AHFS Class:

• Fifth Generation Cephalosporins 8:12.06.20

Generic Name(s):

• Ceftolozane Sulfate and Tazobactam Sodium

• Ceftolozane Sulfate

• Tazobactam Sodium

Ceftolozane sulfate and tazobactam sodium is a fixed combination of ceftolozane (a fifth generation cephalosporin) and tazobactam (a β-lactamase inhibitor);1,2 tazobactam inactivates certain bacterial β-lactamases and expands ceftolozane's spectrum of activity against some bacteria that produce these β-lactamases.1,3,6,11,13,21

Intra-abdominal Infections

Ceftolozane and tazobactam is used in conjunction with metronidazole for the 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 .1

Clinical Experience

Efficacy and safety of ceftolozane and tazobactam for the treatment of complicated intra-abdominal infections are based on results from 2 identical phase 3, randomized, double-blind, placebo-controlled studies in 979 hospitalized adults with complicated intra-abdominal infections, including appendicitis, cholecystitis, diverticulitis, gastric or duodenal perforation, intestinal perforation, or other causes of intra-abdominal abscesses and peritonitis.1,4 Patients were randomized in a 1:1 ratio to receive 4-14 days of treatment with the fixed combination of ceftolozane and tazobactam (1.5 g [ceftolozane 1 g and tazobactam 0.5 g] given by IV infusion every 8 hours) in conjunction with metronidazole (500 mg given by IV infusion every 8 hours) or treatment with meropenem (1 g given by IV infusion every 8 hours) in conjunction with placebo.1,4 Baseline characteristics were similar between groups (mean age 50-51 years, 56-60% male, 93-94% white, 75% from Eastern Europe, 6.3% from the US, 45-49% with diagnosis of appendiceal perforation or abscess).1,4 In a pooled analysis of both studies, the clinical cure rate (defined as complete resolution or marked improvement in signs and symptoms of the index infection at the test-of-cure visit [24-32 days after first treatment dose]) in the microbiological intent-to-treat (MITT) population was 83% in patients treated with ceftolozane and tazobactam in conjunction with metronidazole and 87.3% in those treated with meropenem.1,4 Based on clinical cure rate in the MITT population at the test-of-cure visit, ceftolozane and tazobactam in conjunction with metronidazole was noninferior to meropenem.4 When results were stratified according to causative organism, clinical cure rates at the test-of-cure visit in patients treated with ceftolozane and tazobactam in conjunction with metronidazole were 80.8% for E. cloacae , 84.7% for E. coli , 87.5% for K. oxytoca , 75.6% for K. pneumoniae , 91.7% for P. mirabilis , 79% for Ps. aeruginosa , 89.4% for B. fragilis , 84.4% for B. ovatus , 84% for B. thetaiotaomicron , 80% for B. vulgatus , 72.2% for S. anginosus , 75% for S. constellatus , and 81.8% for S. salivarius .1

Urinary Tract Infections

Ceftolozane and tazobactam is used for the treatment of complicated urinary tract infections, including pyelonephritis, caused by susceptible E. coli , K. pneumoniae , P. mirabilis , or Ps. aeruginosa .1

Clinical Experience

Efficacy of ceftolozane and tazobactam for the treatment of complicated urinary tract infections is based on results from a phase 3 randomized, double-blind clinical trial in 1068 hospitalized adults with complicated urinary tract infections, including pyelonephritis.1 Patients were randomized to receive 7 days of treatment with the fixed combination of ceftolozane and tazobactam (1.5 g [ceftolozane 1 g and tazobactam 0.5 g] given by IV infusion every 8 hours) or levofloxacin (750 mg given by IV infusion once daily).1 The MITT population had a median age of 51 years, 74% were female, 82% were diagnosed with pyelonephritis, 76% were enrolled in Eastern Europe, and 1.8% were enrolled in the US.1 The composite end point of microbiologic and clinical cure rate (defined as complete resolution or marked improvement in signs and symptoms and microbiologic eradication at the test-of-cure visit [approximately 7 days after the last treatment dose]) in the MITT population was 76.9% in patients treated with ceftolozane and tazobactam and 68.4% in those treated with levofloxacin.1 When results were stratified according to causative organism, the composite end point of microbiologic and clinical cure rates at the test-of-cure visit in patients treated with ceftolozane and tazobactam were 81% for E. coli , 66.7% for K. pneumoniae , 91.7% for P. mirabilis , and 75% for Ps. aeruginosa .1

Administration

Ceftolozane and tazobactam is administered by IV infusion.1

IV Infusion

IV solutions of ceftolozane and tazobactam should not be admixed with or added to solutions containing other drugs.1

Reconstitution and Dilution

Ceftolozane and tazobactam powder must be reconstituted and further diluted prior to IV infusion.1

