Zerbaxa Drug Information
Generic name: CEFTOLOZANE AND TAZOBACTAM
Uses of Zerbaxa
Complicated Intra-abdominal Infections
ZERBAXA used in combination with metronidazole is indicated for the treatment of adult and pediatric patients (at least 32 weeks gestational age) with complicated intra-abdominal infections (cIAI) caused by the following susceptible 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 ZERBAXA is indicated for the treatment of adult and pediatric patients (at least 32 weeks gestational age) with complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.
Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia ZERBAXA is indicated for the treatment of adult and pediatric patients (at least 32 weeks gestational age) with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), caused by the following susceptible Gram-negative microorganisms: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Serratia marcescens.
Usage to Reduce Development of Drug-Resistant Bacteria
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat or prevent 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 & Administration of Zerbaxa
Preparation of Solutions
ZERBAXA does not contain a bacteriostatic preservative. Aseptic technique must be followed in preparing the infusion solution. Preparation of doses: Constitute each vial of 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 4 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. For doses above 1.5 g, reconstitute a second vial in the same manner as the first one, withdraw an appropriate volume (per Table 5), and add to the same infusion bag. Discard unused portion.
Table 5: Preparation of Inspect drug products visually for particulate matter and discoloration prior to use. 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.
Compatibility Compatibility of ZERBAXA with other drugs has not been established. ZERBAXA should not be mixed with other drugs or physically added to solutions containing other drugs.
Storage of Constituted Solutions
Upon constitution with sterile water for injection or 0.9% sodium chloride injection, reconstituted ZERBAXA solution may be held for 1 hour prior to transfer and dilution in a suitable infusion bag. Discard unused portion. Constituted ZERBAXA solution or diluted ZERBAXA infusion should not be frozen.
| Infection | Dose | Duration of Treatment |
|---|---|---|
| cIAI Used in conjunction with metronidazole 500 mg intravenously every 8 hours | ZERBAXA 1.5 g Administer all doses of ZERBAXA intravenously every 8 hours over 1 hour Provides 1 g ceftolozane and 0.5 g tazobactam | 4 to 14 days |
| cUTI, Including Pyelonephritis | ZERBAXA 1.5 g | 7 days |
| HABP/VABP | ZERBAXA 3 g Provides 2 g ceftolozane and 1 g tazobactam | 8 to 14 days |
| Infection | Dose | Duration of Treatment |
|---|---|---|
| cIAI Used in conjunction with metronidazole. | ZERBAXA 30 mg/kg Provides 20 mg/kg ceftolozane and 10 mg/kg tazobactam. Pediatric patients with cIAI or cUTI weighing greater than 50 kg should not exceed a maximum dose of 1.5 g. up to a maximum dose of 1.5 g Administer all doses of ZERBAXA intravenously every 8 hours over 1 hour in pediatric patients with cIAI or cUTI. Provides 1 g ceftolozane and 0.5 g tazobactam. | 5 to 14 days |
| cUTI, Including Pyelonephritis | ZERBAXA 30 mg/kg up to a maximum dose of 1.5 g | 7 to 14 days |
| HABP/VABP (at least 32 weeks gestational age to less than 2 years) | ZERBAXA 60 mg/kg Provides 40 mg/kg ceftolozane and 20 mg/kg tazobactam. up to a maximum dose of 3 g Administer all doses of ZERBAXA intravenously every 8 hours over 2 hours in pediatric patients with HABP/VABP. Provides 2 g ceftolozane and 1 g tazobactam. Pediatric patients with HABP/VABP weighing greater than 40 kg should not exceed a maximum dose of 3 g. | 8 to 14 days |
| HABP/VABP (from 2 years and older) | ZERBAXA 75 mg/kg Provides 50 mg/kg ceftolozane and 25 mg/kg tazobactam. up to a maximum dose of 3 g | 8 to 14 days |
| Infection | Dose | Frequency | Infusion Time | Duration of Treatment |
|---|---|---|---|---|
| Complicated Intra-abdominal Infections Used in conjunction with metronidazole 500 mg intravenously every 8 hours | ZERBAXA 1.5 g Provides 1 g ceftolozane and 0.5 g tazobactam | Every 8 Hours | 1 hour | 4 to 14 days |
| Complicated Urinary Tract Infections, Including Pyelonephritis | ZERBAXA 1.5 g | Every 8 Hours | 1 hour | 7 days |
| Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia | ZERBAXA 3 g Provides 2 g ceftolozane and 1 g tazobactam | Every 8 Hours | 1 hour | 8 to 14 days |
| Infection | Age Range | Dose | Frequency | Infusion time | Duration of treatment |
|---|---|---|---|---|---|
| Complicated Intra-abdominal Infections Used in conjunction with metronidazole. | All pediatric patients (at least 32 weeks gestational age) | ZERBAXA 30 mg/kg Provides 20 mg/kg ceftolozane and 10 mg/kg tazobactam. up to a maximum dose of 1.5 g For pediatric patients with cUTI or cIAI weighing greater than 50 kg, do not exceed a maximum dose of 1.5 g. Provides 1 g ceftolozane and 0.5 g tazobactam | Every 8 hours | 1 hour | 5 to 14 days |
