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Ticarcillin Disodium

Ticarcillin, an extended-spectrum penicillin antibiotic, is a semisynthetic a-carboxypenicillin structurally related to carbenicillin.

Uses

Ticarcillin shares many of the uses of other extended-spectrum penicillins and is used principally for the treatment of infections caused by susceptible gram-negative aerobic bacilli (e.g., susceptible strains of Proteus vulgaris, Providencia rettgeri, Morganella morganii, P. mirabilis, Escherichia coli, Enterobacter, Pseudomonas aeruginosa).

The drug also has been used for the treatment of anaerobic or mixed aerobic-anaerobic bacterial infections or for empiric anti-infective therapy in febrile granulocytopenic patients. For specific information on the uses of ticarcillin, seeUses in the Extended-Spectrum Penicillins General Statement 8:12.16.16. For information on the uses of ticarcillin in a fixed-ratio combination with clavulanic acid.

Dosage and Administration

Reconstitution and Administration

Ticarcillin disodium is administered by slow IV injection or infusion or by deep IM injection. The drug should be given IV rather than IM for the treatment of serious infections and generally is given IM only for the treatment of uncomplicated urinary tract infections. If an aminoglycoside is administered concomitantly with ticarcillin, the drugs should be administered separately.

Reconstituted solutions of ticarcillin disodium should be inspected visually for particulate matter and discoloration prior to administration.

Intermittent IV Injection

For direct intermittent IV injection, each gram of ticarcillin should be reconstituted with 4 mL of sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection to provide a solution containing approximately 200 mg/mL; if desired, this solution may be further diluted. The appropriate dose should then be injected directly into a vein. To minimize vein irritation, IV injections should be made as slowly as possible and solutions of the drug containing 50 mg/mL or less should be used.

Intermittent or Continuous IV Infusion

For IV infusion, reconstituted solutions of ticarcillin disodium should be further diluted with a compatible IV solution to a concentration of 10-100 mg/mL and administered by continuous or intermittent infusion. Intermittent IV infusions of ticarcillin usually should be infused over 30 minutes to 2 hours; in neonates, IV infusions of the drug should be given over 10-20 minutes.

IM Injection

IM injections of ticarcillin disodium are prepared by reconstituting each gram of ticarcillin with 2 mL of sterile water for injection, sodium chloride injection, or 1% lidocaine hydrochloride injection (without epinephrine). The resultant solutions contain approximately 385 mg of ticarcillin per mL (each 2.6 mL contains 1 g of ticarcillin). Ticarcillin is administered IM by deep injection into a large muscle mass using usual techniques and precautions. No more than 1 g of ticarcillin should be given in a single IM injection.

Dosage

Dosage of ticarcillin disodium is expressed in terms of ticarcillin.

Adult Dosage

The usual adult dosage of ticarcillin for the treatment of uncomplicated urinary tract infections is 1 g every 6 hours given IM or by direct IV injection. The usual adult dosage for complicated urinary tract infections is 150-200 mg/kg daily given by IV infusion in divided doses every 4 or 6 hours. For an average (70 kg) adult, the usually recommended dosage is 3 g given 4 times daily.

For the treatment of septicemia, respiratory tract infections, intra-abdominal infections, infections of the female pelvis and genital tract, or skin and skin structure infections, the usual adult dosage is 200-300 mg/kg daily given by IV infusion in divided doses every 4 or 6 hours. Seriously ill patients should receive the higher dosages. Depending on the weight of the patient and severity of the infection, the usual dosage is 3 g given every 4 hours (18 g daily) or 4 g given every 6 hours (16 g daily).

When used in conjunction with other anti-infectives for empiric therapy in febrile granulocytopenic patients, 4 g of ticarcillin has been given every 4 hours by IV infusion over 2 hours. Alternatively, a ticarcillin dosage of 300 mg/kg daily or 12 g/m2 daily has been given IV in divided doses every 6 hours. Published protocols for the treatment of infections in granulocytopenic patients should be consulted for specific information on selection of anti-infective regimens, recommended dosage schedules, and duration of anti-infective therapy in these patients.

