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.

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.

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.

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.

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.

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.

Reducción de la tasa de protrombina causada por la administración de N-acetilcisteína en el tratamiento de la intoxicación por Amanita phalloides / Reduction of the prothrombin ratio induced by the adminis - tration of N-acetil-cysteine in the treatment of Amanita phalloides poisoning

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Cefazolin-induced hypoprothrombinemia.

PURPOSE: A case of cefazolin-induced hypoprothrombinemia in a patient with renal failure is reported. SUMMARY: A 50-year-old African-American woman was transferred from the orthopedics service to the internal medicine service for management of acute renal failure. Before her transfer, she had spinal surgery and subsequently developed a wound infection complicated by Escherichia coli bacteremia. After trials of multiple antibiotics, she developed acute interstitial nephritis and renal failure. On the day of her transfer to the internal medicine service, i.v. cefazolin sodium 1 g was administered every 24 hours to eradicate the E. coli detected in blood cultures. Her baseline International Normalized Ratio (INR) was 1.3. On day 7 of cefazolin therapy, her INR increased to 4.0. Because of her recent history of bleeding and hypotension, vitamin K 10 mg i.v. was administered, followed by 5 mg orally for the next two days. Her INR decreased and normalized at 1.1. The patient had no changes to other drug therapies and had no medical conditions known to independently affect prothrombin time during this episode. The score on the Naranjo et al. adverse-event probability scale revealed a probable relationship between cefazolin and hypoprothrombinemia in this patient. CONCLUSION: A patient with a postsurgery wound infection and acute renal failure developed hypoprothrombinemia after receiving cefazolin for seven days.

Iatrogenic vitamin K deficiency and life threatening coagulopathy.

A man was admitted with abdominal pain. Treatment for acute diverticulitis was instituted with intravenous antibiotics and oral limitation. Imaging demonstrated a complex inflammatory mass. Prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen were within normal limits. However, repeat preoperative clotting studies demonstrated a severe unexpected coagulopathy to have developed since admission that could have caused fatal intraoperative exsanguination. Direct assays showed severe, isolated deficiency of vitamin K dependent clotting factors, and mixing studies normalised both the PT and APTT, ruling out a coagulation inhibitor. The coagulopathy responded to intravenous vitamin K administration. Dietary insufficiency underlies vitamin K deficiency in the presence of normal biliary and enteral function. A significant coagulopathy can result with additional eradication of intestinal microflora. Hypoprothombinaemia is recognised as a consequence of protracted treatment with broad spectrum antibiotics, and vigilance is required for those at risk. The development of such a rapid and unexpected coagulopathy posed a complex preoperative management issue delaying operative intervention; although avoided by fortuitous preoperative screening, it could have caused significant intraoperative bleeding. The remarkably specific lack of vitamin K dependent clotting factors strongly suggested a vitamin K deficiency and administration of coumarins was ruled out.

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.

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.

Warfarin-cranberry juice interaction resulting in profound hypoprothrombinemia and bleeding.

Few published reports have suggested a substantial interaction between cranberry juice and warfarin, although a definite link could not be established. We encountered a patient taking stable doses of warfarin who developed major bleeding and high INR soon after starting daily cranberry juice. No other identifiable reasons for the high INR were apparent. The patient resumed his usual dose of warfarin after stopping the juice. This case suggests a definite relationship between cranberry juice and warfarin.

Enhanced hypoprothrombinemia with warfarin due to azithromycin.

OBJECTIVE: To report a case of probable azithromycin-warfarin drug interaction with enhanced hypoprothrombinemic effect of warfarin. CASE SUMMARY: An 83-year-old African American man stabilized on warfarin therapy (10 mg on Wednesdays, 7.5 mg on other days) developed a prolonged prothrombin time one day after starting azithromycin 500 mg. The elevated prothrombin time normalized 3 days after azithromycin was discontinued. After the initial increase in the international normalized ratio, the absence of any significant confounding factors affecting the anticoagulant effect of warfarin in our patient and the numerous reports of such interactions indicate that an interaction between azithromycin and warfarin may have been responsible for the elevated prothrombin time seen in this patient. An objective causality assessment revealed that the adverse event was probably related to the combination of these drugs. DISCUSSION: Azithromycin, unlike erythromycin and clarithromycin, is not known to inhibit the cytochrome P450 enzyme system and is presumed to be the macrolide of choice in patients already on warfarin. However, previously reported cases of azithromycin-warfarin interactions support the possibility that azithromycin does interact with warfarin, although the exact mechanism is not understood. CONCLUSIONS: Azithromycin may interact with warfarin and enhance its hypoprothrombinemic effects. This effect may be delayed for 4-8 days after a course of azithromycin has been completed. Periodic monitoring of the prothrombin time is recommended when using azithromycin in patients taking warfarin.

A study of Vitamin K status in children on prolonged antibiotic therapy.

