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    Cephalosporin and Beta-Lactamase Inhibitor Combination Antibiotics

    DEA CLASS

    Rx

    DESCRIPTION

    Combination intravenous anti-infective, including a cephalosporin and beta-lactamase inhibitor
    For complicated intra-abdominal infections and complicated urinary tract infections in adults
    Decreased efficacy seen in patients with baseline CrCl 30 to <= 50 ml/min during clinical trials; monitor SCr daily and adjust the dose as needed

    COMMON BRAND NAMES

    ZERBAXA

    HOW SUPPLIED

    ZERBAXA Intravenous Inj Pwd F/Sol: 1-0.5g

    DOSAGE & INDICATIONS

    For the treatment of complicated intraabdominal infections including appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intraabdominal abscess and peritonitis.
    Intravenous dosage
    Adults

    1.5 g (1 g ceftolozane and 0.5 g tazobactam) IV every 8 hours in combination with metronidazole (500 mg IV every 8 hours) for 4 to 14 days depending on infection severity as well as clinical and bacteriological progress. In a study comparing ceftolozane; tazobactam plus metronidazole to meropenem, clinical cure rates were similar. Intraabdominal infections treated during the study included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intraabdominal abscesses and peritonitis.

    For the treatment of complicated urinary tract infection (UTI), including pyelonephritis.
    Intravenous dosage
    Adults

    1.5 g (1 g ceftolozane and 0.5 g tazobactam) IV every 8 hours for 7 days. In a study comparing ceftolozane; tazobactam to levofloxacin, clinical cure rates were similar among patients infected with levofloxacin-susceptible organisms. Concomitant bacteremia was identified in 7.8% of patients.

    For the treatment of sepsis†.
    Intravenous dosage
    Adults

    1.5 g (1 g ceftolozane and 0.5 g tazobactam) IV every 8 hours has been used for other indications. Start within 1 hour of recognition as part of empiric multi-drug therapy. Duration of therapy is generally 7 to 10 days, but may be shorter or longer depending upon patient response, site of infection, and pathogen(s) isolated. Treatment may be narrowed with pathogen identification and/or adequate clinical response.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    4.5 g/day IV (3 g/day ceftolozane and 1.5 g/day tazobactam).

    Geriatric

    4.5 g/day IV (3 g/day ceftolozane and 1.5 g/day tazobactam).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    CrCl more than 50 mL/minute: No dosage adjustment needed.
    CrCl 30 to 50 mL/minute: 750 mg (500 mg ceftolozane and 250 mg tazobactam) IV every 8 hours.
    CrCl 15 to 29 mL/minute: 375 mg (250 mg ceftolozane and 125 mg tazobactam) IV every 8 hours.
     
    Intermittent hemodialysis (HD)
    For patients with end-stage renal disease (ESRD) on hemodialysis, a single loading dose of 750 mg (500 mg ceftolozane and 250 mg tazobactam) IV, then a 150 mg (100 mg ceftolozane and 50 mg tazobactam) IV maintenance dose every 8 hours for the remainder of the treatment period. Administer the dose at the earliest possible time after the completion of dialysis on hemodialysis days.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
    Do not mix with other drugs or physically add to solutions containing other drugs.
    Each vial contains 1 g of ceftolozane and 500 mg of tazobactam.

    Intravenous Administration

    Reconstitution:
    Reconstitute the vial with 10 mL of Sterile Water for Injection or 0.9% Sodium Chloride Injection.
    Gently shake to dissolve.
    The final volume after reconstitution is approximately 11.4 mL.
    Further dilution is required.
    Storage: The reconstituted solution may be stored for 1 hour prior to further dilution. Do not freeze.
     
    Dilution:
    To prepare the required dose, withdraw the appropriate volume from the reconstituted vial and aseptically add to an IV infusion bag containing 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
    To prepare a dose of 1.5 g (1 g ceftolozane and 0.5 g tazobactam), withdraw 11.4 mL (entire contents) of the reconstituted vial.
    To prepare a dose of 750 mg (500 mg ceftolozane and 250 mg tazobactam), withdraw 5.7 mL of the reconstituted vial.
    To prepare a dose of 375 mg (250 mg ceftolozane and 125 mg tazobactam), withdraw 2.9 mL of the reconstituted vial.
    To prepare a dose of 150 mg (100 mg ceftolozane and 50 mg tazobactam), withdraw 1.2 mL of the reconstituted vial.
    Storage: The diluted solution may be stored for 24 hours at room temperature or for 7 days when refrigerated (2—8 degrees C or 36—46 degrees F). Do not freeze.
     
