Timentin Pharmacology, Pharmacokinetics, Studies, Metabolism - Ticarcillin and Clavulanate

Timentin Pharmacology, Pharmacokinetics, Studies, Metabolism - Ticarcillin and Clavulanate

CLINICAL PHARMACOLOGY

After an intravenous infusion (30 min.) of 3.1 grams or 3.2 grams Timentin , peak serum concentrations of both ticarcillin and clavulanic acid are attained immediately after completion of infusion. Ticarcillin serum levels are similar to those produced by the administration of equivalent amounts of ticarcillin alone with a mean peak serum level of 330 µg/mL for the 3.1 gram and 3.2 gram formulations. The corresponding mean peak serum levels for clavulanic acid were 8 µg/mL and 16 µg/mL for the 3.1 gram and 3.2 gram formulations, respectively. (See following table.)

The mean area under the serum concentration curves for ticarcillin was 485 µg.hr./mL for the Timentin 3.1 gram and 3.2 gram formulations. The corresponding areas under the serum concentration curves for clavulanic acid were 8.2 µg.hr./mL and 15.6 µg.hr./mL for the Timentin 3.1 gram and 3.2 gram formulations, respectively.

The mean serum half-lives of ticarcillin and clavulanic acid in healthy volunteers are 1.1 hours and 1.1 hours, respectively, following administration of 3.1 grams or 3.2 grams of Timentin .

In pediatric patients receiving approximately 50 mg/kg Timentin (30:1 ratio ticarcillin to clavulanate), mean ticarcillin serum half-lives were 4.4 hours in neonates (n=18) and 1.0 hour in infants and children (n=41). The corresponding clavulanate serum half-lives averaged 1.9 hours in neonates (n=14) and 0.9 hour in infants and children (n=40). Area under the serum concentration time curves averaged 339 µg.hr./mL in infants and children (n=41), whereas the corresponding mean clavulanate area under the serum concentration time curves was approximately 7 µg.hr./mL in the same population (n=40).

Approximately 60% to 70% of ticarcillin and approximately 35% to 45% of clavulanic acid are excreted unchanged in urine during the first 6 hours after administration of a single dose of Timentin to normal volunteers with normal renal function. Two hours after an intravenous injection of 3.1 grams or 3.2 grams Timentin , concentrations of ticarcillin in urine generally exceed 1500 µg/mL. The corresponding concentrations of clavulanic acid in urine generally exceed 40 µg/mL and 70 µg/mL following administration of the 3.1 gram and 3.2 gram doses, respectively. By 4 to 6 hours after injection, the urine concentrations of ticarcillin and clavulanic acid usually decline to approximately 190 µg/mL and 2 µg/mL, respectively, for both doses. Neither component of Timentin is highly protein bound; ticarcillin has been found to be approximately 45% bound to human serum protein and clavulanic acid approximately 9% bound.

Somewhat higher and more prolonged serum levels of ticarcillin can be achieved with the concurrent administration of probenecid; however, probenecid does not enhance the serum levels of clavulanic acid.

Ticarcillin can be detected in tissues and interstitial fluid following parenteral administration.

Penetration of ticarcillin into bile and pleural fluid has been demonstrated. The results of experiments involving the administration of clavulanic acid to animals suggest that this compound, like ticarcillin, is well distributed in body tissues.

An inverse relationship exists between the serum half-life of ticarcillin and creatinine clearance. The dosage of Timentin need only be adjusted in cases of severe renal impairment. (See DOSAGE AND ADMINISTRATION.)

Ticarcillin may be removed from patients undergoing dialysis; the actual amount removed depends on the duration and type of dialysis.

MICROBIOLOGY:   Ticarcillin is a semisynthetic antibiotic with a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria.

Ticarcillin is, however, susceptible to degradation by (beta)-lactamases and, therefore, the spectrum of activity does not normally include organisms which produce these enzymes.

Clavulanic acid is a (beta)-lactam, structurally related to the penicillins, which possesses the ability to inactivate a wide range of (beta)-lactamase enzymes commonly found in microorganisms resistant to penicillins and cephalosporins. In particular, it has good activity against the clinically important plasmid-mediated (beta)-lactamases frequently responsible for transferred drug resistance.

The formulation of ticarcillin with clavulanic acid in Timentin protects ticarcillin from degradation by (beta)-lactamase enzymes and effectively extends the antibiotic spectrum of ticarcillin to include many bacteria normally resistant to ticarcillin and other (beta)-lactam antibiotics. Thus Timentin possesses the distinctive properties of a broad-spectrum antibiotic and a (beta)-lactamase inhibitor.

