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Ticarcillin Disodium and Clavulanate Potassium

Ticarcillin disodium and clavulanate potassium is a fixed combination of ticarcillin disodium (a semisynthetic extended-spectrum penicillin antibiotic) and the potassium salt of clavulanic acid (a b-lactamase inhibitor); clavulanic acid synergistically expands ticarcillin’s spectrum of activity against many strains of b-lactamase-producing bacteria.

Cautions

Adverse effects reported with ticarcillin disodium and clavulanate potassium are similar to those reported with ticarcillin alone. For information on adverse effects reported with ticarcillin and other extended-spectrum penicillins, see Cautions in the Extended-Spectrum Penicillins General Statement 8:12.16.16.

Hypersensitivity Reactions

Rash, pruritus, urticaria, and fever have been reported with ticarcillin disodium and clavulanate potassium. In addition, arthralgia, myalgia, chills, chest discomfort, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and anaphylactic reactions may occur.

Hematologic Effects

Eosinophilia has been reported in about 5.5% of patients receiving ticarcillin disodium and clavulanate potassium, and thrombocytosis, leukopenia, and neutropenia have been reported rarely. Other hematologic effects including thrombocytopenia, decreased hemoglobin or hematocrit, or prolongation of prothrombin time or bleeding time may occur. Positive direct antiglobulin (Coombs’) test results have been reported in patients who received ticarcillin disodium and clavulanate potassium. In one study in immunocompromised patients, positive direct antiglobulin test results occurred during 44% of the courses of therapy with ticarcillin and clavulanic acid and concomitant tobramycin.

Positive reactions occurred within 48 hours after initiation of therapy and reverted to negative within 2-4 months after completion of therapy. These reactions appear to result from nonimmunologic adsorption of proteins onto erythrocytes in the presence of clavulanic acid; this nonimmunologic mechanism is similar to that observed with cephalosporins.

Nonimmunologic adsorption of proteins onto erythrocyte membranes and positive direct antiglobulin test results also occurred in vitro when erythrocytes obtained from healthy individuals were exposed to clavulanic acid; however, exposure of erythrocytes to ticarcillin alone under various conditions did not result in a positive reaction.

GI Effects

Diarrhea, nausea, epigastric pain, disturbances of taste or smell, stomatitis, flatulence, and vomiting may occur in patients receiving ticarcillin disodium and clavulanate potassium. Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by toxin-producing clostridia has been reported with the use of anti-infectives including ticarcillin and clavulanate potassium. C. difficile-associated diarrhea and colitis may occur during or following discontinuance of ticarcillin and clavulanate potassium and ranges in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of the drug alone, but diagnosis and management of moderate to severe cases should include appropriate bacteriologic studies and treatment with fluid, electrolyte, and protein supplementation as indicated; rarely, cautious use of sigmoidoscopy (or other appropriate endoscopic examination) may be considered necessary. If colitis is moderate to severe and is not relieved by discontinuance of the drug, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin) should be administered.

Renal and Electrolyte Effects

Hyperkalemia or hypokalemia have been reported rarely with ticarcillin disodium and clavulanate potassium. Hypernatremia, decreased serum uric acid concentration, and increased serum creatinine and/or BUN concentrations may occur with the drug.

Hepatic Effects

Transient increases in serum concentrations of AST (SGOT), ALT (SGPT), and alkaline phosphatase have been reported with ticarcillin disodium and clavulanate potassium. Increased serum concentrations of LDH and bilirubin may occur. Transient hepatitis and cholestatic jaundice have occurred rarely during therapy with the drug.

Nervous System Effects

Headache, blurred vision, mental deterioration, and hallucinations, have been reported rarely with ticarcillin disodium and clavulanate potassium. Giddiness, neuromuscular hyperirritability, or seizures may occur with the drug. Very high doses of ticarcillin disodium and clavulanate potassium, especially in those with renal impairment, may result in neurotoxic reactions.

Local Effects

Thrombophlebitis and local reactions at the IV infusion site, including pain, burning, swelling, and induration, may occur with ticarcillin disodium and clavulanate potassium.

Precautions and Contraindications

Ticarcillin disodium and clavulanate potassium is contraindicated in patients who are hypersensitive to any penicillin. Ticarcillin disodium and clavulanate potassium 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 disodium and clavulanate potassium, 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, cephamycins, and 1-oxa-b-lactams. Renal, hepatic, and hematologic function should be evaluated periodically during prolonged therapy with ticarcillin disodium and clavulanate potassium. Although hypokalemia has only been reported rarely with ticarcillin disodium and clavulanate potassium, serum potassium should be monitored and the possibility of hypokalemia should be considered during prolonged therapy with the drug, especially in patients with fluid and electrolyte imbalance.

