Zerbaxa

Zerbaxa

Manufacturer:

Merck Sharp & Dohme

Distributor:

Zuellig
Full Prescribing Info
Contents
Ceftolozane sulfate, tazobactam sodium.
Description
Each vial contains: Ceftolozane sulfate 1.147 g (equivalent to Ceftolozane 1 g) and Tazobactam sodium 537 mg (equivalent to Tazobactam 500 mg).
Chemistry: Ceftolozane/Tazobactam (ZERBAXA) is an antibacterial combination product consisting of the cephalosporin antibacterial drug ceftolozane sulfate and the beta-lactamase inhibitor tazobactam sodium for intravenous administration.
Ceftolozane sulfate is a semi-synthetic antibacterial drug of the beta-lactam class for parenteral administration. The chemical name of ceftolozane sulfate is 1H-Pyrazolium, 5-amino-4-[[[(2-aminoethyl)amino]carbonyl]amino]-2-[[(6R,7R)-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-[(1-carboxy-1-methylethoxy)imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl]-1-methyl-,sulfate (1:1). The molecular formula is C23H31N12O8S2+•HSO4- and the molecular weight is 764.77.
Tazobactam sodium, a derivative of the penicillin nucleus, is a penicillanic acid sulfone. Its chemical name is sodium (2S,3S,5R)-3-methyl-7-oxo-3-(1H-1,2,3-triazol-1-ylmethyl)-4-thia-1-azabicyclo [3.2.0]heptane-2-carboxylate-4,4-dioxide. The chemical formula is C10H11N4NaO5S and the molecular weight is 322.3.
Ceftolozane/Tazobactam (ZERBAXA) for injection is a white to yellow sterile powder for reconstitution consisting of ceftolozane 1 g (equivalent to 1.147 g ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g tazobactam sodium) per vial packaged in single-dose glass vials. The product contains sodium chloride (487 mg/vial) as a stabilizing agent, citric acid (21 mg/vial), and L-arginine (approximately 600 mg/vial) as excipients.
Action
Therapeutic Class: Ceftolozane-tazobactam is a beta-lactam and beta-lactamase inhibitor.
Pharmacology: Mechanism of Action: Ceftolozane/Tazobactam (ZERBAXA) is an antibacterial drug.
Pharmacodynamics: As with other beta-lactam antibacterial agents, the time that the plasma concentration of ceftolozane exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to be the best predictor of efficacy in animal models of infection.
For tazobactam the PD index associated with efficacy was determined to be the percentage of the dose interval during which the plasma concentration of tazobactam exceeds a threshold value (%T>threshold). The time above a threshold concentration has been determined to be the parameter that best predicts the efficacy of tazobactam in in vitro and in vivo nonclinical models.
The exposure-response analyses in efficacy and safety clinical trials for cIAI, cUTI, and nosocomial pneumonia support the recommended dose regimens of Ceftolozane/Tazobactam (ZERBAXA).
Cardiac Electrophysiology: In a randomized, positive and placebo-controlled crossover thorough QTc study, 51 healthy subjects were administered a single therapeutic dose of Ceftolozane/Tazobactam (ZERBAXA) 1.5 gram (ceftolozane 1 g and tazobactam 0.5 g) and a supratherapeutic dose of Ceftolozane/Tazobactam (ZERBAXA) 4.5 gram (ceftolozane 3 g and tazobactam 1.5 g). No significant effects of Ceftolozane/Tazobactam (ZERBAXA) on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, Ceftolozane/Tazobactam (ZERBAXA) does not affect cardiac repolarization.
Clinical Studies: Complicated Intra-abdominal Infections: A total of 979 adults hospitalized with cIAI were randomized and received study medications in a multinational, double-blind study comparing Ceftolozane/Tazobactam (ZERBAXA) intravenously every 8 hours plus metronidazole (500 mg intravenously every 8 hours) to meropenem (1 g intravenously every 8 hours) for 4 to 14 days of therapy. Complicated intra-abdominal infections included appendicitis, cholecystitis, diverticulitis, gastric/duodenal perforation, perforation of the intestine, and other causes of intra-abdominal abscesses and peritonitis.
The primary efficacy endpoint was clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 24 to 32 days after the first dose of study drug. The primary efficacy analysis population was the Clinically Evaluable (CE) population, which included all protocol adherent patients that received an adequate amount of study drug. The key secondary efficacy endpoint was clinical response at the TOC visit in the Intent-to-Treat (ITT) population, which included all randomized subjects regardless of whether or not the subjects went on to receive study drug.
The CE population consisted of 774 patients; the median age was 49 years and 58.7% were male. The most common diagnosis was appendiceal perforation or peri-appendiceal abscess, occurring in 47.7% of patients. Diffuse peritonitis at baseline was present in 35.9% of patients.
Ceftolozane/Tazobactam (ZERBAXA) plus metronidazole was non-inferior to meropenem with regard to clinical cure rates at the TOC visit in the CE population. Clinical cure rates at the TOC visit are displayed by patient population in Table 1. Clinical cure rates at the TOC visit by pathogen in the Microbiologically Evaluable (ME) population are presented in Table 2. The ME included all protocol adherent patients with at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. (See Tables 1 and 2.)

