brl-28500 and Hemorrhagic-Disorders

Sixty-four severe infections in hospitalized patients were treated with intravenous Timentin. Most patients (mean age: 50.5 years, range 18-85) had serious underlying conditions such as agranulocytosis, heart failure, cancer, diabetes mellitus, chronic alcoholism or other functional or anatomical abnormalities. Forty-three episodes were bacteriologically proved, and bacteraemia was diagnosed in 18. The sites of infection were: lower respiratory tract (10), upper respiratory tract (10), soft tissues (9), urinary tract (7), bones (6), peritoneal cavity (3), meninges (1) and pelvis (1). In addition, 13 episodes of fever and four of septicaemia in patients with agranulocytosis were treated with Timentin plus amikacin. Overall, 59% of the episodes were cured, 14% improved and 17% failed to respond. In 9% of cases the efficacy of the Timentin was unassessable mainly because of concurrent administration of other antimicrobials. Failure appeared to be more frequent in soft tissue and intra-abdominal infections, in patients infected with bacteria susceptible to Timentin but resistant to ticarcillin and in patients superinfected with Timentin-resistant strains. Major side effects were haemorrhagic diathesis with platelet dysfunction (1), severe water sodium overload (1), and possibly pancreatitis (1). Other side effects were mild: catheter-related phlebitis, and abnormal but clinically insignificant laboratory test results. Timentin appears to be an effective and safe broad-spectrum combination which compares favourably with third-generation cephalosporins in the treatment of severe hospital infections. More experience is needed to decide whether the somewhat lower response rate in patients infected with ticarcillin-resistant strains is significant.

Topics: Acute Disease; Adolescent; Adult; Aged; Amikacin; Bacteria; Bacterial Infections; Clavulanic Acids; Cross Infection; Drug Combinations; Drug Evaluation; Drug Therapy, Combination; Female; Hemorrhagic Disorders; Humans; Male; Middle Aged; Pancreatitis; Penicillin Resistance; Penicillins; Ticarcillin

Fifty patients were treated for suspected serious bacterial infection with Timentin 3.2 g 6-8-hourly. Three patients did not complete a minimum of 48 h treatment. Pathogens were isolated from 28 of the remaining 47 patients; 13 were resistant to ticarcillin but fully sensitive to Timentin; six of these isolates were Staphylococcus aureus. Five of the patients with Timentin-sensitive organisms or no significant growth failed to respond or relapsed after Timentin but also failed on subsequent therapy. An additional patient relapsed because of inadequate duration of treatment and one patient, with salmonella enteritis, became an asymptomatic carrier. The Timentin-resistant organisms were a Pseudomonas aeruginosa which responded to ceftazidime, a Klebsiella pneumoniae which was of doubtful clinical significance and an Escherichia coli which caused a relapse of pyelonephritis 16 days after apparently successful treatment with Timentin. No serious adverse reactions were seen. Timentin was effective against ticarcillin-resistant organisms but its final role will depend on the prevalence and significance of in-vitro resistance to the combination amongst Enterobacteriaceae and pseudomonads.

Topics: Adolescent; Adult; Aged; Bacteria; Bacterial Infections; Clavulanic Acids; Drug Combinations; Drug Evaluation; Hemorrhagic Disorders; Humans; Liver Function Tests; Middle Aged; Penicillin Resistance; Penicillins; Ticarcillin

The safety and tolerance of four intravenous formulations of Timentin (ticarcillin + clavulanic acid) have been evaluated in 1659 patients (1512 adults and 147 paediatric) included in clinical trials conducted in Europe and U.S.A. Timentin 3.2 and 5.2 g were administered respectively to 877 and 635 adults and Timentin 1.6 and 2.6 g to 117 and 30 paediatric patients three, four or six times daily for between 7.7 and 9.0 days in adults and 8.0 and 12.0 days in paediatric cases. Patients with septicaemia were 16%, 14% and 28% respectively of the Timentin 3.2, 5.2 g and paediatric groups, which together with respiratory tract and other serious miscellaneous infections accounted for the majority of cases treated within these three groups. Of the 1659 patients studied, 161 adverse reactions were reported from 151 patients (9.1%), 36 of which (2.2%) resulted in discontinuation of treatment. The reactions were at the injection site in 86 cases (5.2%), hypersensitivity in 35 (2.1%) and miscellaneous systemic symptoms in 40 cases (2.4%). Local reactions, i.e. phlebitis, pain and erythema, were self-limiting and did not necessitate early cessation of treatment. Hypersensitivity reactions occurred equally in all groups and necessitated cessation of treatment in about half of the patients. Gastro-intestinal disturbances were observed in eight, four and one patient within the Timentin 3.2, 5.2 g and paediatric groups. Changes in haemostatic status were reported in nine patients treated with Timentin. In all cases they were associated with contributory pathology and/or concurrent use of anticoagulants. Laboratory monitoring revealed transient variations in haemoglobin, blood cellular or plasma composition and plasma enzymatic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Child, Preschool; Clavulanic Acids; Cross Infection; Drug Combinations; Drug Evaluation; Drug Hypersensitivity; Female; Gastrointestinal Diseases; Hemorrhagic Disorders; Humans; Infant; Infant, Newborn; Male; Middle Aged; Penicillins; Phlebitis; Sepsis; Ticarcillin

Clavulanate potentiated ticarcillin contains two components with an established safety record. Ticarcillin used clinically alone and with clavulanate, a component of clavulanate potentiated amoxycillin, given orally or intravenously. No pharmacokinetic interaction occurs between the two components when given together in man or animals in which metabolism is qualitatively similar to man. Safety evaluation studies carried out in the animals established as suitable for studying the toxicology of ticarcillin have shown no unexpected synergistic or antagonistic toxic effects of Timentin not predicted from the toxicological evaluation of clavulanate alone. Reproductive mutagenic, cardiovascular and general pharmacological studies have shown no significant hazard from Timentin. Clinical experience with ticarcillin has been reviewed, and impairment of platelet function, seen at supratherapeutic doses, has been shown in an animal model not to be influenced by clavulanate. The assessment of the safety of ticarcillin and clavulanate for therapeutic use in man is thus comprised of the clinical experience with ticarcillin and parenteral clavulanate in clavulanate potentiated amoxycillin, animal safety evaluation studies, and the clinical experience with Timentin reported in this symposium.

Topics: Animals; Chemical and Drug Induced Liver Injury; Clavulanic Acids; Dogs; Drug Combinations; Drug Evaluation, Preclinical; Female; Guinea Pigs; Hemorrhagic Disorders; Humans; Kinetics; Lethal Dose 50; Male; Mice; Penicillins; Platelet Aggregation; Pregnancy; Rats; Reproduction; Ticarcillin