Hypoprothrombinemia During Cefmetazole Treatment: A Case Report.

BACKGROUND Cefmetazole (CMZ), containing an N-methyl-tetrazole-thiol (NMTT) side chain, is a therapeutic option for diverticulitis in Japan. Cephems containing an NMTT, a methyl-thiadiazol, and a thiadiazolethiol side chain are known to induce coagulation disorders. CASE REPORT A 76-year-old woman developed hypoprothrombinemia after receiving oral levofloxacin (LVFX) 250 mg q24h for 2 days followed by intravenous CMZ 2 g q8h for sigmoid diverticulitis. On day 5 of CMZ administration (after 12 doses in total), black stool was observed. On the following day (after 14 doses), prothrombin time (PT) prolongation was noted; PT and international normalized ratio (INR) were 37.1 s and 2.47, respectively. We diagnosed the patient with hypoprothrombinemia because of vitamin K deficiency caused by markedly elevated protein levels induced by vitamin K absence or antagonist-II on day 6 of CMZ administration. Intravenous vitamin K administration and CMZ cessation rapidly restored PT and led to the disappearance of black stool. CONCLUSIONS The causes of vitamin K deficiency were considered to be an impaired vitamin K cycle due to CMZ and decreased vitamin K intake because of malnutrition. These findings are consistent with CMZ's reported adverse effects. Decreased vitamin K production due to alterations in the gut bacterial flora by LVFX and CMZ was also postulated as a cause. If a bleeding tendency is noted during diverticulitis treatment with NMTT-containing cephems, switching to intravenous quinolones or carbapenems is recommended. It remains unclear how this reaction can be avoided; however, prudent monitoring of bleeding signs and PT-INR is recommended.

A case of sulphasalazine potentiating the hypoprothombinemic effect of warfarin resulting in bleeding.

WHAT IS KNOWN AND OBJECTIVE: One case report demonstrated warfarin resistance associated with sulphasalazine therapy. Our objective is to report on a case of warfarin potentiation rather than resistance, associated with sulphasalazine therapy. CASE SUMMARY: The patient was taking warfarin for two mechanical heart valves and was prescribed sulphasalazine for inflammatory bowel disease. He had stable international normalized ratios (INRs) before sulphasalazine administration. Approximately 3 weeks after starting sulphasalazine, he presented to the anticoagulation clinic with bruising and an INR of 6·1. The sulphasalazine was stopped, and the warfarin was held for 3 days; then the previous dose was resumed. Three weeks later, the INR returned to a therapeutic level. WHAT IS NEW AND CONCLUSION: This is the first case of sulphasalazine potentiating the effect of warfarin. Sulphasalazine may potentiate the hypoprothombinemic effect of warfarin.

The Association Between Cephalosporin and Hypoprothrombinemia: A Systematic Review and Meta-Analysis.

Cephalosporins that contain the N-methylthiotetrazole side chain (NMTT-cephalosporin) have been reported to be associated with coagulation-related adverse events; however, a comprehensive evaluation regarding the association is lacking. A systematic review and meta-analysis were conducted to assess the safety profile of NMTT-cephalosporins with respect to hypoprothrombinemia and bleeding. The MEDLINE, Embase, Cochrane, and RISS databases were systematically searched for clinical studies up to October 2018. The association between NMTT-cephalosporins and hypoprothrombinemia was estimated using an odds ratio (OR) with a 95% confidence interval (CI). A total of 15 studies on cefamandole, cefoperazone, cefotetan, cefmetazole, and moxalactam were identified and included in the meta-analysis. Hypoprothrombinemia (OR 1.676, 95% CI 1.275-2.203) and prothrombin time (PT) prolongation (OR 2.050, 95% CI 1.398-3.005) were significantly associated with NMTT-cephalosporins, whereas bleeding was not (OR 1.359, 95% CI 0.920-2.009). Subgroup analyses revealed that cefoperazone (OR 2.506, 95% CI 1.293-4.860), cefamandole (OR 3.247, 95% CI 1.083-9.733), and moxalactam (OR 3.367, 95% CI 1.725-6.572) were significantly associated with hypoprothrombinemia. An Antimicrobial Stewardship Program led by a multidisciplinary team could play a critical role in monitoring cephalosporin-related hypoprothrombinemia or PT prolongation in patients with underlying clinical conditions at risk for bleeding. The multidisciplinary team could also assist in communicating the potential safety concerns regarding NMTT-cephalosporin use with healthcare professionals to decrease the risk of adverse events.