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In a subset of the E. coli and K. pneumoniae isolates from both arms of the cIAI Phase 3 trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 53/601 (9%). Cure rates in this subset were similar to the overall trial results. In vitro susceptibility testing showed that some of these isolates were susceptible to Ceftolozane/Tazobactam (ZERBAXA), while some others were not susceptible. Isolates of a specific genotype were seen in patients who were deemed to be either successes or failures.
Complicated Urinary Tract Infections, including Pyelonephritis: A total of 1068 adults hospitalized with complicated urinary tract infections (including pyelonephritis) were randomized and received study medications in a multinational, double-blind study comparing Ceftolozane/Tazobactam (ZERBAXA) (1.5 g IV every 8 hours) to levofloxacin (750 mg IV once daily) for 7 days of therapy. The primary efficacy endpoint was defined as microbiological eradication (all uropathogens found at baseline at ≥105 were reduced to <103 CFU/mL) at the test-of-cure (TOC) visit 7 (± 2) days after the last dose of study drug. The primary efficacy analysis population was the microbiologically evaluable (ME) population, which included protocol-adherent microbiologically modified intent-to-treat (mMITT) patients with a urine culture at the TOC visit. The key secondary efficacy endpoint was microbiological eradication at the TOC visit in the mMITT population, which included all patients who received study medication and had at least 1 baseline uropathogen.
The ME population consisted of 693 patients with cUTI, including 567 (82%) with pyelonephritis. The median age was 50 years and 73% were female. Concomitant bacteremia was identified in 50 (7.2%) patients at baseline.
Ceftolozane/Tazobactam (ZERBAXA) was superior to levofloxacin with regard to the microbiological eradication rates at the TOC visit in both the ME and mMITT populations (Table 3).
Microbiological eradication rates at the TOC visit by pathogen in the ME population are presented in Table 4. (See Tables 3 and 4.)

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In patients with levofloxacin-resistant pathogens at baseline, Ceftolozane/Tazobactam (ZERBAXA) was superior to levofloxacin with regards to microbiological eradication rate in the ME population, 58/89 (65.2%) in the Ceftolozane/Tazobactam (ZERBAXA) treatment arm and 42/99 (42.4%) in the levofloxacin treatment arm (95% CI: 22.7 [8.47, 35.73]).
In the ME population, the microbiological eradication rate in patients with concurrent bacteremia were 21/24 (87.5%) for Ceftolozane/Tazobactam (ZERBAXA) and 20/26 (76.9%) for levofloxacin.
In a subset of the E. coli and K. pneumoniae isolates from both arms of the cUTI Phase 3 trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 104/687 (15%). Cure rates in this subset were similar to the overall trial results. In vitro susceptibility testing showed that some of these isolates were susceptible to Ceftolozane/Tazobactam (ZERBAXA), while some others were not susceptible. Isolates of a specific genotype were seen in patients who were deemed to be either successes or failures.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia: A total of 726 adult patients hospitalized with ventilated nosocomial pneumonia (including hospital-acquired pneumonia and ventilator-associated pneumonia) were enrolled in a multinational, double-blind study comparing Ceftolozane/Tazobactam (ZERBAXA) 3 g (ceftolozane 2 g and tazobactam 1 g) intravenously every 8 hours to meropenem (1 g intravenously every 8 hours) for 8 to 14 days of therapy.
The primary efficacy endpoint was all-cause mortality at Day 28. Clinical response, defined as complete resolution or significant improvement in signs and symptoms of the index infection at the test-of-cure (TOC) visit which occurred 7 to 14 days after the end of treatment was a pre-specified key secondary endpoint. The analysis population for both the primary and key secondary endpoints was the intent-to-treat (ITT) population, which included all randomized patients.
Of the 726 patients in the ITT population the median age was 62 years and 44% of the population was greater than or equal to 65 years of age, with 22% of the population greater than or equal to 75 years of age. The majority of patients were white (83%), male (71%) and were from Eastern Europe (64%). The median APACHE II score was 17 and 33% of subjects had a baseline APACHE II score of greater than or equal to 20. All subjects were on mechanical ventilation and 519 (71%) had VAP. At randomization, the majority of subjects had been hospitalized for greater than or equal to 5 days (77%), ventilated for greater than or equal to 5 days (49%) and in an ICU (92%). Approximately 36% of patients had renal impairment at baseline and 14% had moderate or severe impairment (CrCL less than 50 mL/min). Approximately 13% of subjects had failed prior antibiotic treatment for nosocomial pneumonia and bacteremia was present at baseline in 15% of patients. Key comorbidities included chronic obstructive pulmonary disease (COPD), diabetes mellitus, and congestive heart failure at rates of 12%, 22% and 16%, respectively.
In the ITT population, Ceftolozane/Tazobactam (ZERBAXA) was non-inferior to meropenem with regard to the primary endpoint of all-cause mortality at Day 28 and key secondary endpoint of clinical cure rates at the TOC visit (Table 5). (See Table 5.)

