Development and Validation of a Risk Scoring System for Cephamycin-Associated Hemorrhagic Events.

Cephamycin-associated hemorrhages have been reported since their launch. This research aimed to determine risk factors for cephamycin-associated hemorrhagic events and produce a risk scoring system using National Taiwan University Hospital (NTUH) database. Patients who were older than 20 years old and consecutively used study antibiotics for more than 48 hours (epidode) at NTUH between January 1st, 2009 and December 31st, 2015 were included. The population was divided into two cohorts for evaluation of risk factors and validation of the scoring system. Multivariate logistic regression was used for the assessment of the adjusted association between factors and the outcome of interest. Results of the multivariate logistic regression were treated as the foundation to develop the risk scoring system. There were 46402 and 22681 episodes identified in 2009-2013 and 2014-2015 cohorts with 356 and 204 hemorrhagic events among respective cohorts. Use of cephamycins was associated with a higher risk for hemorrhagic outcomes (aOR 2.03, 95% CI 1.60-2.58). Other risk factors included chronic hepatic disease, at least 65 years old, prominent bleeding tendency, and bleeding history. A nine-score risk scoring system (AUROC = 0.8035, 95% CI 0.7794-0.8275; Hosmer-Lemeshow goodness-of-fit test p = 0.1044) was developed based on the identified risk factors, with higher scores indicating higher risk for bleeding. Use of cephamycins was associated with more hemorrhagic events compared with commonly used penicillins and cephalosporins. The established scoring system, CHABB, may help pharmacists identify high-risk patients and provide recommendations according to the predictive risk, and eventually enhance the overall quality of care.

Cefotetan-induced haemolytic anaemia. A review of 85 cases.

OBJECTIVE: Reports of cefotetan-associated haemolytic anaemia have prompted a US Food and Drug Administration (FDA) review of the overall number, severity, and causality of such cases. METHODS/RESULTS: A search of the FDA's Spontaneous Reporting System and the World Health Organization's database revealed 85 cases of haemolytic anaemia since the approval of cefotetan in 1985, 15 of them fatal. Moderate to severe haemolysis was reflected in a mean fall in haemoglobin levels by 6.65 mg/dl (n = 20) and a mean final haemoglobin concentration of 5.2 mg/dl (n = 52). Transfusion of packed red blood cells was required in 47 patients (55.3%). New onset renal dysfunction was noted in 7 patients (8.2%). The direct antiglobulin test was positive in 50 patients (59%), and serological studies revealed antibodies to cefotetan in 30 patients (35%). CONCLUSION: These data suggest that treatment with cefotetan may induce severe autoimmune haemolytic anaemia.

Cutaneous drug reaction case reports: from the world literature.

Skin disorders are the most common adverse reactions attributed to drugs. Any skin disorder can be imitated, induced or aggravated by drugs. To help you keep up-to-date with the very latest skin reactions occurring with both new and established drugs, this section of the journal brings you information selected from the adverse drug reaction alerting service Reactions Weekly. The following case reports are selected from the very latest to be published in the world dermatology literature. Any claim of a first report has been verified by a search of AdisBase (a proprietary database of Adis International, Auckland, New Zealand) and Medline. Each case report is assessed for seriousness using the FDA MedWatch definition of serious (patient outcome is: death; life-threatening; hospitalization; disability; congenital anomaly; or requires intervention to prevent permanent impairment or damage).

Cefotetan-induced hemolytic anemia: a case report and review of the literature.

Cefotetan disodium-induced hemolytic anemia has been reported previously, and some of these cases have been severe or fatal. We describe a case of severe hemolytic anemia that occurred in an 80-year-old woman who received cefotetan prophylactically after surgery for a small bowel obstruction. Eight days after the first dose of cefotetan, the patient developed a severe Coomb test-positive hemolytic anemia. Using flow cytometry, we demonstrated cefotetan-specific antibodies in her posttreatment serum, which were detectable at a serum dilution up to 1:10 000. The patient received corticosteroid therapy and blood transfusions, with improvement of her hematologic parameters, but died 54 days after admission for respiratory failure. To our knowledge, this is the first use of flow cytometry for the detection of cefotetan-induced red blood cell antibodies. This technique offers a sensitive, rapid, objective method for detecting drug-induced antibodies.

Cefotetan-induced hemolysis associated with antibiotic prophylaxis for cesarean delivery.

We describe 3 cases of antibiotic-induced hemolysis associated with cefotetan prophylaxis during cesarean delivery. Each of the 3 patients showed development of significant anemia with documented cefotetan-induced hemolysis. When postpartum anemia is associated with antibiotic use, immune hemolytic anemia should be considered and included in the differential diagnosis.