For long-term prophylaxis of acute exacerbations of Ps. aeruginosa infections in patients with cystic fibrosis, 1 g of ticarcillin and 80 mg of tobramycin have been administered twice daily by oral inhalation using a hand-held nebulizer; however, further study is needed to evaluate safety and efficacy of prophylactic use of anti-infective aerosols in these patients.

Pediatric Dosage

Children weighing 40 kg or more may receive the usual adult dosage of ticarcillin. In children older than 1 month of age who weigh less than 40 kg, uncomplicated urinary tract infections may be treated with a ticarcillin dosage of 50-100 mg/kg daily given IM or by direct IV injection in divided doses every 6 or 8 hours and complicated urinary tract infections may be treated with 150-200 mg/kg daily given by IV infusion in divided doses every 4 or 6 hours.

The usual dosage of ticarcillin for the treatment of septicemia, respiratory tract infections, skin and soft-tissue infections, intra-abdominal infections, or infections of the female pelvis and genital tract in children older than 1 month of age who weigh less than 40 kg is 200-300 mg/kg given by IV infusion in divided doses every 4 or 6 hours. Total daily dosage in children should not exceed the recommended adult dosages.

The American Academy of Pediatrics (AAP) recommends that children 1 month of age or older receive IM or IV ticarcillin in a dosage of 100-200 mg/kg daily given in 4 divided doses for the treatment of mild to moderate infections or 200-300 mg/kg daily given in 4-6 divided doses for the treatment of severe infections. For the treatment of severe systemic infections (sepsis) in neonates caused by susceptible strains of Pseudomonas, Proteus, or Escherichia coli, ticarcillin is given IM or as a 10- to 20-minute IV infusion.

To maintain peak serum ticarcillin concentrations of 125-150 mcg/mL and trough serum concentrations of 25-50 mcg/mL in neonates weighing less than 2 kg, the manufacturer recommends that ticarcillin doses of 75 mg/kg be given every 12 hours (150 mg/kg daily) during the first week of life; dosage may be increased to 75 mg/kg every 8 hours (225 mg/kg daily) when the neonate is older than 7 days of age. In neonates weighing more than 2 kg, the manufacturer recommends that ticarcillin doses of 75 mg/kg be given every 8 hours (225 mg/kg daily) during the first week of life; dosage may be increased to 100 mg/kg every 8 hours (300 mg/kg daily) when the infant is older than 7 days. The AAP recommends that neonates younger than 1 week of age receive IM or IV ticarcillin in a dosage of 75 mg/kg every 12 hours if they weigh 2 kg or less or 75 mg/kg every 8 hours if they weigh more than 2 kg. Neonates 1-4 weeks of age should receive 75 kg/kg every 8 hours if they weigh 2 kg or less (75 mg/kg every 12 hours for those weighing less than 1.2 kg) or 75 mg/kg every 6 hours if they weigh more than 2 kg.

Dosage in Renal and Hepatic Impairment

In patients with impaired renal and/or hepatic function, doses and/or frequency of administration of ticarcillin must be modified in response to the degree of impairment, severity of the infection, and susceptibility of the causative organism. The manufacturer recommends that adults with impaired renal function receive an initial IV loading dose of 3 g and the following maintenance dosage based on the patient’s creatinine clearance: Creatinine Clearance (mL/min) Dosage 30-60 2 g IV every 4 h 10-30 2 g IV every 8 h <10 2 g IV every 12 h or 1 g IM every 6 h The manufacturer states that adults undergoing hemodialysis who have serious systemic infections should receive 2 g of ticarcillin every 12 hours and an additional 3-g dose of the drug after each dialysis period. Adults undergoing peritoneal dialysis should receive 3-g IV doses of ticarcillin every 12 hours. In adults with hepatic dysfunction and creatinine clearances less than 10 mL/minute, 2 g of ticarcillin may be given IV once daily or 1 g may be given IM every 12 hours. Children with renal and/or hepatic impairment who weigh 40 kg or more should receive the dosages recommended for adults with renal and/or hepatic impairment. The manufacturer states that clinical data are insufficient for dosage recommendations for children with renal and/or hepatic impairment who weigh less than 40 kg.

Cautions

Adverse Effects

Adverse effects reported with ticarcillin are similar to those reported with other extended-spectrum penicillins. For information on adverse effects reported with extended-spectrum penicillins.

