Pharmacology: Mechanism of Action: ZERBAXA is an antibacterial drug [see Microbiology as follows].
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. 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 ZERBAXA.
Cardiac Electrophysiology: In a randomized, positive and placebo-controlled crossover thorough QTc study, 51 healthy subjects were administered a single therapeutic dose of ZERBAXA 1.5 gram (ceftolozane 1 g and tazobactam 0.5 g) and a supratherapeutic dose of ZERBAXA 4.5 gram (ceftolozane 3 g and tazobactam 1.5 g). No significant effects of ZERBAXA on heart rate, electrocardiogram morphology, PR, QRS, or QT interval were detected. Therefore, 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 ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) 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.
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.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
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 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 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 ≥10
5 were reduced to <10
3 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.
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.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In patients with levofloxacin-resistant pathogens at baseline, ZERBAXA was superior to levofloxacin with regards to microbiological eradication rate in the ME population, 58/89 (65.2%) in the 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 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 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 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. All patients had to be intubated and on mechanical ventilation at randomization.
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.
Following a diagnosis of HABP/VABP and prior to receipt of first dose of study drug, if required, patients could have received up to a maximum of 24 hours of active non-study antibacterial drug therapy in the 72 hours preceding the first dose of study drug. Patients who had failed prior antibacterial drug therapy for the current episode of HABP/VABP could be enrolled if the baseline lower respiratory tract (LRT) culture showed growth of a Gram-negative pathogen while the patient was on the antibacterial therapy and all other eligibility criteria were met. Empiric therapy at baseline with linezolid or other approved therapy for Gram-positive coverage was required in all patients pending baseline LRT culture results. Adjunctive Gram-negative therapy was optional and allowed for a maximum of 72 hours in centers with a prevalence of meropenem-resistant
P. aeruginosa more than 15%.
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 both treatment groups, most subjects (63.1%) received between 8 and 14 days of study therapy as specified in the protocol.
In the ITT population, Day 28 all-cause mortality and clinical cure rates in patients with CrCL greater than or equal to 150 mL/min were similar between ZERBAXA and meropenem. In patients with bacteremia at baseline, Day 28 all-cause mortality rates were 23/64 (35.9%) for ZERBAXA-treated patients and 13/41 (31.7%) for meropenem-treated patients; clinical cure rates were 30/64 (46.9%) and 15/41 (36.6%), respectively.
In the ITT population, 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 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 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 ZERBAXA and 13/41 (31.7%) for meropenem; clinical cure rates were 30/64 (46.9%) and 15/41 (36.6%), respectively.
In the ventilated HABP sub-group, a favorable response for ZERBAXA in 28-day all-cause mortality was observed, 24.2% (24/99) for ZERBAXA and 37.0% (40/108) for meropenem, respectively, for a weighted proportion difference of 12.8 (stratified 95% CI: 0.18, 24.75). In the VABP subgroup, 28-day all-cause mortality was 24.0% (63/263) for ZERBAXA and 20.3% (52/256) for meropenem, for a weighted proportion difference of -3.6 (stratified 95% CI: -10.74, 3.52).
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 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 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.)
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
In the mITT population, per subject microbiologic cure was achieved in 193/264 (73.1%) of 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, CTXM, OXA) in 157/511 (30.7%). Cure rates in this subset were similar to the overall trial results.
Pharmacokinetics: The mean pharmacokinetic parameters of ZERBAXA in healthy adults with normal renal function after multiple 1-hour intravenous infusions of 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 administrations. The C
max and AUC of ceftolozane and tazobactam increase in proportion to dose. The elimination half-life (t½) of ceftolozane or tazobactam is independent of dose. (See Table 8.)
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The mean steady-state population pharmacokinetic parameters of ZERBAXA in patients with cIAI and cUTI receiving 1 hour intravenous infusion of ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) or patients with nosocomial pneumonia receiving 1 hour intravenous infusion of 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 ZERBAXA in healthy adult males (n=51) following a single intravenous dose of 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 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 ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g).
Elimination: Ceftolozane is eliminated from the body by renal excretion with a half-life of approximately 3 hours. Tazobactam is eliminated by renal excretion and metabolism with a plasma half-life of approximately 1 hour.
Metabolism: Ceftolozane is not a substrate for CYP enzymes and 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.
Excretion: Ceftolozane, tazobactam and the tazobactam metabolite M1 are excreted by the kidneys. Following administration of a single ZERBAXA 1.5 g (ceftolozane 1 g and tazobactam 0.5 g) intravenous dose to healthy male adults, greater than 95% of ceftolozane was excreted in the urine as unchanged parent drug. More than 80% of tazobactam was excreted as the parent compound with the remainder excreted as the tazobactam M1 metabolite. After a single dose of ZERBAXA, renal clearance of ceftolozane (3.41-6.69 L/h) was similar to plasma CL (4.10 to 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. Tazobactam is a substrate for OAT1 and OAT3 transporters and its elimination has been shown to be inhibited by probenecid, an inhibitor of OAT1/3.