Single-dose vials of ceftolozane and tazobactam labeled as containing 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) should be reconstituted by adding 10 mL of sterile water for injection or 0.9% sodium chloride injection to the vial and shaking gently until the contents are dissolved.1 Reconstituted ceftolozane and tazobactam solutions may be stored for up to 1 hour prior to transfer and dilution;1 reconstituted solutions should not be frozen.1

Prior to IV infusion, reconstituted ceftolozane and tazobactam solutions must be further diluted.1 To prepare the indicated dose, the appropriate volume of reconstituted solution should be withdrawn from the vial and added to 100 mL of 0.9% sodium chloride or 5% dextrose injection.1 (See Table 1.)

The reconstituted and diluted solution of ceftolozane and tazobactam should be inspected visually for particulate matter and discoloration prior to administration;1 the solution should appear clear and colorless to slightly yellow.1

Following reconstitution and dilution, ceftolozane and tazobactam solutions may be stored at room temperature for up to 24 hours or at 2-8°C for up to 7 days;1 diluted solutions should not be frozen.1

Rate of Administration

IV infusions of ceftolozane and tazobactam should be given over 1 hour.1

Dispensing and Dosage and Administration Precautions

FDA alerted healthcare professionals about the risk of medication errors with ceftolozane and tazobactam.22 There have been reports of errors occurring during preparation of IV solutions of the drug that resulted in administration of incorrect dosage (50% overdosage in some cases); the errors were due to confusion about how dosage of ceftolozane and tazobactam 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.22 To prevent such errors, vial labels and carton packaging have been revised to indicate the strength of the fixed combination as the total of the 2 active components.22

Healthcare professionals should 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).1,22 This dosage convention should be considered when prescribing, preparing, and dispensing ceftolozane and tazobactam.22 FDA urges healthcare professionals and patients to report any medication errors and adverse effects involving the drug to the FDA MedWatch program.22

Dosage

Ceftolozane and tazobactam is a fixed combination containing a 2:1 ratio of ceftolozane to tazobactam.1

The ceftolozane component is provided as ceftolozane sulfate (dosage of this component is expressed in terms of ceftolozane);1 the tazobactam component is provided as tazobactam sodium (dosage of this component is expressed in terms of tazobactam).1

Dosage of the fixed combination of ceftolozane and tazobactam is expressed in terms of the total of the ceftolozane and tazobactam content.1

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

Adult Dosage

Intra-abdominal Infections

The recommended dosage of ceftolozane and tazobactam for the treatment of complicated intra-abdominal infections in adults is 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) every 8 hours in conjunction with metronidazole (500 mg given by IV infusion every 8 hours).1

The recommended duration of treatment is 4-14 days.1 Duration should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress.1

Urinary Tract Infections

The recommended dosage of ceftolozane and tazobactam for the treatment of complicated urinary tract infections in adults is 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) every 8 hours.1

The recommended duration of treatment is 7 days.1 Duration should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress.1

Dosage in Renal Impairment

Dosage of ceftolozane and tazobactam must be adjusted in adults with creatinine clearances of 50 mL/minute or less, including those undergoing hemodialysis.1 (See Table 2.)

Creatinine clearance should be monitored at least once daily in patients with changing renal function and dosage of ceftolozane and tazobactam adjusted accordingly.1

Dosage in Hepatic Impairment

Dosage adjustments are not needed when ceftolozane and tazobactam is used in adults with hepatic impairment.1

Dosage in Geriatric Patients

Dosage adjustments based solely on age are not needed when ceftolozane and tazobactam is used in geriatric patients.1 However, because geriatric patients are more likely to have decreased renal function and because dosage of ceftolozane and tazobactam needs to be adjusted based on renal impairment, dosage should be selected with caution and it may be useful to monitor renal function.1

Adverse Effects

Adverse effects reported in 5% or more of patients receiving ceftolozane and tazobactam in phase 3 clinical trials include GI effects (nausea,1,4 diarrhea1,4 ), headache,1 and pyrexia.1,4

Precautions and Contraindications

Sensitivity Reactions

Ceftolozane and tazobactam is contraindicated in patients with known serious hypersensitivity to ceftolozane and/or tazobactam, the fixed combination of piperacillin and tazobactam, or other β-lactams.1

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactam antibacterials.1 Before initiating therapy with ceftolozane and tazobactam, the clinician should carefully inquire about the patient's previous hypersensitivity reactions to other cephalosporins, penicillins, or other β-lactams.1 Ceftolozane and tazobactam should be used with caution in patients allergic to cephalosporins, penicillins, or other β-lactams since cross-sensitivity among β-lactam antibacterials has been established.1

Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment.1

If an anaphylactic reaction occurs, ceftolozane and tazobactam should be discontinued and appropriate therapy initiated.1

Reduced Efficacy in Patients with Moderate Renal Impairment

Results of a subgroup analysis of a phase 3 clinical trial in patients with complicated intra-abdominal infections indicated that the clinical cure rate in patients with moderate renal impairment (baseline creatinine clearances of 30-50 mL/minute) was lower than the clinical cure rate in those with normal renal function or only mild renal impairment (creatinine clearances of 50 mL/minute or greater), and this difference was more marked in those treated with ceftolozane and tazobactam in conjunction with metronidazole than in those treated with the comparator drug (meropenem).1 The clinical cure rate in patients treated with ceftolozane and tazobactam in conjunction with metronidazole was 47.8% in those with baseline creatinine clearances of 30-50 mL/minute compared with 85.2% in those with baseline creatinine clearances of 50 mL/minute or greater.1 A similar trend also was observed in a clinical trial evaluating ceftolozane and tazobactam for treatment of complicated urinary tract infections.1

Creatinine clearance should be monitored at least once daily in patients with changing renal function and dosage of ceftolozane and tazobactam adjusted accordingly.1 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)

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

Use of ceftolozane and tazobactam may result in emergence and overgrowth of nonsusceptible bacteria or fungi.1 The patient should be carefully monitored and appropriate therapy instituted if superinfection occurs.1

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,12,14,15 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported in patients receiving nearly all anti-infectives, including ceftolozane and tazobactam, and may range in severity from mild diarrhea to fatal colitis.1,12,14,15 C. difficile produces toxins A and B which contribute to development of CDAD;1,12 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.1

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,12,14,15 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,12 Patients should be managed with 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.1,12,14,15

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of ceftolozane and tazobactam and other antibacterials, the drug should be used only for treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Patients should be advised that antibacterials (including ceftolozane and tazobactam) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with ceftolozane and tazobactam or other antibacterials in the future.1

Precautions Related to Use of Fixed Combinations

When ceftolozane and tazobactam is used, the cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination must be considered.1 Cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) should be considered for each drug.1

When prescribing, preparing, and dispensing ceftolozane and tazobactam, healthcare professionals should 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).1 (See Dispensing and Dosage and Administration Precautions under Administration; IV Infusion, in Dosage and Administration.)

Other Precautions and Contraindications

Ceftolozane and tazobactam are substantially eliminated by the kidneys, and the risk of adverse reactions may be greater in patients with renal impairment.1 In addition, a lower cure rate has been reported in some patients with moderate renal impairment (see Reduced Efficacy in Patients with Moderate Renal Impairment under Cautions: Precautions and Contraindications).1 Dosage of ceftolozane and tazobactam should be adjusted in patients with moderate or severe renal impairment (creatinine clearances of 50 mL/minute or less), including those undergoing hemodialysis.1 In patients with changing renal function, creatinine clearance should be monitored at least once daily and dosage adjusted accordingly.1 (See Dosage and Administration: Dosage in Renal Impairment.)

Pediatric Precautions

Safety and efficacy of ceftolozane and tazobactam have not been established in patients younger than 18 years of age.1

Geriatric Precautions

In phase 3 trials evaluating ceftolozane and tazobactam for the treatment of complicated intra-abdominal infections or complicated urinary tract infections, 24.6% of patients were 65 years of age or older, while about 11% were 75 years of age or older.1 The incidence of adverse effects reported in geriatric patients treated with ceftolozane and tazobactam was higher than that reported in younger adults treated with the drug.1 In addition, in adults 65 years of age or older with complicated intra-abdominal infections, the clinical cure rate was 69% in those treated with ceftolozane and tazobactam in conjunction with metronidazole compared with 82.4% in those treated with the comparator drug.1 A difference in cure rates between the ceftolozane and tazobactam regimen and the comparator regimen was not observed in geriatric patients with complicated urinary tract infections.1

Ceftolozane and tazobactam are substantially eliminated by the kidneys, and the risk of adverse effects may be greater in those with impaired renal function.1 Because geriatric patients are more likely to have reduced renal function, dosage should be selected with caution and renal function monitoring should be considered.1 Dosage adjustments in geriatric patients should be based on renal function.1

Pregnancy, Fertility, and Lactation

Pregnancy

Embryofetal development studies in mice and rats using ceftolozane dosages associated with exposures approximately 7 and 4 times, respectively, the exposure expected in humans receiving a ceftolozane dosage of 1 g three times daily did not reveal evidence of fetal toxicity.1 In a study in rats, ceftolozane administered during pregnancy and lactation was associated with decreased auditory startle response in male pups at postnatal day 60.1