Cefoperazone induced gastro-intestinal haemorrhage. A case report.

Cefoperazone is a parenteral third generation cephalosporin which is active against many Gram positive and Gram negative organisms. Cefaperazone, like other cephalosporins which contain methyltiotetrazole side chain, can cause hypoprotrombinaemia and bleeding problems. Here we report a nine-year old child with Meckel's diverticulum who had cefoperazone induced massive gastrointestinal bleeding on the fifth day following the operation.

Hypoprothrombinemia and severe perioperative haemorrhagic complications in cardiac surgery patients treated with high-dose cefazolin for infective endocarditis.

Endocarditis is a serious and common disease that requires prolonged antimicrobial therapy. The recent shortage of oxacillin has led to the use of other antimicrobial agents such as cefazolin to treat endocarditis due to methicillin-sensitive Staphylococcus aureus. We describe four cases of life-threatening haemorrhagic complications (fatal in two cases) in patients treated with high-dose cefazolin. All of these patients with major bleeding presented with hypoprothrombinemia secondary to hypovitaminosis K. This adverse event may be due to inhibition of vitamin K epoxide reductase and/or gamma-glutamyl-carboxylase by the 2-methyl-1,2,3-thiadiazol-5-thiol group of cefazolin. This inhibition may result in hypoprothrombinemia by altering the synthesis of vitamin K-dependent coagulation factors. The increasing use of cefazolin, especially at a high dose and for a prolonged period of time, should be accompanied by regular monitoring of coagulation, including prothrombin index, and vitamin K supplementation.

Severe INR elevation in a patient with choledocholithiasis receiving cefoperazone.

Cefoperazone is a third-generation cefalosporin that contains the N-methyl- thio-tetrazole (NMTT) side chain, which inhibits vitamin K-dependent carboxylation. Administration of NMTT-containing cefalosporins can cause alterations in the hepatic glutathione redox state, resulting in a dose-related increase in oxidised glutathione, which is responsible for the inhibition of microsomal reduction of vitamin K epoxide. In addition, cefoperazone is not metabolised and is excreted predominantly through the bile. In patients with hepatic impairment, the clearance of cefoperazone has been shown to be significantly reduced and the half-life prolonged. We report a case of choledocholithiasis related to a prolonged prothrombin time and INR secondary to cefoperazone therapy.

Use of Hypoprothrombinemia-Inducing Cephalosporins and the Risk of Hemorrhagic Events: A Nationwide Nested Case-Control Study.

OBJECTIVE: Existing data regarding the risk of hemorrhagic events associated with exposure to hypoprothrombinemia-inducing cephalosporins are limited by the small sample size. This population-based study aimed to examine the association between exposure to hypoprothrombinemia-inducing cephalosporins and hemorrhagic events using National Health Insurance Research Database in Taiwan. DESIGN: A nationwide nested case-control study. SETTING: National Health Insurance Research database. PARTICIPANTS: We conducted a nested case-control study within a cohort of 6191 patients who received hypoprothrombinemia-inducing cephalosporins and other antibiotics for more than 48 hours. Multivariable conditional logistic regressions were used to calculate the adjusted odds ratio (aOR) and 95% confidence interval (CI) for hemorrhagic events associated with exposure to hypoprothrombinemia-inducing cephalosporins (overall, cumulative dose measured as defined daily dose (DDD), and individual cephalosporins). RESULTS: Within the cohort, we identified 704 patients with hemorrhagic events and 2816 matched controls. Use of hypoprothrombinemia-inducing cephalosporins was associated with increased risk of hemorrhagic events (aOR, 1.71; 95% CI, 1.42-2.06), which increased with higher cumulative doses (<3 DDDs, aOR 1.62; 3-5 DDDs, aOR 1.78; and >5 DDDs, aOR 1.89). The aOR for individual cephalosporin was 2.88 (95% CI, 2.08-4.00), 1.35 (1.09-1.67) and 4.57 (2.63-7.95) for cefmetazole, flomoxef, and cefoperazone, respectively. Other risk factors included use of anticoagulants (aOR 2.08 [95% CI, 1.64-2.63]), liver failure (aOR 1.69 [1.30-2.18]), poor nutritional status (aOR 1.41 [1.15-1.73]), and history of hemorrhagic events (aOR 2.57 [1.94-3.41]) 6 months prior to the index date. CONCLUSIONS: Use of hypoprothrombinemia-inducing cephalosporins increases risk of hemorrhagic events. Close watch for hemorrhagic events is recommended when prescribing these cephalosporins, especially in patients who are at higher risk.