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In the ITT population, Day 28 all-cause mortality rates in patients with renal hyperclearance at baseline (CrCL greater than or equal to 150 mg/mL) were 10/67 (14.9%) for Ceftolozane/Tazobactam (ZERBAXA) and 7/64 (10.9%) for meropenem; the clinical cure rates were 40/67 (59.7%) and 39/64 (60.9%), respectively. In those patients who failed prior antibiotic therapy for nosocomial pneumonia, Day 28 all-cause mortality rates were 12/53 (22.6%) for Ceftolozane/Tazobactam (ZERBAXA) and 18/40 (45%) for meropenem; the clinical cure rates were 26/53 (49.1%) and 15/40 (37.5%), respectively. In patients with bacteremia at baseline, Day 28 all-cause mortality rates were 23/64 (35.9%) for Ceftolozane/Tazobactam (ZERBAXA) and 13/41 (31.7%) for meropenem; clinical cure rates were 30/64 (46.9%) and 15/41 (36.6%), respectively.
Per pathogen clinical and microbiologic responses were assessed in the microbiologic intention to treat population (mITT), which consisted of all randomized subjects who had a baseline lower respiratory tract (LRT) pathogen that was susceptible to at least one of the study therapies, and in the microbiologically evaluable (ME) population, which included protocol-adherent mITT patients with a baseline LRT pathogen that grew at the appropriate colony-forming unit (CFU)/mL threshold. In the mITT and ME populations, Klebsiella pneumoniae (34.6% and 38.6%, respectively) and Pseudomonas aeruginosa (25% and 28.8%, respectively) were the most prevalent pathogens isolated from baseline LRT cultures. Among all Enterobacteriaceae, 157 (30.7%) in the mITT and 84 (36.1%) in the ME were ESBL-positive; among all K. pneumoniae isolates, 105 (20.5%) in the mITT and 57 (24.5%) in the ME were ESBL-positive. AmpC-overexpression among P. aeruginosa was detected in 15 (2.9%) and 9 (3.9%) of the P. aeruginosa isolates in the mITT and ME populations, respectively. Clinical cure rates at TOC by pathogen in the mITT and ME populations are presented in Table 6. In the mITT population clinical cure rates in patients with a Gram-negative pathogen at baseline were 157/259 (60.6%) for Ceftolozane/Tazobactam (ZERBAXA) and 137/240 (57.1%) for meropenem; results were consistent in the ME population with 85/113 (75.2%) and 78/117 (66.7%) clinical cure rates, respectively. Microbiologic response rates at TOC by pathogen in the mITT and ME populations are presented in Table 7. In the mITT population microbiologic response rates in patients with a Gram-negative pathogen at baseline were 189/259 (73%) for Ceftolozane/Tazobactam (ZERBAXA) and 163/240 (67.9%) for meropenem; results were consistent in the ME population with 79/113 (69.9%) and 73/117 (62.4%) microbiologic response rates, respectively. (See Tables 6 and 7.)

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In the mITT population, per subject microbiologic cure was achieved in 193/264 (73.1%) of Ceftolozane/Tazobactam (ZERBAXA)-treated patients and in 168/247 (68.0%) of meropenem-treated patients. Similar results were achieved in the ME population in 81/115 (70.4%) and 74/118 (62.7%) patients, respectively.
In a subset of Enterobacteriaceae isolates from both arms of the trial that met pre-specified criteria for beta-lactam susceptibility, genotypic testing identified certain ESBL groups (e.g., TEM, SHV, CTX-M, OXA) in 157/511 (30.7%). Cure rates in this subset were similar to the overall trial results.
Pharmacokinetics: General Introduction: The mean pharmacokinetic parameters of Ceftolozane/Tazobactam (ZERBAXA) in healthy adults with normal renal function after multiple 1-hour intravenous infusions of Ceftolozane/Tazobactam (ZERBAXA) 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or 3 g (ceftolozane 2 g and tazobactam 1 g) administered every 8 hours are summarized in Table 8. Ceftolozane and tazobactam pharmacokinetics are similar following single- and multiple-dose administration. The Cmax and AUC of ceftolozane and tazobactam increase in proportion to dose. The elimination half-life (t1/2) of ceftolozane or tazobactam is independent of dose. (See Table 8.)

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The mean steady-state population pharmacokinetic parameters of Ceftolozane/Tazobactam (ZERBAXA) in patients with cIAI and cUTI receiving 1 hour intravenous infusion of Ceftolozane/Tazobactam (ZERBAXA) 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or patients with nosocomial pneumonia receiving 1 hour intravenous infusion of Ceftolozane/Tazobactam (ZERBAXA) 3 g (ceftolozane 2 g and tazobactam 1 g) every 8 hours are summarized in Table 9. (See Table 9.)

