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Ticarcillin and Clavulanate Potassium

Pronunciation

(tye kar SIL in & klav yoo LAN ate poe TASS ee um)

Index Terms

  • Ticarcillin and Clavulanic Acid
  • Ticarcillin/K Clavulanate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = discontinued product

Infusion [premixed, frozen]:

Timentin: Ticarcillin 3 g and clavulanic acid 0.1 g (100 mL [DSC]) [contains sodium 4.51 mEq and potassium 0.15 mEq per g]

Injection, powder for reconstitution:

Timentin: Ticarcillin 3 g and clavulanic acid 0.1 g (3.1 g [DSC], 31 g [DSC]) [contains sodium 4.51 mEq and potassium 0.15 mEq per g]

Brand Names: U.S.

  • Timentin [DSC]

Pharmacologic Category

  • Antibiotic, Penicillin

Pharmacology

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs), which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysins and murein hydrolases) while cell wall assembly is arrested.

Distribution

Ticarcillin is distributed into tissue, interstitial fluid, pleural fluid, and bile; low concentrations of ticarcillin distribute into the CSF but increase when meninges are inflamed; Vdss:

Ticarcillin: 0.22 L/kg

Clavulanic acid: 0.4 L/kg

Metabolism

Clavulanic acid is metabolized hepatically

Excretion

Children: Ticarcillin: Urine (71% 50% as unchanged drug over 4 hour); Clavulanic acid: Urine (50% as unchanged drug over 4 hours)

Adults: Ticarcillin: Urine (60% to 70% as unchanged drug); Clavulanic acid: Urine (35% to 45% as unchanged drug)

Time to Peak

Immediately following completion of 30-minute infusion

Half-Life Elimination

Neonates: Ticarcillin: 4.4 hours; Clavulanic acid: 1.9 hours

Children (1 month to 9.3 years): Ticarcillin: 66 minutes; Clavulanic acid: 54 minutes

Adults: Ticarcillin: 66 to 72 minutes; 13 hours (in patients with renal failure); Clavulanic acid: 66 to 90 minutes; clavulanic acid does not affect the clearance of ticarcillin

Protein Binding

Ticarcillin: ~45%; Clavulanic acid: ~25%

Use: Labeled Indications

Bone and joint infections: Treatment of bone and joint infections caused by beta-lactamase-producing isolates of Staphylococcus aureus.

Endometritis: Treatment of endometritis caused by beta-lactamase-producing isolates of Prevotella melaninogenicus, Enterobacter species (including E. cloacae), Klebsiella pneumoniae, Escherichia coli, S. aureus, or Staphylococcus epidermidis.

Lower respiratory tract infections: Treatment of lower respiratory tract infections caused by beta-lactamase-producing isolates of S. aureus, Haemophilus influenzae, or Klebsiella species.

Peritonitis: Treatment of peritonitis caused by beta-lactamase-producing isolates of E. coli, K. pneumonia, or Bacteroides fragilis group.

Septicemia: Treatment of septicemia (including bacteremia) caused by beta-lactamase-producing isolates of Klebsiella species, E. coli, S. aureus, or Pseudomonas aeruginosa (or other Pseudomonas species).

Skin and skin structure infections: Treatment of skin and skin structure infections caused by beta-lactamase-producing isolates of S. aureus, Klebsiella species, or E. coli.

Urinary tract infections: Treatment of complicated and uncomplicated urinary tract infections caused by beta-lactamase-producing isolates of E. coli, Klebsiella species, P. aeruginosa (and other Pseudomonas species), Citrobacter species, Enterobacter cloacae, Serratia marcescens, or S. aureus.

Use: Unlabeled

Treatment of complicated intra-abdominal infections (Solomkin 2010), cystic fibrosis exacerbations (Zobell, 2013)

Contraindications

Hypersensitivity (history of a serious reaction [eg, anaphylaxis, Stevens-Johnson syndrome]) to ticarcillin, clavulanate, or to other beta-lactams (eg, penicillins, cephalosporins)

Dosing: Adult

Note: Timentin (ticarcillin/clavulanate) is a combination product; each 3.1 g dosage form contains 3 g ticarcillin disodium and 0.1 g clavulanic acid.

Gynecologic infections (eg endometritis): IV:

Moderate infections: 200 mg ticarcillin/kg/day in divided doses every 6 hours (maximum: 12 g daily)

Severe infections: 300 mg ticarcillin/kg/day in divided doses every 4 hours (maximum: 18 g daily)

Systemic infections: IV:

<60 kg: 200-300 mg ticarcillin/kg/day in divided doses every 4-6 hours (maximum: 18 g daily)

≥60 kg: 3.1 g every 4-6 hours

Urinary tract infections: IV:

<60 kg: 200-300 mg ticarcillin/kg/day in divided doses every 4-6 hours (maximum: 18 g daily)

≥60 kg: 3.1 g every 4-6 hours

Intra-abdominal infection, complicated, community-acquired, mild-to-moderate (off-label use): IV: 3.1 g every 6 hours for 4-7 days (provided source controlled) (Solomkin, 2010)

Dosing: Geriatric

Refer to adult dosing

Dosing: Pediatric

Note: Timentin (ticarcillin/clavulanate) is a combination product; each 3.1 g dosage form contains 3 g ticarcillin disodium and 0.1 g clavulanic acid.