The possibility of sodium overload also should be considered when the drug is administered to patients whose sodium intake is restricted. Because C. difficile-associated diarrhea and colitis has been reported with the use of anti-infective agents including ticarcillin and clavulanate potassium, it should be considered in the differential diagnosis of patients who develop diarrhea during ticarcillin and clavulanate potassium 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 ticarcillin disodium and clavulanate potassium should be considered, especially when the drug is used in patients with renal impairment. If bleeding manifestations occur, ticarcillin disodium and clavulanate potassium should be discontinued and appropriate therapy instituted. For a more complete discussion of these and other precautions associated with the use of ticarcillin.

Pediatric Precautions

Ticarcillin disodium and clavulanate potassium is used in children 3 months of age or older. The manufacturer states that safety and efficacy of ticarcillin disodium and clavulanate potassium in children 3 months to 16 years of age is supported by evidence from adequate and well-controlled studies in adults and additional efficacy, safety, and pharmacokinetic data from comparative and noncomparative clinical studies in pediatric patients. However, data are insufficient to date to support the use of the drug in children younger than 3 months of age or for the treatment of septicemia and/or infections suspected or known to be caused by Haemophilus influenzae type b in children 3 months to 16 years of age. Pediatric patients with meningeal infection originating from a distant infection site, those with suspected or documented meningitis, or those requiring prophylaxis for CNS infections should receive alternative therapy with drugs with proven efficacy for these conditions. The manufacturer states that the adverse effect profile in pediatric patients receiving the drug is similar to that in adults.

Mutagenicity and Carcinogenicity

Studies have not been performed to date to evaluate the carcinogenic potential of ticarcillin disodium and clavulanate potassium. No evidence of mutagenicity was seen when ticarcillin and clavulanate potassium was evaluated in several in vitro and in vivo tests.

Pregnancy, Fertitlity and Lactation

Safe use of ticarcillin disodium and clavulanate potassium during pregnancy has not been definitely established. Reproduction studies in rats using dosages up to 1.05 g/kg daily of the 30:1 fixed-ratio combination and a 15:1 fixed-ratio combination have not revealed evidence of impaired fertility or harm to the fetus. Because animal reproduction studies are not always predictive of human response and because there are no adequate or controlled studies using ticarcillin disodium and clavulanate potassium in pregnant women, the drug should be used during pregnancy only when clearly needed. Because penicillins and clavulanic acid are distributed into milk, ticarcillin disodium and clavulanate potassium should be used with caution in nursing women.

Drug Interactions

Aminoglycosides

The antibacterial activity of ticarcillin and aminoglycosides is additive or synergistic in vitro against some strains of Enterobacteriaceae and Pseudomonas aeruginosa. For information on synergism between ticarcillin and aminoglycosides. Like other penicillins, ticarcillin is physically and/or chemically incompatible with aminoglycosides and can inactivate the drugs in vitro. In vitro inactivation of aminoglycosides by the drug can occur if the drugs are administered in the same syringe or IV infusion container; therefore, when concomitant therapy is indicated, in vitro mixing of aminoglycosides and ticarcillin disodium and clavulanate potassium should be avoided. In vitro inactivation of aminoglycosides by penicillins also occurs in serum samples obtained from patients receiving concomitant therapy with the drugs. This could adversely affect results of serum aminoglycoside assays performed on the serum samples. For further information on in vitro and in vivo incompatibility of ticarcillin and aminoglycosides.

Probenecid

Oral probenecid administered shortly before or concomitantly with ticarcillin disodium and clavulanate potassium slows the rate of renal tubular secretion of ticarcillin and produces higher and prolonged serum concentrations of ticarcillin. However, concomitant administration of probenecid with ticarcillin disodium and clavulanate potassium does not affect serum concentrations of clavulanic acid.

Laboratory Test Interferences

Tests for Urinary Proteins

The manufacturer states that ticarcillin reportedly may interfere with a variety of test methods used to determine urinary proteins, including turbidimetric methods that use sulfosalicylic acid, trichloroacetic acid, acetic acid, or nitric acid. The drug also reportedly interferes with tests for urinary protein that use the biuret method, but does not appear to interfere with tests that use bromphenol blue (Albustix®, Albutest®, Multi-Stix®).

