Pharmacokinetics and Tolerability of Single and Multiple Intravenous Doses of Cefotetan Disodium in Healthy Chinese Volunteers.

BACKGROUND: Cefotetan is highly stable to penicillinase and cephalosporin produced by gram-negative bacteria, and it has strong antimicrobial activity against most gram-negative bacteria, some anaerobic bacteria and streptococcus. The objective of this study was to evaluate the pharmacokinetic profile and tolerability of single and multiple intravenous doses of cefotetan disodium in healthy Chinese volunteers. METHODS: In this single-center, open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1 h intravenous infusion. After completion of the single-dose phase, subjects continued into the multiple-dose phase, in which they received 1.0 g cefotetan disodium BID for 7 consecutive days. Plasma samples were assayed by a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Tolerability was assessed based on physical examinations, vital signs, laboratory tests, and subject interviews. RESULTS: After intravenous administration of single doses of 0.5, 1.0, and 2.0 g cefotetan disodium, the pharmacokinetics of cefotetan were as follows: Cmax was 69.49±12.10 µg·mL-1, 132.03±22.56 µg·mL-1 and 237.75±42.12 µg·mL-1, respectively; AUClast was 278.29±51.13 µg·mL-1·h, 543.25±92.44 µg·mL-1·h and 1003.8±172.39 µg·mL-1·h, respectively; AUC∞ was 284.42±50.76 µg·mL-1·h, 551.38±95.83 µg·mL-1·h and 1020.18±181.19 µg·mL-1·h, respectively; t1/2 was 4.21±0.83 h, 4.39±0.53 h and 4.27±0.74 h, respectively; CL was 1.81±0.33 L·h-1, 1.86±0.32 L·h-1 and 2.02±0.38 L·h-1, respectively; Vd was 10.80±1.89L, 11.78±2.20L and 12.25±1.99L, respectively. In the multiple-dose study, the pharmacokinetics of cefotetan were as follows: Cmax,ss was 147.58±22.71 µg·mL-1; Cmin,ss was 12.92±3.70 µg·mL-1; Cavg was 45.10±7.78 µg·mL-1; AUCτ,ss was 541.15±93.36 µg·mL-1·h; AUC∞ was 612.06±114.23 µg·mL-1·h; t1/2 was 4.30±0.63 h; CL was 1.90±0.35L·h-1; Vd was 8.91±1.57L; DF was 300.92±33.28%; Accumulation Index was 1.17±0.05. No serious adverse events were reported. Adverse events were generally mild. CONCLUSION: Cefotetan disodium showed favorable tolerability in this study. The Cmax and AUCs of cefotetan disodium demonstrated dose-dependent pharmacokinetic characteristics after single dose over a dose range (0.5-2.0 g) in healthy subjects, whereas the t1/2 was independent of dose. Except for Vd, there was no difference in other pharmacokinetic parameters between multiple and single administration.

Cefotetan-Induced Hemolytic Anemia: Case Series and Review.

PURPOSE: To raise awareness of cefotetan-induced hemolytic anemia, a known rare but serious side effect that occurred in 5 patients at our medical center. SUMMARY: Five cases of cefotetan-induced hemolytic anemia, which presented over the period of a single year at our center, are described. In each case, hemolytic anemia was confirmed by testing for the presence of anti-cefotetan antibodies. Each case occurred approximately 1 to 2 weeks following exposure to the drug. All five patients survived. A brief review of drug-induced immune hemolytic anemia (DIIHA) is also discussed. CONCLUSION: DIIHA may be difficult to distinguish from other causes of hemolytic anemia, but should be included in the differential in patients exposed to medications associated with DIIHA. Once suspected, antibody testing should be performed, and once diagnosed, further exposure should be avoided.

Maternal anaphylactic shock in pregnancy: A case report.

