Zevtera Drug Information

Generic name: CEFTOBIPROLE MEDOCARIL SODIUM

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Uses of Zevtera

Staphylococcus aureus Bloodstream Infection (Bacteremia) ZEVTERA is indicated for the treatment of adult patients with Staphylococcus aureus bloodstream infection (bacteremia) (SAB), including those with right-sided infective endocarditis, caused by methicillin-susceptible and methicillin-resistant isolates.

Acute Bacterial Skin and Skin Structure Infections ZEVTERA is indicated for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (methicillin-susceptible and methicillin-resistant isolates), Streptococcus pyogenes, and Klebsiella pneumoniae.

Community-Acquired Bacterial Pneumonia ZEVTERA is indicated for the treatment of adult and pediatric patients (3 months to less than 18 years old) with community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following gram-positive and gram-negative microorganisms: Staphylococcus aureus (methicillin-susceptible isolates), Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Escherichia coli, and Klebsiella pneumoniae.

Usage

To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZEVTERA and other antibacterial drugs, ZEVTERA 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 Zevtera

Recommended Dosage and Administration for SAB, ABSSSI and CABP in Adult Patients The recommended dosage of ZEVTERA for the treatment of adult patients with SAB, ABSSSI and CABP is described in Table 1. The duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP. Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL to adult patients.

Table 1: Recommended Dosage Regimen for Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL

Recommended Dosage and Administration for CABP in Pediatric Patients (3 months to less than 18 years old) For treatment of pediatric patients with CABP, the recommended dosage of ZEVTERA is described in Table 2, based on patient age and weight. In adult patients with augmented renal clearance (CL CR greater than 150 mL/min), increase the ZEVTERA dosage to 667 mg every 6 hours. Creatinine Clearance, CL CR (mL/min) Based on calculated creatinine clearance.

There is insufficient information to recommend dosage adjustments in pediatric patients 2 years of age and older with an eGFR less than 15 mL/min/1.73m 2. There is insufficient information to recommend dosage adjustments in pediatric patients less than 2 years of age with any degree of renal impairment.

Preparation of ZEVTERA Infusion Solution ZEVTERA must first be reconstituted in the vial and then further diluted prior to administration by intravenous infusion over a period of 2 hours. Aseptic technique must be followed in preparing the infusion solution. See additional instructions for reconstitution and dilution below.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The solution for infusion should be clear to slightly opalescent and yellowish in color. Discard if discoloration or visible particles are observed.

Reconstitution of ZEVTERA in the Vial For adult and pediatric patients 12 years of age and older, reconstitute ZEVTERA lyophilized powder in the vial with 10 mL of sterile water for injection or 10 mL of 5% dextrose injection. After reconstitution, shake the reconstituted ZEVTERA vial vigorously until dissolution is completed, which in some cases may take up to 10 minutes. The volume of the resulting reconstituted solution is approximately 10.6 mL.

Allow any foam formed to dissipate and then inspect the reconstituted solution visually to ensure the product is in solution and particulate matter is absent. The reconstituted solution contains 66.7 mg/mL of ceftobiprole medocaril sodium and must be further diluted using aseptic technique with the appropriate diluent as described below, prior to administration. If it is not possible to dilute the reconstituted solution immediately, the reconstituted solution may be stored refrigerated for up to 24 hours, and at room temperature for up to 1 hour.

Discard any unused reconstituted solution. Dilution of Reconstituted ZEVTERA Solution and Administration of the Diluted Product After reconstitution with the appropriate diluent, further dilute the reconstituted ZEVETRA solution, using aseptic technique with the appropriate diluent, to the appropriate volume of ZEVTERA infusion solution as described in Table 5. Table 5: Preparation of Diluted ZEVTERA Solution for Infusion

Storage of Reconstituted and Diluted Infusion Solutions Storage of Reconstituted ZEVTERA Solution in Vials Upon reconstitution with the appropriate diluent, the reconstituted ZEVTERA solution in the vial should be transferred and diluted into the appropriate container. Storage of Diluted ZEVTERA Solution in Infusion Bags ZEVTERA solutions for infusions can be stored at room temperature or refrigerated at 2 °C to 8 °C. If the infusion solution is stored in the refrigerator, it should be equilibrated to room temperature prior to administration.

ZEVTERA solutions should not be exposed to direct sunlight. The infusion solution does not need to be protected from light during administration. Do not freeze ZEVTERA solutions for infusions.

The compatibility of ZEVTERA with other drugs and infusion solutions other than 5% dextrose injection or 0.9% sodium chloride injection, has not been established. ZEVTERA must not be mixed or administered simultaneously with calcium-containing solutions. Do not mix ZEVTERA with, or co-administer through, the same intravenous line or cannula with other drug products.

Indication in Adults	Dose	Frequency
SAB	667 mg	Every 6 hours on Days 1 to 8
SAB	667 mg	Every 8 hours from Day 9
ABSSSI	667 mg	Every 8 hours
CABP	667 mg	Every 8 hours

Pediatric Age Group for CABP	Dose	Frequency
12 years to less than 18 years old	13.3 mg/kg (up to 667 mg/dose)	Every 8 Hours
Greater than or equal to 3 months and less than 12 years old	20 mg/kg (up to 667 mg/dose)	Every 8 Hours

Table 1: Recommended Dosage Regimen for SAB, ABSSSI and CABP in Adult Patients
Indication Duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP.	Dose	Frequency Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL [see Dosage and Administration (2.5) ]
SAB	667 mg 667 mg of ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole.	Every 6 hours on Days 1 to 8
SAB		Every 8 hours from Day 9
ABSSSI	667 mg	Every 8 hours
CABP	667 mg	Every 8 hours

Table 2: Recommended Dosage Regimen in Pediatric Patients with CABP
Pediatric Age Group	Dose Duration of treatment for CABP in pediatric patients is 7 days to 14 days.	Frequency
12 years to less than 18 years old	13.3 mg/kg (up to 667 mg/dose 13.3 mg/kg of ceftobiprole medocaril sodium is equivalent to 10 mg/kg of ceftobiprole; 20 mg/kg ceftobiprole medocaril sodium is equivalent to 15 mg/kg of ceftobiprole. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole. )	Every 8 Hours Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL for patients 12 years to less than 18 years old [see Dosage and Administration (2.5) ].
3 months to less than 12 years old	20 mg/kg (up to 667 mg/dose )	Every 8 Hours Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 5.33 mg/mL for patients greater than or equal to 3 months to less than 12 years old [see Dosage and Administration (2.5) ].