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Distribution: The binding of ceftolozane and tazobactam to human plasma proteins is approximately 16% to 21% and 30%, respectively. The mean (CV%) steady-state volume of distribution of Ceftolozane/Tazobactam (ZERBAXA) in healthy adult males (n=51) following a single intravenous dose of Ceftolozane/Tazobactam (ZERBAXA) 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) was 13.5 L (21%) and 18.2 L (25%) for ceftolozane and tazobactam, respectively, similar to extracellular fluid volume.
Following 1 hour intravenous infusions of Ceftolozane/Tazobactam (ZERBAXA) 3 g (ceftolozane 2 g and tazobactam 1 g) or adjusted based on renal function every 8 hours in ventilated patients with confirmed or suspected pneumonia (N=22), ceftolozane and tazobactam concentrations in pulmonary epithelial lining fluid were greater than 8 mcg/mL and 1 mcg/mL, respectively, over 100% of the dosing interval. Mean pulmonary epithelial-to-free plasma AUC ratios of ceftolozane and tazobactam were approximately 50% and 62%, respectively and are similar to those in healthy subjects (approximately 61% and 63%, respectively) receiving Ceftolozane/Tazobactam (ZERBAXA) 1.5 g (ceftolozane 1 g and tazobactam 0.5 g).
Metabolism: Ceftolozane is mainly eliminated in the urine as unchanged parent drug and thus does not appear to be metabolized to any appreciable extent. The beta-lactam ring of tazobactam is hydrolyzed to form the pharmacologically inactive, tazobactam metabolite M1.
Elimination: Ceftolozane, tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys. Following administration of a single 1 g/0.5 g IV dose of ceftolozane/tazobactam to healthy male adults greater than 95% of ceftolozane was excreted in the urine as unchanged parent substance. More than 80% of tazobactam was excreted as the parent compound with the remaining amount excreted as the tazobactam M1 metabolite. After a single dose of Ceftolozane/Tazobactam (ZERBAXA), renal clearance of ceftolozane (3.41-6.69 L/h) was similar to plasma clearance (4.10-6.73 L/h) and similar to the glomerular filtration rate for the unbound fraction, suggesting that ceftolozane is eliminated by the kidney via glomerular filtration.
The mean terminal elimination half-life of ceftolozane and tazobactam in healthy adults with normal renal function is approximately 3 hours and 1 hour, respectively.
Special Populations: Renal Impairment: Ceftolozane, tazobactam and the tazobactam metabolite M1 are eliminated by the kidneys.
The ceftolozane dose normalized geometric mean AUC increased up to 1.26-fold, 2.5-fold, and 5-fold in subjects with mild, moderate, and severe renal impairment, respectively, compared to healthy subjects with normal renal function. The respective tazobactam dose normalized geometric mean AUC increased approximately up to 1.3-fold, 2-fold, and 4-fold. To maintain similar systemic exposures to those with normal renal function, dosage adjustment is required [see Dosage & Administration].
In subjects with ESRD on HD, approximately two-thirds of the administered ceftolozane/tazobactam dose is removed by HD. The recommended dose in cIAI or cUTI subjects with ESRD on HD is a single loading dose of Ceftolozane/Tazobactam (ZERBAXA) 750 mg (ceftolozane 500 mg and tazobactam 250 mg), followed by a Ceftolozane/Tazobactam (ZERBAXA) 150 mg (ceftolozane 100 mg and tazobactam 50 mg) maintenance dose administered every 8 hours for the remainder of the treatment period. The recommended dose in nosocomial pneumonia subjects with ESRD on HD is a single loading dose of Ceftolozane/Tazobactam (ZERBAXA) 2.25 g (ceftolozane 1.5 g and tazobactam 0.75 g), followed by a Ceftolozane/Tazobactam (ZERBAXA) 450 mg (ceftolozane 300 mg and tazobactam 150 mg) maintenance dose administered every 8 hours for the remainder of the treatment period. With HD, the dose should be administered immediately following completion of dialysis [see Dosage & Administration].
Augmented renal clearance: Following a single 1 hour intravenous infusion of Ceftolozane/Tazobactam (ZERBAXA) 3 g (ceftolozane 2 g and tazobactam 1 g) to critically ill patients with CrCL greater than or equal to 180 mL/min (N=10), mean terminal half-life values of ceftolozane and tazobactam were 2.6 hours and 1.5 hours, respectively. Free plasma ceftolozane concentrations were greater than 8 mcg/mL over 70% of an 8-hour period; free tazobactam concentrations were greater than 1 mcg/mL over 60% of an 8-hour period. No dose adjustment of Ceftolozane/Tazobactam (ZERBAXA) is recommended for nosocomial pneumonia patients with augmented renal clearance [see Pharmacology: Pharmacodynamics: Clinical Studies previously].
Hepatic impairment: As ceftolozane/tazobactam does not undergo hepatic metabolism, the systemic clearance of ceftolozane/tazobactam is not expected to be affected by hepatic impairment. No dose adjustment is recommended for Ceftolozane/Tazobactam (ZERBAXA) in subjects with hepatic impairment [see Dosage & Administration].
Elderly: In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in AUC were observed with regard to age. No dose adjustment of Ceftolozane/Tazobactam (ZERBAXA) based on age alone is recommended. Dosage adjustment for ZERBAXA in elderly patients should be based on renal function [see Dosage & Administration].
Paediatric patients: Safety and efficacy in paediatric patients have not been established.
