Cefoperazone Induced Gastrointestinal Bleeding

Cefoperazone is a beta-lactam antibiotic which is frequently used in treating a variety of gram positive and gram negative infections. The chemical structure of cefoperazone contains a side chain of N-methylthiotetrazole which can inhibit vitamin K metabolism resulting in hypoprothombinemia. We report a case of cefoperazone induced coagulopathy manifesting as gastrointestinal bleeding. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient’s coagulation function disorder and her use of the suspect drug.

A 73-year-old elderly female reported to was seen in the outpatient department of our hospital. She was suffering from high grade fever, dysuria and multiple episodes of vomiting which started three days prior to presentation. She denied history of oliguria, haematuria, pedal oedema, pain abdomen, haemetemesis or melena. Patient was a known diabetic for the past 15 years and she was on long acting insulin for the last three years. She had underwent surgery for cataract in both eyes 10 years ago. The patient denied history of microvascular complications of diabetes like retinopathy, neuropathy or nephropathy. Examination of the patient at admission was unremarkable except for pallor. Patient was provisionally diagnosed as a case of urinary tract infection.

Baseline blood investigations revealed neutrophilic leukocytosis with deranged renal parameters (eGFR of 37ml/min). There was microcytic hypochromic anaemia. Serum electrolytes, liver function tests and coagulation parameters were within normal limits. Patient’s urine microscopy showed numerous White Blood Cells (WBC) but no Red Blood Cells (RBC). Urine dipstick was positive for sugar but negative for protein. Ultrasonography of abdomen and pelvis was unremarkable. Blood and urine sample were sent for culture and patient was started on third generation cephalosporin (ceftriaxone) empirically. The blood and urine cultures grew-multi drug resistant E.coli. Based on the sensitivity pattern, patient was started on cefoperazone-sulbactam after dose modification (2 grams of cefoperazone plus 0.5 gram of sulbactam 12^th hourly) based on estimated Glomerular Filtration Rate (eGFR). Patient was also on Intra-venous (IV) fluids (isotonic normal saline), insulin, paracetamol and Proton Pump Inhibitors (PPI). Patient improved clinically and repeat investigations showed improvement of leukocytosis and renal parameters.

On day 5 of admission, patient complained of pain abdomen and passage of dark coloured stools. Patient had pallor which worsened since admission and mild tenderness of abdomen. Ryles tube insertion was done with suspicion of upper Gastrointestinal (GI) bleeding. It showed brown coloured aspirate suggestive of upper GI bleed. blood investigations showed a drop in hemoglobin and elevated prothrombin time with International Normalized Ratio (INR) of 6.0. Platelet counts, activated partial thromboplastin time and liver function tests were within normal limts. Cefoperazone was thought to be the cause of coagulopathy and stopped immediately and vitamin K was administered. Vitamin K 10milligrams was given intravenous, eighth hourly for one day. Oral feeds were withheld and pantoprazole infusion was started. Blood parameters on the next day showed normalisation of prothrombin time and INR. Ryle’s Tube aspiration showed no fresh Upper gostro intestinal (UGI) bleed. Patient had pain abdomen and melena for two more days. Patient was started on alternative antibiotic (Meropenem) for her urinary tract infection. Coagulation parameters were monitored daily but no further derangement was noted. A Naranjo assessment score of 5 was obtained, indicating a probable relationship between the patient’s coagulation function disorder and her use of the suspect drug.

Patient recovered completely at discharge with no pyuria and renal parameters were normalised. Patient was followed up after 1 month and she was clinically stable and Laboratory Investigations were within normal limits albeit mild anaemia as depicted in [Table/Fig-1].

Vitamin K deficiency impairs the carboxylation and activation of factors II, VII, IX, and X, causing functional deficiencies of these factors. The use of various antibiotics may cause hypoprothrombinemia because they could eradicate the intestinal bacterial source of vitamin K [1].

Cefoperazone is a third generation cephalosporin which is prescribed for a wide variety of respiratory, skin, and urinary tract infections. Ceftazidime and cefoperazone are the only third-generation drugs that provide antipseudomonal coverage. The third-generation cephalosporins except for cefoperazone penetrate cerebrospinal fluid and are indicated for the treatment of bacterial meningitis [2]. Cefoperazone acts by inhibiting bacterial wall synthesis and it is given usually with a combination of sulbactam which is a beta-lactamase inhibitor. Cefoperazone has a methy thiotetrazole side chain which on metabolism produces free N-methylthiotetrazole. (NMTT) [3]. NMTT can cause hypoprothrombinemia by inhibiting vitamin K epoxide reductase [4]. Patients with normal vitamin K concentrations do not manifest with coagulopathy where as vitamin K deficient patients are at high risk of coagulopathy secondary to the drug administration probably due to any of the above mentioned reasons. Isolated prolongation of prothrombin time following Cefoperazone administration and rapid correction following vitamin K supplementation is suggestive of Cefoperazone induced coagulopathy.