Immunohematology Tests

Positive direct antiglobulin (Coombs’) test results have been reported in patients who received ticarcillin disodium and clavulanate potassium and appear to be caused by clavulanic acid.This reaction may interfere with hematologic studies or transfusion cross-matching procedures and should be considered in patients receiving the drug.

Acute Toxcicity

The manufacturer states that overdosage of ticarcillin disodium and clavulanate potassium may cause neurotoxic effects, especially in patients with renal impairment. If overdosage of the drug occurs, hemodialysis can be used to enhance elimination of ticarcillin and clavulanic acid.

Mechanism of Action

Ticarcillin disodium and clavulanate potassium is usually bactericidal in action. Concurrent administration of clavulanic acid does not alter the mechanism of action of ticarcillin.

However, because clavulanic acid has a high affinity for and binds to certain b-lactamases that generally inactivate ticarcillin by hydrolyzing its b-lactam ring, concurrent administration of the drug with ticarcillin results in a synergistic bactericidal effect which expands the spectrum of activity of ticarcillin against many strains of b-lactamase-producing bacteria that are resistant to ticarcillin alone.

For information on the mechanism of action of ticarcillin. In vitro studies indicate that clavulanic acid generally inhibits staphylococcal penicillinases, b-lactamases produced by Bacteroides fragilis, b-lactamases produced by Branhamella catarrhalis (formerly Neisseria catarrhalis), and b-lactamases classified as Richmond-Sykes types II, III (TEM-type), IV, and V. Clavulanic acid can inhibit some cephalosporinases produced by Proteus vulgaris, B. fragilis, and Pseudomonas cepacia, but generally does not inhibit inducible, chromosomally mediated cephalosporinases classified as Richmond-Sykes type I. Clavulanic acid generally acts as an irreversible, competitive inhibitor of b-lactamases.

The mechanism by which clavulanic acid binds to and inhibits b-lactamases varies depending on the specific b-lactamase involved. Because clavulanic acid is structurally similar to penicillins and cephalosporins, it initially acts as a competitive inhibitor and binds to the active site on the b-lactamase.

An inactive acyl intermediate is then formed but is only transiently inactive since the intermediate can be hydrolyzed, resulting in restoration of b-lactamase activity and release of clavulanic acid degradation products. With many types of b-lactamases, however, subsequent reactions occur that lead to irreversible inactivation of the b-lactamase. Synergism does not occur between ticarcillin and clavulanic acid if resistance to ticarcillin is intrinsic (i.e., results from the presence of a permeability barrier in the outer membrane of the organism or alterations in the properties of the penicillin-binding proteins).

Synergism between the drugs also does not generally occur against organisms that are susceptible to ticarcillin alone. Clavulanic acid, like cefoxitin and imipenem, can induce production of chromosomally mediated type I cephalosporinases in certain gram-negative bacteria that possess these enzymes (e.g., some strains of Enterobacter, Pseudomonas aeruginosa, Morganella morganii).

Concomitant use of clavulanic acid with a b-lactam antibiotic that is inactivated by inducible b-lactamases theoretically could result in an antagonistic effect against organisms that possess these enzymes. However, high concentrations of clavulanic acid generally are required to induce production of these b-lactamases, and the clinical importance of this effect has not been determined. Spectrum Ticarcillin disodium and clavulanate potassium is active in vitro against organisms susceptible to ticarcillin alone. In addition, because clavulanic acid can inhibit certain b-lactamases that generally inactivate ticarcillin, ticarcillin disodium and clavulanate potassium is active in vitro against many b-lactamase-producing organisms that are resistant to ticarcillin alone. Clavulanic acid alone has some antibacterial activity and is active in vitro against some gram-positive and gram-negative bacteria, including Branhamella catarrhalis (formerly Neisseria catarrhalis),

Bacteroides fragilis, Haemophilus influenzae, Legionella, Neisseria gonorrhoeae, and Staphylococcus aureus. However, high concentrations of clavulanic acid are necessary to inhibit most susceptible organisms and the drug is not therapeutically useful alone.

In Vitro Susceptibility Testing

To test in vitro susceptibility to ticarcillin disodium and clavulanate potassium, a 7.5:1 ratio of ticarcillin to clavulanic acid generally is used for disk-diffusion procedures. For agar or broth dilution procedures, varying concentrations of ticarcillin have been used in the presence of 1, 2, 5, or 10 mcg/mL of clavulanic acid. It has been suggested that because the ratios of ticarcillin to clavulanic acid used in these in vitro tests do not correspond to the 30:1 ratio contained in the commercially available fixed-combination preparation of ticarcillin disodium and clavulanate potassium and because varying ratios of the drugs are generally attained in serum and tissues following administration of the fixed-combination preparation, results of these in vitro susceptibility tests do not necessarily correlate with in vivo efficacy of the drug.