Gender: In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in AUC were observed for ceftolozane and tazobactam. No dose adjustment is recommended based on gender.
Race: In a population pharmacokinetic analysis of ceftolozane/tazobactam, no clinically relevant differences in ceftolozane/tazobactam AUC were observed in Caucasians compared to other races. No dose adjustment is recommended based on race.
Drug Interaction Studies: See Interactions.
Animal Toxicology: Carcinogenesis: Long-term carcinogenicity studies in animals have not been conducted with Ceftolozane/Tazobactam (ZERBAXA), ceftolozane, or tazobactam.
Mutagenesis: Ceftolozane/Tazobactam (ZERBAXA) was not genotoxic in vivo. Ceftolozane/Tazobactam (ZERBAXA) was negative for genotoxicity in an in vitro mouse lymphoma assay and an in vivo rat bone marrow micronucleus assay. In an in vitro chromosomal aberration assay in Chinese hamster ovary cells, Ceftolozane/Tazobactam (ZERBAXA) was positive for structural aberrations, but only at highly toxic concentrations.
Ceftolozane was negative for genotoxicity in the in vitro microbial mutagenicity (Ames) assay, the in vitro chromosomal aberration assay in Chinese hamster lung fibroblast cells, the in vitro mouse lymphoma assay, the in vitro HPRT assay in Chinese hamster ovary cells, the in vivo mouse micronucleus assay, and the in vivo unscheduled DNA synthesis (UDS) assay.
Tazobactam was negative for genotoxicity in an in vitro microbial mutagenicity (Ames) assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, a mammalian point-mutation (Chinese hamster ovary cell HPRT) assay, an in vivo rat chromosomal aberration assay, an in vivo mouse bone marrow micronucleus assay, and a UDS assay. Tazobactam was positive for genotoxicity in an in vitro mouse lymphoma assay at ≥3000 mcg/mL.
Reproduction: Ceftolozane had no adverse effect on fertility in male or female rats at intravenous doses up to 1000 mg/kg/day. The mean plasma exposure (AUC) value at this dose is approximately 1.4 times the mean daily human ceftolozane exposure value at the highest recommended human dose of 2 grams every 8 hours.
In a rat fertility study with intraperitoneal tazobactam twice-daily, male and female fertility parameters were not affected at doses less than or equal to 640 mg/kg/day (approximately 4 times the recommended human dose of 1 gram every 8 hours based on body surface comparison).
Development: See Use in Pregnancy & Lactation.
Microbiology: Mechanism of Action: Ceftolozane belongs to the cephalosporin class of antimicrobials. Ceftolozane exerts bactericidal activity through binding to important penicillin-binding proteins (PBPs), resulting in inhibition of bacterial cell wall synthesis and subsequent cell death. Ceftolozane is an inhibitor of PBPs of P. aeruginosa (e.g., PBP1b, PBP1c and PBP3) and E. coli (e.g., PBP3).
Tazobactam is a beta-lactam structurally related to penicillin. It is an inhibitor of many Molecular Class A beta-lactamases, including CTX M, SHV, and TEM enzymes [see Resistance as follows].
Ceftolozane/Tazobactam (ZERBAXA) demonstrated in vitro activity against Enterobacteriaceae in the presence of some extended-spectrum beta-lactamases (ESBLs) and other beta-lactamases of the following groups: TEM, SHV, CTX-M, and OXA. Ceftolozane/Tazobactam (ZERBAXA) also demonstrated in vitro activity against P. aeruginosa isolates tested that had chromosomal AmpC, loss of outer membrane porin (OprD), or up-regulation of efflux pumps (MexXY, MexAB).
In the 2017 PACTS (Program to Assess Ceftolozane/Tazobactam Susceptibility) surveillance study the overall ceftolozane/tazobactam susceptibility of 3937 Enterobacteriaceae isolates collected from all sources from US hospitals was 95.6% and against extended spectrum beta-lactamase (ESBL), non-carbapenem resistant Enterobacteriaceae isolates the percent ceftolozane/tazobactam susceptibility was 93.5%. The overall ceftolozane/tazobactam susceptibility of 910 P. aeruginosa isolates collected from US hospitals was 97.7%. When ceftolozane/tazobactam was tested against isolates non-susceptible to ceftazidime, meropenem or piperacillin/tazobactam, the percent susceptibility to ceftolozane/tazobactam was 87.2%, 91.3% and 89.5%, respectively.
Resistance: Mechanisms of bacterial resistance to ceftolozane and tazobactam include: Production of beta-lactamases that can hydrolyse ceftolozane and which are not inhibited by tazobactam (see as follows); Modification of PBPs.
Tazobactam does not inhibit all Class A enzymes.
In addition, tazobactam does not inhibit the following types of beta-lactamase: Serine-based carbapenemases (e.g., Klebsiella pneumoniae carbapenemases [KPCs]); Metallo-beta-lactamases (e.g., New Delhi metallo-beta-lactamase [NDM]); Ambler Class D beta-lactamases (OXA-carbapenemases).
Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.
Cross-Resistance: Isolates resistant to other cephalosporins may be susceptible to ceftolozane and tazobactam, although cross-resistance may occur.
Interaction with Other Antimicrobials: In vitro synergy studies suggest no antagonism between ceftolozane and tazobactam and other antibacterial drugs (e.g. meropenem, amikacin, aztreonam, levofloxacin, tigecycline rifampin, linezolid, daptomycin, vancomycin, and metronidazole).
List of Microorganisms: Ceftolozane/Tazobactam (ZERBAXA) has been shown to be active against the following bacteria, both in vitro and in clinical infections [see Indications]. (See Table 10.)