    Intermittent IV infusion:
    Infuse over 1 hour.

    STORAGE

    ZERBAXA:
    - Do not freeze
    - Protect from light
    - Reconstituted product is stable for up to 24 hours at or below 86 degrees F, or for up to 7 days if refrigerated (41 degrees F)
    - Store between 36 to 46 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    In the complicated intraabdominal infection trials, there was an increased mortality associated with patients receiving ceftolozane; tazobactam plus metronidazole (2.5%) compared to those receiving meropenem (1.5%). The causes of death varied and included worsening and/or complications of infection, surgery, and underlying conditions.

    Colitis, diarrhea, GI disease, inflammatory bowel disease, pseudomembranous colitis, ulcerative colitis

    Almost all antibacterial agents, including ceftolozane; tazobactam, have been associated with pseudomembranous colitis (antibiotic-associated colitis), which may range in severity from mild to life-threatening. In the colon, overgrowth of Clostridia may exist when normal flora is altered subsequent to antibacterial administration. The toxin produced by Clostridium difficile is a primary cause of pseudomembranous colitis. It is known that systemic use of antibiotics predisposes patients to development of pseudomembranous colitis. Consideration should be given to the diagnosis of pseudomembranous colitis in patients presenting with diarrhea after ceftolozane; tazobactam administration. Systemic antibiotics should be prescribed with caution to patients with inflammatory bowel disease such as ulcerative colitis or other GI disease. If diarrhea develops during therapy, the drug should be discontinued. After a diagnosis of pseudomembranous colitis, therapeutic measures should be instituted. In milder cases, the colitis may respond to discontinuation of the offending agent. In moderate to severe cases, fluids and electrolytes, protein supplementation, and treatment with an antibacterial effective against Clostridium difficile may be warranted. Products inhibiting peristalsis are contraindicated in this clinical situation. Practitioners should be aware that antibiotic-associated colitis has occurred over two months or more after the discontinuation of systemic antibiotic therapy; a careful medical history should be taken.

    Carbapenem hypersensitivity, cephalosporin hypersensitivity, penicillin hypersensitivity

    Ceftolozane; tazobactam is contraindicated in patients with known serious ceftolozane; tazobactam hypersensitivity, piperacillin; tazobactam hypersensitivity, cephalosporin hypersensitivity, or other beta-lactam hypersensitivity. Use caution if cetolozane; tazobactam is to be given to a patient with penicillin hypersensitivity, cephalosporin hypersensitivity, or carbapenem hypersensitivity as cross-sensitivity has occurred. Monitor for signs and symptoms of hypersensitivity. If such a reaction occurs, discontinue the infusion and initiate appropriate supportive care.

    Antimicrobial resistance, viral infection

    Ceftolozane; tazobactam does not treat viral infection (e.g., common cold). Prescribing in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (antimicrobial resistance). Patients should be told to complete the full course of treatment, even if they feel better earlier.

    Dialysis, renal failure, renal impairment

    Ceftolozane; tazobactam should be used with caution in patients with renal impairment, renal failure (ESRD), or those receiving dialysis since both drugs in the combination are eliminated via the kidneys. Dosage adjustment recommendations are available for adult patients with varying degrees of renal impairment and in patients with ESRD on hemodialysis. In a subgroup analysis, clinical cure rates were lower in patients with a baseline creatinine clearance of 30 to <= 50 mL/min compared to those with a CrCl >= 50 mL/min.

    Coagulopathy, hypoprothrombinemia, vitamin K deficiency

    Many cephalosporins have been rarely associated with a fall in prothrombin activity (hypoprothrombinemia). Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Cephalosporins that contain the NMTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have been particularly associated with an increased risk for bleeding. Cephalosporins should be used cautiously in patients with a preexisting coagulopathy (e.g., vitamin K deficiency), since these patients may be at a higher risk for these complications. Also, positive direct Coombs' tests have been reported in patients receiving cephalosporins, including ceftolozane; tazobactam. In patients receiving cephalosporins and undergoing hematologic testing, a positive Coombs' test should be considered as possibly being caused by the antibiotic. If anemia develops during or after treatment with ceftolozane; tazobactam, drug-induced hemolytic anemia should be considered.

    Pregnancy

    Ceftolozane; tazobactam is classified as FDA pregnancy category B. There are no adequate and well-controlled trials with either ceftolozane or tazobactam in pregnant women. Animal studies showed no evidence of embryo or fetal toxicity at doses with mean plasma exposure (AUC) values that superceded comparable human exposure. Ceftolozane; tazobactam should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.