RATIONALE: Anaphylaxis is a very rare event in pregnancy, triggering maternal hypotension leading to intrapartum hypoxic-ischemic encephalopathy in infant. Furthermore, cesarean sections are performed at a high rate in anaphylactic pregnant women. PATIENT CONCERNS: A 34-year-old pregnant woman presented with maternal anaphylaxis following prophylactic antibiotic injection for cesarean section. Within a few minutes after initiation of intradermal skin test with cefotetan, the pregnant woman developed generalized itchy rash, chest tightness, and dyspnea. DIAGNOSES: Several minutes after the injection of antibiotics, a diffuse urticarial rash was detected over her face and trunk followed by complaints of chest tightness and dyspnea. She was diagnosed with hypotension and hypoxia. Further, fetal heart tones showed bradycardia. A presumptive diagnosis of anaphylactic reaction induced by cefotetan was made for surgical prophylaxis. INTERVENTIONS: The patient was managed for anaphylaxis, via administration of epinephrine, glucocorticoid, and antihistamine. Emergency cesarean section performed under general anesthesia resulted in a favorable perinatal outcome for the fetus. OUTCOMES: Maternal and fetal outcomes were good after prompt treatment for anaphylaxis and emergency cesarean section. LESSONS: This is the first reported case of anaphylaxis following cefotetan administration in pregnancy. Cefotetan, a second-generation cephalosporin, is a commonly prescribed antibiotic used to treat a wide range of bacterial infections. The case demonstrated life-threatening anaphylactic reaction during pregnancy. Even a skin test using antibiotics alone triggered anaphylaxis.

Higher versus Lower Dose of Cefotetan or Cefoxitin for Surgical Prophylaxis in Patients Weighing One Hundred Twenty Kilograms or More.

BACKGROUND: Clinical practice guidelines recommend a 2-g dose of cefotetan and cefoxitin for surgical prophylaxis. Pharmacokinetic data suggest benefit from higher cefotetan and cefoxitin dosing in obese patients. However, clinical studies examining higher dosing strategies in this at-risk population are lacking. The purpose of this study was to determine whether 3 g of cefotetan or cefoxitin administered pre-operatively for patients who weigh 120 kg or more is associated with a lower proportion of surgical site infection (SSI) compared with 2 g. PATIENTS AND METHODS: Medical records of patients weighing 120 kg or more who had received cefotetan or cefoxitin (2 or 3 g) as surgical prophylaxis for intra-abdominal procedures between July 2012 and August 2015 were reviewed for the development of an SSI (primary outcome), study drug-related adverse events, and re-admissions attributed to SSIs (secondary outcomes). Relative risk calculations were performed for analysis of the primary and secondary outcomes. RESULTS: One-hundred seventy-five procedures in 169 patients were included in the study. Cefotetan was used in 81% (141/175) of procedures. Three grams of cefotetan or cefoxitin was used in 20% (35/175) of procedures. The median body mass index (BMI) in both dosing groups was 42 kg/m2 and patients who received 3 g more often weighed more than 130 kg (relative risk [RR] 1.36, 1.01-1.76; p = 0.04). Surgical site infections occurred in 20.7% within the 2-g group and 22.9% in the 3-g group (RR 1.10, 0.55-2.20; p = 0.78). There was no difference in the number of study drug-related adverse effects in the 3-g compared with the 2-g group. Thirty-day re-admissions because of SSI also did not differ between the 2-g and 3-g groups (7.9% vs. 17.1%, respectively; p = 0.11). CONCLUSION: This small retrospective study did not find a difference in SSI rates between 3-g and 2-g surgical prophylaxis dosing for patients 120 kg or more with a median BMI >40 kg/m2.

Immune hemolytic anemia caused by drugs.

INTRODUCTION: Drug-induced immune hemolytic anemia (DIIHA) is a rare cytopenia; about 130 drugs have been incriminated. The antibodies causing DIIHA can be i) drug-independent (drug not needed to be present to detect antibodies in vitro)-DIIHA caused by this type of antibody presents clinically and serologically as an autoimmune hemolytic anemia (AIHA) with red cell (RBC) autoantibodies in patients' sera and in eluates from their RBCs; or (2) drug-dependent (antibodies react in vitro with RBCs only in the presence of drug, on the RBC membrane or when added to the patient's plasma and RBCs). AREAS COVERED: Literature is reviewed regarding pathophysiology of DIIHA (mechanisms; incidence of drugs involved; the clinical, hematological, and serological characteristics of the most common antibodies causing DIIHA). EXPERT OPINION: DIIHA is often poorly investigated and many reports do not provide data to support the diagnosis (i.e., no serology to support an immune etiology). The three most common drugs currently causing DIIHA are piperacillin, cefotetan, and ceftriaxone. All three (especially piperacillin) can cause in vitro and in vivo effects mimicking AIHA, and in transfused patients, hemolytic transfusion reactions. It is important to exclude DIIHA in such patients as the only treatment needed is to discontinue the drug.

Pharmacokinetics and tolerability of intravenous cefotetan disodium for injection in healthy Chinese volunteers: A randomized, open-label, single- and multiple-dose study.