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Clinical efficacy has not been established against the following pathogens although in vitro studies suggest that they would be susceptible to Ceftolozane/Tazobactam (ZERBAXA) in the absence of acquired mechanisms of resistance. (See Table 11.)

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OPTION A. Based on CLSI Breakpoints. (See Table 12.)

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A report of "Susceptible" indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control: Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test. Standard ceftolozane and tazobactam powder should provide the following range of MIC values provided in Table 13. For the diffusion technique using the 30 mcg ceftolozane/10 mcg tazobactam disk the criteria provided in Table 13 should be achieved. (See Table 13.)

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Indications/Uses
Ceftolozane/Tazobactam (ZERBAXA) for injection is indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms: Complicated Intra-abdominal Infections: Ceftolozane/Tazobactam (ZERBAXA) used in combination with metronidazole is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.
Complicated Urinary Tract Infections, including Pyelonephritis: Ceftolozane/Tazobactam (ZERBAXA) is indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, with or without concurrent bacteremia, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia: Ceftolozane/Tazobactam (ZERBAXA) is indicated for the treatment of nosocomial pneumonia, including ventilator-associated pneumonia (VAP), caused by the following Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella (Enterobacter) aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens.
Usage: To reduce the development of drug-resistant bacteria and maintain the effectiveness of Ceftolozane/Tazobactam (ZERBAXA) and other antibacterial drugs, Ceftolozane/Tazobactam (ZERBAXA) should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
Dosage/Direction for Use
General: Recommended Dosage: The recommended dosage regimen of Ceftolozane/Tazobactam (ZERBAXA) for injection is 1.5 gram (g) (ceftolozane 1 g and tazobactam 0.5 g) for cIAI and cUTI and 3 g (ceftolozane 2 g and tazobactam 1 g) for nosocomial pneumonia administered every 8 hours by intravenous infusion over 1 hour in patients 18 years or older and creatinine clearance (CrCL) greater than 50 mL/min. The duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriological progress as shown in Table 14. (See Table 14.)

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Preparation of Solutions: Ceftolozane/Tazobactam (ZERBAXA) does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparing the infusion solution.
Preparation of doses: Constitute each vial of Ceftolozane/Tazobactam (ZERBAXA) with 10 mL of sterile water for injection or 0.9% Sodium Chloride for injection, USP and gently shake to dissolve. The final volume is approximately 11.4 mL per vial. CAUTION: THE CONSTITUTED SOLUTION IS NOT FOR DIRECT INJECTION.
To prepare the required dose, withdraw the appropriate volume determined from Table 15 from the reconstituted vial(s). Add the withdrawn volume to an infusion bag containing 100 mL of 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP. (See Table 15.)

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Inspect drug products visually for particulate matter and discoloration prior to use. Ceftolozane/Tazobactam (ZERBAXA) infusions range from clear, colorless solutions to solutions that are clear and slightly yellow. Variations in color within this range do not affect the potency of the product.
Storage of Constituted Solutions: Upon constitution with sterile water for injection or 0.9% sodium chloride injection, reconstituted Ceftolozane/Tazobactam (ZERBAXA) solution may be held for 1 hour prior to transfer and dilution in a suitable infusion bag.
Following dilution of the solution with 0.9% Sodium Chloride or 5% Dextrose, Ceftolozane/Tazobactam (ZERBAXA) is stable for 24 hours when stored at room temperature or 7 days when stored under refrigeration at 2 to 8°C (36 to 46°F).
Constituted Ceftolozane/Tazobactam (ZERBAXA) solution or diluted Ceftolozane/Tazobactam (ZERBAXA) infusion should not be frozen.
Compatibility: Compatibility of Ceftolozane/Tazobactam (ZERBAXA) with other drugs has not been established. Ceftolozane/Tazobactam (ZERBAXA) should not be mixed with other drugs or physically added to solutions containing other drugs.
Renal Impairment: Dose adjustment is required for patients whose CrCL is 50 mL/min or less. Renal dose adjustments are listed in Table 16. For patients with changing renal function, monitor CrCL at least daily and adjust the dosage of Ceftolozane/Tazobactam (ZERBAXA) accordingly [see Precautions]. (See Table 16.)