Table 3: ZEVTERA Recommended Dosage Regimens for SAB, ABSSSI and CABP in Adult Patients with Renal Impairment
Indication Duration of treatment in adult patients is up to 42 days for SAB and 5 days to 14 days for ABSSSI and CABP.	Creatinine Clearance, CL CR (mL/min) Based on calculated creatinine clearance [see Use in Specific Populations (8.6) ].	Dose 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole; 333 mg ceftobiprole medocaril sodium is equivalent to 250 mg of ceftobiprole.	Frequency Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL [see Dosage and Administration (2.5) ].
SAB	30 to less than 50 mL/min	667 mg	Every 8 hours on Days 1 to 8
	30 to less than 50 mL/min	667 mg	Every 12 hours from Day 9
	15 to less than 30 mL/min	333 mg	Every 8 hours on Days 1 to 8
	15 to less than 30 mL/min	333 mg	Every 12 hours from Day 9
	Less than 15 mL/min, including hemodialysis Administer ZEVTERA after intermittent hemodialysis on hemodialysis days, because ceftobiprole is removed by hemodialysis.	333 mg	Every 24 hours
ABSSSI or CABP	30 to less than 50	667 mg	Every 12 hours
	15 to less than 30	333 mg	Every 12 hours
	Less than 15 mL/min, including hemodialysis	333 mg	Every 24 hours

Table 4: ZEVTERA Recommended Dosage Regimens for Pediatric Patients (2 Years to less than 18 Years Old) with CABP and with Renal Impairment
Pediatric Age Group Duration of treatment for CABP in pediatric patients (2 years to less than 18 years old) and with renal impairment is 7 days to 14 days.	eGFR (mL/min/1.73 m 2 ) Calculate using a validated GFR estimating equation for the approved age of the pediatric population.	Dosage Regimen 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole; 333 mg ceftobiprole medocaril sodium is equivalent to 250 mg of ceftobiprole; 10 mg/kg of ceftobiprole medocaril sodium is equivalent to 7.5 mg/kg of ceftobiprole; 13.3 mg/kg ceftobiprole medocaril sodium is equivalent to 10 mg/kg of ceftobiprole.
12 years to less than 18 years old	30 to less than 50	10 mg/kg (up to 667 mg) Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 2.67 mg/mL for pediatric patients 12 years to less than 18 years old [see Dosage and Administration (2.5) ]. every 12 hours
12 years to less than 18 years old	15 to less than 30	10 mg/kg (up to 333 mg) every 12 hours
6 years to less than 12 years old	30 to less than 50	10 mg/kg (up to 667 mg) Administer each prepared intravenous infusion solution of ZEVTERA over 2 hours at a concentration of 5.33 mg/mL for pediatric patients 2 years to less than 12 years old [see Dosage and Administration (2.5) ]. every 12 hours
6 years to less than 12 years old	15 to less than 30	10 mg/kg (up to 333 mg) every 24 hours
2 years to less than 6 years old	30 to less than 50	13.3 mg/kg every 12 hours (up to 667 mg)
2 years to less than 6 years old	15 to less than 30	13.3 mg/kg every 24 hours (up to 333 mg)

Table 5: Preparation of Diluted ZEVTERA Solution for Infusion
Patient Age Group	Volume of diluent to be added to the vial	Volume of reconstituted solution to be withdrawn from the vial	Volume of Infusion solution to be administered Gently invert 5-10 times to form a homogenous solution. Avoid vigorous agitation to prevent foaming.	Concentration and final volume of the diluted product
Adult (18 years of age and older)	10 mL	10 mL	250 mL 0.9% sodium chloride or 5% dextrose injection	2.67 mg/mL in a 250 mL infusion bag (667 mg/250 mL)
Adult patients with renal Impairment (CL CR less than 30 mL/min)	10 mL	5 mL	125 mL 0.9% sodium chloride or 5% dextrose injection	2.67 mg/mL in a 125 mL infusion bag (333 mg/125 mL)
Pediatric Patients 12 Years of Age to Less than 18 Years of Age	10 mL	Refer to Table 2 for the dose to determine volume of reconstituted solution needed according to weight-based dosing	The final volume to be administered should be calculated based on the patient body weight and must not exceed a maximum of 250 mL of 0.9% sodium chloride or 5% dextrose injection (do not exceed maximum of 667 mg/250 mL dose at a concentration of 2.67 mg/mL)
Pediatric Patients 12 Years of Age to Less than 18 Years of Age with renal Impairment	10 mL	Renal Impairment: Refer to Table 4 for the dose to determine volume of reconstituted solution needed according to weight-based dosing	The final volume to be administered should be calculated based on the patient body weight and must not exceed a maximum of 250 mL of 0.9% sodium chloride or 5% dextrose injection (do not exceed maximum of 667 mg/250 mL dose at a concentration of 2.67 mg/mL)
Pediatric Patients 3 months to Less than 12 Years of Age	10 mL	Refer to Table 2 for the dose to determine the volume of reconstituted solution needed according to weight-based dosing For administration via infusion bags, bottles, or syringes: For example, for a dose equal to 667 mg, withdraw 10 mL of the reconstituted solution from the vial and inject into a suitable container of 125 mL of infusion solution., For administration via a 50 mL syringe if the calculated dose does not exceed 267 mg: For example, for a dose equal to 267 mg, withdraw 4 mL of the reconstituted solution from the vial and withdraw 46 mL of the appropriate infusion solution into the syringe for infusion.	The final volume to be administered should be calculated based on the patient body weight and must not exceed a maximum of 125 mL of 5% dextrose injection (do not exceed maximum of 667 mg/125 mL at a concentration of 5.33 mg/mL)
Pediatric Patients 2 years to less than 12 years of age with renal impairment	10 mL	Renal Impairment: Refer to Table 4 for the dose to determine the volume of reconstituted solution needed according to weight-based dosing,	The final volume to be administered should be calculated based on the patient body weight and must not exceed a maximum of 125 mL of 5% dextrose injection (do not exceed maximum of 667 mg/125 mL at a concentration of 5.33 mg/mL)