The manufacturer suggests that the ratio of ticarcillin to clavulanic acid used in these tests is not as important as the concentration of clavulanic acid since the antibacterial activity of the combination is governed by the concentration of clavulanic acid rather than the ratio of the drugs. Results of in vitro susceptibility tests with ticarcillin disodium and clavulanate potassium may be affected by inoculum size. The manufacturer, the National Committee for Clinical Laboratory Standards (NCCLS), and most clinicians recommend that strains of staphylococci resistant to penicillinase-resistant penicillins also be considered resistant to ticarcillin disodium and clavulanate potassium, although results of in vitro susceptibility tests may indicate that the organism is susceptible to the drug.

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ticarcillin disodium and clavulanate potassium, a disk containing 75 mcg of ticarcillin and 10 mcg of clavulanic acid is used. When the procedure is performed according to NCCLS standardized procedures, Enterobacteriaceae or Acinetobacter with growth inhibition zones of 20 mm or greater are susceptible to ticarcillin disodium and clavulanate potassium, 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 disodium and clavulanate potassium and those with zones of 14 mm or less are resistant to the drug. When the NCCLS standardized procedure is used to test susceptibility of staphylococci, those with growth inhibition zones of 23 mm or greater are susceptible to ticarcillin disodium and clavulanate potassium and those with zones of 22 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, varying concentrations of ticarcillin are used in the presence of 2 mcg/mL of clavulanic acid and the MIC of ticarcillin disodium and clavulanate potassium is expressed in terms of the ticarcillin concentration in the presence of 2 mcg/mL of clavulanic acid. When this method is used, Enterobacteriaceae with ticarcillin MICs of 16 mcg/mL or less in the presence of 2 mcg/mL of clavulanic acid are susceptible to ticarcillin disodium and clavulanate potassium, those with ticarcillin 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 ticarcillin MICs of 64 mcg/mL or less in the presence of 2 mcg/mL of clavulanic acid are susceptible to ticarcillin disodium and clavulanate potassium and those with ticarcillin MICs of 128 mcg/mL or greater are resistant to the drug. When susceptibility of staphylococci are tested in the presence of 2 mcg/mL of clavulanic acid using NCCLS standardized procedures, those with a ticarcillin MIC of 8 mcg/mL or less are susceptible to ticarcillin disodium and clavulanate potassium and those with a ticarcillin MIC of 16 mcg/mL or greater are resistant to ticarcillin disodium and clavulanate potassium.

Clavulanate Potassium

Gram-positive Aerobic Bacteria

Ticarcillin disodium and clavulanate potassium is active in vitro against most gram-positive aerobic cocci including penicillinase-producing and nonpenicillinase-producing strains of Staphylococcus aureus, S. epidermidis, and S. saprophyticus; group A b-hemolytic streptococci; Streptococcus pneumoniae; group B streptococci (S. agalactiae); Enterococcus faecalis (formerly S. faecalis); S. bovis; and viridans streptococci. Ticarcillin disodium and clavulanate potassium is active in vitro against many strains of penicillinase-producing staphylococci that are resistant to ticarcillin alone; however, staphylococci resistant to penicillinase-resistant penicillins are generally also resistant to ticarcillin disodium and clavulanate potassium. The MIC90 (minimum inhibitory concentration of the drug at which 90% of strains tested are inhibited) of ticarcillin in the presence of 2 mcg/mL of clavulanic acid for both penicillinase-producing and nonpenicillinase-producing strains of S. aureus is 2-4 mcg/mL. The MIC90 of ticarcillin in the presence of 2 mcg/mL of clavulanic acid for penicillinase-producing or nonpenicillinase-producing strains of S. epidermidis is 8 or 16 mcg/mL, respectively. In the presence of 2 mcg/mL of clavulanic acid, group A b-hemolytic streptococci have a ticarcillin MIC90 of 0.5 mcg/mL, group B streptococci and viridans streptococci have a ticarcillin MIC90 of 2-4 mcg/mL, and S. pneumoniae has a ticarcillin MIC90 of 16 mcg/mL. Both the MIC50 and MIC90 of ticarcillin for E. faecalis are 64 mcg/mL in the presence of 2 mcg/mL of clavulanic acid.