| Complicated Urinary Tract Infections, Including Pyelonephritis | ZERBAXA 30 mg/kg up to a maximum dose of 1.5 g | 1 hour | 7 to 14 days | ||
| Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia | Pediatric patients from at least 32 weeks of gestational age to less than 2 years | ZERBAXA 60 mg/kg Provides 40 mg/kg ceftolozane and 20 mg/kg tazobactam. up to a maximum dose of 3 g For pediatric patients with HABP/VABP weighing greater than 40 kg, do not exceed a maximum dose of 3 g. Provides 2 g ceftolozane and 1 g tazobactam. | 2 hours | 8 to 14 days | |
| Pediatric patients from 2 years and older | ZERBAXA 75 mg/kg Provides 50 mg/kg ceftolozane and 25 mg/kg tazobactam. up to a maximum dose of 3 g |
| Estimated CrCl (mL/min) Estimated CrCl using the Cockcroft-Gault formula | Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis | Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia | ||
|---|---|---|---|---|
| Dosage | Infusion time | Dosage | Infusion time | |
| 51 to less than 90 | ZERBAXA 1.5 g Provides 1 g ceftolozane and 0.5 g tazobactam. intravenously every 8 hours | 1 hour | ZERBAXA 3 g Provides 2 g ceftolozane and 1 g tazobactam. intravenously every 8 hours | 1 hour |
| 30 to 50 | ZERBAXA 750 mg Provides 500 mg ceftolozane and 250 mg tazobactam. intravenously every 8 hours | ZERBAXA 1.5 g intravenously every 8 hours | ||
| 15 to 29 | ZERBAXA 375 mg Provides 250 mg ceftolozane and 125 mg tazobactam. intravenously every 8 hours | ZERBAXA 750 mg intravenously every 8 hours | ||
| Less than 15 (not receiving intermittent hemodialysis) | ZERBAXA dosage not established | ZERBAXA dosage not established | ||
| Receiving Intermittent Hemodialysis | A single loading dose of ZERBAXA 750 mg followed by a ZERBAXA 150 mg Provides 100 mg ceftolozane and 50 mg tazobactam. maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on intermittent hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) | A single loading dose of ZERBAXA 2.25 g Provides 1.5 g ceftolozane and 0.75 g tazobactam. followed by a ZERBAXA 450 mg Provides 300 mg ceftolozane and 150 mg tazobactam. maintenance dose administered intravenously every 8 hours for the remainder of the treatment period (on intermittent hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) | ||
| Estimated GFR Estimate eGFR using an equation validated in pediatric patients in the approved age range. (mL/min/1.73 m 2 ) | Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, including Pyelonephritis | Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia | ||
|---|---|---|---|---|
| Dosage | Infusion time | Dosage | Infusion time | |
| 51 to less than 90 | ZERBAXA 30 mg/kg Provides 20 mg/kg ceftolozane and 10 mg/kg tazobactam. intravenously every 8 hours | 1 hour | ZERBAXA 75 mg/kg Provides 50 mg/kg ceftolozane and 25 mg/kg tazobactam. intravenously every 8 hours | 2 hours |
| 30 to 50 | ZERBAXA 15 mg/kg Provides 10 mg/kg ceftolozane and 5 mg/kg tazobactam. intravenously every 8 hours | ZERBAXA 37.5 mg/kg Provides 25 mg/kg ceftolozane and 12.5 mg/kg tazobactam. intravenously every 8 hours | ||
| 15 to 29 | ZERBAXA 7.5 mg/kg Provides 5 mg/kg ceftolozane and 2.5 mg/kg tazobactam intravenously every 8 hours | ZERBAXA 18.75 mg/kg Provides 12.5 mg/kg ceftolozane and 6.25 mg/kg tazobactam. intravenously every 8 hours | ||
| Less than 15 (not receiving intermittent hemodialysis) | ZERBAXA dosage not established | ZERBAXA dosage not established | ||
| Receiving Intermittent Hemodialysis | A single loading dose of ZERBAXA 15 mg/kg followed by a ZERBAXA 3 mg/kg Provides 2 mg/kg ceftolozane and 1 mg/kg tazobactam. maintenance dose administered every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) | A single loading dose of ZERBAXA 45 mg/kg Provides 30 mg/kg ceftolozane and 15 mg/kg tazobactam followed by a ZERBAXA 9 mg/kg Provides 6 mg/kg ceftolozane and 3 mg/kg tazobactam maintenance dose administered every 8 hours for the remainder of the treatment period (on hemodialysis days, administer the dose at the earliest possible time following completion of dialysis) | ||
| ZERBAXA (ceftolozane and tazobactam) Dose | Volume to Withdraw from Reconstituted Vial(s) |
|---|---|
| ZERBAXA 3 g (2 g and 1 g) | Two vials of 11.4 mL each (entire contents from two vials) |
| ZERBAXA 2.25 g (1.5 g and 0.75 g) | 11.4 mL from one vial (entire contents) and 5.7 mL from a second vial |
| ZERBAXA 1.5 g (1 g and 0.5 g) | 11.4 mL (entire contents from one vial) |
| ZERBAXA 750 mg (500 mg and 250 mg) | 5.7 mL |
| ZERBAXA 450 mg (300 mg and 150 mg) | 3.5 mL |
| ZERBAXA 375 mg (250 mg and 125 mg) | 2.9 mL |
| ZERBAXA 150 mg (100 mg and 50 mg) | 1.2 mL |
Side Effects of Zerbaxa
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and also may not reflect rates observed in practice. 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 most patients (58%) enrolled in the cIAI trial were male.