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Hepatic impairment: No dose adjustment is necessary in patients with hepatic impairment.
Overdosage
In the event of overdose, discontinue Ceftolozane/Tazobactam (ZERBAXA) and provide general supportive treatment. Ceftolozane/Tazobactam (ZERBAXA) can be removed by hemodialysis. Approximately 66% of ceftolozane, 56% of tazobactam, and 51% of the tazobactam metabolite M1 were removed by dialysis. No information is available on the use of hemodialysis to treat overdosage.
Contraindications
Ceftolozane/Tazobactam (ZERBAXA) is contraindicated in patients with: Hypersensitivity to the active substances or to any of the active excipients; Hypersensitivity to any cephalosporin antibacterial agent; Severe hypersensitivity (e.g., anaphylactic reaction, severe skin reaction) to any other type of beta-lactam antibacterial agent (e.g., penicillins or carbapenems).
Special Precautions
Impaired renal function: The Ceftolozane/Tazobactam (ZERBAXA) dose should be adjusted based on renal function [see Dosage & Administration].
In a subgroup analysis of a Phase 3 cIAI trial, clinical cure rates were lower in patients with baseline CrCL of 30 to ≤50 mL/min compared to those with CrCL >50 mL/min. The reduction in clinical cure rates was more marked in the Ceftolozane/Tazobactam (ZERBAXA) plus metronidazole arm compared to the meropenem arm. A similar trend was also seen in the cUTI trial. Patients with renal impairment at baseline should be monitored frequently for any changes in renal function during treatment and the dose of Ceftolozane/Tazobactam (ZERBAXA) should be adjusted as necessary.
Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before initiating therapy with Ceftolozane/Tazobactam (ZERBAXA), make careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactams. If this product is to be given to a patient with a cephalosporin, penicillin, or other beta-lactam allergy, exercise caution because cross sensitivity has been established. If an anaphylactic reaction to Ceftolozane/Tazobactam (ZERBAXA) occurs, discontinue the drug and institute appropriate therapy.
Clostridium difficile-associated Diarrhea: Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Ceftolozane/Tazobactam (ZERBAXA), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile [see Adverse Reactions].
These types of infection may range in severity from mild to life threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or subsequent to the administration of Ceftolozane/Tazobactam (ZERBAXA). In such circumstances, the discontinuation of therapy with Ceftolozane/Tazobactam (ZERBAXA) and the use of supportive measures together with the administration of specific treatment for Clostridium difficile should be considered.
Development of Drug Resistant Bacteria: Prescribing Ceftolozane/Tazobactam (ZERBAXA) in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
Patients with Renal Impairment: Dosage adjustment is required in patients with moderate (CrCL 30 to 50 mL/min) or severe (CrCL 15 to 29 mL/min) renal impairment and in patients with ESRD on HD [see Dosage & Administration and Precautions].
Use in Children: The safety and efficacy of Ceftolozane/Tazobactam (ZERBAXA) in children and adolescents below 18 years of age have not yet been established.
Use in Elderly: In a population pharmacokinetic analysis of ceftolozane and tazobactam, no clinically relevant differences in exposure were observed with regard to age. No dose adjustment of Ceftolozane/Tazobactam (ZERBAXA) based on age alone is recommended.
Ceftolozane/Tazobactam (ZERBAXA) is substantially excreted by the kidney and the risk of adverse reactions to Ceftolozane/Tazobactam (ZERBAXA) may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function. Adjust dosage for elderly patients based on renal function [see Dosage & Administration].
Use In Pregnancy & Lactation
Pregnancy: There are no data on the use of ceftolozane and tazobactam in pregnant women. Because animal reproduction studies are not always predictive of human response, Ceftolozane/Tazobactam (ZERBAXA) should be used during pregnancy only if the potential benefit outweighs the possible risk.
Embryo-fetal development studies performed with intravenous ceftolozane in mice and rats with doses up to 2000 and 1000 mg/kg/day, respectively, revealed no evidence of harm to the fetus. The mean plasma exposure (AUC) values associated with these doses are approximately 3.5 (mice) and 2 (rats) times the mean daily human ceftolozane exposure at the highest recommended human l dose of 2 grams every 8 hours. It is not known if ceftolozane crosses the placenta in animals.
In a pre-postnatal study in rats, intravenous ceftolozane administered during pregnancy and lactation (Gestation Day 6 through Lactation Day 20) was associated with a decrease in auditory startle response in postnatal Day 60 pups at maternal doses of greater than or equal to 300 mg/kg/day. A dose of 300 mg/kg/day to rats was associated with a ceftolozane plasma exposure (AUC) value lower than the ceftolozane plasma AUC value at the highest recommended human dose of 2 grams every 8 hours.
In an embryo-fetal study in rats, tazobactam administered intravenously at doses up to 3000 mg/kg/day (approximately 10 times the highest recommended human dose of 1 gram every 8 hours based on body surface area comparison) produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity. In rats, tazobactam was shown to cross the placenta. Concentrations in the fetus were less than or equal to 10% of those found in maternal plasma.
In a pre-postnatal study in rats, tazobactam administered intraperitoneally twice daily at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) produced decreased maternal food consumption and body weight gain at the end of gestation and significantly more stillbirths with a tazobactam dose of 1280 mg/kg/day (approximately 4 times the highest recommended human dose of 1 gram every 8 hours based on body surface area comparison). No effects on the development, function, learning or fertility of F1 pups were noted, but postnatal body weights for F1 pups delivered to dams receiving 320 and 1280 mg/kg/day tazobactam were significantly reduced 21 days after delivery. F2-generation fetuses were normal for all doses of tazobactam. The NOAEL for reduced F1 body weights was considered to be 40 mg/kg/day, a dose lower than the highest recommended human dose of 1 gram every 8 hours based on body surface area comparison.
Nursing Mothers: It is unknown whether ceftolozane and tazobactam are excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Ceftolozane/Tazobactam (ZERBAXA) therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Adverse Reactions
Clinical Trials Experience: Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, including Pyelonephritis: Ceftolozane/Tazobactam (ZERBAXA) was evaluated in Phase 3 comparator-controlled clinical trials of cIAI and cUTI, which included a total of 1015 patients treated with Ceftolozane/Tazobactam (ZERBAXA) (1.5 g every 8 hours, adjusted based on renal function where appropriate) and 1032 patients treated with comparator (levofloxacin 750 mg daily in cUTI or meropenem 1 g every 8 hours in cIAI) for up to 14 days. The mean age of treated patients was 48 to 50 years (range 18 to 92 years), across treatment arms and indications. In both indications, about 25% of the subjects were 65 years of age or older. Most patients (75%) enrolled in the cUTI trial were female, and 58% of patients enrolled in the cIAI trial were male. Table 17 lists adverse reactions occurring in 1% or greater of patients receiving Ceftolozane/Tazobactam (ZERBAXA) in Phase 3 cIAI and cUTI clinical trials. (See Table 17.)

