postoperatively, owing to development of pneumonia, he was started on cefamandole. Three days later, PT and PTT were found to be markedly prolonged to 31 and 39 seconds, respectively. Case IV (BX). This 86 year old white female, a moderately undernourished white female with known diagnosis of chronic brain syndrome and arteriosclerotic cerebrovascular disease, was admitted because of dehydration and fever. An appropriate infectious evaluation was performed because sepsis was suspected. Blood cultures grew anerobic gram negative rods which remained unidentified. Cefamandole was started immediately. On admission she had a slightly prolonged PT of 15.5 seconds and normal PTT of 24 seconds. Four days later, the patient developed extensive ecchymotic areas on the lower extremities and was found to have prolonged PT of 28 seconds and PTT of 39.5 seconds. Methods In all four patients, clinical evaluations have suggested that the coagulopathy was secondary to intravenous cefam andole therapy. Detailed clinical information was obtained including the reason of admission, history of bleeding problem, hepatic function, renal function, hem o gram, and PT and PTT as well as careful correlatio n for possible d ru g effects during hospitalization. Clotting studies including fibrinogen quantitation and assays of various coagulation factors, such as Factors II, V, VII, VIII, IX, and X, w ere perform ed according to standard factor assay methods using a specific coa g u la tio n fa c to r d e fic ie n t s u b s tra te plasm a* w hen PT and PTT w ere prolonged. The relationship betw een cefam andole th erap y and d e v e lo p m e n t of abnormal PT and PTT was carefully exam in ed and th e coagulation profile changes w ere correlated with treatm ent of fresh frozen plasma and vitamin K. F i nally, an in vitro experim ent was carried out to exclude direct effect of cefamandole on PT and PTT at its various concentrations. Blood sam ples w ere obtained from a normal subject and from Case III after his coagulation profile retu rn e d to norm al. T he plasm as w ere tested for PT and PTT after an in vitro incubation for 30 minutes at concentration of cefamandole ranging from 0 to 10,000 xg per ml. Results C l i n i c a l C h a r a c t e r i s t i c s In table I is summarized essential clinical inform ation. All patients w ere elderly and over 70 years old except for Case I who was 58 years old. Cases I and II had severe bleeding diathesis with un- * Dade Diagnostic, Inc., Miami, FL.

controlable epistaxis and hem atem esis, and a huge abdom inal wall hematoma, respectively. Case IV had extensive purpura in lower extrem ities but Case III had no clinical b leed in g. N u tritio n al status prior to and during this admission was norm al in all patients except Case IV, w ho was a d m itte d from a n u rsin g home and was m oderately undernourished. None of these patients had a history of alcoholism, and liver function tests including bilirubin and enzym es w ere normal. Because of severe infections such as pneum onitis, peritonitis, and sepsis, the patients w ere started on intravenous cefamandole. Although platelet count was normal, mild anem ia was present in all patients. W ithin 10 days after initiation of cefamandole, all patients developed a m arkedly prolonged PT and PTT. Abnormal renal function was present in all patients in mild to modest degree, characterized by the elevation of blood urea nitrogen and creatinine. C o a g u l a t i o n S t u d i e s W hen PT and PTT w ere prolonged, assays of various coagulation factors w ere perform ed and the results are shown in C E F A M A N D O L E A N D C O A G U LO PA T H Y 421 TABLE I I C o ag ulation T ests o f P a tie n ts table II. All the vitamin K dependent factors: II, VII, IX, X, w ere dim inished in all patients. Among these factors, factor V II was m ost profoundly d im in ish ed. Factors V and VIII, which are not the vitam in K d e p e n d e n t factors, w ere normal. No