Most patients (>70%) in both trials were enrolled in Eastern Europe and were White. The most common adverse reactions (5% or greater in either indication) occurring in patients receiving ZERBAXA were nausea, diarrhea, headache, and pyrexia. Table 7 lists adverse reactions occurring in 1% or greater of patients receiving ZERBAXA in Phase 3 cIAI and cUTI clinical trials.
Renal impairment (including the terms renal impairment, renal failure, and renal failure acute) led to discontinuation of treatment in 5/1015 (0.5%) subjects receiving ZERBAXA and none in the comparator arms. The causes of death varied and included worsening and/or complications of infection, surgery, and underlying conditions. Less Common Adverse Reactions in Phase 3 cIAI and cUTI Clinical Trials The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 1%: Cardiac disorders: tachycardia, angina pectoris Gastrointestinal disorders: gastritis, abdominal distension, dyspepsia, flatulence, ileus paralytic General disorders and administration site conditions: infusion site reactions Infections and infestations: candidiasis including oropharyngeal and vulvovaginal, fungal urinary tract infection 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 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia ZERBAXA was evaluated in a Phase 3 comparator-controlled clinical trial for HABP/VABP (Trial 3), which included a total of 361 patients treated with 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. Most patients (71%) enrolled in the trial were male. All subjects were mechanically ventilated at randomization and 92% were in an intensive care unit (ICU) at randomization.
The median APACHE II score was 17, and 33% of subjects had a baseline APACHE II score of ≥20, indicating a high severity of illness for many patients enrolled in this trial. Table 8 lists adverse reactions occurring in 2% or greater of patients receiving ZERBAXA in a Phase 3 HABP/VABP clinical trial. Less Common Adverse Reactions in a Phase 3 HABP/VABP Clinical Trial The following selected adverse reactions were reported in ZERBAXA-treated subjects at a rate of less than 2%: Investigations: blood alkaline phosphatase increased, gamma-glutamyltransferase increased, Coombs direct test positive Pediatric Patients Complicated Intra-abdominal Infections and Complicated Urinary Tract Infections, Including Pyelonephritis ZERBAXA was evaluated in two blinded, randomized, active-controlled clinical studies in pediatric patients from birth to less than 18 years of age, one in cIAI (Trial 4) and the other in cUTI (Trial 5), which included a total of 170 pediatric patients treated with ZERBAXA and 54 pediatric patients treated with the comparator.
The ZERBAXA dosing regimen was the same in each trial. Patients were randomized 3:1 to receive ZERBAXA plus metronidazole or meropenem plus placebo in the cIAI study and ZERBAXA or meropenem in the cUTI study. In these pediatric patients, the type of adverse reactions were generally comparable to those observed in adults.
Table 9 lists adverse reactions occurring in 4% or greater of pediatric patients receiving ZERBAXA in either the pediatric cIAI or cUTI clinical trial. The safety profile of ZERBAXA in pediatric patients with HABP/VABP was similar to that in pediatric patients with cIAI and cUTI and adult patients with HABP/VABP. The most common adverse reactions that occurred in greater than 7% of pediatric patients included thrombocytosis, pyrexia, increased AST and ALT, anemia, diarrhea, and leukopenia.
Laboratory Values The development of a positive direct Coombs test may occur during treatment with ZERBAXA. The incidence of seroconversion to a positive direct Coombs test was 0.2% in patients receiving ZERBAXA and 0% in patients receiving the comparator in the adult cUTI and cIAI clinical trials. The incidence of seroconversion to a positive direct Coombs test was 31.2% in patients receiving ZERBAXA and 3.6% in patients receiving meropenem in the adult HABP/VABP clinical trial.