While in vitro studies have demonstrated the susceptibility of most strains of the following organisms, clinical efficacy for infections other than those included in the INDICATIONS AND USAGE section has not been documented:

GRAM-NEGATIVE BACTERIA:    Pseudomonas aeruginosa ((beta)-lactamase and non-(beta)-lactamase producing), Pseudomonas species including P. maltophilia ((beta)-lactamase and non-(beta)-lactamase producing), Escherichia coli ((beta)-lactamase and non-(beta)-lactamase producing), Proteus mirabilis ((beta)-lactamase and non-(beta)-lactamase producing), Proteus vulgaris ((beta)-lactamase and non-(beta)-lactamase producing), Providencia rettgeri (formerly Proteus rettgeri ) ((beta)-lactamase and non-(beta)-lactamase producing), Providencia stuartii ((beta)-lactamase and non-(beta)-lactamase producing), Morganella morganii (formerly Proteus morganii ) ((beta)-lactamase and non-(beta)-lactamase producing), Enterobacter species (Although most strains of Enterobacter species are resistant in vitro , clinical efficacy has been demonstrated with Timentin in urinary tract infections caused by these organisms.), Acinetobacter species ((beta)-lactamase and non-(beta)-lactamase producing), Hemophilus influenzae ((beta)-lactamase and non-(beta)-lactamase producing), Branhamella catarrhalis ((beta)-lactamase and non-(beta)-lactamase producing), Serratia species including S. marcescens ((beta)-lactamase and non-(beta)-lactamase producing), Neisseria gonorrhoeae ((beta)-lactamase and non-(beta)-lactamase producing), Neisseria meningitidis *, Salmonella species ((beta)-lactamase and non-(beta)-lactamase producing), Klebsiella species including K. pneumoniae ((beta)-lactamase and non-(beta)-lactamase producing), Citrobacter species including C. freundii, C. diversus and C. amalonaticus ((beta)-lactamase and non-(beta)-lactamase producing).

GRAM-POSITIVE BACTERIA:    Staphylococcus aureus ((beta)-lactamase and non-(beta)-lactamase producing), Staphylococcus saprophyticus, Staphylococcus epidermidis (coagulase-negative staphylococci) ((beta)-lactamase and non-(beta)-lactamase producing), Streptococcus pneumoniae * ( D. pneumoniae ), Streptococcus bovis*, Streptococcus agalactiae* (Group B), Streptococcus faecalis * ( Enterococcus ), Streptococcus pyogenes * (Group A, (beta)-hemolytic), Viridans group streptococci*.

ANAEROBIC BACTERIA:    Bacteroides species, including B. fragilis group ( B. fragilis, B. vulgatus ) ((beta)-lactamase and non-(beta)-lactamase producing), non- B. fragilis ( B. melaninogenicus ) ((beta)-lactamase and non-(beta)-lactamase producing), B. thetaiotaomicron, B. ovatus, B. distasonis ((beta)-lactamase and non-(beta)-lactamase-producing), Clostridium species including C. perfringens, C. difficile, C. sporogenes, C. ramosum and C. bifermentans*, Eubacterium species, Fusobacterium species including F. nucleatum and F. necrophorum*, Peptococcus species*, Peptostreptococcus species*, Veillonella species.

*These are non-(beta)-lactamase-producing strains and therefore are susceptible to ticarcillin alone. Some of the (beta)-lactamase-producing strains are also susceptible to ticarcillin alone.

In vitro synergism between Timentin and gentamicin, tobramycin or amikacin against multiresistant strains of Pseudomonas aeruginosa has been demonstrated.

SUSCEPTIBILITY TESTING:

Diffusion Technique:   An 85 mcg Timentin (75 mcg ticarcillin plus 10 mcg clavulanic acid) diffusion disk is available for use with the Kirby-Bauer method. Based on the zone sizes given below, a report of "Susceptible" indicates that the infecting organism is likely to respond to Timentin therapy, while a report of "Resistant" indicates that the organism is not likely to respond to therapy with this antibiotic. A report of "Intermediate" susceptibility indicates that the organism would be susceptible to Timentin at a higher dosage or if the infection is confined to tissues or fluids (e.g., urine) in which high antibiotic levels are attained.

Dilution Technique:   Broth or agar dilution methods may be used to determine the minimal inhibitory concentration (MIC) values for bacterial isolates to Timentin . Tubes should be inoculated with the test culture containing 10 ⁴ to 10 ⁵ CFU/mL or plates spotted with a test solution containing 10 ³ to 10 ⁴ CFU/mL.

The recommended dilution pattern utilizes a constant level of clavulanic acid, 2 mcg/mL, in all tubes together with varying amounts of ticarcillin. MICs are expressed in terms of the ticarcillin concentration in the presence of 2 mcg/mL clavulanic acid.

CLINICAL STUDIES

Timentin has been studied in a total of 296 pediatric patients (excluding neonates and infants less than 3 months) in six controlled clinical trials. The majority of patients studied had intra-abdominal infections, and the primary comparator was clindamycin and gentamicin with or without ampicillin. At the end-of-therapy visit, comparable efficacy was reported in the Timentin and appropriate comparator arms.

Timentin was also evaluated in an additional 408 pediatric patients (excluding neonates and infants less than 3 months) in three uncontrolled U.S. clinical trials. Patients were treated across a broad range of presenting diagnoses including: infections in bone and joint, skin and skin structure, lower respiratory tract, urinary tract, as well as intra-abdominal and gynecologic infections. Patients received Timentin either 300 mg/kg/day (based on the ticarcillin component) divided q4h for severe infection or 200 mg/kg/day (based on the ticarcillin component) divided q6h for mild to moderate infections. The efficacy rates were comparable to those obtained in the controlled trials.

The adverse event profile in these 704 Timentin -treated pediatric patients was comparable to that seen in adult patients.