Specific Populations: Patients with Renal Impairment: ZERBAXA 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 Patients with Renal Impairment under Dosage & Administration].
In subjects with ESRD on HD, approximately two-thirds of the administered ZERBAXA dose is removed by HD. The recommended dose in cIAI or cUTI subjects with ESRD on HD is a single loading dose of ZERBAXA 750 mg (ceftolozane 500 mg and tazobactam 250 mg), followed by a 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 ZERBAXA 2.25 g (ceftolozane 1.5 g and tazobactam 0.75 g), followed by a ZERBAXA 450 mg (ceftolozane 300 mg and tazobactam 150 mg) maintenance dose administered every 8 hours for the remainder of the treatment period. On HD days, administer the dose at the earliest possible time following completion of HD [see Patients with Renal Impairment under Dosage & Administration].
Augmented renal clearance: Following a single 1 hour intravenous infusion of 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 ZERBAXA is recommended for nosocomial pneumonia patients with augmented renal clearance [see previously mentioned Pharmacodynamics: Clinical Studies: Nosocomial Pneumonia, including Ventilator-associated Pneumonia].
Patients with Hepatic Impairment: As ZERBAXA does not undergo hepatic metabolism, the systemic clearance of ZERBAXA is not expected to be affected by hepatic impairment.
No dose adjustment is recommended for ZERBAXA in subjects with hepatic impairment.
Geriatric Patients: In a population pharmacokinetic analysis of ZERBAXA, no clinically relevant differences in exposure were observed with regard to age.
No dose adjustment of ZERBAXA based on age is recommended. Dosage adjustment for ZERBAXA in elderly patients should be based on renal function [see Patients with Renal Impairment under Dosage & Administration].
Pediatric Patients: Safety and effectiveness in pediatric patients have not been established.
Gender: In a population pharmacokinetic analysis of ZERBAXA, 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 ZERBAXA, no clinically relevant differences in ZERBAXA AUC were observed in Caucasians compared to other races combined.
No dose adjustment is recommended based on race.
Drug Interactions: No drug-drug interaction was observed between ceftolozane and tazobactam in a clinical study in 16 healthy subjects.
In vitro and
in vivo data indicate that ZERBAXA is unlikely to cause clinically relevant drug-drug interactions related to CYPs and transporters at therapeutic concentrations.
Drug Metabolizing Enzymes:
In vivo data indicated that ZERBAXA is not a substrate for CYPs. Thus clinically relevant drug-drug interactions involving inhibition or induction of CYPs by other drugs are unlikely to occur.
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.
In vitro induction studies in primary human hepatocytes demonstrated that ceftolozane, tazobactam, and the tazobactam metabolite M1 decreased CYP1A2 and CYP2B6 enzyme activity and mRNA levels in primary human hepatocytes as well as CYP3A4 mRNA levels at supratherapeutic plasma concentrations. Tazobactam metabolite M1 also decreased CYP3A4 activity at supratherapeutic plasma concentrations. A clinical drug-drug interaction study was conducted and results indicated drug interactions involving CYP1A2 and CYP3A4 inhibition by ZERBAXA are not anticipated.
Membrane Transporters: Ceftolozane and tazobactam were not substrates for P-gp or BCRP, and tazobactam was not a substrate for OCT2,
in vitro at therapeutic concentrations.
Tazobactam is a known substrate for OAT1 and OAT3. Co-administration of tazobactam with the OAT1/OAT3 inhibitor probenecid has been shown to prolong the half-life of tazobactam by 71%. Co-administration of ZERBAXA with drugs that inhibit OAT1 and/or OAT3 may increase tazobactam 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
in vitro 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.
In vitro, tazobactam inhibited human OAT1 and OAT3 transporters with IC
50 values of 118 and 147 mcg/mL, respectively. A clinical drug-drug interaction study was conducted and results indicated clinically relevant drug interactions involving OAT1/OAT3 inhibition by ZERBAXA are not anticipated.
Nonclinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Long-term carcinogenicity studies in animals have not been conducted with ZERBAXA, ceftolozane, or 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, ZERBAXA was positive for structural aberrations.
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 mouse bone-marrow micronucleus assay, and a UDS assay.
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 2 times the highest recommended human dose of 1 gram every 8 hours based on body surface comparison).