The incidence of seroconversion to a positive direct Coombs test was 45.3% in patients receiving ZERBAXA and 33.3% in patients receiving meropenem in the pediatric cIAI clinical trial. The incidence of seroconversion to a positive direct Coombs test was 29.7% in patients receiving ZERBAXA and 8.7% in patients receiving meropenem in the pediatric cUTI clinical trial. In clinical trials, there was no evidence of hemolysis in patients who developed a positive direct Coombs test in any treatment group.
| Adverse Reaction | Complicated Intra-abdominal Infections | Complicated Urinary Tract Infections, Including Pyelonephritis | ||
|---|---|---|---|---|
| ZERBAXA The ZERBAXA for injection dose was 1.5 g intravenously every 8 hours, adjusted to match renal function where appropriate. In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=482) n (%) | Meropenem (N=497) n (%) | ZERBAXA (N=533) n (%) | Levofloxacin (N=535) n (%) | |
| Nausea | 38 (7.9) | 29 (5.8) | 15 (2.8) | 9 (1.7) |
| Headache | 12 (2.5) | 9 (1.8) | 31 (5.8) | 26 (4.9) |
| Diarrhea | 30 (6.2) | 25 (5) | 10 (1.9) | 23 (4.3) |
| Pyrexia | 27 (5.6) | 20 (4) | 9 (1.7) | 5 (0.9) |
| Constipation | 9 (1.9) | 6 (1.2) | 21 (3.9) | 17 (3.2) |
| Insomnia | 17 (3.5) | 11 (2.2) | 7 (1.3) | 14 (2.6) |
| Vomiting | 16 (3.3) | 20 (4) | 6 (1.1) | 6 (1.1) |
| Hypokalemia | 16 (3.3) | 10 (2) | 4 (0.8) | 2 (0.4) |
| ALT increased | 7 (1.5) | 5 (1) | 9 (1.7) | 5 (0.9) |
| AST increased | 5 (1) | 3 (0.6) | 9 (1.7) | 5 (0.9) |
| Anemia | 7 (1.5) | 5 (1) | 2 (0.4) | 5 (0.9) |
| Thrombocytosis | 9 (1.9) | 5 (1) | 2 (0.4) | 2 (0.4) |
| Abdominal pain | 6 (1.2) | 2 (0.4) | 4 (0.8) | 2 (0.4) |
| Anxiety | 9 (1.9) | 7 (1.4) | 1 (0.2) | 4 (0.7) |
| Dizziness | 4 (0.8) | 5 (1) | 6 (1.1) | 1 (0.2) |
| Hypotension | 8 (1.7) | 4 (0.8) | 2 (0.4) | 1 (0.2) |
| Atrial fibrillation | 6 (1.2) | 3 (0.6) | 1 (0.2) | 0 |
| Rash | 8 (1.7) | 7 (1.4) | 5 (0.9) | 2 (0.4) |
| Adverse Reactions | ZERBAXA The ZERBAXA for injection dose was 3 g intravenously every 8 hours, adjusted to match renal function where appropriate. N=361 n (%) | Meropenem N=359 n (%) |
|---|---|---|
| Hepatic transaminase increased Includes alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hepatic enzyme increased, hypertransaminasemia, liver function test abnormal. | 43 (11.9) | 26 (7.2) |
| Renal impairment/renal failure Includes acute renal failure, anuria, azotemia, oliguria, prerenal failure, renal failure, renal impairment. | 32 (8.9) | 22 (6.1) |
| Diarrhea | 23 (6.4) | 25 (7.0) |
| Intracranial hemorrhage Includes cerebellar hemorrhage, cerebral hematoma, cerebral hemorrhage, hemorrhage intracranial, hemorrhagic stroke, hemorrhagic transformation stroke, intraventricular hemorrhage, subarachnoid hemorrhage, subdural hematoma. | 16 (4.4) | 5 (1.4) |
| Vomiting | 12 (3.3) | 10 (2.8) |
| Clostridioides difficile colitis Includes Clostridioides difficile colitis, Clostridioides difficile infection, Clostridioides test positive. | 10 (2.8) | 2 (0.6) |
| Adverse Reaction | Complicated Intra-abdominal Infections | Complicated Urinary Tract Infections, Including Pyelonephritis | ||
|---|---|---|---|---|
| ZERBAXA In the cIAI trials, ZERBAXA was given in conjunction with metronidazole. (N=70) n (%) | Meropenem (N=21) n (%) | ZERBAXA (N=100) n (%) | Meropenem (N=33) n (%) | |
| Thrombocytosis Includes platelet count increased. | 11 (16) | 3 (14) | 9 (9) | 3 (9) |
| Diarrhea | 12 (17) | 5 (24) | 7 (7) | 3 (9) |
| Pyrexia Includes hyperthermia. | 9 (13) | 3 (14) | 7 (7) | 1 (3) |
| Leukopenia Includes neutropenia and neutrophil count decreased. | 3 (4) | 0 (0) | 8 (8) | 0 (0) |
| Abdominal pain Includes upper abdominal pain. | 8 (11) | 0 (0) | 2 (2) | 1 (3) |
| AST increased | 5 (7) | 1 (5) | 4 (4) | 2 (6) |
| Vomiting | 7 (10) | 1 (5) | 1 (1) | 1 (3) |
| ALT increased | 4 (6) | 1 (5) | 4 (4) | 2 (6) |
| Anemia | 5 (7) | 0 (0) | 2 (2) | 0 (0) |
| Phlebitis Includes superficial phlebitis. | 4 (6) | 0 (0) | 1 (1) | 1 (3) |
| Hypertension | 3(4) | 0 (0) | 0 (0) | 1 (3) |
| Gastritis | 3 (4) | 0 (0) | 0 (0) | 0 (0) |
| Hypokalemia Includes blood potassium decreased. | 3 (4) | 0 (0) | 0 (0) | 0 (0) |
| Bradypnea Includes respiratory rate decreased., | 3 (4) | 0 (0) | 0 (0) | 0 (0) |
Warnings & Cautions for Zerbaxa
Clostridioides difficile -Associated Diarrhea
Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including 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. C. difficile produces toxins A and B which contribute to the development of CDAD.
CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is confirmed, discontinue antibacterials not directed against C. difficile, if possible.
Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.
Development of Drug-resistant Bacteria Prescribing ZERBAXA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and risks the development of drug-resistant bacteria.
| Baseline Renal Function | ZERBAXA plus Metronidazole n/N (%) | Meropenem n/N (%) |
|---|---|---|
| CrCl greater than 50 mL/min | 312/366 (85.2) | 355/404 (87.9) |
| CrCl 30 to 50 mL/min | 11/23 (47.8) | 9/13 (69.2) |
Pregnancy Safety for Zerbaxa
Pregnancy Risk Summary There are no data available on ZERBAXA, ceftolozane or tazobactam use in pregnant women to allow assessment of a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades have not identified an association of cephalosporin use during pregnancy with major birth defects, miscarriage, or other adverse maternal or fetal outcomes (see Data ). Neither ceftolozane nor tazobactam produced embryo-fetal toxicity when administered to rodents during the period of organogenesis at ceftolozane doses approximately 3.5 times higher in mice and 2 times higher in rats than the maximum recommended human dose (MRHD) of 2 grams every 8 hours based on plasma AUC comparison or at tazobactam doses approximately 10 times higher in rats than the MRHD of 1 gram every 8 hours based on body surface area comparison.
In pre-postnatal studies, where pregnant rats were administered intravenous ceftolozane or intraperitoneal tazobactam in gestation and through the lactation period, ceftolozane was associated with a decrease in auditory startle response in first generation offspring at a dose lower than the MRHD based on AUC comparison, and tazobactam was associated with reduced maternal body weight gain and increased stillbirths at a dose equivalent to approximately 4 times the MRHD and reduced fetal body weights in first generation offspring at a dose approximately equivalent to the MRHD based on body surface area comparison (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. In mice, ceftolozane was not associated with maternal or embryo-fetal toxicity with doses up to the highest dose of 2000 mg/kg/ day (approximately 3.5 times the MRHD of 2 grams every 8 hours based on plasma AUC comparison).
In rats, no embryo-fetal toxicity was observed, but maternal body weight gain was reduced at a ceftolozane dose of 1000 mg/kg/day. No adverse maternal effects in rats were observed at a dose of 300 mg/kg/day and no adverse embryo-fetal effects were observed at a dose of 1000 mg/kg/day (respectively equivalent to approximately 0.7- and 2-times the MRHD based on plasma AUC comparison). 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 male pups at maternal doses greater than or equal to 300 mg/kg/day.
No adverse effects were observed in rats at a dose of 100 mg/kg/day, a dose lower than the MRHD of 2 grams every 8 hours based on plasma AUC comparison. The high dose of 3000 mg/kg/day produced maternal toxicity (decreased food consumption and body weight gain) but was not associated with fetal toxicity. No adverse maternal effects were observed at a dose of 500 mg/kg/day and no adverse fetal effects were observed at a dose of 3000 mg/kg/day (respectively equivalent to approximately 2- and 10-times the MRHD of 1 gram every 8 hours based on body surface area comparison).
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 in doses of 40, 320, and 1280 mg/kg/day at the end of gestation and during lactation (Gestation Day 17 through Lactation Day 21) was associated with decreased maternal food consumption and body weight gain at the end of gestation and significantly more stillbirths at the high dose of 1280 mg/kg/day.
No effects on the physical development, neurological function, or fertility and reproductive ability of first generation (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. The second generation (F2) fetuses were normal for all doses of tazobactam.