Drug-induced hemolysis: cefotetan-dependent hemolytic anemia mimicking an acute intravascular immune transfusion reaction.

Numerous cases of drug-induced hemolytic anemia have been described in patients treated with penicillin or cephalosporin. Second and third generation cephalosporins are more commonly implicated in hemolytic reactions than first generation cephalosporins. We report a case of severe cefotetan-induced hemolytic anemia in a previously healthy 46-year-old woman undergoing an elective hysterectomy. The patient received 2 g of intravenous cefotetan intraoperatively and subsequently at 12 and 24 h post-operatively. She complained of diarrhea and fever on the third post-operative day and was seen in her gynecologist's office on the fifth post-operative day (hemoglobin = 10.5 g/dL). On the seventh post-operative day, she complained of fever and soreness around the suprapubic catheter site and was given a prescription for 500 mg oral cephalexin four times a day. The next day she was seen in the gynecologist's office and reported feeling better. Ten days after the operation her fatigue worsened and her hemoglobin was 4.8 g/dL. She was transfused with 3 units of packed red blood cells (PRBC) and was given 1 g of cefotetan intravenously. During the transfusion of the second unit of PRBC nursing staff observed gross hemoglobinuria and she subsequently developed acute renal failure. Laboratory chemistry parameters were consistent with severe acute hemolysis. The patient's direct antiglobulin test was reactive and her serum reacted with cefotetan-coated red blood cells (RBCs) and serum plus soluble cefotetan reacted with untreated RBCs. The titration endpoint of the serum against cefotetan-coated RBCs was 40,960, while the serum plus soluble cefotetan against uncoated RBCs was 2,560. This case of severe cefotetan-induced hemolysis was complicated by an acute hemolytic event that occurred during the transfusion of PRBC. Clinical and transfusion service staff must consider drug-induced hemolysis in the differential diagnosis of acute anemia.

Severe immune hemolytic anemia associated with prophylactic use of cefotetan in obstetric and gynecologic procedures.

Second- and third-generation cephalosporins, especially cefotetan, are increasingly associated with severe, sometimes fatal immune hemolytic anemia. We noticed that 10 of our 35 cases of cefotetan-induced hemolytic anemias were in patients who had received cefotetan prophylactically for obstetric and gynecologic procedures. Eight of these cases of severe immune hemolytic anemia are described.

Double-blind comparison of single-dose alatrofloxacin and cefotetan as prophylaxis of infection following elective colorectal surgery. Trovafloxacin Surgical Group.

BACKGROUND: Alatrofloxacin, the prodrug of trovafloxacin, is a novel fluoroquinolone antimicrobial agent with a broad spectrum, including activity against gram-positive and gram-negative aerobes and anaerobes. Its pharmacokinetic properties (long half-life, excellent tissue distribution, and good safety profile) suggest a role in surgical prophylaxis. This prospective, multicenter, double-blind trial compared alatrofloxacin with cefotetan, an approved drug for surgical prophylaxis, in reducing postoperative infections. METHODS: The efficacy and safety of a single 200-mg intravenous dose of alatrofloxacin were compared to a single 2-g intravenous dose of cefotetan in 492 patients undergoing elective colorectal surgery. The efficacy of alatrofloxacin as a prophylaxis for wound, intra-abdominal, or remote-site postoperative infectious complications was compared with cefotetan in 317 clinically evaluable patients; 161 received alatrofloxacin and 156 received cefotetan. The patients were monitored for infections and safety for 30 days postoperatively. RESULTS: No statistically significant between-treatment difference was detected in successful clinical response rates at the end of the study (72% for each group). The incidence of primary wound infections at the time of hospital discharge was also similar: 21% in patients treated with alatrofloxacin and 18% in those treated with cefotetan. Safety, established by the incidence of adverse events, did not differ statistically between the groups. CONCLUSIONS: A single intravenous dose of alatrofloxacin given within 4 hours prior to surgery was as effective as an intravenous dose of cefotetan in the prevention of postoperative infectious complications in patients undergoing elective colorectal surgery. The safety profiles of the two medications were similar.

Clostridium difficile infection in obstetric and gynecologic patients.