Table 6: Storage Time for Diluted ZEVTERA Infusion Solutions for Adult and Pediatric Patients 12 Years to Less than 18 Years Old (2.67 mg/mL)
Reconstitution solution diluent (vial)	Infusion solution diluent	Infusion solutions stored at 25 °C NOT protected from light	Infusion solutions stored at 2 °C to 8 °C Protected from light
5% Dextrose solution for injection	5% Dextrose solution for injection	6 hours	94 hours
5% Dextrose solution for injection	0.9% Sodium chloride solution for injection	4 hours	24 hours
Sterile water for injection	5% Dextrose solution for injection or 0.9% Sodium chloride solution for injection	6 hours	94 hours

Table 7: Storage Time for Diluted ZEVTERA Infusion Solutions for Pediatric Patients Less than 12 Years Old (5.33 mg/mL)
Reconstitution solution diluent (vial)	Infusion solution diluent	Infusion solutions stored at 25 °C NOT protected from light	Infusion solutions stored at 2 °C to 8 °C Protected from light
5% Dextrose solution for injection	5% Dextrose solution for injection	6 hours	24 hours

Side Effects of Zevtera

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 may not reflect the rates observed in practice. The median age of patients treated with ZEVTERA was 56 years, ranging between 18 and 95 years old. Patients treated with ZEVTERA were predominantly male (64%) and White (82%).

Although HABP was included in the safety data, the safety and effectiveness of ZEVTERA for the treatment of HABP has not been established and ZEVTERA is not approved for the treatment of HABP. Adult Patients with Staphylococcus aureus Bloodstream Infection (Bacteremia) ZEVTERA was evaluated in an active-controlled randomized, double-blind, multicenter phase 3 trial (Trial 1) in patients with Staphylococcus aureus bloodstream infection (bacteremia) (SAB) including right-sided infective endocarditis. The dose of study drugs were adjusted based on renal function.

Patients treated with ZEVTERA were predominantly male (68%), White (95%), and from Europe (93%). The median duration of treatment was 21 days in both treatment arms. In patients treated with ZEVTERA, the most common adverse reactions leading to discontinuation were nausea, vomiting, rash, and urticaria, each occurring in 2/191 (1%).

Common Adverse Reactions Table 8 lists the most common adverse reactions occurring in ≥ 2% of SAB adult patients receiving ZEVTERA in Trial 1. Table 8: Selected Adverse Reactions Occurring in ≥ 2% of SAB Adult Patients Receiving ZEVTERA in Trial 1 Trial 1 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the ZEVTERA and the daptomycin plus or minus aztreonam treatment groups. Adult Patients with Acute Bacterial Skin And Skin Structure Infections ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter phase 3 trial (Trial 2) in patients with acute bacterial skin and skin structure infections (ABSSSI).

Aztreonam was administered as a 1 gram fixed dose as a 0.5-hour IV infusion every 12 hours and the requirement for aztreonam therapy was reassessed at the 72-hour study visit. Patients treated with ZEVTERA were mostly male (59%), White (95%), and from the United States (60%). Patients across treatment arms received treatment for a median duration of 6 days.

In patients treated with ZEVTERA, the most common adverse reactions leading to discontinuation were dysgeusia and both pruritus and rash, occurring in 1/334 (0.3%). Common Adverse Reactions Table 9 lists the most common adverse reactions occurring in ≥ 2% of ABSSSI patients receiving ZEVTERA in Trial 2. Adult Patients with Community-Acquired Bacterial Pneumonia ZEVTERA was evaluated in an active-controlled, randomized, double-blind, multicenter phase 3 study in adult patients with community-acquired bacterial pneumonia (CABP).

The dose of ZEVTERA was adjusted based on renal function. Approximately 62% of patients were White, 45% were from outside Europe or the United States, and 57% were male. The most common adverse reaction leading to discontinuation in patients treated with ZEVTERA was vomiting, occurring in 4/310 (1.3%).

Common Adverse Reactions Table 10 lists the most common adverse reactions occurring in ≥ 2% of CABP adult patients receiving ZEVTERA in Trial 3. Approximately 81% of the patients were White, most were outside of the United States (88%) and 72% were male. Common Adverse Reactions Common adverse reactions occurring in >2% of HABP/VABP adult patients who received ceftobiprole in Trial 4 include diarrhea, hypokalemia, hyponatremia, hepatic enzyme increased, vomiting, anemia, rash, phlebitis, nausea, abdominal pain, and seizures.

ZEVTERA was administered by intravenous infusion every 8 hours, age-adjusted for dose and infusion duration (2-hour or 4-hour infusion). The median age of study patients was 5 years, ranging from 0.6 to 17 years. All patients were from Europe, 100% were classified as White and 56% of patients were male.