Mild to moderate infections: Infants ≥3 months, Children, and Adolescents: IV:

<60 kg: 200 mg ticarcillin/kg/day in divided doses every 6 hours (maximum: 12 g daily)

≥60 kg: 3.1 g every 6 hours

Severe infections: Infants ≥3 months, Children, and Adolescents: IV:

<60 kg: 300 mg ticarcillin/kg/day in divided doses every 4 hours. (maximum: 18 g daily)

≥60 kg: 3.1 g every 4 hours

Cystic fibrosis (off-label use): Infants, Children, and Adolescents: IV: 400 mg ticarcillin/kg/day in divided doses every 6 hours; higher doses have been used: 400-750 mg ticarcillin/kg/day in divided doses every 6 hours (maximum: 24-30 g ticarcillin daily) (Zobell, 2013)

Intra-abdominal infection, complicated (off-label use): Infants, Children, and Adolescents: IV: 200-300 mg ticarcillin/kg/day in divided every 4-6 hours (Solomkin, 2010)

Dosing: Renal Impairment

Loading dose: IV: 3.1 g one dose, followed by maintenance dose based on creatinine clearance:

CrCl 30-60 mL/minute: Administer 2 g of ticarcillin component every 4 hours

CrCl 10-30 mL/minute: Administer 2 g of ticarcillin component every 8 hours

CrCl <10 mL/minute: Administer 2 g of ticarcillin component every 12 hours

CrCl <10 mL/minute with concomitant hepatic dysfunction: 2 g of ticarcillin component every 24 hours

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): Dialyzable (20% to 50%): 2 g of ticarcillin component every 12 hours; supplemented with 3.1 g (ticarcillin/clavulanate) after each dialysis session. Alternatively, administer 2 g every 8 hours without a supplemental dose for deep-seated infections (Heintz, 2009). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.

Peritoneal dialysis (PD): 3.1 g every 12 hours

Continuous renal replacement therapy (CRRT) (Heintz, 2009; Trotman, 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1-2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 3.1g followed by 2 g every 6-8 hours

CVVHD: Loading dose of 3.1 g followed by 3.1 g every 6-8 hours

CVVHDF: Loading dose of 3.1 g followed by 3.1 g every 6 hours

Note: Do not administer in intervals exceeding every 8 hours. Clavulanate component is hepatically eliminated; extending the dosing interval beyond 8 hours may result in loss of beta-lactamase inhibition.

Dosing: Hepatic Impairment

With concomitant renal dysfunction (Clcr <10 mL/minute): 2 g of ticarcillin component every 24 hours.

Reconstitution

Reconstitute 3.1 g vials with 13 mL sterile water for injection or NS; shake well; resulting concentration is ticarcillin 200 mg/mL and clavulanic acid 6.7 mg/mL. Reconstitute 31 g bulk vials with 76 mL sterile water for injection or NS; shake well; resulting concentration is ticarcillin 300 mg/mL and clavulanic acid 10 mg/mL. Further dilute to a final concentration of 10-100 mg/mL in D5W, LR, or NS.

Administration

Infuse over 30 minutes.

Some penicillins (eg, carbenicillin, ticarcillin, and piperacillin) have been shown to inactivate aminoglycosides in vitro. This has been observed to a greater extent with tobramycin and gentamicin, while amikacin has shown greater stability against inactivation. Concurrent use of these agents may pose a risk of reduced antibacterial efficacy in vivo, particularly in the setting of profound renal impairment. However, definitive clinical evidence is lacking. If combination penicillin/aminoglycoside therapy is desired in a patient with renal dysfunction, separation of doses (if feasible), and routine monitoring of aminoglycoside levels, CBC, and clinical response should be considered.

Dietary Considerations

Some products may contain potassium and/or sodium.

Compatibility

Stable in D5W, LR, NS, SWFI.

Y-site administration: Incompatible with amphotericin B cholesteryl sulfate complex, azithromycin.

