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.

[Drug-induced immune hemolytic anemia caused by cefmetazole].

A 56-year-old female who was diagnosed with acute calculous cholecystitis received intravenous administration of cefmetazole (CMZ) from the day of admission; she underwent laparoscopic cholecystectomy on the 13th hospital day. She was referred to our department because of hematuria that persisted for 3 days and progressive anemia on the day after the surgery. Laboratory data showed the following results: hemoglobin (Hb) level, 6.8 g/dl; reticulocyte count, 3.4%; serum lactate dehydrogenase, 1,505 IU/l; serum creatinine, 1.1 mg/dl; and undetectable haptoglobin. The direct globulin test showed that the patient was positive for IgG. Thus, drug-induced immune hemolytic anemia (DIIHA) was considered. All drugs, including CMZ, were immediately discontinued, and steroid was administered. The signs of hemolysis began to subside 3 days after the initiation of steroid therapy, and the administration of steroid was discontinued on the 5th day of the treatment. The patient's Hb level gradually increased, and the direct globulin test showed that the patient was negative for IgG on the 21st day from the onset of hematuria. Antibodies against CMZ-coated red blood cells were observed in the serum preserved at the onset of hemolysis. DIIHA is a rare but life-threatening disease. Immediate discontinuation of any suspected drugs and the initiation of steroid therapy as necessary are important in cases wherein DIIHA is suspected.

[The clinical efficacy and safety of intravenous cefmetazole in treatment of 1,522 patients with aspiration pneumonia].

OBJECTIVE: To evaluate the efficacy and safety of intravenous cefmetazole in the treatment of patients with aspiration pneumonia. METHODS: A multicenter, prospective and open-labeled trial was conducted. A total of 1522 patients were enrolled at the beginning, and only 1324 were evaluated at the endpoint. The duration of treatment was 7 - 14 days. During the treatment and follow-up periods, we recorded any unexpected symptoms and abnormal laboratory tests. At last, we evaluated its efficacy and safety. RESULTS: The total effective rate of cefmetazole was 79.8%(1056/1324). The total bacterial eradication rate was 75.0% (342/456). The bacterial eradication rates of Klebsiella pneumonia, Escherichia, Staphylococcus aureus and anaerobic bacteria were 78.2% (97/124), 80.8% (80/99), 89.0% (81/91), 9/11, respectively. CONCLUSIONS: Cefmetazole is effective and safe in the treatment of aspiration pneumonia.

Cefpirome sulphate for gynaecological infections and prophylaxis of non-laparotomy surgery in patients with benign disease.

We organized a study group to conduct a clinical trial in patients with various gynaecological infections, and we also assessed the efficacy of a single dose of cefpirome sulphate as prophylaxis after vaginal hysterectomy. Cefpirome sulphate (CROM) was administered to 100 patients with gynaecological infections and the clinical and antibacterial efficacy was evaluated in 88 patients. The improvement rate was 77.0% (67/87) and the bacterial eradication rate 67.8% (40/59). Nineteen of the 210 patients enrolled in the comparison of CROM with cefmetazole sodium (CMET) prophylaxis developed postoperative infections. The incidence of infection showed no significant difference between the CROM group (n=11, 10.6%) and the CMET group (n=8, 7.5%) (P=0.56). Although these results suggest that CROM may be effective for the treatment of gynaecological infections and has a good safety profile, it was not superior to CMET as prophylaxis in women undergoing non-laparotomy procedures at our hospital.

Hypoprothrombinemia associated with cefmetazole.

OBJECTIVE: To report a case of hypoprothrombinemia associated with the use of cefmetazole sodium, define patients at risk for this adverse effect, and identify options to prevent this problem. CASE SUMMARY: A malnourished patient with endstage renal disease received cefmetazole following a below-the-knee amputation of the right leg. Three days later, a prothrombin time (PT) and an international normalized ratio (INR) were obtained and were markedly elevated from baseline; however, the patient had no clinical symptoms of bleeding. Cefmetazole was discontinued. Vitamin K and fresh frozen plasma were administered. The PT and INR normalized within 24 hours and remained normal throughout the remainder of hospitalization. DISCUSSION: The incidence of hypoprothrombinemia associated with cefmetazole reported in the literature is conflicting and not consistent. There are three proposed mechanisms of cephalosporin-associated hypoprothrombinemia, two of which involve the N-methylthiotetrazole (NMTT) chain. The most plausible mechanism is NMTT inhibition of vitamin K epoxide reductase in the liver. Patients at an increased risk for this adverse event include those with low vitamin K stores, specifically patients who are malnourished, with low albumin concentrations and poor food intake. The elderly and patients with liver or renal dysfunction are examples of populations at risk. CONCLUSIONS: Hypoprothrombinemia may occur with cephalosporins and is especially problematic with those containing an NMTT side chain. Clinicians need to identify patients at risk for developing antibiotic-associated hypoprothrombinemia, monitor them closely, and give vitamin K as prophylaxis accordingly.