    Breast-feeding

    According to the manufacturer, it is not known whether ceftolozane or tazobactam is excreted in human milk. The manufacturer recommends that caution be exercised when administering it to women who are breast-feeding. While there are no studies with ceftolozane; tazobactam, the American Academy of Pediatrics (AAP) does suggest that a number of other cephalosporins are compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    ADVERSE REACTIONS

    Severe

    atrial fibrillation / Early / 0.2-1.2
    ileus / Delayed / 0-1.0
    stroke / Early / 0-1.0
    thrombosis / Delayed / 0-1.0
    renal failure (unspecified) / Delayed / 0-1.0

    Moderate

    constipation / Delayed / 1.9-3.9
    hypokalemia / Delayed / 0.8-3.3
    thrombocytosis / Delayed / 0.4-1.9
    elevated hepatic enzymes / Delayed / 1.0-1.7
    hypotension / Rapid / 0.4-1.7
    anemia / Delayed / 0.4-1.5
    gastritis / Delayed / 0-1.0
    candidiasis / Delayed / 0-1.0
    hyperglycemia / Delayed / 0-1.0
    hypophosphatemia / Delayed / 0-1.0
    hypomagnesemia / Delayed / 0-1.0
    angina / Early / 0-1.0
    sinus tachycardia / Rapid / 0-1.0
    dyspnea / Early / 0-1.0
    pseudomembranous colitis / Delayed / Incidence not known

    Mild

    nausea / Early / 2.8-7.9
    diarrhea / Early / 1.9-6.2
    headache / Early / 2.5-5.8
    fever / Early / 1.7-5.6
    insomnia / Early / 1.3-3.5
    vomiting / Early / 1.1-3.3
    anxiety / Delayed / 0.2-1.9
    rash / Early / 0.9-1.7
    abdominal pain / Early / 0.8-1.2
    dizziness / Early / 0.8-1.1
    flatulence / Early / 0-1.0
    dyspepsia / Early / 0-1.0
    infection / Delayed / 0-1.0
    injection site reaction / Rapid / 0-1.0
    urticaria / Rapid / 0-1.0

    DRUG INTERACTIONS

    Probenecid: (Minor) Probenecid may prolong serum concentrations of tazobactam when coadministered with ceftolozane; tazobactam. Probenecid has been shown to prolong the half-life of tazobactam by 71% when coadministered. The clinical significance of this interaction has not been established.
    Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution.

    PREGNANCY AND LACTATION

    Pregnancy

    Ceftolozane; tazobactam is classified as FDA pregnancy category B. There are no adequate and well-controlled trials with either ceftolozane or tazobactam in pregnant women. Animal studies showed no evidence of embryo or fetal toxicity at doses with mean plasma exposure (AUC) values that superceded comparable human exposure. Ceftolozane; tazobactam should only be used during pregnancy if the potential benefit to the mother outweighs the potential risk to the fetus.

    According to the manufacturer, it is not known whether ceftolozane or tazobactam is excreted in human milk. The manufacturer recommends that caution be exercised when administering it to women who are breast-feeding. While there are no studies with ceftolozane; tazobactam, the American Academy of Pediatrics (AAP) does suggest that a number of other cephalosporins are compatible with breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Ceftolozane is a semi-synthetic cephalosporin antibacterial agent with bactericidal action resulting from the inhibition of cell wall biosynthesis mediated through binding to penicillin-binding proteins (PBPs). It is an inhibitor of PBPs of P. aeruginosa (PBP1b, PBP1c, PBP3) and E. coli (PBP3). Tazobactam has little clinically relevant in vitro antibacterial activity; however, it is an irreversible inhibitor of some beta-lactamase (certain penicillinases and cephalosporinases) and can covalently bind to some chromosomal and plasmid-mediated bacterial beta-lactamases.
     
    Beta-lactams, including ceftolozane, exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T > MIC). This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Cephalosporins require free drug concentrations to be above the MIC for 35—40% of the dosing interval for bacteriostatic activity and 60—70% of the dosing interval for bactericidal activity.
     
    The manufacturer delineates the susceptibility interpretive criteria for ceftolozane; tazobactam by pathogen. The MICs are defined for Enterobacteriaceae as susceptible <= 2/4 mcg/mL, intermediate 4/4 mcg/mL, and resistant >= 8/4 mcg/mL. For P. aeruginosa, the MICs are defined as susceptible <= 4/4 mcg/mL, intermediate 8/4 mcg/mL, and resistant >= 16/4 mcg/mL. For S. anginosus, S. constellatus, S. salivarius, and B. fragilis, the MICs are defined as susceptible <= 8/4 mcg/mL, intermediate 16/4 mcg/mL, and resistant >= 32/4 mcg/mL.
     