Discontinuation of treatment due to any adverse reaction occurred in 4/94 (4.3%) of patients treated with ZEVTERA and 0/44 patients treated in the comparator group. Adverse reactions leading to treatment discontinuation in patients who received ZEVTERA included aggravated pneumonia, pleuritis, urticaria, and hypersensitivity, each occurring in 1/94 (1.1%). There were no deaths in either arm of the pediatric study.

The most common adverse reactions, occurring in ≥ 2% of pediatric patients treated with ZEVTERA were vomiting (7.4%), headache (3.2%), hepatic enzyme increased (including alanine aminotransferase increased and aspartate aminotransferase increased) (3.2%), diarrhea, infusion site reaction, phlebitis, and pyrexia (all 2.1%).

Postmarketing Experience

The following adverse reactions and altered laboratory tests have been identified during post-approval use of ZEVTERA and ceftobiprole outside of the United States, or other cephalosporin-class antibacterial drugs. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Altered Laboratory Tests: Positive direct Coombs' test, false-positive test for urinary glucose.

Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia. Hepatobiliary disorders: Hepatic dysfunction including cholestasis. Immune system disorders: Drug fever, serum sickness-like reaction.

Nervous system disorders: Myoclonus. Renal and urinary disorders: Renal dysfunction, toxic nephropathy. Vascular disorders: Hemorrhage, hypertension.

Table 8: Selected Adverse Reactions Occurring in ≥ 2% of SAB Adult Patients Receiving ZEVTERA in Trial 1 Trial 1 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the ZEVTERA and the daptomycin plus or minus aztreonam treatment groups.
Adverse Reaction	ZEVTERA ZEVTERA 667 mg IV over 2-hours every 6 hours from Day 1 to Day 8, and every 8 hours from Day 9 onwards, with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole. N = 191	Daptomycin Daptomycin 6 mg/kg up to 10 mg/kg IV over 0.5 hour every 24 hours, with dosing adjustment based on renal function. ± Aztreonam N = 198
SAB = Staphylococcus aureus bacteremia.
Anemia Anemia includes the following terms: anemia, hemoglobin decreased, hypochromic anemia, and normochromic normocytic anemia.	12%	13%
Nausea	10%	4%
Hypokalemia Hypokalemia replaces the term blood potassium decreased.	9%	3%
Vomiting	8%	2%
Hepatic enzyme and bilirubin increased Hepatic enzyme increased includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood bilirubin increased, and hyperbilirubinemia.	8%	10%
Diarrhea	7%	3%
Blood creatinine increased Blood creatinine increased includes the following terms: acute kidney injury, blood creatinine increased, creatinine renal clearance decreased, oliguria, and renal impairment.	7%	5%
Hypertension Hypertension includes the following terms: hypertension, blood pressure increased, and hypertensive crisis.	5%	2%
Leukopenia Leukopenia includes the following terms: leukopenia, lymphocyte count decreased, lymphopenia, neutropenia, neutrophil count decreased, and white blood cell count decreased.	4%	3%
Pyrexia Pyrexia includes the following terms: hyperthermia and pyrexia.	4%	3%
Abdominal pain Abdominal pain includes the following terms: abdominal pain upper and abdominal tenderness.	3%	1%
Fungal infection Fungal infection includes the following terms: candida infection, candida sepsis, fungal test positive, oral candidiasis, vulvovaginal candidiasis, and tinea pedis.	3%	2%
Headache	3%	3%
Dyspnea Dyspnea includes the following terms: dyspnea and respiratory distress.	2%	1%

Table 9: Selected Adverse Reactions Occurring in ≥ 2% of ABSSSI Adult Patients Receiving ZEVTERA in Trial 2 Trial 2 was not designed to evaluate meaningful comparisons of the incidence of adverse reactions in the ZEVTERA and the vancomycin plus or minus aztreonam treatment groups.
Adverse Reaction	ZEVTERA ZEVTERA 667 mg IV over 2-hours every 8 hours with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole. N = 334	Vancomycin plus Aztreonam Vancomycin IV, as fixed 1 gram or 15 mg/kg, administered over 2 hours every 12 hours with dosing adjustment based on renal function; aztreonam IV 1 gram over 0.5 hour every 12 hours with dosing adjustment based on renal function. N = 342
ABSSSI = Acute Bacterial Skin and Skin Structure Infections.
Nausea	11%	6%
Diarrhea	6%	5%
Headache	6%	7%
Injection site reaction Infusion site reaction includes the following terms: injection site reaction and infusion-related reaction.	2%	3%
Hepatic enzyme increased Hepatic enzyme increased includes the following terms: alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, and gamma-glutamyltransferase increased.	2%	3%
Rash Rash includes the following terms: rash, drug eruption, and dermatitis.	2%	3%
Vomiting	2%	2%
Dysgeusia	2%	0%

Table 10: Selected Adverse Reactions Occurring in ≥ 2% of CABP Adult Patients Receiving ZEVTERA in Safety Analysis Set in Trial 3
Adverse Reaction	ZEVTERA ZEVTERA 667 mg IV over 2-hours every 8 hours with dosing adjustment based on renal function. 667 mg ceftobiprole medocaril sodium is equivalent to 500 mg of ceftobiprole. N = 310	Ceftriaxone Ceftriaxone 2 grams IV over 0.5 hour every 24 hours, with or without linezolid 600 mg IV over 1 hour every 12 hours. ± linezolid N = 322
CABP = Community-Acquired Bacterial Pneumonia.
Nausea	10%	4%
Hepatic enzyme increased Hepatic enzyme increased includes the following terms: aspartate aminotransferase increased, gamma-glutamyltransferase increased, blood alkaline phosphatase increased, alanine aminotransferase increased, hepatic enzyme increased, transaminases increased, alanine aminotransferase, and liver function test increased.	10%	11%
Vomiting	9%	3%
Diarrhea	7%	9%
Headache	7%	7%
Rash Rash includes the following terms: dermatitis contact, dermatitis allergic, rash, and rash pruritic.	5%	2%
Insomnia	5%	4%
Abdominal pain Abdominal pain includes the following terms: abdominal discomfort, abdominal pain, and abdominal pain upper.	4%	3%
Phlebitis Phlebitis includes the following terms: phlebitis, and injection site phlebitis.	4%	2%
Hypertension Hypertension includes the following terms: hypertension, blood pressure increased, and hypertensive crisis.	4%	4%
Dizziness	3%	2%