Phenylbutazone and sulfinpyrazone interaction with oral anticoagulant phenprocoumon.

To compare the marked hypoprothrombinemic augmentation in man of racemic warfarin sodium by the pyrazolons phenylbutazone and sulfinpyrazone with that of the coumarin anticoagulant phenprocoumon, these interactions were studied prospectively in six normal subjects. Large single doses of racemic phenprocoumon, 0.6 mg/kg orally, were administered with and without daily phenylbutazone, 300 mg, or sulfinpyrazone, 400 mg, beginning three days before phenprocoumon and continuing for 14 days. Daily blood samples were drawn for phenprocoumon content and one-stage prothrombin time. Phenylbutazone markedly increased both the phenprocoumon concentrations and prothrombin times, whereas sulfinpyrazone did not.

Hypoprothrombinemia associated with cefamandole use in a rural teaching hospital.

The incidence of hypoprothrombinemia (prothrombin time greater than or equal to 2 s above the highest control) associated with concurrent cefamandole nafate usage in our institution was determined. Of 77 patients receiving cefamandole for no less than 48 hours, serial prothrombin time was monitored in 31 (40.2%). Four (12.9%) of 31 in whom a baseline normal prothrombin time was obtained developed hypoprothrombinemia during cefamandole therapy. An additional three patients for whom baseline prothrombin time was not determined were noted to have hypoprothrombinemia during therapy with cefamandole. Two patients had clinically significant bleeding episodes. The prothrombin time normalized in six of seven patients following administration of fresh frozen plasma, phytonadione therapy, discontinuation of cefamandole, or a combination of the three. This study illustrated that the incidence of hypoprothrombinemia associated with concurrent cefamandole use is relatively high. Serial prothrombin time monitoring is indicated when patients receive cefamandole.

Hypoprothrombinemia in patients with cancer receiving cefoperazone and mezlocillin.

Forty-one patients with cancer who were receiving cefoperazone sodium plus mezlocillin sodium were prospectively followed up for the development of abnormal bleeding or hypoprothrombinemia. Ten of 41 patients developed an increased prothrombin time, three with a hemorrhagic episode. Serum transport proteins and serum carotene were measured in 18 patients, six of whom developed hypoprothrombinemia. Low serum prealbumin and low serum carotene levels were associated with the development of hypoprothrombinemia. Patients with cancer are especially predisposed to the development of antibiotic-associated hypoprothrombinemia. This is probably a result of protein-calorie malnutrition and low vitamin K stores.

Lovastatin. Warfarin interaction.

Two patients who developed hypoprothrombinemia and bleeding due to lovastatin-warfarin drug interaction are described. Because of the wider use of lovastatin and warfarin, heightened clinical awareness of this potentially serious interaction must be publicized. Therefore, prothrombin time should be monitored diligently when warfarin is prescribed to patients receiving lovastatin.

Role of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.

OBJECTIVE: To determine prophylactic role of single dose of vitamin K in prevention of antibiotic induced hypoprothrombinemia. METHODS: This prospective comparative study included critically ill children in age group 2 mo to 12 y, admitted to a tertiary care hospital in India, likely to receive prolonged antibiotic therapy. One hundred twenty children, 60 in each group (A & B) were enrolled in the study. Patient allocation was done on alternate basis. Group A children received prophylactic vitamin K while group B did not. Baseline coagulation studies and other investigations were done in all children. Coagulation studies were repeated on day 10 and day 14 of antibiotic therapy and in between if required clinically. Children who developed deranged INR were given therapeutic vitamin K. If deranged INR returns to normal at 12 h of vitamin K administration then it indirectly confirms vitamin K deficiency. Analysis was done by fisher's t test and chi square test. RESULTS: In children on prolonged antibiotic therapy, vitamin K deficiency was a common problem (15%). It was common in male sex, severe grade of protein energy malnutrition (PEM), N-methylthiotetrazole (NMTT) group containing antibiotics use and duration of antibiotic more than 10 d. It was same in children whether they received or did not receive prophylactic vitamin K on day 1 of antibiotic therapy (95% CI; p value 0.79). CONCLUSIONS: Vitamin K deficiency is common problem in patients on prolonged antibiotic therapy. There is no role of single dose of prophylactic vitamin K in preventing antibiotic induced hypoprothrombinemia.