BACKGROUND: Cefotetan disodium for injection is a semisynthetic cephamycin antibiotic that exerts its bactericidal effects by inhibition of cell-wall synthesis. Despite being widely used in the treatment of various infections, little information is available on the pharmacokinetic properties of cefotetan disodium in Chinese subjects. OBJECTIVES: This study evaluated the pharmacokinetics of single and multiple intravenous doses of a generic formulation of cefotetan disodium in healthy Chinese volunteers. The effect of sex on the pharmacokinetics of cefotetan disodium was evaluated as a secondary objective. METHODS: In this open-label, dose-escalating study, subjects were randomized to receive a single dose of cefotetan disodium 0.5, 1.0, or 2.0 g administered as a 1-hour intravenous infusion. Those allocated to the 1.0-g dose continued into the multiple-dose phase, in which they received 1.0 g BID for 7 consecutive days. During the single-dose phase, blood samples were collected at regular intervals from 0 to 15 hours after drug administration and were analyzed using a validated HPLC method. During the multiple-dose phase, blood samples were obtained before drug administration on days 5, 6, and 7 to determine the C(min) at steady state; on day 7, blood samples were also collected from 0 to 15 hours after drug administration. Tolerability was assessed based on physical examinations, vital signs, laboratory tests (hematology, biochemistry, hepatic and renal function, and urinalysis), and subject interviews. RESULTS: Three groups, each consisting of 5 men and 5 women, were enrolled in the single-dose phase. The mean (SD) age of subjects was 23.2 (2.2) years (range, 19-30 years). Their mean weight was 57.0 (6.3) kg (range, 46.4-72.0 kg), and their mean height was 1.66 (0.08) m (range, 1.48-1.81 m). After intravenous administration of single doses of 0.5, 1.0, and 2.0 g, the cefotetan disodium C(max) was 35.01 (6.98), 76.67 (10.52), and 154.33 (27.17) mg/L, respectively; the AUC0₋15(h) was 145.35 (18.36), 307.45 (33.07), and 746.09 (103.07) mg · h/L; the AUC0₋(∞) was 171.51 (20.61), 347.25 (44.20), and 843.84 (131.13) mg · h/L; the t(1/2) was 5.80 (1.29), 4.91 (1.15), and 5.04 (1.26) hours; the CL was 2.96 (0.41), 2.92 (0.39), and 2.42 (0.39) L/h; and the V(d) was 24.55 (5.19), 20.37 (3.66), and 17.30 (3.52) L. After administration of multiple doses, the cefotetan disodium C(max,ss) was 80.53 (10.04) mg/L; the C(mix,ss) was 11.00 (4.04) mg/L; the AUC(ss) was 347.92 (50.04) mg · h/L; the steady-state plasma concentration was 28.99 (4.17) mg/L; the t(1/2) was 6.24 (2.52) hours; the CL was 2.32 (0.64) L/h; and the Vd was 19.19 (4.58) L. No significant differences in pharmacokinetic parameters were noted by sex in the multiple-dose phase. Cefotetan disodium appeared to be well tolerated. CONCLUSIONS: In these healthy Chinese subjects, the cefotetan disodium AUC and C(max) increased in a dose-proportional manner, whereas the t(1/2) was independent of dose. The pharmacokinetic properties of cefotetan disodium were linear at doses of 0.5 to 2.0 g. After multiple doses, the pharmacokinetic parameters of cefotetan disodium were consistent with those after single doses. At the doses studied, cefotetan disodium appeared to be well tolerated in these healthy volunteers.

One center's experience: the serology and drugs associated with drug-induced immune hemolytic anemia--a new paradigm.