evidence of dissem inated intravascular coagulation or pathologic fibrinolysis was present. R e l a t i o n s h i p B e t w e e n C e f a m a n d o l e T h e r a p y a n d P T a n d P T T Two patients w ere treated with fresh frozen plasm a and th ree patients w ith p a re n te ra l p h y to n ad io n e, an aqueous colloidal solution of vitamin K. Either one or both treatm ents effectively corrected a prolonged PT and PTT within 24 hours as seen in Cases II and IV (figures 1 and 3). In Case II, as cefamandole was discontinued and three units of fresh frozen plasma were transfused, PT dropped from 94 seconds to 22 seconds; it gradually retu rn e d to norm al w ith th e vitam in K therapy. H ow ever, Case III was observed w ithout treatm ent of vitamin K or fresh frozen plasma. As seen in figure 2, PT and PTT began to im prove within 24 hours and returned to normal in five days. C a s e I (HX) C a s e I I (SM ) C a s e I I I (F X ) C a s e I V (BX) Date 2/26/81 2/27/81 4/9/81 5/27/81 6/11/81 Normal values AM PM PT (sec.) 12-14 115 16 22 31 19.5 PTT (sec.) 19-33 68 43 33 44 39 32 Fibrinogen quantitation 200-400 840 380 750 450 (mg per dl) Factor II (%) 80-100 35 30 25 30 Factor V (%) 80-100 100 90 100 86 Factor VII (%) 80-100 48 9.5 3.5 10 Factor VIII (%) 80-100 100 100 100 Factor IX (%) 80-100 32 25 45 43 Factor X {%) 80-100 37 25 17 37 Soluble fibrin monomer <-> <-> (-) (-) Fibrin split product (-) (±> (±) (+) PT: Prothrombin time PTT: Activated partial thromboplastin time

4 22 C H A N G Cefamandole (gm./day) 4 '...W///////////////////M. Fresh Frozen Plasma g 1 Phytonadione (mg.) 5 1. Prothrombin 40 Time (PT) (sec.) 30 Partial 20 Thromboplastin Time (PTT) 10 (sec.) 'PTV ''^ l S P l o" \ V*. j 1. 1i i 1 1i 1i i 1 Ii I i 6 8 10 12 14 16 18 20 June 1981 F ig u r e 3. Case IV (BX): Restoration of PT and PTT to normal with either fresh frozen plasma or vitamin K while continuing on cefamandole. 5 7 9 11 13 15 17 19 21 April 1981 F i g u r e 1. Case II (SM): Effect of cefamandole, fresh frozen plasma, and vitamin K (phytonadione) on prothrombin time (PT) and activated partial thromboplastin time (PTT). Note prompt correction of the coagulopathy by fresh frozen plasma and vitamin K. A pparently in all patients cefam andole in d u ced coagulopathy d ev elo p ed in a short period, and the recovery was also prom pt with or without a specific therapy. In figure 3 is shown the effect of vitam in K in Case IV while continuing on cefam andole. In sp ite of continuous treatm ent of the drug, PT and PTT still re tu rn e d to norm al. This finding indicates that vitamin K is an effective agent in preventing cefamandole induced coagulopathy, and also suggests that cefam andole has no direct inhibitory effect on vitamin K activity or utilization. F i g u r e 2. Case III ( F X ) : Effect correction of abnormal PT and PTT in a few days by withdrawal of cefamandole. In V itro E f f e c t o f C e f a m a n d o l e o n PT AND PTT Following an in vitro incubation of the plasmas of both normal subject and Case III with cefamandole, PT and PTT were normal at a concentration of cefamandole up to 4,000 xg p er ml (table III). Slightly prolonged PT and PTT w ere noted only at concentration higher than 8,000 fig per ml in plasm a of b o th su b jects. T hese findings are in agreem ent with the study of C uster et al.6 Discussion In addition to broad -spectrum antibiotics, several cephalosporin antibiotics have been known to induce hemostatic defects in certain patients in rare in sta n c e s.3'4 1214 C efam andole, a new er sem isynthetic broad-spectrum cephalosporin antibiotic which has effectiveness against various bacterial organisms such as Staphylococcus aureus, beta-hem o lytic and other streptococci, Escherichia coli, Klebsiella and Proteus species, and certain an ero b ic organism s, has b een suspected to have an effect on blood coagulation.3 67 G astrointestinal bleeding has been reported owing to vitamin K deficiency in patients on parenteral cefamandole. 10