Pediatric Use of Zerbaxa
Pediatric Use The safety and effectiveness of ZERBAXA for the treatment of cIAI, cUTI, and HABP/VABP have been established in pediatric patients at least 32 weeks gestational age and older. Use of ZERBAXA in this age group is supported by evidence from adequate and well-controlled trials of ZERBAXA in adults with additional pharmacokinetic and safety data from trials in pediatric patients with cUTI, cIAI, and HABP/VABP. The safety profile of ZERBAXA in pediatric patients was similar to adults with cIAI, cUTI, and HABP/VABP treated with ZERBAXA.
See Table 4 for recommended dosage in pediatric patients 2 years of age and older with renal impairment. There is insufficient information to establish dosing for pediatric patients younger than 2 years of age with renal impairment. The safety and effectiveness of ZERBAXA have not been established in pediatric patients less than 32 weeks gestational age.
ZERBAXA is not recommended in pediatric patients younger than 2 years of age with renal impairment.
Contraindications for Zerbaxa
ZERBAXA is contraindicated in patients with known serious hypersensitivity to the components of ZERBAXA (ceftolozane and tazobactam), piperacillin/tazobactam, or other members of the beta-lactam class.
Overdosage Information for Zerbaxa
In the event of overdose, discontinue ZERBAXA and provide general supportive treatment. ZERBAXA can be removed by intermittent 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 intermittent hemodialysis to treat overdosage.
Clinical Studies of Zerbaxa
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 majority of patients (75%) were from Eastern Europe; 6.3% were from the United States. 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 microbiological intent-to-treat (MITT) population, which included all patients who had at least 1 baseline intra-abdominal pathogen regardless of the susceptibility to study drug. The key secondary efficacy endpoint was clinical response at the TOC visit in the microbiologically evaluable (ME) population, which included all protocol-adherent MITT patients. The MITT population consisted of 806 patients; the median age was 52 years and 57.8% were male.
The most common diagnosis was appendiceal perforation or peri-appendiceal abscess, occurring in 47% of patients. Diffuse peritonitis at baseline was present in 34.2% of patients. ZERBAXA plus metronidazole was non-inferior to meropenem with regard to clinical cure rates at the TOC visit in the MITT population.
Clinical cure rates at the TOC visit are displayed by patient population in Table 14. Clinical cure rates at the TOC visit by pathogen in the MITT population are presented in Table 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 (MIC ≤2 mcg/mL), while some others were not susceptible (MIC >2 mcg/mL). Isolates of a specific genotype were seen in patients who were deemed to be either successes or failures. Pediatric Patients The pediatric cIAI trial was a randomized, double-blind, multi-center, active controlled trial conducted in hospitalized patients from at least 33 weeks post-menstrual age to less than 18 years (NCT03217136; Trial 4).
Patients received IV study treatment for a minimum of 3 days before an optional switch to oral step-down therapy at the discretion of the investigator to complete a total of 5 to 14 days of antibacterial therapy. The modified intent-to-treat (MITT) population consisted of 91 patients (N=70 in the ZERBAXA plus metronidazole group; N=21 in the meropenem plus placebo group) who were randomized and received at least one dose of study treatment. The median age of patients was 8.2 years and 8.5 years in the ZERBAXA plus metronidazole and meropenem plus placebo groups, respectively.
Patients treated with ZERBAXA plus metronidazole were predominantly male (67%) and White (87%). Patients treated with meropenem plus placebo were predominantly female (71%) and White (91%). Most patients in the MITT population had a diagnosis of complicated appendicitis at baseline (ZERBAXA plus metronidazole: 91.4%; meropenem plus placebo: 100%).
The median (range) duration of IV study treatment was comparable between patients in the ZERBAXA plus metronidazole (6.3 days) and meropenem plus placebo (6.0 days) groups. The primary objective of the study was to evaluate the safety and tolerability of ZERBAXA. Efficacy assessments were not powered for formal hypothesis testing of between-treatment group comparisons.
At the TOC visit, which occurred 7 to 14 days after the last dose of study drug, a favorable clinical response was defined as complete resolution or marked improvement in signs and symptoms of the cIAI or return to pre-infection signs and symptoms such that no further antibiotic therapy (IV or oral) or surgical or drainage procedure was required for treatment of the cIAI. A summary of clinical response rates in the MITT and clinically evaluable (CE) populations at the TOC visit are presented in Table 16. The CE included all protocol adherent MITT patients with a clinical outcome at the visit of interest.
The primary efficacy analysis population was the microbiologically modified intent-to-treat (mMITT) population, which included all patients who received study medication and had at least 1 baseline uropathogen. The mMITT population consisted of 800 patients with cUTI, including 656 (82%) with pyelonephritis. The median age was 50.5 years and 74% were female.