Gram-negative Aerobic Bacteria

Haemophilus Ticarcillin disodium and clavulanate potassium is active in vitro against most b-lactamase-producing and non-b-lactamase producing strains of Haemophilus influenzae. The MIC90 of ticarcillin in the presence of 2 mcg/mL of clavulanic acid for both b-lactamase-producing and non-b-lactamase-producing strains of H. influenzae is 0.5 mcg/mL or less.

Enterobacteriaceae

Ticarcillin disodium and clavulanate potassium is generally active in vitro against the following Enterobacteriaceae: Citrobacter amalonaticus, C. diversus, C. freundii, Enterobacter agglomerans, Escherichia coli, Klebsiella, Morganella morganii (formerly Proteus morganii), Proteus mirabilis, P. vulgaris, Providencia rettgeri (formerly Proteus rettgeri), Salmonella, and Shigella. Ticarcillin disodium and clavulanate potassium is active in vitro against many strains of Citrobacter diversus, Klebsiella pneumoniae, K. oxytoca, P. vulgaris, P. rettgeri, and P. stuartii and some strains of Enterobacter, E. coli, and Serratia that are resistant to ticarcillin alone. Although C. diversus, E. agglomerans, K. pneumoniae, and P. stuartii are generally resistant to ticarcillin alone, the MIC90 of ticarcillin in the presence of 2 mcg/mL of clavulanic acid for these organisms is 4-32 mcg/mL. The MIC90 of ticarcillin in the presence of 2 mcg/mL of clavulanic acid is 16-64 mcg/mL for E. coli or E. cloacae and 64 mcg/mL for E. aerogenes.

Pseudomonas

Ticarcillin disodium and clavulanate potassium is active in vitro against some strains of Pseudomonas acidovorans, Ps. maltophilia, and Ps. aeruginosa. Although ticarcillin disodium and clavulanate potassium is more active in vitro on a weight basis than ticarcillin alone against Ps. acidovorans and Ps. maltophilia, the combination is generally no more active than ticarcillin alone against Ps. aeruginosa. In the presence of 2 mcg/mL of clavulanic acid, the MIC90 of ticarcillin reported for Ps. aeruginosa is 32-64 mcg/mL.

Other Gram-Negative Aerobic Bacteria

Ticarcillin disodium and clavulanate potassium is active in vitro against Neisseria meningitidis and penicillinase-producing and nonpenicillinase-producing Neisseria gonorrhoeae. In the presence of 2 mcg/mL of clavulanic acid, the MIC90 of ticarcillin for N. meningitidis and penicillinase-producing and nonpenicillinase-producing N. gonorrhoeae is 0.5 mcg/mL or less. Ticarcillin disodium and clavulanate potassium is active in vitro against both b-lactamase-producing and non-b-lactamase-producing strains of Moraxella catarrhalis (formerly Branhamella or Neisseria catarrhalis). Ticarcillin disodium and clavulanate potassium is active in vitro against some strains of Acinetobacter; however, the drug is generally no more active in vitro on a weight basis than ticarcillin alone against the organism. In one in vitro study, the MIC90 of ticarcillin in the presence of 2 mcg/mL of clavulanic acid was 16 mcg/mL for A. calcoaceticus subsp. anitratus and 32 mcg/mL for A. calcoaceticus subsp. lwoffi.

Anaerobic Bacteria

Ticarcillin disodium and clavulanate potassium is active in vitro against gram-positive anaerobic bacteria including Clostridium, Eubacterium, Peptococcus, and Peptostreptococcus. In the presence of 2 mcg/mL of clavulanic acid, the MIC90 of ticarcillin for Peptococcus and Peptostreptococcus is 2 mcg/mL and the MIC90 of the drug for C. bifermentans, C. difficile, C. perfringens, C. ramosum, and C. sporogenes is 8 mcg/mL. Ticarcillin disodium and clavulanate potassium is also active in vitro against some gram-negative anaerobic bacteria including Bacteroides, Fusobacterium, and Veillonella. The drug is active against many strains of Bacteroides resistant to ticarcillin alone. In one in vitro study, the MIC90 of ticarcillin in the presence of 2 mcg/mL of clavulanic acid was 2 mcg/mL for B. melaninogenicus and 4 mcg/mL for B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, and B. vulgatus. Resistance Strains of ticarcillin-resistant Enterobacter, Pseudomonas aeruginosa, and Serratia marcescens that produce Richmond-Sykes type I chromosomally mediated b-lactamases are also generally resistant to ticarcillin disodium and clavulanate potassium since clavulanic acid does not inhibit most type I b-lactamases.