Vitamin K deficiency is known to cause coagulopathy and bleeding in patients on prolonged antibiotic therapy. This study was conducted to evaluate the status of vitamin K deficiency in hospitalized children on prolonged antibiotic therapy and its role in reversing the coagulopathy. A prospective non-randomized study was conducted on children on antibiotic therapy at a tertiary care hospital. Children in the 1 month-1 year age group developed significant coagulopathy as compared to other age groups. Coagulation abnormalities were also seen to be more in children with greater grades of malnutrition, on a more prolonged course of antibiotics and in children who were critically ill in intensive care. Hypoprothrombinemia previously reported to be due to B-lactam antibiotics containing the N-Methyl Thio Tetrazole (NMTT) group also resulted from antibiotics without this side chain. Inhibition of intestinal microorganisms by antibiotics was thought to be a likely explanation of this phenomenon. We suggest Vitamin K prophylaxis in severely ill patients, on extended periods of antibiotics and inadequate diet to prevent morbidity and mortality.

Cefazolin administration and 2-methyl-1,3,4-thiadiazole-5-thiol in human tissue: possible relationship to hypoprothrombinemia.

Cephalosporin antibiotics with structures that include the heterocyclic leaving group 1-methyltetrazole-5-thiol (MTT) can cause hypoprothrombinemia and hemorrhage as a result of MTT-dependent inhibition of the gamma-carboxylation of glutamate. The structure of cefazolin also includes a heterocyclic thiol, 2-methyl-1,3,4-thiadiazole-5-thiol (MTD), and this compound can also inhibit the gamma-carboxylation of glutamate. However, unlike MTT, which is known to be present in vivo after the administration of drugs that include this structure, there have been no reports that MTD is present in vivo after cefazolin administration. We set out to determine whether MTD might be present in the tissues of patients treated with cefazolin prior to surgery. To do that, we took advantage of the fact that heterocyclic thiols can undergo S-methylation catalyzed by the genetically polymorphic drug-metabolizing enzyme thiopurine S-methyltransferase (TPMT). Initially, we tested recombinant human TPMT as a "reagent" to S-methylate MTD. MTD was a substrate for TPMT-catalyzed S-methylation, with an apparent K(m) value of 63 micro M. Recombinant TPMT, with [(14)C-methyl]S-adenosyl-L-methionine as a cosubstrate, was then used to radioactively label a methyl acceptor substrate present in liver and kidney cytosol preparations from patients who had been treated preoperatively with cefazolin. Pooled renal cytosol from 10 of those patients was used to purify and isolate the methylated product by reverse-phase high-performance liquid chromatography. That methylated compound coeluted with S-methyl MTD. When the methylated product was subjected to tandem mass spectrometry, it was identified as S-methyl MTD. Therefore, MTD is present in the tissues of patients treated with cefazolin. These observations also raise the possibility that the TPMT genetic polymorphism may represent a risk factor for cefazolin-induced hypoprothrombinemia since subjects who genetically lack TPMT would be unable to catalyze this MTD biotransformation pathway.

Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and hypoprothrombinemia.

Gastrointestinal side effects from nonsteroidal anti-inflammatory drugs (NSAIDs) result mainly from inhibition of the enzyme cyclooxygenase (COX)-1; it is responsible for the synthesis of prostaglandin E2, which leads to increased mucosal blood flow, increased bicarbonate secretion, and mucus production, thus protecting the gastrointestinal mucosa. In inflammation, COX-2 is induced, causing synthesis of the prostaglandins in conditions such as osteoarthritis and rheumatoid arthritis. Two NSAIDs (celecoxib and rofecoxib) with very high specificity for COX-2 and virtually no activity against COX-1 at therapeutic doses have been approved for clinical use. In trials of celecoxib and rofecoxib, only 0.02% of patients had clinically significant gastrointestinal bleeding, compared to a 1% to 2% yearly incidence of severe gastrointestinal side effects with NSAIDs. Our patient had arthritis of the hips and chronic atrial fibrillation and was on warfarin therapy for stroke prevention; less than a week after starting celecoxib therapy, gastrointestinal bleeding and hypoprothrombinemia occurred.

Ciprofloxacin-warfarin coagulopathy: a case series.

Ciprofloxacin, when given to patients previously anticoagulated with warfarin, can occasionally cause an exaggerated hypoprothombinemic response and bleeding diatheses. Two such cases encountered at our institution are presented and data is combined with 64 cases reported to the Food and Drug Administration's (FDA) Spontaneous Reporting System (SRS) database, which included all cases reported from 1987 through 1997. Of 66 total cases the median age was 72 (range 36-94). The mean time to detection of the coagulopathy following the ciprofloxacin challenge was 5.5 days (n = 50). Hospitalization was reported in 15 cases, bleeding in 25 cases, and death in one case. The median prothrombin time (PT) and International Normalized Ratio (INR) was 38.0 (n = 13) and 10.0 (n = 23), respectively. The mean number of medications taken was 6.5 (n = 45). The mean time to correction was significantly shorter between the treated (2.5 days) and the untreated (4.0 days) groups (P < 0. 008). The ciprofloxacin-warfarin coagulopathy occurred most commonly in patients in their seventh decade and in those who require polypharmacy. Active treatment of the coagulopathy results in more rapid resolution than observation alone. Clinicians should be aware of the potential bleeding complications that can occur with the ciprofloxacin-warfarin drug-drug interaction.