We reviewed hospital records of women on the obstetrics and gynecologic services with a diagnosis of antibiotic-associated diarrhea, pseudomembranous colitis, or Clostridium difficile infection to better characterize the incidence and course of women with C difficile infection. Cases were included if there was identification of C difficile by culture or toxin or endoscopic verification of pseudomembranous colitis. Between January 1985 and June 1995, there were 74,120 admissions to the obstetrics and gynecology services at two tertiary level hospitals. Eighteen women were found to have documented C difficile infection (0.02%)--3 from the obstetric services, 10 from the benign gynecologic services, and 5 from the gynecologic/oncology services. Diarrhea developed from 2 days to 30 days after antibiotics had been given (mean, 10 days). Nine patients had fever, six had nausea and vomiting, and five had abdominal pain. Antimicrobial agents given before infection included cephalexin, cefoxitin, imipenem, ciprofloxacin, trimethoprim/sulfamethoxazole, ampicillin, gentamicin, and clindamycin. All patients were treated successfully with inpatient antimicrobial agents-15 with metronidazole and 3 with vancomycin. There was one possible recurrence.

Antibiotic-induced iatrogenic hemobilia.

A classical triad of clinical signs defines hemobilia: GI bleeding, right upper quadrant abdominal pain, and jaundice. Although there are a number of causes, it is largely described in conjunction with blunt or penetrating liver trauma and as an iatrogenic complication of therapeutic hepatobiliary interventions. We present a case of antibiotic-induced vitamin K deficiency that resulted in hemobilia complicating acalculous cholecystitis.

[Effectiveness of cefotetan in clinical practice]. / Effektivnost' tsefotetana v klinicheskoi praktike.

Forty five patients at the age of 15 to 84 years with signs of infection requiring active antibacterial therapy were treated with cefotetan. In the majority of the patients pulmonary affections such as double pneumonia, pleurisy or bronchopneumonia were stated. In some patients bronchopulmonary pathological processes were associated with pancreatitis, cholecystitis or other diseases of the gastrointestinal tract. A separate group included patients with diseases of the small pelvis organs (pelvioperitonitis, metroendometritis or prostatitis) and diseases of the urogenital system (pyelonephritis) arachnoiditis. In all the patients except for one with bronchopneumonia at the background of chronic myeloleukemia and agranulocytosis the results of the treatment were good and satisfactory. Cefotetan proved to be efficient in the treatment of purulent affections of the skin and subcutaneous fat (abscesses and phlegmona), trophic disturbances at the background of pathological processes in the vessels and pyoseptic condition. Cefotetan practically had no side effects. Only in 2 patients insignificant nausea during the first 2 days of the treatment was recorded. In some patients the antibiotic intramuscular injections were painful with formation of cold infiltrates. After intravenous administration of cefotetan no adverse reactions were observed.

[Occupational asthma caused by cefmetazole and 7-aminocephalosporanic acid: description of a clinical case]. / Asma professionale da cefmetazolo ed acido 7-amino-cefalosporinico: descrizione di un caso clinico.

A case of professional asthma, following exposure to cefmetazole and 7-ACA, occurring in a non atopic subject with remarkable bronchial hyperreactivity, is described. From the diagnostic point of view the execution of specific bronchial stimulation tests was conclusive. It is probable that the occurrence of the illness is due, in this case, to the ability of the inhaled substances to cause inflammation in a subject with bronchial hyperreactivity, without inducing an immunologic mechanism.

Postmarketing surveillance on side-effects of cefminox sodium (Meicelin).

A postmarketing surveillance of cefminox sodium (Meicelin, CMNX) for intravenous injection was conducted for about 4 years from August 1987 through June 1991, and 13,431 patients were followed up to evaluate the safety of the drug. The incidence of side-effects was 1.76%. By organ, the most frequently observed were hepatic and of the bile duct system (0.87%) followed by those on leukocytes and reticuloendothelial system (0.24%), skin and adnexa (0.24%) and digestive tract (0.16%) indicating a tendency similar to that of other injectable cephalosporins. The incidence of the side-effects among elderly patients (65 years old or older) was 2.12%, whereas among patients 64 years old or younger it was 1.58% with no significant differences between the two groups. No side-effects specific to the elderly were observed. Among children 15 years old or younger the incidence was 0.59%, which was lower than that for patients 16 years old or older (1.90%). Potential side-effects on pregnant women (n = 101) and their babies were also checked. No side-effects occurred among the 52 pregnant women evaluated and no abnormalities were detected in their babies who were followed up for up to 4 years. Cefminox is thus considered to be a highly safe cephalosporin antibiotic.

Formulary evaluation of second-generation cephamycin derivatives using decision analysis.