Pharmacokinetics

Concomitant administration of clavulanate potassium with ticarcillin disodium does not appear to affect the pharmacokinetics of ticarcillin; it is not known if concomitant administration of the drugs affects the pharmacokinetics of clavulanate potassium. For additional information on the absorption, distribution, and elimination of ticarcillin.

Absorption

Although clavulanate potassium is well absorbed following oral administration, ticarcillin disodium is not appreciably absorbed from the GI tract. Therefore, ticarcillin disodium and clavulanate potassium must be administered parenterally. Following IV infusion over 30 minutes of a single 3.1-g dose of the fixed-ratio combination containing 3 g of ticarcillin and 100 mg of clavulanic acid in healthy adults, peak serum concentrations of ticarcillin and of clavulanic acid average 324 and 8 mcg/mL, respectively, immediately following completion of the infusion. At 0.25, 0.5, 1, 1.5, 3.5, and 5.5 hours after completion of the infusion, serum concentrations of ticarcillin average 223, 176, 131, 90, 27, and 6 mcg/mL, respectively, and serum concentrations of clavulanic acid average 4.6, 2.6, 1.8, 1.2, 0.3, and 0 mcg/mL, respectively.

Although the pharmacokinetics of ticarcillin disodium and clavulanate potassium have also been determined using a fixed-ratio combination containing 3 g of ticarcillin and 200 mg of clavulanic acid, this fixed-ratio combination is not commercially available in the US. In one study in children with cystic fibrosis who received the fixed-ratio combination containing 3 g of ticarcillin and 100 mg of clavulanic acid in a single dose of 75 mg/kg of ticarcillin given by IV infusion over 30 minutes, serum concentrations of ticarcillin and of clavulanic acid averaged 241 and 5.2 mcg/mL, respectively, 30 minutes after completion of the infusion and 23 and 0.2 mcg/mL, respectively, 6 hours after completion of the infusion.

Distribution

Following IV administration of ticarcillin disodium and clavulanate potassium, ticarcillin and clavulanic acid are both distributed into blister fluid. Both drugs also are distributed into peritoneal fluid and bone. In one study in healthy adults who received ticarcillin disodium and clavulanate potassium, the apparent volume of distribution of ticarcillin and of clavulanic acid averaged 0.167-0.173 and 0.315-0.342 L/kg, respectively. In children with cystic fibrosis, the volume of distribution of ticarcillin and of clavulanic acid at steady state averaged 0.231 and 0.364 L/kg, respectively.

Only low concentrations of ticarcillin generally are attained in CSF following IV administration of ticarcillin, although CSF concentrations of the drug may be higher when meninges are inflamed than when meninges are uninflamed. In addition, only low concentrations of clavulanic acid are attained in CSF following IV administration. Ticarcillin is 45-65% bound to serum proteins.

At a concentration of 1-100 mcg/mL, clavulanic acid is reportedly 22-30% bound to serum proteins in vivo following oral administration or in vitro. Like other penicillins, ticarcillin probably crosses the placenta and is distributed into milk in low concentrations. Clavulanic acid readily crosses the placenta and is distributed into milk in low concentrations.

Elimination

Serum concentrations of ticarcillin and clavulanic acid both decline in a biphasic manner and half-lives of the drugs are similar. Following IV administration of ticarcillin disodium and clavulanate potassium in adults with normal renal function, ticarcillin has a distribution half-life of 0.27 hours and an elimination half-life of 1.1-1.5 hours and clavulanic acid has a distribution half-life of 0.42 hours and an elimination half-life of 1.1-1.2 hours. In one study in children with cystic fibrosis who received a single IV dose of ticarcillin disodium and clavulanate potassium, the serum half-life of ticarcillin and of clavulanic acid averaged 1.2 and 0.8 hours, respectively.

The metabolic fate of clavulanate potassium has not been fully elucidated; however, the drug appears to be extensively metabolized. In rats and dogs, the major metabolite of clavulanic acid is 1-amino-4-hydroxybutan-2-one; this metabolite has also been found in human urine following administration of clavulanic acid. Clavulanic acid is excreted in urine principally by glomerular filtration. Studies in dogs and rats using radiolabeled clavulanic acid indicate that 34-52, 25-27, and 16-33% of a dose of the drug is excreted in urine, feces, and respired air, respectively.