Blood and lymphatic system disorders:	Thrombocytosis, Thrombocytopenia
Gastrointestinal disorders:	Dyspepsia, Dysphagia
General disorders and administration site conditions:	Fatigue, Chills, Facial swelling, Infusion site pain
Immune system disorders:	Hypersensitivity, Angioedema, Anaphylactic shock
Infections and infestations:	Mucocutaneous fungal infections
Investigations:	Blood lactate dehydrogenase increased, Blood triglycerides increased, Prothrombin time prolonged
Psychiatric disorders:	Anxiety, Irritability
Renal and urinary disorders:	Pollakiuria
Respiratory, thoracic and mediastinal disorders:	Bronchospasm, Wheezing
Skin and subcutaneous tissue disorders:	Pruritus
Vascular disorders:	Thrombosis

Warnings & Cautions for Zevtera

Increased Mortality with Unapproved Use in Ventilator-Associated Bacterial Pneumonia Patients In Trial 4, an increase in mortality was seen in the subgroup of patients with ventilator-associated bacterial pneumonia (VABP) who were treated with ZEVTERA (35/103 versus 24/102 in comparator-treated patients). The cause of this increased mortality has not been established. Generally, deaths were associated with complications of infection or underlying co-morbidities.

The safety and effectiveness of ZEVTERA for the treatment of VABP has not been established and the use of ZEVTERA for VABP is not approved.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis, were observed in ZEVTERA-treated patients in clinical trials. Serious and occasionally fatal hypersensitivity reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with ZEVTERA is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or other beta-lactam antibacterial drugs should be made.

Maintain clinical supervision if this product is to be given to a penicillin- or other beta-lactam-allergic patient, because cross sensitivity among beta-lactam antibacterial agents has been established. Discontinue ZEVTERA if a hypersensitivity reaction occurs, and institute appropriate treatment.

Seizures and Other Central Nervous System Reactions Seizures and other adverse central nervous system (CNS) reactions have been reported during treatment with ZEVTERA and other cephalosporins. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust ZEVTERA dosing based on creatinine clearance.

Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions, including seizures, occur, patients should undergo a neurological evaluation to determine whether ZEVTERA should be discontinued.

Clostridioides difficile -Associated Diarrhea

Clostridioides difficile -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including ZEVTERA, 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.

Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. 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 suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, 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 ZEVTERA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug Interactions with Zevtera

Drug-Laboratory Test Interactions Dipstick Tests ZEVTERA may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests. Serological Testing Treatment with ZEVTERA has the potential to interfere with serological testing, such as the Coombs test.

In clinical studies there was no evidence of hemolytic anemia in adults or children. However, the possibility that hemolytic anemia may occur cannot be ruled out. Patients experiencing anemia during or after treatment should be investigated for this possibility.

Pregnancy Safety for Zevtera

Pregnancy Risk Summary There are no available data with use of ZEVTERA in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Available data from published observational studies and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups, and cannot definitively establish the absence of risk.

Intravenous administration of ceftobiprole medocaril to pregnant rats and monkeys during organogenesis showed no evidence of adverse fetal developmental outcomes at doses approximately 1.4 times and 0.9 times, respectively, the maximum recommended human dose (MRHD). Some evidence of maternal toxicity (slight reduction in body weight and food consumption) was noted in pregnant monkeys at 0.9 times the MRHD. Intravenous administration of ceftobiprole medocaril to rats 2-weeks prior to mating, during organogenesis, and through lactation resulted in no adverse fertility or fetal development effects in offspring at doses approximately 1.4 times the MRHD ( see Data ).

The 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 risks of major birth defects and miscarriage in clinically recognized pregnancies is respectively.

Data Animal Data Pregnant rats administered ceftobiprole medocaril intravenously at doses up to 360 mg/kg/day (approximately 1.4 times the MRHD based on total body surface area (BSA)-normalized comparisons) during organogenesis on gestation days (GD) 6 to 17 showed no adverse fetal development effects. Maternal body weight gain and food consumption were slightly decreased at 360 mg/kg/day. Maternal body weight gain and food consumption were slightly reduced at 120 mg/kg/day.

This dose was associated with a slight increase in abortion rate (approximately 10% above historical controls). No other fetal development adverse effects (i.e., no fetal malformations) were observed at the high dose. In a pre- and post-natal development toxicity study, ceftobiprole medocaril was administered intravenously to pregnant rats during organogenesis starting at GD 6 and continuing to lactation day 21 (L21) at doses up to 360 mg/kg (approximately 1.4 times the MRHD based on BSA comparisons).

Maternal toxicity (mortality, reduced food consumption and body weight gain in surviving females during gestation) was observed at the high dose. Effects in the offspring were also observed at the high dose during the post-natal pre-weaning period (decrease in the number of pups born per litter and decreased post-natal survival up to day 4 after birth). No adverse effects were observed in surviving pups during the post-natal postweaning development period (days 5-22) at doses up to 360 mg/kg.

Pediatric Use of Zevtera

Pediatric Use The safety and effectiveness of ZEVTERA have been established for the treatment of CABP in pediatric patients 3 months to less than 18 years. Use of ZEVTERA in this age group is supported by evidence from an adequate and well-controlled trial of ZEVTERA in adults, with additional pharmacokinetic, safety and efficacy data from pediatric trials. The safety and effectiveness of ZEVTERA have not been established for the treatment of ABSSSI and SAB in pediatric patients.