ZERBAXA demonstrated efficacy with regard to the composite endpoint of microbiological and clinical cure at the TOC visit in both the mMITT and ME populations (Table 17). Composite microbiological and clinical cure rates at the TOC visit by pathogen in the mMITT population are presented in Table 18. In the mMITT population, the composite cure rate in ZERBAXA-treated patients with concurrent bacteremia at baseline was 23/29 (79.3%).
Although a statistically significant difference was observed in the ZERBAXA arm compared to the levofloxacin arm with respect to the primary endpoint, it was likely attributable to the 212/800 (26.5%) patients with baseline organisms non-susceptible to levofloxacin. Among patients infected with a levofloxacin-susceptible organism at baseline, the response rates were similar (Table 17). Table 17: Composite Microbiological and Clinical Cure Rates in a Phase 3 Trial of Complicated Urinary Tract Infections Trial Table 18: Composite Microbiological and Clinical Cure Rates in a Phase 3 Trial of Complicated Urinary Tract Infections, in Subgroups Defined by 6/8 7/15 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%).
Eligible patients were randomized in a 3:1 ratio to IV ZERBAXA or meropenem, respectively. The microbiologic modified intent-to-treat (mMITT) population consisted of 95 patients (N=71 in the ZERBAXA group; N=24 in the meropenem group) who were randomized and received at least one dose of study treatment and had an eligible uropathogen isolated from a baseline urine culture. The median age of patients was 2.7 years and 1.6 years in the ZERBAXA and meropenem groups, respectively.
Patients treated with ZERBAXA were predominantly female (56%) and White (99%). Patients treated with meropenem were predominantly female (63%) and White (100%). Most patients in the mMITT population had a diagnosis of pyelonephritis (ZERBAXA: 84.5%; meropenem: 79.2%).
A summary of clinical and microbiologic response rates in the mMITT population at the TOC visit is presented in Table 19. All patients had to be intubated and on mechanical ventilation at randomization. Efficacy was assessed based on all-cause mortality at Day 28 and clinical cure, 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.
The analysis population 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%. 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 VABP. Patients with end-stage renal disease (CrCl less than 15 mL/min) were excluded from the trial.
Approximately 13% of subjects were failing their current antibacterial drug therapy for HABP/VABP, and bacteremia was present at baseline in 15% of patients. Key comorbidities included diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease at rates of 22%, 16%, and 12%, respectively. In both treatment groups, most subjects (63.1%) received between 8 and 14 days of study therapy as specified in the protocol.
Table 20 presents the results for Day 28 all-cause mortality and clinical cure at the TOC visit overall and by ventilated HABP and VABP. Table 20: Day 28 All-cause Mortality and Clinical Cure Rates at TOC from a Phase 3 Study of Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (Trial 3; ITT Population) 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. Per pathogen Day 28 all-cause mortality and clinical cure at TOC 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 both study treatments.
Day 28 all-cause mortality and clinical cure rates at TOC by pathogen in the mITT population are presented in Table 21.
| Analysis Population | ZERBAXA plus Metronidazole ZERBAXA 1.5 g intravenously every 8 hours + metronidazole 500 mg intravenously every 8 hours n/N (%) | Meropenem 1 gram intravenously every 8 hours n/N (%) | Treatment Difference (95% CI) The 95% confidence interval (CI) was calculated as an unstratified Wilson Score CI. |
|---|---|---|---|
| MITT | 323/389 (83) | 364/417 (87.3) | -4.3 (-9.2, 0.7) |
| ME | 259/275 (94.2) | 304/321 (94.7) | -0.5 (-4.5, 3.2) |
| Organism Group Pathogen | ZERBAXA plus Metronidazole n/N (%) | Meropenem n/N (%) |
|---|---|---|
| Aerobic Gram-negative | ||
| Escherichia coli | 216/255 (84.7) | 238/270 (88.1) |