BACKGROUND: Drug-induced immune hemolytic anemia (DIIHA) is an uncommon finding characterized by a sudden decrease in hemoglobin after treatment with the putative drug. The full range of drugs causing DIIHA and the initial serologic presentation are not fully appreciated. This work identifies additional drugs associated with DIIHA and offers additional insights about diagnosis. STUDY DESIGN AND METHODS: A 20-year retrospective review of testing in one laboratory was performed. Patient sex, age, medication history, initial direct antiglobulin test (DAT) and indirect antiglobulin test, method of drug-dependent antibody (DDA) detection, and specificity were reviewed. RESULTS: Seventy-one patients with 73 DDAs to 23 different drugs were identified. The following DDA specificities were identified: cephalosporins (37), penicillin and/or penicillin derivatives (12), nonsteroidal anti-inflammatory drugs (NSAIDs) (11), quinine and/or quinidine (7), and others (6). Fifty-two percent (37) were due to cephalosporins with 27 cefotetan-dependent antibodies detected. Four NSAIDs required urinary metabolite for detection. DAT was strongly positive, at least 2+, in 75 percent (51/68) of patients with a positive DAT. Initial eluate was negative in 52 patients, weak positive (<2+) in 14 patients, and strong positive (>or=2+) in 2 patients. Serologic results showed characteristics of warm autoimmune hemolytic anemia (AIHA) in 22 or 31 percent of all cases and cold-reactive AIHA in 2 cases. CONCLUSIONS: It is important to consider DIIHA when a patient serologically presents as either warm- or cold-type AIHA to avoid erroneous diagnosis. Based on these findings, the strength of the initial DAT is much stronger than previously reported for all types of drug-induced immune hemolysis. This report is also unique in the number of NSAIDs reported. A new classification of categorizing DDA is proposed.

Ertapenem versus cefotetan prophylaxis in elective colorectal surgery.

BACKGROUND: Ertapenem, a long-acting carbapenem, may be an alternative to the recommended prophylactic antibiotic cefotetan. METHODS: In this randomized, double-blind trial, we assessed the efficacy and safety of antibiotic prophylaxis with ertapenem, as compared with cefotetan, in patients undergoing elective colorectal surgery. A successful outcome was defined as the absence of surgical-site infection, anastomotic leakage, or antibiotic use 4 weeks postoperatively. All adverse events were collected until 14 days after the administration of antibiotic prophylaxis. RESULTS: Of the 1002 patients randomly assigned to study groups, 901 (451 in the ertapenem group and 450 in the cefotetan group) qualified for the modified intention-to-treat analysis, and 672 (338 in the ertapenem group and 334 in the cefotetan group) were included in the per-protocol analysis. After adjustment for strata, in the modified intention-to-treat analysis, the rate of overall prophylactic failure was 40.2% in the ertapenem group and 50.9% in the cefotetan group (absolute difference, -10.7%; 95% confidence interval [CI], -17.1 to -4.2); in the per-protocol analysis, the failure rate was 28.0% in the ertapenem group and 42.8% in the cefotetan group (absolute difference, -14.8%; 95% CI, -21.9 to -7.5). Both analyses fulfilled statistical criteria for the superiority of ertapenem. In the modified intention-to-treat analysis, the most common reason for failure of prophylaxis in both groups was surgical-site infection: 17.1% in the ertapenem group and 26.2% in the cefotetan group (absolute difference, -9.1; 95% CI, -14.4 to -3.7). In the treated population, the overall incidence of Clostridium difficile infection was 1.7% in the ertapenem group and 0.6% in the cefotetan group (P=0.22). CONCLUSIONS: Ertapenem is more effective than cefotetan in the prevention of surgical-site infection in patients undergoing elective colorectal surgery but may be associated with an increase in C. difficile infection. (ClinicalTrials.gov number, NCT00090272 [ClinicalTrials.gov].).

Radiation recall dermatitis with cefotetan: a case study.

Radiation recall dermatitis (RRD) is an inflammatory skin reaction that occurs in a previously irradiated body part following drug administration. This phenomenon may occur from days to years following exposure to ionizing radiation. The case of a 54-year-old Caucasian woman who was initially treated with external-beam radiation to the right thoracic region following the diagnosis of a poorly differentiated squamous cell carcinoma of the right lung is reported. She received four cycles of consolidated chemotherapy with docetaxel and carboplatin. Four months later, she was admitted to the hospital for acute cholecystitis and was placed on cefotetan. She developed a tender, erythematous rash on the posterior region of her right thorax 48 hours later. The drug was withdrawn, supportive care was instituted, and the patient subsequently improved. RRD should be suspected in patients who develop an erythematous rash in a previously irradiated region. To our knowledge this entity has not been associated with cefotetan previously.

Cefotetan-induced hemolytic anemia after perioperative prophylaxis.