Contraindications for Zevtera

ZEVTERA is contraindicated in patients with a known history of severe hypersensitivity to ZEVTERA, or to other members of the cephalosporin class.

Overdosage Information for Zevtera

There is no information on clinical signs and symptoms associated with an overdose of ZEVTERA. For patients who receive doses greater than the recommended dosage regimen and have unexpected adverse reactions associated with ZEVTERA, discontinue ZEVTERA, treat symptomatically, and institute general supportive treatment. ZEVTERA can be removed by hemodialysis.

However, no information is available on the use of hemodialysis to treat overdose.

Clinical Studies of Zevtera

Staphylococcus aureus Bloodstream Infection (Bacteremia) in Adults The efficacy of ZEVTERA in the treatment of adult patients with SAB, including right-sided infective endocarditis, was demonstrated in a randomized, controlled, double-blind, multinational, multicenter trial (Trial 1, NCT03138733). Randomization was stratified by study site, dialysis status, and use of prior antibacterial drugs. The study was performed in two cohorts based on findings in animal studies.

The initial cohort was enrolled to receive a maximum treatment duration of 28 days. Based on a safety evaluation of cohort 1, patients could be enrolled in cohort 2 to receive a treatment duration of up to 42 days. The duration of study treatment was based on the investigator's clinical evaluation.

Study patients were required to have at least one positive blood culture for S. aureus obtained within 72 hours prior to randomization, signs and symptoms of bacteremia (fever, elevated white blood cell count or immature neutrophils, tachycardia, or hypotension), and at least one of the following conditions of complicated S. aureus bacteremia: chronic dialysis, persistent SAB, acute bacterial skin and skin structure infection, metastatic infections of native tissue, osteomyelitis, epidural or cerebral abscess, or definite native-valve right-sided infective endocarditis by Modified Duke's Criteria. Patients with uncomplicated S. aureus bacteremia, left-sided infective endocarditis, prosthetic heart valves, foreign body material that could not be removed, severe neutropenia, or pneumonia, were excluded from the study. Upon entry, patients were classified for likelihood of endocarditis using the modified Duke's criteria (definite, possible, or rejected).

Echocardiography, including a transesophageal echocardiogram, was to be performed during screening or within 7 days following study enrollment. Final diagnoses were to be made by the study investigators within 7 days of randomization. The final diagnosis for persistent S. aureus bacteremia was made by an independent treatment-blinded Data Review Committee (DRC).

The modified ITT (mITT) population was used for the primary efficacy analysis, comprising 387 patients (189 ZEVTERA, 198 daptomycin ± aztreonam) who received study drugs and had a baseline blood culture positive for S. aureus. Patient demographic and baseline characteristics were balanced between the treatment groups. A total of 6.5% of patients had definite right-sided infective endocarditis.

A total of 24% had bacteremia caused by methicillin-resistant S. aureus (MRSA). The primary efficacy outcome in the study was overall success at the post-treatment evaluation (PTE) visit at 70 days post-randomization in the mITT population, as assessed by the independent DRC. Overall success required survival, symptom improvement, S. aureus bacteremia bloodstream clearance, no new S. aureus bacteremia complications, and no use of other potentially effective antibacterial drugs.

The overall primary study outcome and in pre-defined subgroups in the mITT population is shown in Table 12. Table 12: Data Review Committee Overall Success Rate at the PTE Visit in the mITT Population from the Adult SAB Patients in Trial 1 For patients enrolled in Ukraine, overall success rates at the PTE visit in the mITT population were 77/84 (84.1%) in patients treated with ZEVTERA and 82/92 (89.1%) in patients treated with the comparator. Other key secondary efficacy outcomes included microbiological eradication at the PTE visit in the mITT population, which was achieved in 82% of patients treated with ZEVTERA and 77% of patients treated with the comparator, and the development of new S. aureus bacteremia complications, which occurred in 6% of patients treated with ZEVTERA and 6% of patients treated with the comparator.

S. aureus bloodstream clearance, defined as 2 consecutive study days with negative blood cultures for S. aureus with no subsequent S. aureus relapse or reinfection, was achieved after a median of 4 days in each treatment group. S. aureus bloodstream clearance in patients with MSSA was achieved after a median of 3 days in patients treated with ZEVTERA and after a median of 4 days in patients treated with the comparator. S. aureus bloodstream clearance in patients with MRSA was achieved after a median of 5 days in each treatment group.

Failure of treatment due to relapse of S. aureus bacteremia was assessed by the DRC in two patients (1%) treated with ZEVTERA, and in four patients (2%) treated in the comparator arm. No increase in ceftobiprole MIC was observed for the two isolates from the ZEVTERA-treated patients.

Acute Bacterial Skin and Skin Structure Infections (ABSSSI) in Adults The efficacy of ZEVTERA in the treatment of adult patients with ABSSSI was demonstrated in a randomized, controlled, double-blind, multinational, multicenter trial (Trial 2, NCT03137173). Randomization was stratified by study site and type of ABSSSI. Treatment duration was 5 to 14 days.

Patients could receive concomitant metronidazole for suspected anaerobic infection. A switch to oral therapy was not allowed. The study enrolled adult patients with ABSSSI (cellulitis/erysipelas, major cutaneous abscess, wound infection) with a lesion area of at least 75 cm 2, systemic or regional signs of infection, and a requirement for IV antibiotic treatment.

Patients with other forms of ABSSSI, uncomplicated skin and skin structure infections, or infections related to prosthetic devices, were excluded. The primary endpoint, assessed in the ITT population, was early clinical response 48–72 hours after start of treatment. The ITT primary analysis population comprised all patients randomized.

