Introduction

Antibacterial; β-lactam antibiotic; fixed combination of ceftolozane (a fifth generation cephalosporin) and tazobactam (a β-lactamase inhibitor).

Uses for Ceftolozane/Tazobactam (Systemic)

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by susceptible Enterobacter colacae, Escherichia coli, Klebsiella oxytoca, K. pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, S. constellatus, or S. salivarius; used in conjunction with metronidazole.

Urinary Tract Infections

Treatment of complicated urinary tract infections, including pyelonephritis, caused by susceptible E. coli, K. pneumoniae, P. mirabilis, or Ps. aeruginosa.

Ceftolozane/Tazobactam (Systemic) Dosage and Administration

Administration

Administer by IV infusion.

IV Administration

Do not admix with or add to solutions containing other drugs.

Reconstitution

Reconstitute single-dose vials of ceftolozane and tazobactam labeled as containing 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) by adding 10 mL of sterile water for injection or 0.9% sodium chloride injection to the vial; shake gently until contents dissolve.

Dilution

Prior to IV infusion, reconstituted solution must be further diluted.

To prepare indicated dose, withdraw appropriate volume of reconstituted solution from the vial and add to 100 mL of 0.9% sodium chloride or 5% dextrose injection. (See Table 1.) Solution should appear clear and colorless to slightly yellow.

Rate of Administration

Administer by IV infusion over 1 hour.

Dispensing and Dosage and Administration Precautions

FDA alerted healthcare professionals about risk of medication errors with ceftolozane and tazobactam. Errors occurred during preparation of solutions for IV infusion, resulted in administration of incorrect dosage (50% overdosage in some cases), and were due to confusion about how dosage of the fixed combination is expressed (total of the dosage of each of the 2 active components) and how drug strength was displayed on vial labels and carton packaging. To prevent such errors, vial labels and carton packaging were revised to indicate strength of the fixed combination as the total the 2 active components.

Be aware that dosage of ceftolozane and tazobactam is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of ceftolozane plus dosage of tazobactam). Consider this dosage convention when prescribing, preparing, and dispensing ceftolozane and tazobactam. FDA urges healthcare professionals and patients to report medication errors and adverse effects involving the drug to the FDA MedWatch program.

Dosage

Available as fixed combination containing 2:1 ratio of ceftolozane to tazobactam.

Ceftolozane component provided as ceftolozane sulfate (dosage of this component expressed in terms of ceftolozane); tazobactam component provided as tazobactam sodium (dosage of this component expressed in terms of tazobactam).

Dosage of ceftolozane and tazobactam fixed combination expressed in terms of the total of the ceftolozane and tazobactam content.

Each single-dose vial contains a total of 1.5 g (i.e., 1 g of ceftolozane and 0.5 g of tazobactam).

Adults

Intra-abdominal Infections

IV

1.5 g (ceftolozane 1 g and tazobactam 0.5 g) every 8 hours given in conjunction with metronidazole (500 mg IV every 8 hours).

Recommended treatment duration is 4–14 days. Duration depends on site and severity of infection and patient’s clinical and bacteriologic progress.

Urinary Tract Infections

IV

1.5 g (ceftolozane 1 g and tazobactam 0.5 g) every 8 hours.

Recommended treatment duration is 7 days. Duration depends on site and severity of infection and patient’s clinical and bacteriologic progress.

Special Populations

Hepatic Impairment

Dosage adjustments not needed in adults with hepatic impairment.

Renal Impairment

Adjust dosage in adults with Cl_cr ≤50 mL/minute, including those undergoing hemodialysis. (See Table 2.)

Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly.

On hemodialysis days, administer dose as soon as possible after dialysis.

Geriatric Patients

Dosage adjustments based solely on age not needed. Select dosage with caution and monitor renal function since geriatric patients more likely to have decreased renal function than younger adults.

Contraindications

• Known serious hypersensitivity to ceftolozane and/or tazobactam, the fixed combination of piperacillin and tazobactam, or other β-lactams.

Warnings/Precautions

Sensitivity Reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions reported in patients receiving β-lactam antibacterials. Before initiating therapy, carefully inquire about patient's previous hypersensitivity reactions to other cephalosporins, penicillins, or other β-lactams.