Cephalosporin-induced hemolytic anemia is an acquired form of hemolytic anemia caused by interaction of drug with the immune system. Drug adsorption, drug-dependent antibody, and autoimmune induction are the three mechanisms of hemolysis. Cefotetan-induced hemolytic anemia (CIHA) has been described to occur through all three mechanisms. We report four cases of CIHA that occurred after appropriate perioperative use of cefotetan. All of our patients developed an acute and severe hemolytic episode that caused significant symptoms and led to hospitalization within 1-2 weeks after exposure to cefotetan. The hemolytic process was self-limited, and all our patients responded to supportive measures and blood transfusion. This report adds to our knowledge of CIHA, a rare complication of cefotetan use. Our cases suggest that cefotetan-induced acute severe hemolysis is caused by membrane modification (nonimmunologic protein adsorption) in addition to immune complex formation. Prompt diagnosis and aggressive supportive measures are essential in minimizing morbidity and mortality from hemolysis. Physicians should warn their patients about this complication. Given that hemolysis occurs when the subject is no longer under direct clinical supervision, patient awareness on how to recognize signs and symptoms of hemolysis is paramount to reducing the likelihood of this potentially lethal side effect. Finally, physicians might consider restricting cefotetan use.

Cefotetan-induced immune hemolytic anemia following prophylaxis for cesarean delivery.

Second- and third-generation cephalosporins, notably cefotetan, are increasingly implicated in severe, sometimes fatal immunemediated hemolytic anemia. We describe a 26-year-old woman who developed severe hemolytic anemia 2 weeks after receiving a single prophylactic dose of cefotetan during cesarean delivery. The patient's DAT was weakly reactive for IgG and her serum reacted with cefotetan-coated RBCs. The antibody had a titer of 4,096 by antiglobulin testing. The patient required treatment with two units of PRBCs and experienced gradual resolution of hemolysis. Our case emphasizes the need for increased awareness of delayed onset hemolytic anemia following prophylactic use of cefotetan.

Persistence of cefotetan on red blood cells.

BACKGROUND: Cefotetan can cause severe immune hemolytic anemia that may persist long after the drug is discontinued. To study the binding of cefotetan to RBCs, patients who received cefotetan were followed and tested for the presence of antibody to cefotetan. STUDY DESIGN AND METHODS: Patients receiving cefotetan were identified from pharmacy and nursing records. Blood samples obtained for routine hematology tests were analyzed. Cefotetan binding to patients' RBCs was tested using a previously characterized high-titer anticefotetan serum by gel technique. To determine the minimum amount of drug necessary for binding to occur, RBCs were incubated with serial dilutions of cefotetan at pH 7.4. RESULTS: Sixty patients receiving 1 to 25 g i.v. (median, 2 g) of cefotetan were followed for 1 to 123 days (median, 18 days). All were initially positive, for cefotetan on RBCs. Positivity persisted for up to 98 days after the last dose of drug. Fifteen patients became negative during follow-up. The first negative sample occurred at Day 30 to 123. Using the midpoint between the last positive and first negative to estimate of the duration of positivity, we estimate that cefotetan remains RBC-bound for 16.5 to 92 days (median, 67.5 days). During the follow-up period, five patients developed anticefotetan detectable in the serum. Twenty patients receiving other cephalosporin antibiotics showed no specific reactivity of their RBCs with anticefotetan. In vitro studies showed a minimum necessary drug concentration of 1 micromol/L at physiologic pH, which was not significantly altered by RBC pretreatment with ficin, sialydase, or DTT. CONCLUSIONS: Cefotetan is tightly bound to RBCs after intravenous administration and remains detectable for weeks after the last dose. Antibodies to cefotetan may occur in about 8 percent of patients receiving the drug. The minimum necessary concentration for RBC binding is low compared to an estimated plasma concentration of 240 micromol/L from a single i.v. dose of 1 g.

Clinical and laboratory study of an episode of cefotetan-induced severe hemolytic anemia.

BACKGROUND: Cephalosporins are frequently associated with positive direct antiglobulin tests (DAT) and may rarely cause immune hemolytic anemia (IHA). We describe a patient who developed hemolytic anemia while she was receiving intravenous cefotetan. STUDY DESIGN AND METHODS: Immunohematologic studies of drug-dependent antibodies were performed by using cefotetan-treated red blood cells (RBCs) and untreated RBCs in the presence of cefotetan. RESULTS: The patient's serum contained antibodies that reacted with both drug-coated RBCs (adsorption mechanism) and with uncoated RBCs when cefotetan was added to the serum (immune complex mechanism). The prompt recognition of the problem and discontinuation of the drug prevented the onset of renal failure and rapidly resolved the hemolytic reaction. CONCLUSION: Our report underlines the importance of close laboratory and immunohematologic monitoring of patients treated with cephalosporins in order to recognize swiftly any hemolytic reaction due to these antibiotics thus reducing the chance of serious sequelae.

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.