Precautions and Contraindications

Ticarcillin is contraindicated in patients who are hypersensitive to any penicillin. Ticarcillin shares the toxic potentials of the penicillins, including the risk of hypersensitivity reactions, and the usual precautions of penicillin therapy should be observed. Prior to initiation of therapy with ticarcillin, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, or other drugs.

There is clinical and laboratory evidence of partial cross-allergenicity among penicillins and other b-lactam antibiotics including cephalosporins and cephamycins. Renal, hepatic, and hematologic systems should be evaluated periodically during prolonged therapy with ticarcillin.

Serum electrolytes and cardiac status should be monitored during ticarcillin therapy. Because abnormal platelet aggregation and prolonged prothrombin time or bleeding time have been reported rarely during therapy with ticarcillin, the possibility that bleeding complications could occur during therapy with the drug should be considered, especially when the drug is used in patients with renal impairment. If bleeding manifestations occur, ticarcillin should be discontinued and appropriate therapy instituted.

For a more complete discussion of these and other precautions associated with the use of ticarcillin.

Pregnancy, Fertitlity and Lactation

Safe use of ticarcillin during pregnancy has not been definitely established. In reproduction studies in mice, an increased incidence of fetuses with unossified or reduced sternebrae occurred at ticarcillin doses of 250 mg/kg and an increased incidence of bipartite and/or asymmetric sternebrae occurred at doses of 500 mg/kg; wavy ribs occurred in rats whose mothers received doses of 250 and 500 mg/kg. The manufacturer states that reproduction studies in mice and rats have not revealed evidence of impaired fertility or harm to the fetus. There are no adequate or controlled studies to date using ticarcillin in pregnant women, and the drug should be used during pregnancy only when clearly needed. Because penicillins are distributed into milk, ticarcillin should be used with caution in nursing women. Spectrum Based on its spectrum of activity, ticarcillin is classified as an extended-spectrum penicillin. Ticarcillin has a spectrum of activity similar to that of carbenicillin; however, ticarcillin is more active in vitro on a weight basis against Pseudomonas aeruginosa than carbenicillin.

In Vitro Susceptibility Testing

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ticarcillin, a disk containing 75 mcg of the drug is used. When the disk-diffusion procedure is performed as recommended by the National Committee for Clinical Laboratory Standards (NCCLS), Enterobacteriaceae with growth inhibition zones of 20 mm or greater are susceptible to ticarcillin, those with zones of 15-19 mm have intermediate susceptibility, and those with zones of 14 mm or less are resistant to the drug. Ps. aeruginosa with growth inhibition zones of 15 mm or greater are susceptible to ticarcillin and those with zones of 14 mm or less are resistant to the drug.

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is performed according to NCCLS standardized procedures, Enterobacteriaceae with MICs of 16 mcg/mL or less are susceptible to ticarcillin, those with MICs of 32-64 mcg/mL have intermediate susceptibility, and those with MICs of 128 mcg/mL or greater are resistant to the drug. Ps. aeruginosa with MICs of 64 mcg/mL or less are susceptible to ticarcillin and those with MICs of 128 mcg/mL or greater are resistant to the drug. Other non-Enterobacteriaceae gram-negative bacilli (e.g., other Pseudomonas spp., Acinetobacter, Stenotrophomonas maltophilia) with MICs of 16 mcg/mL or less are susceptible to ticarcillin, those with MICs of 32-64 mcg/mL have intermediate susceptibility, and those with MICs of 128 mcg/mL or greater are resistant to the drug.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, ticarcillin was administered as the disodium salt; dosages and concentrations of the drug are expressed in terms of ticarcillin.

Absorption

Ticarcillin disodium is not appreciably absorbed from the GI tract and must be given parenterally. Ticarcillin is readily absorbed from IM injection sites.

Following IM injection of a single 500-mg, 1-g, or 2-g dose of ticarcillin in healthy adults with normal renal function, peak serum concentrations of the drug are generally attained within 30-75 minutes and average 8.6-18, 22-35, and 63.6 mcg/mL, respectively; serum concentrations usually are low or may be undetectable 6 hours after administration. In one study in healthy adults with normal renal function, serum concentrations of ticarcillin 1, 2, 4, and 6 hours after a single 1-g IM dose of the drug averaged 27.8,20.6,7.2, and 3.1 mcg/mL, respectively.