CEFAM ANDOLE AND COAGULOPATHY TABLE I I I 4 23 In Vitro Effect of Cefamandole on PT and PTT P la s m a C e fa m a n d o le ( l ig /m l) P T ( s e c. ) N o r m a l S u b j e c t C a s e I I I (F X ) P T T ( s e c. ) N o r m a l S u b j e c t C a s e I I I (F X ) 0 12.0 12.2 100 12.1 12.0 400 11.9 11.9 800 12.6 12.2 1,000 12.5 12.3 4,000 13.5 12.8 8,000 16.2 15.7 10,000 17.8 16.6 26.5 24.7 26.5 25.0 27.5 24.6 27.3 23.9 26.2 24.3 26.8 24.4 30.6 28.4 34.0 30.9 PT: PTT: Prothrombin time Activated partial thromboplastin time All patients had normal PT and PTT except a slight prolongation of PT in Case IV prior to or during the early stage of treatm ent with cefamandole as shown in figures 1, 2, and 3. Since the developm ent of prolonged PT and PTT certainly coincided with the treatm ent of cefamandole, the diagnosis of cefamandole induced coagulopathy is well established. The occurrence of four clinical cases of cefamandole induced coagulopathy within a span of four m onths at a 550 bed comm unity hospital suggests that this condition, w hen com pared with other antibiotics in clu d in g o th e r cep halosporin derivatives, may be a common complication of cefamandole therapy in clinical practice. Unlike the cases seen with other b ro ad -sp ectru m antib io tics, th ese p a tients had fairly good nutritional status. However, another clinical feature common to all four cases was mild to moderate renal function impairment. As coagulopathy was detected and cefamandole discontinued, abnormal coagulation profile rapidly returned to normal within five days w ith or w ithout treatment of fresh frozen plasma and/or vitamin K. W hen parenteral vitamin K and fresh frozen plasma were given, restoration to norm al PT and PTT o ccurred within 48 hours; without vitamin K administration and fresh frozen plasma, the restoration was less prompt. Normalization of PT and PTT was still com plete a few days after cefamandole was discontinued. Case IV was continuously treated with cefamandole despite the coagulopathy and was still found to have prom pt correction of th e clotting abnorm ality when treated with vitamin K. Cefamandole induced coagulopathy appears to be an acute phenom enon and is correctable without any specific treatm ent w hen the drug is discontinued. The coagulopathy can be m anaged more effectively in acute p hase by tre a tm e n t w ith e ith e r fresh frozen plasma or vitamin K. Failure of in vitro incubation of normal subject and patient s plasma with cefamandole to show any effect on PT and PTT indicates that cefamandole has no direct and significant interference on activity of vitamin K dependent factors. Although a slight prolongation of PT and PTT occurred at concentration higher than 8,000 jxg p er ml, this concentration is m uch higher than in vivo therapeutic plasma level. The fact that the prothrombin time was corrected by vitam in K adm inistration despite continued treatm ent with cefam andole excludes direct inhibition of synthesis of clotting factors as an etiologic m echanism. T herefore, it is postulated that cefamandole results in inhibition of

4 2 4 CHANG vitam in K synthesis ra th e r than direct action on vitamin K dependent clotting factors or inhibitory action on vitamin K activity or utilization. The clinical observation that cefamandole induced coagulopathy occurred in patients with an impaired renal function suggests it has an important role. Metabolic studies showed cefam andole was excreted in both bile and urine, and the level of cefamandole was found to be several times higher in bile of norm al subjects w hen compared with other cephalosporin derivatives such as cefazolin and cephalothin.16 Still, 65 percent to 80 percent of cefamandole is excreted primarily by the kidneys, largely as an unm etabolized d ru g.1 T herefore, w hen ren al functio n im p airm en t is present, a m uch higher concentration of the drug will reach the intestinal lumen via