Embryofetal development studies in rats using tazobactam dosages approximately 19 times the recommended human dosage revealed evidence of maternal toxicity (decreased food consumption and body weight gain), but no evidence of fetal toxicity.1 In a study in rats, tazobactam administered during pregnancy and lactation in dosages approximately 8 times the recommended human dosage produced decreased maternal food consumption and body weight gain at the end of gestation and an increased incidence of stillbirths.1 Although pups of dams receiving tazobactam in dosages of 320-1280 mg/kg daily had substantially reduced postnatal body weight at 21 days after delivery, there was no evidence of effects on development, function, learning, or fertility of the pups.1

There are no adequate and controlled studies using ceftolozane and tazobactam in pregnant women, and the drug should be used during pregnancy only if potential benefits to the woman justify potential risks to the fetus.1

Fertility

Ceftolozane showed no evidence of impaired fertility in male or female rats receiving ceftolozane dosages approximately 3 times higher than the recommended human dosage based on mean plasma exposure.1

Tazobactam showed no evidence of impaired fertility in male or female rats receiving tazobactam dosages approximately 4 times higher than the recommended human dosage based on body surface area.1

Lactation

Because it is not known whether ceftolozane or tazobactam is distributed into human milk, the fixed combination of ceftolozane and tazobactam should be used with caution in nursing women.1

The following drug interactions are based on studies using the fixed combination containing ceftolozane and tazobactam, ceftolozane alone, or tazobactam alone.1 When ceftolozane and tazobactam is used, interactions associated with both drugs in the fixed combination should be considered.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Drug interactions are not expected between ceftolozane and tazobactam and inhibitors or inducers of cytochrome P-450 (CYP) enzymes.1

In vivo data indicate ceftolozane and tazobactam is not a substrate for CYP enzymes.1 In vitro, ceftolozane, tazobactam, and the M1 metabolite of tazobactam do not inhibit CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 and do not induce CYP1A2, 2B6, or 3A4 at therapeutic concentrations.1

Results from in vitro induction studies show that ceftolozane, tazobactam, and the M1 metabolite of tazobactam decrease CYP1A2 and 2B6 enzyme activity and mRNA levels in human hepatocytes and decrease CYP3A4 mRNA levels at supratherapeutic plasma concentrations.1 In addition, the M1 metabolite of tazobactam decreased CYP3A4 activity at supratherapeutic plasma concentrations.1 A clinical drug interaction study showed that drug interactions involving inhibition of CYP1A2 or 3A4 by ceftolozane and tazobactam are not expected.1

Drugs Affecting or Affected by Organic Anion Transporters

Tazobactam is a substrate of organic anion transporter (OAT) 1 and OAT3.1 Therefore, concomitant use of OAT1 and/or OAT3 inhibitors (e.g., probenecid) with ceftolozane and tazobactam may increase tazobactam plasma concentrations.1 (See Drug Interactions: Probenecid.)

In vitro, tazobactam inhibits OAT1 and OAT3;1 ceftolozane does not inhibit OAT1 or OAT3.1 Clinically important interactions involving OAT1 or OAT3 inhibition by ceftolozane and tazobactam are not expected.1

Drugs Affecting or Affected by Other Membrane Transporters

In vitro, ceftolozane and tazobactam are not substrates or inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP);1 tazobactam is not a substrate of organic cation transporter (OCT) 2.1

In vitro data indicate that ceftolozane and tazobactam do not inhibit organic anion transporting polypeptide (OATP) 1B1 or 1B3, organic cation transporter (OCT) 1 or 2, or bile salt export pump (BSEP) at therapeutic plasma concentrations.1 In addition, ceftolozane does not inhibit multidrug resistance-associated protein (MRP) or multidrug and toxin extrusion (MATE) 1 or 2-K.1

Anti-infectives

There is no in vitro evidence of antagonistic antibacterial effects between ceftolozane and tazobactam and amikacin, aztreonam, daptomycin, levofloxacin, linezolid, meropenem, metronidazole, rifampin, tigecycline, or vancomycin.1

Probenecid

Concomitant use of probenecid (an OAT1/OAT3 inhibitor) prolongs the half-life of tazobactam by 71%.1

Mechanism of Action

Ceftolozane and tazobactam is bactericidal in action.1,21

Like other cephalosporins, the antibacterial activity of ceftolozane results from inhibition of mucopeptide synthesis in the bacterial cell wall and is mediated through binding to penicillin-binding proteins (PBPs).1,3,10,21