Following IV administration of a single dose of ticarcillin disodium and clavulanate potassium in adults with normal renal function, approximately 60-70% of the ticarcillin dose and 35-45% of the clavulanic acid dose is excreted unchanged in urine within 6 hours. Following IV infusion over 30 minutes of a single 3.1-g dose of a fixed-ratio combination containing 3 g of ticarcillin and 100 mg of clavulanic acid, urinary concentrations of ticarcillin average 1.5 mg/mL and urinary concentrations of clavulanic acid average 40 mcg/mL in urine collected over the first 2 hours after the dose.

Urinary concentrations of ticarcillin and of clavulanic acid in urine collected 4-6 hours after the dose average 190 and 2 mcg/mL, respectively. In one study in healthy adults who received a single IV dose of ticarcillin disodium and clavulanate potassium, serum clearance of ticarcillin and of clavulanic acid averaged 116 and 241 mL/minute, respectively. Serum concentrations of ticarcillin and of clavulanic acid are higher and the serum half-lives prolonged in patients with renal impairment. In one study in patients with impaired renal function, the elimination half-life of ticarcillin and of clavulanic acid averaged 4.9 and 2.3 hours, respectively, in those with creatinine clearances of 11-37 mL/minute and averaged 8.5 and 2.9 hours, respectively, in those with creatinine clearances less than 8 mL/minute.

Oral probenecid administered shortly before or with ticarcillin disodium and clavulanate potassium competitively inhibits renal tubular secretion of ticarcillin and produces higher and prolonged serum concentrations of ticarcillin; however, probenecid does not appreciably affect the pharmacokinetics of clavulanic acid. Ticarcillin and clavulanic acid are both removed by hemodialysis. Small amounts of ticarcillin and clavulanic acid are also removed by peritoneal dialysis.

Chemistry and Stability

Chemistry

Ticarcillin disodium and clavulanate potassium is a fixed combination of ticarcillin disodium and the potassium salt of clavulanic acid. Ticarcillin is a semisynthetic a-carboxypenicillin and generally is classified as an extended-spectrum penicillin.Clavulanic acid is a b-lactamase inhibitor produced by fermentation of Streptomyces clavuligerus. Clavulanic acid contains a b-lactam ring and is structurally similar to penicillins and cephalosporins; however, the b-lactam ring in clavulanic acid is fused with an oxazolidine ring rather than a thiazolidine ring as in penicillins or a dihydrothiazine ring as in cephalosporins.

Although clavulanic acid has only weak antibacterial activity when used alone, the combined use of clavulanic acid and certain cephalosporins or penicillins (e.g., amoxicillin, ampicillin, carbenicillin, cefoperazone, cefotaxime, penicillin G, ticarcillin) results in a synergistic effect which expands the spectrum of activity of the cephalosporin or penicillin against many strains of b-lactamase-producing bacteria.

Clavulanic acid and its salts currently are commercially available in the US only in fixed combination with other drugs. Ticarcillin disodium and clavulanate potassium is commercially available for IV administration as a sterile powder containing a 30:1 ratio of ticarcillin to clavulanic acid.

Although commercially available ticarcillin disodium and clavulanate potassium contains ticarcillin as the disodium salt and clavulanic acid as the potassium salt, potency of ticarcillin disodium is expressed in terms of ticarcillin and potency of clavulanate potassium is expressed in terms of clavulanic acid; vials of the drug are labeled in terms of the combined potency of the drugs as a fixed-ratio combination. Each vial labeled as containing 3.1 g of the 30:1 ratio of the drugs has a potency of 3 g of ticarcillin and 100 mg of clavulanic acid.

Commercially available sterile ticarcillin disodium and clavulanate potassium occurs as a white to pale yellow powder. The drug has a solubility of more than 600 mg/mL in water at approximately 22°C. Ticarcillin has pKas of 2.55 and 3.42, and clavulanic acid has a pKa of 2.7. Each gram of commercially available sterile powder containing a 30:1 ratio of ticarcillin to clavulanic acid theoretically contains 4.75 mEq of sodium and 0.15 mEq of potassium. When reconstituted as directed, solutions of ticarcillin disodium and clavulanate potassium have a pH of 5.5-7.5 and are clear and colorless or pale yellow in color.

Ticarcillin disodium and clavulanate potassium also is commercially available for IV administration as a frozen injection containing a 30:1 ratio of ticarcillin to clavulanic acid. Each container labeled as containing 3.1 g of the 30:1 ratio of the drugs has a potency of 3 g of ticarcillin and 100 mg of clavulanic acid.