Early clinical response required a reduction of the primary skin lesion by at least 20%, survival for at least 72 hours, and the absence of concomitant antibacterial treatment or additional unplanned surgery. The main secondary endpoint was investigator-assessed clinical success at the test-of-cure (TOC) visit 15 to 22 days after randomization and at least 5 days after the end-of-treatment. The microbiological ITT (mITT) population included 506 patients with at least one valid baseline pathogen.

A history of diabetes was present in 11% of patients and current injection drug use was reported in 33% of patients. The types of ABSSSI included cellulitis/erysipelas (33%), wound infection (39%), and major cutaneous abscesses (28%). The median area of the primary skin infection was 259 cm 2.

The primary and main secondary outcomes are shown in Table 13. Table 14: Primary Efficacy Outcome by Community-Acquired Bacterial Pneumonia Adult Patients The efficacy of ZEVTERA in the treatment of adult patients with community-acquired bacterial pneumonia (CABP) was demonstrated in a randomized, controlled, double-blind, multinational, multicenter study (Trial 3, NCT00326287). 638 adults hospitalized with CABP and requiring IV antibacterial treatment for at least 3 days were included in the intent-to-treat (ITT) population, comparing ZEVTERA 667 mg (equivalent to 500 mg of ceftobiprole) IV every 8 hours to ceftriaxone (2 grams IV every 24 hours) with optional linezolid (600 mg IV every 12 hours) for the coverage of resistant gram-positive pathogens, including methicillin-resistant S. aureus (MRSA). Randomization was stratified by Pneumonia Outcomes Research Team (PORT) classification I to III versus IV to V, and by the need for adjunctive treatment with linezolid or matching placebo.

The treatment duration was 5–14 days. No adjunctive macrolide therapy was allowed. A switch to oral cefuroxime (500 mg every 12 hours) was allowed after at least 72 hours of IV study treatment for patients who met stringent protocol-specified criteria for improvement and were candidates for hospital discharge.

The study enrolled adult patients hospitalized with CABP based on clinical signs and symptoms, fever and/or leukocytosis/leukopenia, and new radiographic evidence of pulmonary infiltrates. Patients with known bronchial obstruction, pulmonary malignancies, cystic fibrosis, lung abscess, pleural effusion as the primary source of infection, active tuberculosis, or pneumonia known or suspected to be caused by atypical bacteria, were excluded from study participation, as were patients with known or suspected extrapulmonary complications such as concomitant meningitis, endocarditis, septic arthritis, or osteomyelitis. The clinically evaluable (CE) population comprised patients in the ITT population who received at least 48 hours of study medication and met protocol-defined criteria regarding clinical evaluability.

The protocol-specified primary efficacy analyses included clinical cure rates at TOC visit, 7 to 14 days after the end-of-treatment (EOT) in the co-primary ITT and CE populations. The CE population comprised 469 patients, and the microbiological ITT (mITT) population comprised 184 patients with at least one valid baseline pathogen. Approximately 62% of patients were classified as White, and 57% were male.

The median age was 56 years (range 18–94). 48% of patients were categorized at baseline as PORT classification III to V, and 22% of patients as PORT classification IV or V. 40% of patients did not receive any prior antibacterial drugs within 30 days of randomization. 12% of patients in the ceftriaxone arm received adjunctive linezolid, and 52% of patients in the ITT population switched to oral antibacterial therapy after at least 72 hours of IV study treatment. The results for clinical cure at the test-of-cure visit at Day 7 to 14 after end of treatment are shown in Table 15. As this study was designed prior to the current regulatory guidelines, post-hoc re-analyses were conducted to determine the consistency of study results with these guidelines.

These post-hoc analyses evaluated an earlier timepoint—clinical success at Day 3—in the ITT population, based on survival and improvement in at least two (with no worsening in any) of the following symptoms: pleuritic chest pain, cough, purulent sputum production or respiratory secretion, and tachypnea. Clinical success at Day 3 was also evaluated in the following post-hoc-defined analysis populations: 1 Day 3-ITT population, which included 97% (618 of 638) of ITT patients who presented with at least two of the following symptoms at baseline: difficulty breathing, cough, production of purulent sputum, or chest pain; 2 Day 3-modified ITT population, which included patients from the Day 3-ITT population who also met the following criteria at baseline: PORT Risk Class ≥ III, at least two of the following clinical signs—fever, hypothermia, hypotension, tachycardia, and tachypnea, plus at least one of the following: new-onset hypoxemia, rales or pulmonary consolidation, leukocytosis or leukopenia, and new radiographic infiltrates (not related to another disease process) consistent with the diagnosis of bacterial pneumonia; and 3 Day 3-micro ITT population, which was a subset of the Day 3-ITT population who had a valid pathogen at baseline. Results for early clinical success at Day 3 in the Day 3-ITT and Day 3- modified ITT populations are shown in Table 16.

Table 16: Early Clinical Success at Day 3 in Adult Patients with CABP Based on a Post-hoc Analysis of Trial 3 Clinical response rates at TOC by most common baseline pathogen in the mITT population, defined as all randomized patients with a baseline pathogen, are presented in Table 17. Table 17: Clinical Cure at Test of Cure Visit and Post-hoc Outcome of Early Pediatric Patients (3 months to < 18 Years of Age) with CABP The efficacy of ZEVTERA in the treatment of pediatric patients 3 months to < 18 years of age with CABP or hospital-acquired bacterial pneumonia (HABP) requiring IV antibacterial drug treatment was demonstrated in a phase 3, randomized, investigator-blinded, active-controlled study (Trial 5, NCT03439124). Although patients with HABP were included in the study, the safety and effectiveness of ZEVTERA for the treatment of HABP have not been established and ZEVTERA is not approved for the treatment of HABP. 138 pediatric patients were randomized in a 2:1 ratio to ZEVTERA 13.3 mg/kg (equivalent to 10 mg/kg of ceftobiprole) to 26.7 mg/kg (equivalent to 20 mg/kg of ceftobiprole - higher than the recommended approved dose).