Very few cases are reported regarding coagulopathy secondary to Cefoperazone administration [5–7]. A recent article by Z Cai et al., has reviewed the literature (Pubmed) and found that only about 30 articles mentioning cefoperazone-induced hypoprothrombinemia and hemorrhage have been published [8]. A study by Strom et al., has noted the frequency of bleed at various sites secondary to cefoperazone administration. The most frequent site of bleeding was from the urinary tract, and more than 75% of cases of bleeding were microscopic. The second most frequent site was the integument, then bleeding from the nose, mouth, or pharynx, then the digestive system [9].

Mueller et al., reported significant number of patients who developed this complication [10]. Vitamin K supplementation as a preventive measure has been suggested by Mueller et al., but a study done by Rock off et al., did not recommend routine use of vitamin K [11]. Indian literarure regarding cefoperazone induced coagulopathy is limited [12].

Cefoperazone induced coagulopathy is a known but rare manifestation, especially in patients with vitamin K deficiency. The manifestation of this coagulopathy resulting in life threatening complications, like the one seen in our patient is potentially preventable by serial monitoring of coagulation parameters and vitamin K supplementation. However, more studies are required to look for the incidence of coagulopathy and bleeding following cefoperazone administration, in an Indian context and role of vitamin K as a preventive measure.

[1]. Obata H, Iizuka B, Uchida K, Pathogenesis of hypoprothrombinemia induced by antibiotics J Nutr Sci Vitaminol (Tokyo) 1992 :421-24.  [Google Scholar]

[2]. Klein NC, Cunha BA, Third-generation cephalosporins Med Clin North Am 1995 79(4):705-19.  [Google Scholar]

[3]. Shearer MJ, Bechtold H, Andrassy K, Koderisch J, McCarthy PT, Trenk D, Mechanism of cephalosporin-induced hypoprothrombinemia: relation to cephalosporin side chain, vitamin K metabolism, and vitamin K status J Clin Pharmacol 1988 28(1):88-95.  [Google Scholar]

[4]. Shearer MJ, Vitamin K deficiency bleeding (VKDB) in early infancy Blood Rev 2009 23(2):49-59.  [Google Scholar]

[5]. Cristiano P, Hypoprothrombinemia associated with cefoperazone treatment Drug Intell Clin Pharm 1984 18(4):314-16.  [Google Scholar]

[6]. Alitalo R, Ruutu M, Valtonen V, Lehtonen T, Pentikäinen PJ, Hypoprothrombinaemia and bleeding during administration of cefamandole and cefoperazone. Report of three cases Ann Clin Res 1985 17(3):116-19.  [Google Scholar]

[7]. Ozen IO, Moralioğlu S, Karabulut R, Bagbanci B, Turkyilmaz Z, Demirogullari B, Cefoperazone induced gastro-intestinal haemorrhage. A case report Acta Chir Belg 2008 108(6):777-78.  [Google Scholar]

[8]. Cai Z, Yang w, He YY, Chen Q, Wang S, Luo X, Cefoperazone/sulbactam-induced abdominal wall haematoma and upper gastrointestinal bleeding: a case report and review of the literature Drug Saf - Case Rep 2016 3:2  [Google Scholar]

[9]. Strom BL, Schinnar R, Gibson GA, Brennan PJ, Berlin JA, Risk of bleeding and hypoprothrombinaemia associated with NMTT side chain antibiotics: using cefoperazone as a test case Pharmacoepidemiol Drug Saf 1999 8(2):81-94.  [Google Scholar]

[10]. Mueller RJ, Green D, Phair JP, Hypoprothrombinemia associated with cefoperazone therapy South Med J 1987 80(11):1360-62.  [Google Scholar]

[11]. Rockoff SD, Blumenfrucht MJ, Irwin RJ, Eng RH, Vitamin K supplementation during prophylactic use of cefoperazone in urologic surgery Infection 1992 20(3):146-48.  [Google Scholar]

[12]. Farookh A, Patil P, Role of prophylactic vitamin k in preventing antibiotic induced hypoprothrombinemia The Indian Journal of Pediatrics 2015 82(4):363-67.  [Google Scholar]