Use with caution in patients allergic to cephalosporins, penicillins, or other β-lactams; cross-sensitivity among β-lactams established.

If anaphylactic reaction occurs, discontinue ceftolozane and tazobactam and initiate appropriate therapy.

Reduced Efficacy in Patients with Moderate Renal Impairment

In a subgroup analysis of patients with complicated intra-abdominal infections in a phase 3 clinical trial, clinical cure rate in patients with moderate renal impairment (baseline Cl_cr of 30–50 mL/minute) receiving ceftolozane and tazobactam in conjunction with metronidazole was 47.8% compared with a clinical cure rate of 85.2% in those with normal renal function or only mild renal impairment (Cl_cr ≥50 mL/minute). A similar trend also observed in a clinical trial evaluating ceftolozane and tazobactam for complicated urinary tract infections.

Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly. (See Renal Impairment under Cautions.)

Superinfection/Clostridium difficile-associated Diarrhea and Colitis (CDAD)

Possible emergence and overgrowth of nonsusceptible bacteria or fungi. Monitor carefully, institute appropriate therapy if superinfection occurs.

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile infection (CDI) and C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) reported with nearly all anti-infectives, including ceftolozane and tazobactam, and may range in severity from mild diarrhea to fatal colitis. C. difficile produces toxins A and B which contribute to development of CDAD; hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. Obtain careful medical history since CDAD may occur as late as ≥2 months after anti-infective therapy is discontinued.

If CDAD suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible. Initiate appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of ceftolozane and tazobactam and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for both drugs.

When prescribing, preparing, and dispensing ceftolozane and tazobactam, consider that dosage of the fixed combination is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of ceftolozane plus dosage of tazobactam). (See Dispensing and Dosage and Administration Precautions under Dosage and Administration.)

Specific Populations

Pregnancy

Category B.

Use during pregnancy only if potential benefits to the woman justify potential risks to fetus.

No adequate and well-controlled studies in pregnant women. In animals, no evidence of fetal toxicity with ceftolozane or tazobactam dosages tested; ceftolozane associated with decreased auditory startle response in postnatal day 60 male pups; tazobactam associated with decreased maternal food consumption and body weight gain at end of gestation and increased incidence of stillbirths.

Lactation

Not known whether ceftolozane or tazobactam distributed into human milk.

Use with caution in nursing women.

Pediatric Use

Safety and efficacy not established in patients <18 years of age.

Geriatric Use

Incidence of adverse effects higher in patients ≥65 years of age compared with younger adults.

Clinical cure rate in geriatric patients treated with ceftolozane and tazobactam in conjunction with metronidazole for complicated intra-abdominal infections was 69% compared with cure rate of 82.4% in comparator group. Differences in cure rates between ceftolozane and tazobactam regimen and comparator regimen not observed in geriatric patients with complicated urinary tract infections.

Ceftolozane and tazobactam substantially eliminated by kidneys; risk of adverse effects may be greater in those with impaired renal function. Because geriatric patients are more likely to have reduced renal function, select dosage with caution and consider renal function monitoring. Adjust dosage in geriatric patients based on renal function.

Hepatic Impairment

Ceftolozane and tazobactam do not undergo hepatic metabolism; hepatic impairment not expected to affect systemic clearance.

Renal Impairment

Ceftolozane, tazobactam, and tazobactam metabolite M1 are eliminated by the kidneys.

Adjust dosage in adults with moderate or severe renal impairment (Cl_cr ≤50 mL/minute), including those undergoing hemodialysis. Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly. (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

GI effects (nausea, diarrhea ), headache, pyrexia.

Administration

Administer by IV infusion.

IV Administration

Do not admix with or add to solutions containing other drugs.

Reconstitution

Reconstitute single-dose vials of ceftolozane and tazobactam labeled as containing 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) by adding 10 mL of sterile water for injection or 0.9% sodium chloride injection to the vial; shake gently until contents dissolve.

Dilution

Prior to IV infusion, reconstituted solution must be further diluted.

To prepare indicated dose, withdraw appropriate volume of reconstituted solution from the vial and add to 100 mL of 0.9% sodium chloride or 5% dextrose injection. (See Table 1.) Solution should appear clear and colorless to slightly yellow.

Rate of Administration

Administer by IV infusion over 1 hour.