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Treatment discontinuation due to adverse events occurred in 2% (20/1015) of patients receiving Ceftolozane/Tazobactam (ZERBAXA) and 1.9% (20/1032) of patients receiving comparator drugs.
Less Common Adverse Reactions in Phase 3 cIAI and cUTI Clinical Trials: The following selected adverse reactions were reported in Ceftolozane/Tazobactam (ZERBAXA)-treated subjects at a rate of less than 1%: Cardiac disorders: tachycardia, angina pectoris.
Gastrointestinal disorders: gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic.
Infections and infestations: candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection, Clostridium difficile colitis.
Investigations: increased serum gamma-glutamyl transpeptidase (GGT), increased serum alkaline phosphatase, positive Coombs test.
Metabolism and nutrition disorders: hyperglycemia, hypomagnesemia, hypophosphatemia.
Nervous system disorders: ischemic stroke.
Renal and urinary system: renal impairment, renal failure.
Respiratory, thoracic and mediastinal disorders: dyspnea.
Skin and subcutaneous tissue disorders: urticaria.
Vascular disorders: venous thrombosis.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia: Ceftolozane/Tazobactam (ZERBAXA) was evaluated in a Phase 3 comparator-controlled clinical trial for nosocomial pneumonia, which included a total of 361 patients treated with Ceftolozane/Tazobactam (ZERBAXA) (3 g every 8 hours, adjusted based on renal function where appropriate) and 359 patients treated with comparator (meropenem 1 g every 8 hours) for up to 14 days. The mean age of treated patients was 60 years (range 18 to 98 years), across treatment arms. About 44% of the subjects were 65 years of age or older. Most patients (71%) enrolled in the trial were male. All subjects were mechanically ventilated and 92% were in an intensive care unit (ICU) at randomization. The median APACHE II score was 17. Table 18 lists adverse reactions occurring in 2% or greater of patients receiving Ceftolozane/Tazobactam (ZERBAXA) in a Phase 3 nosocomial pneumonia clinical trial. (See Table 18.)

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Treatment discontinuation due to treatment-related adverse events occurred in 1.1% (4/361) of patients receiving Ceftolozane/Tazobactam (ZERBAXA) and 1.4% (5/359) of patients receiving meropenem.
Less Common Adverse Reactions in a Phase 3 Nosocomial Pneumonia Clinical Trial: The following selected adverse reactions were reported in Ceftolozane/Tazobactam (ZERBAXA)-treated subjects at a rate of less than 2%: Infections and infestations: Clostridium difficile infection.
Investigations: liver function test abnormal, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, Clostridium test positive, Coombs direct test positive.
Laboratory Values: The development of a positive direct Coombs test may occur during treatment with Ceftolozane/Tazobactam (ZERBAXA). The incidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving Ceftolozane/Tazobactam (ZERBAXA) and 0% in patients receiving the comparator in the cUTI and cIAI clinical trials. The incidence of seroconversion to a positive direct Coombs test was 31.2% in patients receiving Ceftolozane/Tazobactam (ZERBAXA) and 3.6% in patients receiving meropenem in the nosocomial pneumonia clinical trial. In clinical studies, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.
Drug Interactions
No significant drug-drug interactions are anticipated between Ceftolozane/Tazobactam (ZERBAXA) and substrates, inhibitors, and inducers of cytochrome P450 enzymes (CYPs) based on in vitro and in vivo studies.
In vitro studies demonstrated that ceftolozane, tazobactam and the M1 metabolite of tazobactam did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4 and did not induce CYP1A2, CYP2B6, or CYP3A4 at therapeutic plasma concentrations. A clinical drug-drug interaction study was conducted and results indicated drug interactions involving CYP1A2 and CYP3A4 inhibition by Ceftolozane/Tazobactam (ZERBAXA) are not anticipated.
Ceftolozane and tazobactam were not substrates for P-gp or BCRP, and tazobactam was not a substrate for OCT2, in vitro at therapeutic plasma concentrations. In vitro data indicate that ceftolozane did not inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, MRP, BSEP, OAT1, OAT3, MATE1, or MATE2-K at therapeutic plasma concentrations. In vitro data indicate that neither tazobactam nor the tazobactam metabolite M1 inhibit P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, or BSEP transporters at therapeutic plasma concentrations.
Tazobactam is a substrate for OAT1 and OAT3. In vitro, tazobactam inhibited human OAT1 and OAT3 transporters with IC50 values of 118 and 147 mcg/mL, respectively. Co-administration of ceftolozane and tazobactam with OAT1 and OAT3 substrate furosemide in a clinical study did not significantly increase furosemide plasma exposures (geometric mean ratios of 0.83 and 0.87 for Cmax and AUC, respectively). However, active substances that inhibit OAT1 or OAT3 (e.g., probenecid) may increase tazobactam plasma concentrations. Co-administration of tazobactam with the OAT1/OAT3 inhibitor probenecid has been shown to prolong the half-life of tazobactam by 71%.
Caution For Usage
Incompatibilities: Compatibility of Ceftolozane/Tazobactam (ZERBAXA) with other drugs has not been established. Ceftolozane/Tazobactam (ZERBAXA) should not be mixed with other drugs or physically added to solutions containing other drugs.
Storage
Ceftolozane/Tazobactam (ZERBAXA) vials should be stored refrigerated at 2 to 8°C (36 to 46°F) and protected from light.
For storage conditions after reconstitution or dilution of the medicinal product [see Dosage & Administration].
Shelf Life: 30 months.
MIMS Class
ATC Classification
J01DI54 - ceftolozane and beta-lactamase inhibitor ; Belongs to the class of other cephalosporins and penems. Used in the systemic treatment of infections.
Presentation/Packing
Powd for inj (vial) 20 mL (white to yellow) x 10's.
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