Microbiology: Mechanism of Action: Ceftolozane belongs to the cephalosporin class of antibacterial drugs. The bactericidal action of ceftolozane results from inhibition of cell wall biosynthesis, and is mediated through binding to penicillin-binding proteins (PBPs). Ceftolozane is an inhibitor of PBPs of
P. aeruginosa (e.g., PBP1b, PBP1c, and PBP3) and
E. coli (e.g., PBP3).
Tazobactam sodium has little clinically relevant
in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is an irreversible inhibitor of some beta-lactamases (e.g., certain penicillinases and cephalosporinases), and can bind covalently to some chromosomal and plasmid-mediated bacterial beta-lactamases.
In the 2017 Program to Assess Ceftolozane/Tazobactam Susceptibility (PACTS) 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 beta-lactam resistance may include the production of beta-lactamases, modification of PBPs by gene acquisition or target alteration, up-regulation of efflux pumps, and loss of outer membrane porin.
Clinical isolates may produce multiple beta-lactamases, express varying levels of beta-lactamases, or have amino acid sequence variations, and other resistance mechanisms that have not been identified.
Culture and susceptibility information and local epidemiology should be considered in selecting or modifying antibacterial therapy.
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. ZERBAXA is not active against bacteria that produce serine carbapenemases [
K. pneumoniae carbapenemase (KPC)], and metallo-beta-lactamases.
In ZERBAXA clinical trials, some isolates of Enterobacteriaceae, that produced beta-lactamases, were susceptible to ZERBAXA (minimum inhibitory concentration ≤2 mcg/mL). These isolates produced one or more beta-lactamases of the following enzyme groups: CTX-M, OXA, TEM, or SHV.
Some of these beta-lactamases were also produced by isolates of Enterobacteriaceae that were not susceptible to ZERBAXA (minimum inhibitory concentration >2 mcg/mL). These isolates produced one or more beta-lactamases of the following enzyme groups: CTX-M, OXA, TEM, or SHV.
ZERBAXA 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).
Isolates resistant to other cephalosporins may be susceptible to ZERBAXA, although cross-resistance may occur.
Interaction with Other Antimicrobials: In vitro synergy studies suggest no antagonism between ZERBAXA and other antibacterial drugs (e.g., meropenem, amikacin, aztreonam, levofloxacin, tigecycline, rifampin, linezolid, daptomycin, vancomycin, and metronidazole).
Antimicrobial Activity: ZERBAXA has been shown to be active against the following bacteria, both
in vitro and in clinical infections [see Indications/Uses].
Complicated Intra-abdominal Infections: Gram-negative bacteria:
Enterobacter cloacae,
Escherichia coli,
Klebsiella oxytoca,
Klebsiella pneumoniae,
Proteus mirabilis,
Pseudomonas aeruginosa.
Gram-positive bacteria:
Streptococcus anginosus,
Streptococcus constellatus,
Streptococcus salivarius.
Anaerobic bacteria:
Bacteroides fragilis.
Complicated Urinary Tract Infections, Including Pyelonephritis: Gram-negative bacteria:
Escherichia coli,
Klebsiella pneumoniae,
Proteus mirabilis,
Pseudomonas aeruginosa.
Nosocomial Pneumonia, including Ventilator-associated Pneumonia: Gram-negative bacteria:
Enterobacter cloacae,
Escherichia coli,
Haemophilus influenzae,
Klebsiella oxytoca,
Klebsiella pneumoniae,
Proteus mirabilis,
Pseudomonas aeruginosa,
Serratia marcescens.
The following
in vitro data as follows are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an
in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftolozane and tazobactam against isolates of similar genus or organism group. However, the efficacy of ZERBAXA in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Gram-negative bacteria:
Citrobacter koseri,
Morganella morganii,
Proteus vulgaris,
Providencia rettgeri,
Providencia stuartii,
Serratia liquefaciens,
Klebsiella (Enterobacter)
aerogenes.
Gram-positive bacteria:
Streptococcus agalactiae,
Streptococcus intermedius.
Susceptibility Test Methods: When available, the clinical microbiology laboratory should provide cumulative reports of
in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.
Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). Ceftolozane and tazobactam susceptibility testing is performed with a fixed 4 mcg/mL concentration of tazobactam. These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized test method (broth, and/or agar). The MIC values should be interpreted according to the criteria in Table 10.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method. This procedure uses paper disks impregnated with 30 mcg of ceftolozane and 10 mcg of tazobactam to test the susceptibility of bacteria to ceftolozane and tazobactam. The disk diffusion should be interpreted according to the criteria in Table 10.
Anaerobic Techniques: For anaerobic bacteria, the susceptibility to ceftolozane and tazobactam can be determined by standardized test method. The MIC values obtained should be interpreted according to criteria provided in Table 10. (See Table 10.)
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A report of Susceptible (S) 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 (I) 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 or in situations where a high dose of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) 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 11. For the diffusion technique using the 30 mcg ceftolozane/10 mcg tazobactam disk, the criteria provided in Table 11 should be achieved. (See Table 11.)
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