Tazobactam is a β-lactam β-lactamase inhibitor that inactivates certain β-lactamases, including some extended-spectrum β-lactamases (ESBLs).1,3,5,21,28 Tazobactam binds to and forms covalent, irreversible, acyl-enzyme intermediates with certain β-lactamases.5,21,28 After this complex is formed, functional inhibition of the β-lactamase depends on the relative rates of deacylation, tautomerization, or hydrolysis of the complex.21,28 Tazobactam inactivates many β-lactamases in Ambler class A (e.g., penicillinases, ESBLs) and some in class C (e.g., cephalosporinases such as AmpC).1,3,5,21,28 Tazobactam cannot inactivate Ambler class A carbapenemases (e.g., Klebsiella pneumoniae carbapenemases [KPCs]), Ambler class D β-lactamases, or Ambler class B metallo-β-lactamases (MLBs).1,5,28

Because tazobactam inactivates certain β-lactamases, concomitant use with ceftolozane can protect ceftolozane from degradation by these β-lactamases and expand the spectrum of activity of the cephalosporin to include some β-lactamase-producing bacteria that are resistant to ceftolozane alone.1,2,3,6,11,13,21

Spectrum

Based on its spectrum of activity, ceftolozane and tazobactam is classified as a fifth generation cephalosporin.1,2

Ceftolozane and tazobactam has a wider spectrum of activity than ceftolozane alone.1,3,5,6,21 Ceftolozane and tazobactam is active against many gram-negative aerobic and anaerobic bacteria and select gram-positive bacteria.1,3,5,6,9,21 Ceftolozane and tazobactam is active in vitro against many β-lactamase-producing gram-negative bacteria that are resistant to ceftolozane alone, including Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBLs).1,3,5,6,9,11,13,21

Some bacteria that are resistant to other cephalosporins and/or other anti-infectives because of β-lactamase production may be susceptible to ceftolozane and tazobactam.3 The fixed combination also is active in vitro against some bacteria resistant to other β-lactams (e.g., carbapenems) because of loss of outer membrane porin (OprD).3

In Vitro Susceptibility Testing

When in vitro susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), clinical isolates identified as susceptible to ceftolozane and tazobactam are inhibited by drug concentrations usually achievable when dosage recommended for the site of infection is used.1 A report of intermediate should be considered equivocal and, if the isolate is not fully susceptible to alternative anti-infectives, the test should be repeated.1 The intermediate category implies possible clinical applicability in body sites where the drug is physiologically concentrated and provides a buffer zone which should prevent small, uncontrolled technical factors from causing major discrepancies in interpretation.1 If results of in vitro susceptibility testing indicate that a clinical isolate is resistant to ceftolozane and tazobactam, the strain is not likely to be inhibited by drug concentrations generally achievable with usual dosage schedules and other anti-infective therapy should be selected.1

Disk Susceptibility Tests

When the disk-diffusion procedure is used to test susceptibility to ceftolozane and tazobactam, a disk containing 30 mcg of ceftolozane and 10 mcg of tazobactam is used.1

When disk-diffusion susceptibility testing is performed according to CLSI standardized procedures, Ps. aeruginosa with growth inhibition zones of 21 mm or greater are susceptible to ceftolozane and tazobactam, those with zones of 17-20 mm have intermediate susceptibility, and those with zones of 16 mm or less are resistant to the drug.1

Dilution Susceptibility Tests

When dilution susceptibility testing (agar or broth dilution) is used to test susceptibility to ceftolozane and tazobactam, tests should be performed using serial dilutions of ceftolozane combined with a fixed tazobactam concentration of 4 mcg/mL.1

When dilution susceptibility testing is performed according to CLSI standardized procedures, Enterobacteriaceae with ceftolozane MICs of 2 mcg/mL or less in the presence of 4 mcg/mL of tazobactam are susceptible to ceftolozane and tazobactam, isolates with ceftolozane MICs of 4 mcg/mL in the presence of 4 mcg/mL of tazobactam have intermediate resistance, and those with ceftolozane MICs of 8 mcg/mL or greater in the presence of 4 mcg/mL of tazobactam are resistant to the drug.1

When susceptibility of Ps. aeruginosa is tested using dilution susceptibility testing, those with ceftolozane MICs of 4 mcg/mL or less in the presence of 4 mcg/mL of tazobactam are susceptible to ceftolozane and tazobactam, isolates with ceftolozane MICs of 8 mcg/mL in the presence of 4 mcg/mL of tazobactam have intermediate susceptibility, and those with ceftolozane MICs of 16 mcg/mL or greater in the presence of 4 mcg/mL of tazobactam are resistant to the drug.1

When susceptibility of Bacteroides fragilis , Streptococcus anginosus , S. constellatus , or S. salivarius is tested using dilution susceptibility testing, isolates with ceftolozane MICs of 8 mcg/mL or less in the presence of 4 mcg/mL of tazobactam are susceptible to ceftolozane and tazobactam, those with ceftolozane MICs of 16 mcg/mL in the presence of 4 mcg/mL of tazobactam have intermediate susceptibility, and those with ceftolozane MICs of 32 mcg/mL or greater in the presence of 4 mcg/mL of tazobactam are resistant to the drug.1