Dispensing and Dosage and Administration Precautions

FDA alerted healthcare professionals about risk of medication errors with ceftolozane and tazobactam. Errors occurred during preparation of solutions for IV infusion, resulted in administration of incorrect dosage (50% overdosage in some cases), and were due to confusion about how dosage of the fixed combination is expressed (total of the dosage of each of the 2 active components) and how drug strength was displayed on vial labels and carton packaging. To prevent such errors, vial labels and carton packaging were revised to indicate strength of the fixed combination as the total the 2 active components.

Be aware that dosage of ceftolozane and tazobactam is expressed as the total (sum) of the dosage of each of the 2 active components (i.e., dosage of ceftolozane plus dosage of tazobactam). Consider this dosage convention when prescribing, preparing, and dispensing ceftolozane and tazobactam. FDA urges healthcare professionals and patients to report medication errors and adverse effects involving the drug to the FDA MedWatch program.

Dosage

Available as fixed combination containing 2:1 ratio of ceftolozane to tazobactam.

Ceftolozane component provided as ceftolozane sulfate (dosage of this component expressed in terms of ceftolozane); tazobactam component provided as tazobactam sodium (dosage of this component expressed in terms of tazobactam).

Dosage of ceftolozane and tazobactam fixed combination expressed in terms of the total of the ceftolozane and tazobactam content.

Each single-dose vial contains a total of 1.5 g (i.e., 1 g of ceftolozane and 0.5 g of tazobactam).

Adults

Intra-abdominal Infections

IV

1.5 g (ceftolozane 1 g and tazobactam 0.5 g) every 8 hours given in conjunction with metronidazole (500 mg IV every 8 hours).

Recommended treatment duration is 4–14 days. Duration depends on site and severity of infection and patient’s clinical and bacteriologic progress.

Urinary Tract Infections

IV

1.5 g (ceftolozane 1 g and tazobactam 0.5 g) every 8 hours.

Recommended treatment duration is 7 days. Duration depends on site and severity of infection and patient’s clinical and bacteriologic progress.

Special Populations

Hepatic Impairment

Dosage adjustments not needed in adults with hepatic impairment.

Renal Impairment

Adjust dosage in adults with Cl_cr ≤50 mL/minute, including those undergoing hemodialysis. (See Table 2.)

Monitor Cl_cr at least once daily in patients with changing renal function; adjust dosage accordingly.

On hemodialysis days, administer dose as soon as possible after dialysis.

Geriatric Patients

Dosage adjustments based solely on age not needed. Select dosage with caution and monitor renal function since geriatric patients more likely to have decreased renal function than younger adults.

Ceftolozane, tazobactam, and tazobactam metabolite M1 do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and do not induce CYP1A2, 2B6, or 3A4 in vitro. In vitro, ceftolozane, tazobactam, and M1 decreased CYP1A2 and 2B6 enzyme activity and mRNA levels in human hepatocytes. Ceftolozane, tazobactam, and M1 decreased CYP3A4 mRNA levels in vitro at supratherapeutic plasma concentrations; M1 decreased CYP3A4 activity at supratherapeutic plasma concentrations.

Tazobactam is a substrate of organic anion transporter (OAT) 1 and OAT3.

Tazobactam inhibits OAT1 and OAT3 in vitro; ceftolozane does not inhibit OAT1 or OAT3.

Ceftolozane and tazobactam not substrates or inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP); tazobactam not a substrate of organic cation transporter (OCT) 2.

Ceftolozane and tazobactam do not inhibit organic anion transporting polypeptide (OATP) 1B1 or 1B3, or OCT1 or OCT2, or bile salt export pump (BSEP) at therapeutic plasma concentrations.

Ceftolozane does not inhibit multidrug resistance-associated protein (MRP) or multidrug and toxin extrusion (MATE) 1 or 2-K.

The following drug interactions are based on studies using ceftolozane and tazobactam, ceftolozane alone, or tazobactam alone. When ceftolozane and tazobactam used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP enzyme inhibitors or inducers: Drug interactions not expected.

Drugs Affecting or Affected by Organic Anion Transporters

OAT1 and/or OAT3 inhibitors: Possible increased tazobactam plasma concentrations.

OAT1 or OAT3 substrates: Clinically important interactions not expected.

Specific Drugs