[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.

[Clinical value of cefmetazole and other cephamycin antibiotics]. / Klinicheskoe znachenie tsefmetazola i drugikh cefamitsinovykh antibiotikov.

The review is concerned with the description of the antibiotics belonging to cephamycins. The data on the chemical structure of cefmetazole and other cephamycins and the mechanisms of their action are presented. The peculiarities of the binding to penicillin-binding proteins and the stability to the action of various beta-lactamases are discussed. The spectrum of the antibacterial activity of cefmetazole against gram-positive and gram-negative aerobes and anaerobes, as well as the antibiotic pharmacokinetics is described. The literature data on the clinical efficacy of cefmetazole in the treatment of infectious diseases of various etiology and localization and the data on the drug tolerance and the incidence of adverse reactions are summarized. The indications to the use of cefmetazole and other cephamycins are substantiated.

[Problems of rational chemotherapy and the role of cefmetazole in their solution]. / Nekotorye problemy ratsional'noi khimioterapii i rol' cefmetazola v ikh reshenii.

The paper presents an analysis of the most actual problems of modern antibacterial chemotherapy: mechanisms and distribution of resistance in the most significant clinical gram-positive and gram-negative organisms. Approaches to their solution based on the use of cefmetazole and other cephamycins are indicated.

[Effectiveness of cefmetazole in treatment of wound infection]. / Effektivnost' tsefmetazola pri lechenii ranevoi infektsii.

The cefmetazole efficacy was studied in an open non-comparative clinical trial in the treatment of 40 patients with wound infections. The clinical results were excellent and good in 90 per cent of the cases. In 2.5 per cent of the cases the treatment failed. In 7.5 per cent of the cases the results could not be evaluated. The bacteriological efficacy of cefmetazole was equal to 80 per cent. The drug tolerance was good and only in 3 patients allergic reactions were observed. No hepatotoxic or nephrotoxic effects were recorded. The results were indicative of the advisability of the cefmetazole use in the treatment of wound infections.

[Effectiveness of cefmetazole in treatment of lower respiratory tract infections]. / Effektivnost' tsefmetazola pri lechenii infektsii nizhnikh dykhatel'nykh putei.

The efficacy of cefmetazole was studied in an open non-comparative clinical trial comprising 40 patients with infections of the lower respiratory tracts. The clinical efficacy of cefmetazole was excellent and good in 85 per cent of the cases. The bacteriological efficacy amounted to 75 per cent. Adverse reaction due to the treatment with cefmetazole in 6 patients (15 per cent) were recorded. The adverse reactions were not severe, did not require any special treatment or prolongation of the hospitalization term. The use of cefmetazole in the treatment of infections of the lower respiratory tracts was shown to be advisable.

[Effectiveness of cefmetazole in the treatment of infectious-inflammatory urologic diseases]. / Effektivnost' tsefmetazola pri lechenii infektsionno-vospalitel'nykh urologicheskikh zabolevanii.

An open non-comparative clinical trial of cefmetazole in the treatment of 40 patients with infections of the lower and upper urinary tracts was performed. The clinical results were excellent and good in 100 per cent of the cases. In 75 per cent of the cases the efficacy was bacteriological (complete eradication of the pathogen). No patients showed any adverse reactions to the treatment with cefmetazole. The general estimate of the results was indicative of the cefmetazole high efficacy in the treatment of the infections of the upper and lower urinary tracts.

[Effectiveness of cefmetazole in the treatment of puerperal pyo-septic diseases]. / Effektivnost' tsefmetazola pri lechenii poslerodovykh gnoino-septicheskikh zabolevaii.

An open non-comparative clinical trial of cefmetazole in the treatment of 40 females with postnatal purulent septic diseases was performed. Excellent and good clinical efficacy of cefmetazole was observed in 100 per cent of the cases. The bacteriological efficacy also equaled 100 per cent. No severe side effects of cefmetazole were recorded. The use of cefmetazole was shown to be advisable in the treatment of postnatal purulent septic diseases.