    The mechanisms of beta-lactam resistance may include the production of beta-lactamases, modification of PBP binding sites by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin channels. Ceftolozane;tazobactam demonstrates in vitro activity in the presence of some extended-spectrum beta-lactamase (ESBLs) and other beta-lactamases including TEM, SHV, CTX-M, and OXA. It is not active against bacteria that produce serine carbapenemases (KPC) and metallo-beta lactamases. Ceftolozane; tazobactam also demonstrated in vitro activity against P. aeruginosa isolates that had chromosomal AmpC, loss of outer membrane porin (OprD), or up-regulation of efflux pumps (MexXY, MexAB). Bacterial isolates resistant to other cephalosporins may be susceptible to ceftolozane; tazobactam; however, cross-resistance may occur. There is no antagonism with other antibacterial agents.

    PHARMACOKINETICS

    Ceftolozane; tazobactam is administered intravenously. The binding of ceftolozane to human plasma proteins is approximately 16—21%, while the binding of tazobactam is approximately 30%. The mean steady-state volume of distribution in healthy adult males after a single 1.5 g IV dose is 13.5 L for ceftolozane and 18.2 L for tazobactam, which is similar to extracellular fluid volume.
     
    Ceftolozane is eliminated in the urine as unchanged parent drug and does not appear to be metabolized. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive metabolite M1.
     
    Ceftolozane, tazobactam, and the M1 metabolite, are eliminated renally. After administration of a single 1.5 g IV dose to healthy adult males, more than 95% of ceftolozane is excreted in the urine as unchanged parent drug. More than 80% of tazobactam is excreted as the parent drug, and the remainder is excreted as the M1 metabolite. Renal clearance of ceftolozane was 3.41—6.69 L/h, which is similar to plasma clearance (4.1—6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting the ceftolozane is eliminated by the kidney via glomerular filtration.
     
    Affected cytochrome P450 isoenzymes and drug transporters: OAT1, OAT3
    In vitro and in vivo studies indicate that ceftolozane and tazobactam are not  substrates, inhibitors, or inducers of the CYP450 isoenzyme system at therapeutic concentrations. At supratherapeutic concentrations, in vitro studies of human hepatocytes demonstrated that ceftolozane, tazobactam, and the M1 tazobactam metabolite decrease CYP1A2 and CYP2B6 enzyme activity and mRNA levels as well as CYP3A4 mRNA levels. Additionally, the M1 metabolite decreases CYP3A4 activity at supratherapeutic concentrations. However, drug interaction involving these enzymes is not expected.
     
    Ceftolozane and tazobactam are not substrates for P-glycoprotein (P-gp) or BCRP. Tazobactam is not a substrate for OCT2. Tazobactam is a substrate for OAT1 and OAT3 and coadministration with the OAT1/OAT3 inhibitor probenecid has been shown to increase the half-life of tazobactam by 71%. Concomitant administration of OAT1 and/or OAT3 inhibitors may increase tazobactam plasma concentrations; however, the clinical relevance of this is unknown. Ceftolozane, tazobactam, and M1 do not inhibit the P-gp, BRCP, OATP1B1, OATP1B3, OCT1, OCT2, or BSEP transporters. Ceftolozane does not inhibit the MRP, OAT1, OAT3, MATE1, or MATE2-K transporters. In vitro, tazobactam inhibits human OAT1 and OAT3 transporters; however, clinically relevant drug interactions are not expected.

    Intravenous Route

    The pharmacokinetic parameters of ceftolozane and tazobactam established in healthy adults with normal renal function show the Cmax and AUC increase in proportion to dose; however, plasma concentrations do not increase appreciably after multiple intravenous infusions of up to 3 g IV administered every 8 hours for up to 10 days. After single and multiple dose administration of 1.5 g IV every 8 hours, the Cmax of ceftolozane was 69.1—74.4 mcg/mL and the Cmax of tazobactam was 18—18.4 mcg/mL. The AUC was 172—182 mcg x hour/mL for ceftolozane and 24.4—25 mcg x hour/mL for tazobactam. The tmax for both ceftolozane and tazobactam was approximately 1 hour. The elimination half-life (t1/2) is independent of dose and ranged from 2.77—3.12 hours for ceftolozane and 0.91—1.03 hours for tazobactam.