Following IV injection over 3-5 minutes of a single 1- or 2-g dose of ticarcillin in healthy adults, serum concentrations of the drug are 70-100 or 200-218 mcg/mL, respectively, immediately following administration and serum concentrations are low or undetectable 6-8 hours after the dose. IV injection over 5 minutes of a single 3-g dose results in serum concentrations of 257, 218, 119, 70, and 30 mcg/mL at 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours, respectively, after the dose.

Following IV infusion over 30 minutes of a single 2-g dose of ticarcillin in adults with normal renal function, serum concentrations of the drug immediately, 30 minutes, 1 hour, 2 hours, and 4 hours after completion of the infusion are 60.9,29.3,19.9,8.9, and 2.3 mcg/mL, respectively. IV infusion over 2 hours of 3.5-g doses of ticarcillin every 4 hours in adults with normal renal function results in mean peak ticarcillin serum concentrations of 210 mcg/mL and mean trough serum concentrations of 49 mcg/mL.

Steady-state serum concentrations of ticarcillin reportedly average 105-124 mcg/mL in adults with normal renal function following IV administration of a 1- or 1.35-g loading dose of the drug and continuous IV infusion of 1 or 2 g every hour. In one study in children 5-13 years of age receiving approximately 100 mg/kg of ticarcillin every 6 hours by IV infusion over 20-30 minutes, serum concentrations of the drug averaged 253, 83, 22, and 5 mcg/mL at 30 minutes, 2 hours, 4 hours, and 6 hours, respectively, after completion of the infusion.

Ticarcillin Disodium

Following IM administration of 75 mg/kg every 6 hours in neonates weighing less than 2 kg, mean ticarcillin serum concentrations are 189, 165, 123, and 77 mcg/mL at 1, 2, 4, and 8 hours, respectively, after dosing. IM administration of 75 mg/kg every 6 hours in neonates weighing more than 2 kg results in mean serum concentrations of 159, 144, 98, and 47 mcg/mL at 1, 2, 4, and 6 hours, respectively, after dosing.

Distribution

Ticarcillin is distributed into peritoneal fluid, pleural fluid, interstitial fluid, skin, kidneys, bone, bile, and sputum. The volume of distribution of ticarcillin averages about 0.34-0.42 L/kg in adults and children 5-13 years of age and 0.42-0.76 L/kg in neonates.Concomitant administration of probenecid reportedly increases the volume of distribution of ticarcillin. Like other penicillins, only low concentrations of ticarcillin are attained in CSF; however, CSF concentrations of the drug are generally higher when meninges are inflamed than when meninges are normal. In one study, CSF concentrations of ticarcillin were 6% of concurrent serum concentrations of the drug in patients with normal meninges and 39% of concurrent serum concentrations in patients with inflamed meninges. Concentrations of ticarcillin in bile may be several times higher than concurrent serum concentrations of the drug unless biliary obstruction is present. Ticarcillin is about 45-65% bound to serum proteins. Like other penicillins, ticarcillin probably crosses the placenta and is distributed into milk in low concentrations.

Elimination

Serum concentrations of ticarcillin decline in a biphasic manner. In adults with normal renal function, ticarcillin has a distribution half-life (t1/2a) of 0.10-0.17 hours and an elimination half-life (t1/2b) of 0.93-1.3 hours. Approximately 10-15% of a single IM or IV dose of ticarcillin is metabolized by hydrolysis of the b-lactam ring to penicilloic acids which are microbiologically inactive. An unidentified active metabolite of ticarcillin has also been found in urine in one study.

Ticarcillin and its metabolites are rapidly excreted principally in urine by tubular secretion and glomerular filtration and are also partly excreted in feces via bile. Following IV administration of a single 1- or 2-g dose of ticarcillin in adults with normal renal function, 80-93% of the dose is excreted unchanged in urine within 24 hours; most of the dose is excreted during the first 2-6 hours.