Gram-positive Aerobic Bacteria

Ceftolozane and tazobactam is active in vitro against Streptococcus anginosus ,1 S. constellatus ,1 S. salivarius ,1 S. agalactiae (group B streptococci, GBS),1 S. intermedius ,1 S. pyogenes (group A β-hemolytic streptococci, GAS),1 and S. pneumoniae .1

Gram-negative Aerobic Bacteria

Ceftolozane and tazobactam is active in vitro against many Enterobacteriaceae, including Enterobacter aerogenes ,1 E. cloacae ,1 Escherichia coli ,1,6,9,11 Klebsiella oxytoca ,1,9 K. pneumoniae ,1,6,9,11 Proteus mirabilis ,1,6,9 P. vulgaris ,1 Citrobacter freundii ,1 C. koseri ,1 Morganella morganii ,1 Providencia rettgeri ,1 P. stuartii ,1 Serratia liquefacians ,1 and S. marcescens .1 The fixed combination is active in vitro against some Enterobacteriaceae that produce one or more ESBLs, including certain TEM, SHV, CTX-M, or OXA β-lactamases.1,5,21

Ceftolozane and tazobactam is active in vitro against Ps. aeruginosa , including some multidrug-resistant (MDR) strains.1,3,5,6,7,8,9,11,16,21 The fixed combination is active in vitro against Ps. aeruginosa resistant to some others drugs (e.g., ceftazidime, ciprofloxacin, imipenem, piperacillin and tazobactam, tobramycin) because of chromosomal AmpC β-lactamase, reduction in cell permeability because of loss of OprD, and/or up-regulation of efflux pumps (e.g., MexXY, MexAB).1,3,6,7,8,16

Ceftolozane and tazobactam is active in vitro against Acinetobacter baumannii ,1 Burkholderia cepacia ,1 Haemophilus influenzae ,1 Moraxella catarrhalis ,1 and Pantoea agglomerans .1

Anaerobic Bacteria

Ceftolozane and tazobactam is active in vitro against some gram-negative anaerobic bacteria, including some strains of Bacteroides fragilis ,1,6,17 Fusobacterium ,1,17 and Prevotella .1,17

The fixed combination also is active in vitro against some gram-positive anaerobic bacteria, including Propionibacterium .17

Resistance

Resistance or reduced susceptibility to ceftolozane and tazobactam can occur.1,21

Bacteria that produce Ambler class B metallo-β-lactamases (MLBs) or serine carbapenemases (such as Klebsiella pneumoniae carbapenemase [KPC]) are resistant to ceftolozane and tazobactam because tazobactam does not inhibit these types of β-lactamases.1,3,21 Although some isolates of Escherichia coli and K. pneumoniae producing β-lactamases in certain enzyme groups (e.g., CTX-M, OXA, TEM, SHV) were susceptible to ceftolozane and tazobactam in vitro, other isolates of E. coli and K. pneumoniae producing β-lactamases in these enzyme groups were resistant to the drug.1 Pseudomonas aeruginosa with reduced susceptibility or resistance to ceftolozane and tazobactam have been produced in vitro.16

Cross-resistance between ceftolozane and tazobactam and other cephalosporins may occur;1,16 however, some bacteria resistant to other cephalosporins may be susceptible to ceftolozane and tazobactam.1

Pharmacokinetics

Following IV administration of the fixed combination of ceftolozane sulfate and tazobactam sodium, pharmacokinetic parameters for ceftolozane and tazobactam are similar to those reported when each drug is administered alone.18,23 In addition, pharmacokinetic parameters are similar following single or multiple IV doses of the fixed combination.1,18

Absorption

Peak plasma concentrations and areas under the plasma concentration-time curve (AUCs) of both ceftolozane and tazobactam increase in proportion to the dose of ceftolozane and tazobactam.1

In healthy adults with normal renal function receiving multiple doses of ceftolozane and tazobactam (1.5 g [ceftolozane 1 g and tazobactam 0.5 g]) given by IV infusion over 1 hour every 8 hours for 10 days, peak plasma concentrations of ceftolozane and tazobactam are 74.4 and 18 mcg/mL, respectively, and are attained at approximately 1 hour.1,18

There is no appreciable accumulation of ceftolozane or tazobactam in adults with normal renal function following multiple doses of ceftolozane and tazobactam given by IV infusion every 8 hours for 10 days.1,18,23

In a population pharmacokinetic analysis, age, gender, and race did not result in clinically important differences in ceftolozane and tazobactam exposures.1