biliary excretion, resulting in rapid depletion of vitamin K producing intestinal organisms in a very short period of time. U rem ia has previously been suspected to be an important factor in producing antibiotic induced coagulopathy in certain patients.1215 Cefamandole is a very useful antibiotic in the treatm ent of infection with various bacterial organisms, but it should be used with an extrem e caution and appropriate dosage adjustment in patients with comprom ised renal function and in undernourished patients. Severe coagulopathy seems to occur m ore regularly than with other antibiotics owing to its high excretion rate in bile. This may produce acute and serious bleeding diathesis. If this iatrogenic condition is not recognized early, a serious clinical disaster may ensue. M onitoring can be done easily with a periodic d e te rm in a tio n of PT and PTT. M anagem ent is by an im m ediate withdrawal of the antibiotic and by treatm ent with fresh frozen plasma and/or vitamin K. If continuation of the antibiotic is desired, administration of prophylactic dose of vitamin K can be used during the antibiotic therapy. References 1. A m e r i c a n M e d i c a l A s s o c ia t i o n : A M A Drug Evaluations, 4th ed. Cephalosporins. Chicago, A M A Departm ent of Drugs. 1980, pp. 1229-1248. 2. Ansell, J. E., Kumar, R., and D eykin, D.: The spectrum of vitam in K deficiency. J. Am. Med. Assoc. 238:40-42, 1977. 3. B a n g, N. U., D w y e r, A., C a m p b e l l, S. S., M a r k s, C. A., and H e i d e n r e i c h, R. O.: Mechanism of cephamandole-associated bleeding. 20th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, 1980, Abstract 128. 4. B r o w n, C. H., Ill, N a t e l s o n E. M. W., W il l ia m s, T. W., J r., and A l f r e y, C. P., Jr.: The hemostatic defect produced by carbenicillin. New Eng. J. Med. 291:265-270, 1974. 5. C o l v in, B. T., and L l o y d, M. J.: Severe coagulation defect due to a dietary deficiency of vitamin K. J. Clin. Pathol. 30:1147-1148, 1977. 6. C u s t e r, G. M., B r ig g s, B. R., and S m it h, R. E.: Effect of cefamandole nafate on blood coagulation and platelet function. Antimicrob. Agents Chemother. 16:869-872, 1979. 7. C u s t e r, G. M., B r ig g s, B. R., and S m it h, R. E.: Cefamandole nafate and blood coagulation. Ohio State Med. J. 76:517-521, 1980. 8. F r ic k, P. G., R i e d l e r, G., and B rog l i, H.: Dose response and minimal daily requirement for vitamin K in man. J. Appl. Physiol. 23:387-389, 1967. 9. H a m, J. M.: Hypoprothrombinemia in patients undergoing prolonged intensive care. Med. J. Aust. 2:716-718, 1971. 10. H o o p e r, C. A., H a n e y, B. B., and St o n e, H. H. Gastrointestinal bleeding due to vitamin K deficiency in patients on parenteral cefamandole. Lancet 7:39-40, 1980. 11. K l i p p e l, A. P. and P it s in g e r, B. Hypoprothrombinemia secondary to antibiotic therapy and manifested by massive gastrointestinal hemorrhage. Arch. Surg. 96:266-268, 1968. 12. L e r n e r, P. I, and L u b in, A.: Coagulopathy with cefazolin in uremia. New Eng. J. Med. 290:1324, 1974. 13. M a t s a n io t is, N., M e s s a r it a k is, J., and V l a c h o u, C.: Hypoprothrombinaemic bleeding in infants associated with diarrhea and antibiotics. Report of two cases. Arch. Dis. Child. 45:586-587, 1970. 14. N a t e l s o n, E. A., B r o w n, C. H., Ill, B r a d s h a w, M. W., et al.: Influence of cephalosporin antibiotics on blood coagulation and platelet function. Antimicrob. Agents Chemother. 9:91-93, 1976. 15. P i n e o, G. F., G a l l u s, A. S., and H ir s h, J.: Unexpected vitamin K deficiency in hospitalized patients. Can. Med. Assoc. J. 109:880-883, 1973. 16. R a t z a n, K. R., B a k e r, H. B., and L a u r e d o, I.: Excretion of cefamandole, cefazolin, and cephalothin into T-tube bile. Antimicrob. Agents Chemother, i3:985-987, 1978. 17. Y u d i s, M., M a h o o d, W. H., and M a x w e l l, R.: Bleeding problems with carbenicillin. Lancet 2:599, 1972.