Urinary concentrations of ticarcillin reportedly range from 650 mcg/mL to 2.5 mg/mL in urine collected during the first 3 hours following IV administration of a single 3-g dose of the drug. Serum clearance of ticarcillin ranges from 132-253 mL/minute in adults with normal renal and hepatic function. In one study, the serum clearance of ticarcillin was 31-54 mL/minute per 1.73 m in neonates 7 days of age or younger, 118 mL/minute per 1.73 m in neonates and children 1-8 weeks of age, and 176 mL/minute per 1.73 m in children 5-13 years of age. Serum concentrations of ticarcillin are higher and the serum half-life is prolonged in patients with impaired renal and/or hepatic function.

The serum half-life of ticarcillin ranges from 3-9. hours in patients with creatinine clearances of 10-60 mL/minute and 13.5-16.2 hours in patients with creatinine clearances less than 10 mL/minute. In one patient with both renal and hepatic impairment, the serum half-life of ticarcillin was 28 hours. In neonates, the serum half-life of ticarcillin generally is inversely proportional to birthweight, gestational age, and chronologic age. The serum half-life of the drug is 3.5-5.6 hours in neonates less than 1 week of age, 1.3-2.2 hours in neonates and children 1-8 weeks of age, and 0.9 hours in children 5-13 years of age. Ticarcillin is removed by hemodialysis; however, the amount of drug removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow-rate). Small amounts of ticarcillin are removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Ticarcillin is a semisynthetic a-carboxypenicillin. The drug is the 3-thienyl analog of carbenicillin. Ticarcillin is commercially available as the disodium salt. Potency of ticarcillin disodium is expressed in terms of ticarcillin. Each mg of ticarcillin disodium contains not less than 800 mcg of ticarcillin, calculated on the anhydrous basis. Ticarcillin disodium occurs as a hygroscopic, white to pale yellow powder or lyophilized cake.

Ticarcillin disodium is freely soluble in water. The drug has pKas of 2.55 and 3.42. Ticarcillin disodium also is commercially available in a fixed-ratio combination with clavulanate potassium. The disodium salt of ticarcillin contains 5.2-6.5 mEq of sodium per gram of ticarcillin. When reconstituted as directed, solutions of ticarcillin disodium powder for injection are colorless to pale yellow in color and have a pH of 6-8.

Stability

Commercially available ticarcillin disodium powder for injection should be stored at room temperature or colder. Small amounts of polymer conjugation products reportedly form in solutions of ticarcillin disodium during in vitro storage, especially when high concentrations of the drug are stored at room temperature. Because these polymers may play a role in hypersensitivity reactions to the drug, some clinicians recommend that, although potency may not be adversely affected, reconstituted solutions of ticarcillin disodium should be refrigerated or used within 30 minutes following preparation.

The manufacturer recommends that IM solutions of ticarcillin be used promptly. Ticarcillin disodium solutions containing 10-100 mg of ticarcillin per mL are physically and/or chemically stable for 72 hours at room temperature in sodium chloride injection or 5% dextrose injection or for 48 hours at room temperature in lactated Ringer’s injection. These solutions also are stable for 14 days when refrigerated at 4°C; however, the manufacturer states that refrigerated solutions of ticarcillin stored longer than 72 hours should not be used for multiple-dose purposes.

Extemporaneously prepared ticarcillin disodium solutions containing 10-100 mg/mL in sodium chloride injection, 5% dextrose injection, or lactated Ringer’s injection are stable for up to 30 days if frozen at -18°C immediately after reconstitution. Once thawed, the solutions should be used within 24 hours. In one study, ticarcillin solutions containing 60 mg/mL in 5% dextrose lost less than 10% of their potency when frozen for 30 days at -20°C in plastic IV containers, thawed by exposure to room temperature or microwave radiation, and subsequently stored at room temperature for 24 hours.

Ticarcillin disodium is potentially physically and/or chemically incompatible with some drugs, including aminoglycosides, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information. Because of the potential for incompatibility, ticarcillin disodium and aminoglycosides should not be admixed. For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, laboratory test interferences, and dosage and administration of ticarcillin sodium.

Preparations

Ticarcillin Disodium Parenteral For injection 3 g (of ticarcillin) Ticar®, GlaxoSmithKline

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