Storage

Vials: Store intact vials at ≤24°C (≤75°F). Reconstituted solution is stable for 6 hours at room temperature and 72 hours when refrigerated. IV infusion in NS or LR is stable for 24 hours at room temperature (21°C to 24°C [70°F to 75°F]), 7 days when refrigerated (4°C [39°F]), or 30 days when frozen (-18°C [0°F]). IV infusion in D5W solution is stable for 24 hours at room temperature (21°C to 24°C [70°F to 75°F]), 3 days when refrigerated (4°C [39°F]), or 7 days when frozen (-18°C [0°F]. After freezing, thawed solution is stable for 8 hours at room temperature. Do not refreeze. Darkening of drug indicates loss of potency of clavulanate potassium.

Premixed solution: Store frozen at ≤-20°C (-4°F). Thawed solution is stable for 24 hours at room temperature (22°C [72°F]) or 7 days under refrigeration at (4°C [39°F]); do not refreeze.

Drug Interactions

Aminoglycosides: Penicillins may decrease the serum concentration of Aminoglycosides. Primarily associated with extended spectrum penicillins, and patients with renal dysfunction. Consider therapy modification

BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Monitor therapy

Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Avoid combination

Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Monitor therapy

Methotrexate: Penicillins may increase the serum concentration of Methotrexate. Monitor therapy

Mycophenolate: Penicillins may decrease serum concentrations of the active metabolite(s) of Mycophenolate. This effect appears to be the result of impaired enterohepatic recirculation. Monitor therapy

Probenecid: May increase the serum concentration of Penicillins. Management: Avoid the routine use of penicillins and probenecid, but this combination may be used advantageously in select cases with careful monitoring. Monitor for toxic effects of penicillins if probenecid is initiated or the dose is increased. Consider therapy modification

Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Consider therapy modification

Tetracycline Derivatives: May diminish the therapeutic effect of Penicillins. Consider therapy modification

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 3 days after cessation of antibacterial agents. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): Penicillins may enhance the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

Positive Coombs' test, false-positive urinary proteins

Some penicillin derivatives may accelerate the degradation of aminoglycosides in vitro, leading to a potential underestimation of aminoglycoside serum concentration.

Adverse Reactions

Frequency not defined.

Cardiovascular: Local thrombophlebitis (with IV injection)

Central nervous system: Confusion, drowsiness, headache, seizure

Dermatologic: Skin rash

Endocrine & metabolic: Electrolyte disturbance, hypernatremia, hypokalemia

Gastrointestinal: Clostridium difficile diarrhea, diarrhea, nausea

Genitourinary: Proteinuria (false positive)

Hematologic & oncologic: Bleeding complication, eosinophilia, hemolytic anemia, positive direct Coombs' test (false positive)

Hepatic: Hepatotoxicity, increased serum ALT, increased serum AST, jaundice

Immunologic: Jarisch Herxheimer reaction

Infection: Superinfection (fungal or bacterial)

Renal: Interstitial nephritis (acute)

Miscellaneous: Anaphylaxis

Postmarketing and/or case reports (Limited to important or life-threatening): Altered sense of smell, chest discomfort, chills, decreased hematocrit, decreased hemoglobin, decreased serum potassium, dizziness, dysgeusia, erythema multiforme, flatulence, headache, hemorrhagic cystitis, hypersensitivity reaction, hypouricemia, increased blood urea nitrogen, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum creatinine, injection site reaction (burning, induration, pain, swelling), leukopenia, myalgia, myoclonus, neutropenia, prolonged prothrombin time, pruritus, pseudomembranous colitis (during or after antibacterial treatment), Stevens-Johnson syndrome, stomatitis, thrombocytopenia, toxic epidermal necrolysis, urticaria

Warnings/Precautions

Concern related to adverse effects:

• Hypersensitivity reactions: Serious and occasionally severe or fatal hypersensitivity (anaphylactic) reactions have been reported in patients on penicillin therapy, especially with a history of beta-lactam hypersensitivity, history of sensitivity to multiple allergens, or previous IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria). Use with caution in asthmatic patients.

• Bleeding disorders: Particularly in patients with renal impairment, bleeding disorders have been observed; discontinue if thrombocytopenia or bleeding occurs.

• Hypokalemia: Hypokalemia has been reported; monitor serum potassium in patients with fluid and electrolyte imbalance and in patients receiving prolonged therapy.

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Heart failure (HF): Use with caution in patients with HF, due to high sodium load.

• Renal impairment: Use with caution in patients with renal impairment; dosage adjustment recommended.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.

Monitoring Parameters

Observe for signs and symptoms of anaphylaxis during first dose; serum electrolytes, bleeding time, and periodic tests of renal, hepatic, and hematologic function

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Ticarcillin and clavulanate cross the placenta (Maberry, 1992). Maternal use of penicillins has generally not resulted in an increased risk of adverse fetal effects (Crider, 2009; Santos, 2011). Ticarcillin/clavulanate is approved for the treatment of postpartum gynecologic infections, including endometritis, caused by susceptible organisms.

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