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.

Cefmetazole sodium: pharmacology, pharmacokinetics, and clinical trials.

Cefmetazole sodium is a semisynthetic cephamycin antibiotic. It has a broad spectrum of activity comparable to that of the second-generation cephalosporins, covering gram-positive, gram-negative, and anaerobic bacteria. Unlike the second-generation cephalosporins, cephamycins such as cefmetazole are usually active against Bacteroides fragilis. Cefmetazole is also active against beta-lactamase-producing organisms that are resistant to first-generation cephalosporins or penicillins. The pharmacokinetics of cefmetazole allow parenteral administration (intravenous or intramuscular) 2-3 times daily for treatment of infection. The drug has been studied in gynecologic, intraabdominal, urinary tract, respiratory tract, and skin and soft tissue infections. Administered preoperatively, it may reduce the frequency of infection in certain clean-contaminated or potentially contaminated procedures, including cesarean section, abdominal or vaginal hysterectomy, cholecystectomy (high-risk patients), and colorectal surgery. On the basis of in vitro spectrum, pharmacokinetics, and data from a relatively small number of clinical trials, this agent may be considered when a second-generation cephalosporin is indicated.

Therapeutic dilemmas in the treatment of pelvic infections.

The identification of pathogens and the early recognition of pelvic infections in patients after hysterectomy, cesarean delivery and vaginal delivery were analyzed. Criteria for administering cephamycin therapy were established, as were guidelines for evaluating the progress of the infection. In a comparative study of the safety and efficacy of cefmetazole and cefoxitin in 145 hospitalized patients with pelvic infections there were no significant differences between either the bacteriologic or clinical cure rates of the two antibiotics. Both were efficacious and safe for the treatment of obstetric-gynecologic soft tissue infections.

Cefmetazole (CS-1170), a "new" cephamycin with a decade of clinical experience.

In vitro and in vivo study results were reviewed from cefmetazole, a "new" parenteral cephamycin. Cefmetazole's spectrum of activity was comparable to that of second-generation cephalosporins, which includes clinical coverage of many Enterobacteriaceae, Staphylococcus spp., streptococci, Haemophilus spp., pathogenic Neisseria, Branhamella catarrhalis, and anaerobic bacteria. Cefmetazole was generally more potent (two- to eightfold) than cefoxitin against organisms within their spectrums and was particularly active for staphylococci (MIC90, 2.0 micrograms/ml). Methicillin-resistant S. aureus strains were more susceptible to cefmetazole alone or in combination (fosfomycin) than any other cephamycin. Cefmetazole has demonstrated excellent stability to aerobic and anaerobic organism-produced beta-lactamases. It also inhibits Type I cephalosporinases and, uniquely, some other cephalosporinases produced by the Bacteroides. This superior stability, enzyme interaction, and better penetration into bacterial cells results in a sustained bactericidal effect and a capacity for more infrequent dosing. The cefmetazole serum elimination half-life was 1.5 hr, also justifying use at greater than or equal to 8-hr intervals. Clinical trials in the United States and Japan demonstrated an acceptably high cefmetazole infection cure rate (88% to 100%), especially in direct comparative studies with cefoxitin. Cefmetazole was also proven very effective in minimizing infectious wound morbidity (prophylaxis) using 2 g single- or multidose regimens. Adverse drug reactions were usually minor; in the Japanese surveillance trial (118,318 patients) the rate was only 2.2% (8.8% in United States). Cefmetazole has been extensively and safely used in Japan since 1980.

[Antibiotics-induced agranulocytosis. Patient's IgG inhibits a GM colony formation].

The pathogenesis of Cefmetazole (CMZ) induced agranulocytosis was investigated in the case of a 40-year-old man who developed agranulocytosis while he was under treatment with CMZ. Although concentration of CMZ in serum is not detected, patient's serum drawn at the time of diagnosis suppressed normal allogeneic marrow GM colonies in vitro. Normal IgG purified from serum had no effect on GM colony formation in vitro. However, patient's IgG purified from serum drawn at the time of diagnosis suppressed normal allogeneic marrow GM colony in vitro without CMZ. These studies suggest that CMZ-induced agranulocytosis is immunologically mediated through an IgG inhibitor which seems to exert its effect on GM colony formation.