The commercially available frozen ticarcillin disodium and clavulanate potassium in water injection is a clear, light to dark yellow-colored, sterile, nonpyrogenic solution of the drug and has an osmolality of about 285 mOsm/kg. Ticarcillin disodium and clavulanate potassium in water frozen injections contain sodium citrate as a buffer and hydrochloric acid to adjust pH to 5.5-7.5. Sodium hydroxide also is used to convert ticarcillin monosodium to ticarcillin disodium. Each mL of the commercially available frozen injection containing a 30:1 ratio of ticarcillin to clavulanic acid theoretically contains 0.187 mEq of sodium and 0.005 mEq of potassium.

Stability

Commercially available ticarcillin disodium and clavulanate potassium sterile powder should be stored at 24°C or colder. Ticarcillin disodium and clavulanate potassium sterile powder or solutions of the drug should not be exposed to temperatures warmer than 24°C since this could result in degradation of clavulanate potassium. If the sterile powder or solutions of the drug darken, this indicates degradation of clavulanate potassium and a loss of potency. Following reconstitution of vials or pharmacy bulk packages of the drug with sterile water for injection or sodium chloride injection, ticarcillin disodium and clavulanate potassium solutions containing approximately 200 or 300 mg of ticarcillin per mL and 6.7 or 10 mg of clavulanic acid per mL are stable for 6 hours at 21-24°C or 72 hours when refrigerated at 4°C. Reconstituted solutions of the drug that have been further diluted in sodium chloride injection or lactated Ringer’s injection to a ticarcillin concentration of 10-100 mg/mL are stable for 24 hours at 21-24°C or for up to 30 days frozen at -18°C; at 4°C, these solutions are stable for 4 days when prepared from pharmacy bulk packages and for 7 days when prepared from vials.

Reconstituted solutions of the drug that have been further diluted in 5% dextrose injection to a ticarcillin concentration of 10-100 mg/mL are stable for 24 hours at 21-24°C, for 3 days at 4°C, or for up to 7 days frozen at -18°C. Frozen solutions that have been thawed should be used within 8 hours or discarded; once thawed, these solutions should not be refrozen. When prepared from the pharmacy bulk package, reconstituted solutions that have been further diluted in sterile water for injection to a ticarcillin concentration of 10-100 mg/mL are stable for 24 hours at 21-24°C or 4 days at 4°C.

The manufacturer states that the stability of the commercially available ticarcillin disodium and clavulanate potassium frozen injections may vary. These injections are stable for at least 90 days from the date of shipment when stored at -20°C. The frozen injections should be thawed at room temperature (22°C) or under refrigeration (4-5°C) and, once thawed, should not be refrozen.

Thawed solutions of the commercially available frozen injections are stable for 24 hours at room temperature (22°C) or 7 days when refrigerated at 4°C. The commercially available frozen injections of the drugs are provided in plastic containers fabricated from specially formulated multilayered plastic PL 2040 (Galaxy®). Solutions in contact with the plastic can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies. Ticarcillin disodium and clavulanate potassium is incompatible with sodium bicarbonate.

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). For information on the in vitro and in vivo incompatibility of penicillins and aminoglycosides. Because of the potential for incompatibility, the manufacturer recommends that ticarcillin disodium and clavulanate potassium not be admixed with other anti-infective agents. For further information on chemistry and stability, mechanism of action, spectrum, resistance, pharmacokinetics, uses, cautions, drug interactions, and laboratory test interferences of ticarcillin.

Preparations

Ticarcillin Disodium and Clavulanate Potassium Parenteral For injection 3 g (of ticarcillin) and 100 Timentin®, mg (of clavulanic acid) GlaxoSmithKline (labeled as a combined total potency of 3.1 g) 30 g (of ticarcillin) and 1 Timentin®, g (of clavulanic acid) GlaxoSmithKline (labeled as a combined total potency of 31 g) pharmacy bulk package For injection, for 3 g (of ticarcillin) and 100 Timentin® ADD-Vantage®, IV infusion mg (of clavulanic acid) GlaxoSmithKline (labeled as a combined total potency of 3.1 g) Ticarcillin Disodium and Clavulanate Potassium in Water Parenteral Injection (frozen) 30 mg (of ticarcillin) per Timentin® Iso-osmotic in for IV infusion mL (3 g) and 1 mg (of Sterile Water Injection, clavulanic acid) per mL (100 (Galaxy® [Baxter]) mg) (labeled as a combined GlaxoSmithKline total potency of 3.1 g)

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