| Klebsiella pneumoniae | 31/41 (75.6) | 27/35 (77.1) |
| Pseudomonas aeruginosa | 30/38 (79) | 30/34 (88.2) |
| Enterobacter cloacae | 21/26 (80.8) | 24/25 (96) |
| Klebsiella oxytoca | 14/16 (87.5) | 24/25 (96) |
| Proteus mirabilis | 11/12 (91.7) | 9/10 (90) |
| Aerobic Gram-positive | ||
| Streptococcus anginosus | 26/36 (72.2) | 24/27 (88.9) |
| Streptococcus constellatus | 18/24 (75) | 20/25 (80) |
| Streptococcus salivarius | 9/11 (81.8) | 9/11 (81.8) |
| Anaerobic Gram-negative | ||
| Bacteroides fragilis | 42/47 (89.4) | 59/64 (92.2) |
| Bacteroides ovatus | 38/45 (84.4) | 44/46 (95.7) |
| Bacteroides thetaiotaomicron | 21/25 (84) | 40/46 (87) |
| Bacteroides vulgatus | 12/15 (80) | 24/26 (92.3) |
| Analysis Population | ZERBAXA plus metronidazole n/N (%) | Meropenem n/N (%) | Treatment Difference (95% CI) The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel weights was used. |
|---|---|---|---|
| MITT Population | 56/70 (80.0) | 21/21 (100.0) | -19.1 (-30.2, -2.9) |
| CE Population | 52/58 (89.7) | 19/19 (100.0) | -10.7 (-21.5, 6.8) |
| Analysis Population | ZERBAXA ZERBAXA 1.5 g intravenously every 8 hours n/N (%) | Levofloxacin 750 mg intravenously once daily n/N (%) | Treatment Difference (95% CI) The 95% confidence interval was based on the stratified Newcombe method. |
|---|---|---|---|
| mMITT | 306/398 (76.9) | 275/402 (68.4) | 8.5 (2.3, 14.6) |
| Levofloxacin resistant baseline pathogen(s) | 60/100 (60) | 44/112 (39.3) | |
| No levofloxacin resistant baseline pathogen(s) | 246/298 (82.6) | 231/290 (79.7) | |
| ME | 284/341 (83.3) | 266/353 (75.4) | 8.0 (2.0, 14.0) |
| Pathogen | ZERBAXA n/N (%) | Levofloxacin n/N (%) |
|---|---|---|
| Escherichia coli | 247/305 (81) | 228/324 (70.4) |
| Klebsiella pneumoniae | 22/33 (66.7) | 12/25 (48) |
| Proteus mirabilis | 11/12 (91.7) | 6/12 (50) |
| Pseudomonas aeruginosa | 6/8 (75) | 7/15 (46.7) |
| mMITT Population | ZERBAXA n/N (%) | Meropenem n/N (%) | Treatment Difference (95% CI) The Miettinen & Nurminen method stratified by age group with Cochran-Mantel-Haenszel weights was used. |
|---|---|---|---|
| Clinical Response Rate | 63/71 (88.7) | 23/24 (95.8) | -7.3 (-18.0, 10.1) |
| Microbiologic Response Rate | 60/71 (84.5) | 21/24 (87.5) | -3.0 (-17.1, 17.4) |
| Endpoint | ZERBAXA n/N (%) | Meropenem n/N (%) | Treatment Difference (95% CI) The CI for overall treatment difference was based on the stratified Newcombe method with minimum risk weights. The CI for treatment difference of each primary diagnosis was based on the unstratified Newcombe method. |
|---|---|---|---|
| Day 28 All-cause Mortality | 87/362 (24.0) | 92/364 (25.3) | 1.1 (-5.13, 7.39) |
| VABP | 63/263 (24.0) | 52/256 (20.3) | -3.6 (-10.74, 3.52) |
| Ventilated HABP | 24/99 (24.2) | 40/108 (37.0) | 12.8 (0.18, 24.75) |
| Clinical Cure at TOC Visit | 197/362 (54.4) | 194/364 (53.3) | 1.1 (-6.17, 8.29) |
| VABP | 147/263 (55.9) | 146/256 (57.0) | -1.1 (-9.59, 7.35) |
| Ventilated HABP | 50/99 (50.5) | 48/108 (44.4) | 6.1 (-7.44, 19.27) |
| Baseline Pathogen Category | Day 28 All-cause Mortality | Clinical Cure at TOC | ||
|---|---|---|---|---|
| Baseline Pathogen | ZERBAXA n/N (%) | Meropenem n/N (%) | ZERBAXA n/N (%) | Meropenem n/N (%) |
| Pseudomonas aeruginosa | 12/47 (25.5) | 10/56 (17.9) | 29/47 (61.7) | 34/56 (60.7) |
| Enterobacterales | 27/161 (16.8) | 42/157 (26.8) | 103/161 (64.0) | 87/157 (55.4) |
| Enterobacter cloacae | 2/15 (13.3) | 8/14 (57.1) | 8/15 (53.3) | 4/14 (28.6) |
| Escherichia coli | 10/50 (20.0) | 11/42 (26.2) | 32/50 (64.0) | 26/42 (61.9) |
| Klebsiella oxytoca | 3/14 (21.4) | 3/12 (25.0) | 9/14 (64.3) | 7/12 (58.3) |
| Klebsiella pneumoniae | 7/51 (13.7) | 13/62 (21.0) | 34/51 (66.7) | 39/62 (62.9) |
| Proteus mirabilis | 5/22 (22.7) | 5/18 (27.8) | 13/22 (59.1) | 11/18 (61.1) |
| Serratia marcescens | 3/14 (21.4) | 1/12 (8.3) | 8/14 (57.1) | 7/12 (58.3) |
| Haemophilus influenzae | 0/20 (0) | 2/15 (13.3) | 17/20 (85.0) | 8/15 (53.3) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
Ready to save on Zerbaxa?
Compare prescription prices at over 70,000 pharmacies and start saving today—no enrollment required.
Compare Zerbaxa Prices