Use of decision analysis in the formulary evaluation of the second-generation cephamycin derivatives cefoxitin, cefotetan, and cefmetazole is described. The rating system used was adapted from one used for the third-generation cephalosporins. Data on spectrum of activity, pharmacokinetics, adverse reactions, cost, and stability were taken from the published literature and the FDA-approved product labeling. The weighting scheme used for the third-generation cephalosporins was altered somewhat to reflect the more important aspects of the cephamycin derivatives and their potential role in surgical prophylaxis. Sensitivity analysis was done to assess the variability of the final scores when the assigned weights were varied within a reasonable range. Scores for cefmetazole and cefotetan were similar and did not differ significantly after sensitivity analysis. Cefoxitin scored significantly lower than the other two drugs. In the absence of data suggesting that the N-methyl thiotetrazole side chains of cefmetazole and cefotetan cause substantial toxicity, these two drugs can be considered the most cost-efficient members of the second-generation cephamycins.

[Acquired coagulopathy caused by administration of parenteral broad-spectrum antibiotics].

Between October 1988 and May 1989, four cancer patients treated by broad-spectrum antibiotics developed a hemorrhagic diathesis induced by vitamin k (VK) deficiency. Activated partial thromboplastin time (APTT), prothrombin time (PT), factor II (FII) and protein induced by vitamin k absence of antagonist-II (PIVKA-II) were measured after administration of antibiotics and VK in all 4 patients. All these patients had been receiving intravenous hyperalimentation (IVH) and antibiotics for various infections. But all or them developed hemorrhagic diathesis within five days after the initiation of broad-spectrum cephem antibiotics (LMOX or CMNX). The abnormalities were 1) marked decrease of F II (6-18%), 2) prolongation of APTT (58.4-200 seconds), 3) prolongation of PT (7-21%), 4) marked increase of PIVKA-II (17-80 less than AU/ml). After being treated by intravenous administration of VK, hemorrhagic diathesis and abnormalities of coagulation tests except for PIVKA-II were corrected quickly in three evaluated patients. The measurement of PIVKA-II seemed to be useful to diagnose the hemorrhagic diathesis caused by VK deficiency in the patients during administration of antibiotics.

[Clinical evaluation of cefbuperazone in severe infections complicated with hematological disorders].

The efficacy and the safety of an antibiotic in cephamycin group, cefbuperazone (CBPZ), were investigated in 93 patients with severe infections complicated with hematological disorders. The efficacy evaluation was made in 85 cases with underlying hematological disorders including 49 cases (57.6%) of leukemia and 18 cases (21.2%) of malignant lymphoma. The overall efficacy rate was 50.6% of the 85 evaluable cases. The clinical efficacy rate for sepsis and suspected sepsis was 53.4%. The most frequently used group of antibiotics for combination therapy was aminoglycosides in 37 cases, in which an efficacy rate of 62.2%, a higher rate than the efficacy rate of 48.5% for all the combination therapy cases, was obtained. In 16 cases in which penicillins were used as combination drug, the efficacy rate obtained was low, 31.3%. Efficacy rates obtained for cases with different neutrophil counts at the start of therapies were as follows: 52.2% in 23 cases with neutrophil counts below 100/mm3, 46.2% in 13 cases with neutrophil counts between 100 and 499/mm3 and 51.3% in 39 cases with neutrophil counts equal to or above 500/mm3, thus no significant differences in efficacy rates were observed for patients with different neutrophil counts. These results appear to suggest that CBPZ, alone or in combination with other antibiotic such as aminoglycosides, may be quite useful in the treatment of severe infections in patients with hematological disorders.

Role of new cephamycins in the management of obstetric and gynecologic infections.

The results of in vitro and in vivo studies of cefmetazole, a second-generation cephamycin, were reviewed. Cefmetazole's spectrum of activity includes clinical coverage of many Enterobacteriaceae, staphylococci, streptococci, Haemophilus species, pathogenic Neisseria organisms, Moraxella (Branhamella) catarrhalis and anaerobic bacteria. Cefmetazole is generally two to eight times more potent than cefoxitin against organisms within their spectra and is most active against staphylococci (minimal inhibitory concentration90 = 2.0 micrograms/mL). Methicillin-resistant Staphylococcus aureus strains are more susceptible to cefmetazole, alone or in combination with fosfomycin, than to any other cephamycins, and cefmetazole is remarkably resistant to the beta-lactamases produced by aerobic and anaerobic bacteria. The incidence of adverse drug reactions is low (8.8% in the United States, 2.2% in Japan), and the drug has been demonstrated to have cost-containment potential.