Distribution

The steady-state volumes of distribution of ceftolozane and tazobactam are 13.5 and 18.2 L, respectively, in healthy adult males following a single IV dose of ceftolozane and tazobactam, suggesting that both drugs distribute into extracellular space.1

Ceftolozane and tazobactam were both distributed into pulmonary epithelial lining fluid following IV administration of ceftolozane and tazobactam in healthy adults.20

Ceftolozane is approximately 16-21% bound to plasma proteins;1 tazobactam is 30% bound to plasma proteins.1

It is not known whether ceftolozane crosses the placenta.1 Tazobactam crosses the placenta in rats;1 fetal concentrations in rats are 10% or less of maternal plasma concentrations.1

It is not known whether ceftolozane or tazobactam is distributed into human milk.1

Elimination

Ceftolozane does not appear to be metabolized to any appreciable extent.1,23 Tazobactam is partially metabolized by hydrolysis of the β-lactam ring to form an inactive metabolite, M1.1

Ceftolozane, tazobactam, and the MI metabolite of tazobactam are eliminated by the kidneys.1,18,23 Following a single IV dose of ceftolozane and tazobactam (1.5 g [ceftolozane 1 g and tazobactam 0.5 g]) in healthy adult males, more than 95% of the ceftolozane dose is eliminated in urine unchanged and more than 80% of the tazobactam dose is eliminated in urine unchanged (the remainder is eliminated as the M1 metabolite).1

The plasma elimination half-lives of ceftolozane and tazobactam are approximately 3 and 1 hour, respectively, following multiple doses of ceftolozane and tazobactam in healthy adults with normal renal function.1,18

In adults with mild, moderate, or severe renal impairment, the dose-normalized geometric mean AUC of ceftolozane is increased by 1.26-, 2.5-, or 5-fold, respectively, and the dose-normalized geometric mean AUC of tazobactam is increased by 1.3-, 2-, or 4-fold, respectively, compared with AUCs reported in healthy individuals with normal renal function.1,19

Both ceftolozane and tazobactam are removed by hemodialysis.1,19 In adults with end-stage renal disease, a 4-hour hemodialysis session decreases the AUC of ceftolozane and tazobactam by approximately 66 and 56%, respectively.1,19

Chemistry and Stability

Chemistry

Ceftolozane sulfate and tazobactam sodium is a fixed combination of ceftolozane (a fifth generation cephalosporin antibiotic) and tazobactam (a β-lactamase inhibitor);1,2 tazobactam inactivates certain bacterial β-lactamases and expands ceftolozane's spectrum of activity against some bacteria that produce these β-lactamases.1,3,11,13,21

Ceftolozane is structurally similar to ceftazidime and contains an aminothiadiazole ring that enhances antibacterial activity against gram-negative bacteria, an oxime group that contributes to stability in the presence of β-lactamases, and a dimethylacetic acid moiety that provides enhanced antipseudomonal activity.21 Unlike ceftazidime, ceftolozane contains a pyrazole ring at the 3-position of the cephem ring which prevents hydrolysis and improves stability against AmpC β-lactamase-overproducing Pseudomonas aeruginosa .21

Tazobactam is a penicillanic acid sulfone β-lactamase inhibitor that is structurally similar to sulbactam.5,21,28 Tazobactam contains a β-lactam ring and a triazole group at the C-2 β-methyl position that facilitates binding to β-lactamases.5,21,28

Ceftolozane and tazobactam is commercially available as a white to yellow powder for IV infusion containing a 2:1 ratio of ceftolozane to tazobactam.1 The ceftolozane component is provided as ceftolozane sulfate and the tazobactam component is provided as tazobactam sodium.1 Drug strength and dosage are expressed as the total of the 2 active components.1 (See Dispensing and Dosage and Administration Precautions under Administration: IV Infusion, in Dosage and Administration.)

Each single-dose vial of ceftolozane and tazobactam contains 1.5 g (1 g of ceftolozane [equivalent to 1.147 g of ceftolozane sulfate] and 0.5 g of tazobactam [equivalent to 0.537 g of tazobactam sulfate]).1 Each single-dose vial of the drug also contains 487 mg of sodium chloride as a stabilizing agent and 21 mg of citric acid and approximately 600 mg of L-arginine as excipients.1

Stability

Ceftolozane and tazobactam powder for IV infusion should be stored at 2-8°C and protected from light.1

Following reconstitution and dilution, ceftolozane and tazobactam solutions may be stored for up to 24 hours at room temperature or for up to 7 days when refrigerated at 2-8°C.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care. For further information on chemistry, mechanism of action, spectrum, resistance, uses, cautions, acute toxicity, drug interactions, or laboratory test interferences of cephalosporins, see the Cephalosporins General Statement 8:12.06.