Interaction of secobarbital with warfarin pseudoracemates.

To evaluate the interaction of secobarbital with racemic warfarin or R,S(+/-)-warfarin, S(-)-warfarin was synthesized with 13C-label in the 2-position of the coumarin nucleus and added to 12C-R(+)-warfarin to form a 12C-/13C-warfarin pseudoracemate. Six normal subjects received 1.5 mg/kg of this "cold-labeled" pseudoracemate. It was given with and without a daily oral dose of secobarbital, 100 mg, beginning 7 days before the warfarin and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin and for one-stage prothrombin activity. Unchanged warfarin in plasma was fractionated by forward-phase high-pressure liquid chromatography, and enantiomorphic ratios were determined by chemical ionization-mass spectrometry with pentadeuterio-warfarin as the internal standard. There was a reduction of the hypoprothrombinemia of the pseuoracemate during the secobarbital regimen over that on warfarin alone (p < 0.001). There was an increase in plasma clearance of R-warfarin (p < 0.05) and an increase in plasma clearance of S-warfarin (p < 0.003) during the secobarbital regimen over that on warfarin alone. It was concluded that secobarbital diminished the hypoprothrombinemia of pseudoracemic warfarin by increasing plasma clearance of the more hypoprothrombinemic S-warfarin and by increasing plasma clearance of the less hypoprothombinemic R-warfarin.

Ticrynafen-racemic warfarin interaction: hepatotoxic or stereoselective?

To examine the ticrynafen-warfarin interaction, normal subjects received large single doses of 1.5 mg/kg racemic warfarin with and without daily oral doses of 250 mg ticrynafen beginning 3 days before warfarin and continuing for the duration of hypoprothrombinemia. Daily blood samples were analyzed for one-stage prothrombin time (Quick method) and warfarin concentrations (high-pressure liquid chromatography). Ticrynafen induced augmentations of both prothrombin time and warfarin concentration (P less than 0.001). The interaction was evaluated further with separated warfarin enantiomorphs. Ticrynafen induced augmentation of prothrombin times and warfarin concentrations of S-warfarin, but had little effect on R-warfarin. Thus, ticrynafen probably augments the hypoprothrombinemia of racemic warfarin by reducing metabolic clearance of S-warfarin. The lack of effect of ticrynafen on R-warfarin suggest that the interaction is stereoselective rather than hepatotoxic.

Cefoperazone versus combination antibiotic therapy of hospital-acquired pneumonia.

Cefoperazone monotherapy was compared with combination antibiotic therapy in a randomized prospective evaluation of patients with hospital-acquired pneumonia. Cefoperazone was as effective as either clindamycin/gentamicin or cefazolin/gentamicin (cure rate: 45 of 52 cefoperazone-treated patients [87 percent], versus 44 of 61 combination-therapy patients [72 percent], p = 0.069). With the exception of hypoprothrombinemia in those patients who did not receive prophylactic vitamin K, there was no difference in the incidence of side effects. In addition, no difference was noted in the incidence of superinfections or secondary pneumonias. When antibiotic costs, administration costs, and laboratory costs were considered, cefoperazone monotherapy was the least expensive antibiotic regimen. Cefoperazone is a suitable alternative to combination antibiotic therapy for the treatment of hospital-acquired pneumonia.

Comparative toxicities of third-generation cephalosporins.