1. Cubist Pharmaceuticals, Inc. Zerbaxa^® (ceftolozane sulfate and tazobactam sodium) for injection prescribing information. Lexington, MA; 2015 May.

2. Andes DR, Craig WA. Cephalosporins. In: Bennett JE, Dolin R, Blaser MJ eds. Mandell, Douglas and Bennett's principles and practices of infectious disease. 8th ed. Philadelphia, PA: Saunders, Elsevier; 2015:278-91.

3. Hong MC, Hsu DI, Bounthavong M. Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination. Infect Drug Resist . 2013; 6:215-23. [PubMed 24348053]

4. Solomkin J, Hershberger E, Miller B et al. Ceftolozane/Tazobactam plus metronidazole for complicated intra-abdominal infections in an era of multidrug eesistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis . 2015; 60:1462-71. [PubMed 25670823]

5. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206829Orig1s000: Microbiology/virology review(s). From FDA website. [Web]

6. Sader HS, Rhomberg PR, Farrell DJ et al. Antimicrobial activity of CXA-101, a novel cephalosporin tested in combination with tazobactam against Enterobacteriaceae, Pseudomonas aeruginosa, and Bacteroides fragilis strains having various resistance phenotypes. Antimicrob Agents Chemother . 2011; 55:2390-4. [PubMed 21321149]

7. Bulik CC, Christensen H, Nicolau DP. In vitro potency of CXA-101, a novel cephalosporin, against Pseudomonas aeruginosa displaying various resistance phenotypes, including multidrug resistance. Antimicrob Agents Chemother . 2010; 54:557-9. [PubMed 19917762]

8. Walkty A, Karlowsky JA, Adam H et al. In vitro activity of ceftolozane-tazobactam against Pseudomonas aeruginosa isolates obtained from patients in Canadian hospitals in the CANWARD study, 2007 to 2012. Antimicrob Agents Chemother . 2013; 57:5707-9. [PubMed 23939895]

9. Farrell DJ, Flamm RK, Sader HS et al. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. Hospitals (2011-2012). Antimicrob Agents Chemother . 2013; 57:6305-10. [PubMed 24100499]

10. Moyá B, Zamorano L, Juan C et al. Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa. Antimicrob Agents Chemother . 2010; 54:3933-7. [PubMed 20547785]

11. Bulik CC, Tessier PR, Keel RA et al. In vivo comparison of CXA-101 (FR264205) with and without tazobactam versus piperacillin-tazobactam using human simulated exposures against phenotypically diverse gram-negative organisms. Antimicrob Agents Chemother . 2012; 56:544-9. [PubMed 22064538]

12. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol . 2010; 31:431-55. [PubMed 20307191]

13. Sader HS, Rhomberg PR, Jones RN. Post-β-lactamase-inhibitor effect of tazobactam in combination with ceftolozane on extended-spectrum-β-lactamase-producing strains. Antimicrob Agents Chemother . 2014; 58:2434-7. [PubMed 24449780]

14. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50. [PubMed 9149180]

15. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]

16. Cabot G, Bruchmann S, Mulet X et al. Pseudomonas aeruginosa ceftolozane-tazobactam resistance development requires multiple mutations leading to overexpression and structural modification of AmpC. Antimicrob Agents Chemother . 2014; 58:3091-9. [PubMed 24637685]

17. Snydman DR, McDermott LA, Jacobus NV. Activity of ceftolozane-tazobactam against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother . 2014; 58:1218-23. [PubMed 24277025]

18. Miller B, Hershberger E, Benziger D et al. Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses. Antimicrob Agents Chemother . 2012; 56:3086-91. [PubMed 22450972]

19. Wooley M, Miller B, Krishna G et al. Impact of renal function on the pharmacokinetics and safety of ceftolozane-tazobactam. Antimicrob Agents Chemother . 2014; 58:2249-55. [PubMed 24492369]

20. Chandorkar G, Huntington JA, Gotfried MH et al. Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in healthy adult subjects. J Antimicrob Chemother . 2012; 67:2463-9. [PubMed 22773741]

21. Zhanel GG, Chung P, Adam H et al. Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. Drugs . 2014; 74:31-51. [PubMed 24352909]

22. US Food and Drug Administration. FDA drug safety communication: FDA cautions about dose confusion and medication errors for antibacterial drug Zerbaxa (ceftolozane and tazobactam). 2015 May 20. From FDA website. [Web]

23. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 206829Orig1s000. Clinical pharmacology and biopharmaceutics review(s). From FDA website. [Web]

28. Drawz SM, Bonomo RA. Three decades of beta-lactamase inhibitors. Clin Microbiol Rev . 2010; 23:160-201. [PubMed 20065329]