Data on the adverse effects experienced by 2,539 patients who received ceftazidime were compared with adverse effects reported with cefoperazone, cefotaxime, ceftizoxime, and moxalactam. There were 216 such reactions among the ceftazidime-treated patients; 158 patients (6.2 percent) had reactions that were possibly or probably drug-related. The clinical and laboratory safety profile of ceftazidime in regard to renal, hepatic, hematopoietic, and hemostatic parameters compared favorably with that of other third-generation cephalosporins. An increased serum creatinine level was observed in 0.8 percent of ceftazidime-treated patients, an increased blood urea nitrogen level in 1.6 percent, hepatic abnormalities in approximately 6 percent, diarrhea in 1.3 percent, pseudomembranous colitis in 0.12 percent, increased prothrombin time in 0.5 percent, and clinical bleeding in none. The incidence of colonization (3.8 percent) and superinfections (3 percent) associated with ceftazidime therapy was comparable to rates with other agents in this class.

In vivo effects of beta-lactam antibiotics and heterocyclic thiol compounds on vitamin K-dependent carboxylation activity and blood coagulation factors in vitamin K-deficient rats.

The in vivo effects of heterocyclic thiol compounds, corresponding to the 3'-position substituents of several beta-lactam antibiotics, on blood coagulation factors and on liver microsomal gamma-glutamylcarboxylation (gamma-carboxylation) activity were evaluated in rats maintained on a vitamin K-deficient diet. These rats, when compared to normal control animals, exhibited hypoprothrombinemic changes: prolongation of both prothrombin time and activated partial thromboplastin time, decreases in factor VII and plasma prothrombin, and increases in PIVKA II (descarboxyprothrombin) both in plasma and liver. They also displayed a marked increase in liver microsomal gamma-carboxylation activity. These blood coagulation variables could be altered markedly by administering various heterocyclic thiol compounds to the vitamin K-deficient rats, although these compounds did not inhibit gamma-carboxylation activity in an assay system using phylloquinone. A similar pattern of alteration was observed when some beta-lactam antibiotics were administered. Increased microsomal gamma-carboxylation activity in antibiotic-treated vitamin K-deficient rats was normalized by the administration of vitamin K, concomitant with the recovery of blood coagulation variables to the normal range. The results indicate that antibiotic-induced hypoprothrombinemia in vivo is not caused by inhibition of enzymes of the gamma-carboxylation system, such as vitamin K reductase and gamma-glutamylcarboxylase, but is related to the endogenous vitamin K level.

Gemfibrozil-warfarin drug interaction resulting in profound hypoprothrombinemia.

The following describes a patient on a stable regimen of warfarin who developed severe hypoprothrombinemia and bleeding 4 weeks after starting gemfibrozil. Despite a warning by the manufacturer, only one report of this interaction has been published in the literature. This interaction may be overlooked by clinicians, which may result in a serious bleeding risk for patients on warfarin.

Hypoprothrombinemia and hemorrhage in a surgical patient treated with cefotetan.

For 4 days before surgical repair of a diverticulitic colovesical fistula and for 6 days after, a 63-year-old man was treated with 2 g of intravenous cefotetan disodium every 12 hours for associated urosepsis with bacteremia. Postoperatively, the patient followed a diet of intravenous nutrition only. Uneventful convalescence was interrupted by signs of sudden major blood loss, accompanied by prolonged prothrombin time. After stabilization with packed red blood cells, fresh plasma, crystalloids, and parenteral vitamin K, laparotomy revealed a huge intra-abdominal clot, which was evacuated. This case illustrates the risk of unexpected hypoprothrombinemia and hemorrhage in a cefotetan-treated surgical patient who demonstrated none of the usual comorbid conditions generally described in patients with antibiotic-induced hypoprothrombinemia. Like cefamandole nafate, cefoperazone sodium, moxalactam disodium, and other cephalosporins containing the methylthiotetrazole side chain, cefotetan appears to pose an unusual risk of major bleeding.

Moxalactam. Evaluation of clinical bleeding in patients with abdominal infection.

Previous clinical studies have emphasized that hypoprothrombinemia may occur during treatment with moxalactam disodium, a new broad-spectrum cephalosporin. Usually, this abnormality is corrected by administering vitamin K. Recent case reports have described bleeding complications associated with moxalactam therapy and suggested that platelet function is depressed by this drug. We studied eight patients with abdominal infection who were treated with moxalactam. Six of them had prolonged template bleeding times, and two had clinically significant hemorrhage (epistaxis, hematuria, and rectal bleeding) during treatment with moxalactam. These observations suggest that coagulation studies and template bleeding times should be monitored during moxalactam therapy, especially before major surgery.