A switch to an age-appropriate oral antibacterial drug after study Day 3 was allowed. The primary objective of this study was to evaluate the safety of ZEVTERA. The study was not powered for comparative inferential efficacy analysis, and no efficacy endpoint was identified as primary.

Of the 138 pediatric patients enrolled in the ITT/Safety population, 94% had CABP requiring hospitalization, and 6% had HABP. Patients with ventilator-associated HABP were excluded from the study. The median treatment duration with ZEVTERA was 6.0 days; 88% of patients treated with ZEVTERA switched to oral antibacterial drugs to complete treatment.

The clinical response was determined at study Day 4, the EOT visit, and at the TOC visit 7 to 14 days after the EOT visit. The ITT population included all patients randomized.

Table 12: Data Review Committee Overall Success Rate at the PTE Visit in the mITT Population from the Adult SAB Patients in Trial 1
Group/Subgroup	ZEVTERA n/N (%)	Daptomycin ± aztreonam n/N (%)	Between-group Difference (%) (2-sided 95% CI) Between-group difference of ZEVTERA minus daptomycin ± aztreonam using Cochran-Mantel-Haenszel weights method adjusted for actual stratum (dialysis status and prior antibacterial treatment use).
Overall	132/189 (69.8)	136/198 (68.7)	2.0 (−7.1, 11.1)
MSSA (methicillin-susceptible)	100/141 (70.9)	97/146 (66.4)	4.8 (−5.9, 15.5)
MRSA (methicillin-resistant)	31/45 (68.9)	38/49 (77.6)	−8.3 (−25.3, 8.6)
ABSSSI	81/116 (69.8)	80/121 (66.1)	4.5 (−7.3, 16.3)
Definite right-sided infective endocarditis	10/15 (66.7)	7/10 (70.0)	−6.6 (−40.1, 27.0)

Table 13: Primary and Main Secondary Efficacy Outcomes from the Adult Patients with ABSSSI in Trial 2
	ZEVTERA n/N (%)	Vancomycin plus aztreonam n/N (%)	Between-group Difference (%) (2-sided 95% CI) Between-group difference of ZEVTERA minus vancomycin plus aztreonam, using Cochran-Mantel-Haenszel weights method adjusted for geographical region and actual type of ABSSSI.
Primary endpoint analyses Early clinical response based on at least 20% reduction from baseline in the area of the primary lesion, survival for ≥ 72 hours from the time of administration of the first dose of study drug, no use of concomitant systemic antibacterial treatments or topical antibacterial administration on the primary lesion, and no additional unplanned surgical procedure for the ABSSSI after the start of study treatment.
Early clinical response at 48–72 hours after start of treatment (ITT)	306/335 (91.3)	303/344 (88.1)	3.3 (−1.2, 7.8)
Main secondary endpoint analysis Clinical success was defined as complete (cured) or nearly complete (improved) resolution of baseline signs and symptoms of the primary infection, such that no further antibacterial treatment was needed.
Investigator-assessed clinical success at the TOC visit (ITT)	302/335 (90.1)	306/344 (89.0)	1.0 (−3.5, 5.6)

Table 14: Primary Efficacy Outcome by Pathogen from the Adult Patients with ABSSSI in Trial 2
	Early clinical response at 48–72 hours after start of treatment Early clinical response based on at least a 20% reduction from baseline in the area of the primary lesion, survival for ≥ 72 hours from the time of administration of the first dose of study drug, no use of concomitant systemic antibacterial treatments, or topical antibacterial administration on the primary lesion and no additional unplanned surgical procedure for the ABSSSI after the start of study treatment. (mITT)		Investigator-assessed clinical success at the TOC visit Clinical success was defined as complete (cured) or nearly complete (improved) resolution of baseline signs and symptoms of the primary infection such that no further antibacterial treatment was needed. (mITT)
Pathogen	ZEVTERA n/N (%)	Vancomycin plus aztreonam n/N (%)	ZEVTERA n/N (%)	Vancomycin plus aztreonam n/N (%)
Any Gram-positive pathogen	213/228 (93.4)	220/244 (90.2)	203/228 (89.0)	217/244 (88.9)
Staphylococcus aureus	186/197 (94.4)	185/205 (90.2)	174/197 (88.3)	180/205 (87.8)
Methicillin-susceptible	102/108 (94.4)	112/124 (90.3)	95/108 (88.0)	107/124 (86.3)
Methicillin-resistant	81/86 (94.2)	67/73 (91.8)	76/86 (88.4)	66/73 (90.4)
Streptococcus pyogenes	17/20 (85.0)	23/24 (95.8)	17/20 (85.0)	22/24 (91.7)
Any Gram-negative pathogen	26/27 (96.3)	33/37 (89.2)	24/27 (88.9)	34/37 (91.9)
Enterobacterales	16/16 (100.0)	24/27 (88.9)	15/16 (93.8)	25/27 (92.6)
Klebsiella pneumoniae	8/8 (100.0)	5/5 (100.0)	7/8 (87.5)	5/5 (100.0)

Table 15: Clinical Cure at Test of Cure visit, 7 to 14 days After End-of-Treatment, in Adult Patients with CABP in Trial 3
	ZEVTERA n/N (%)	Ceftriaxone ± Linezolid n/N (%)	Between-group Difference (%) (two-sided 95% CI) Between-group difference of ZEVTERA minus ceftriaxone ± linezolid. Two-sided 95% CI is based on the Normal approximation to the difference of the two proportions.
Clinical cure Clinical cure was defined as survival with resolution of signs and symptoms of the infection or improvement to such an extent that no further antimicrobial therapy was necessary; improvement or stabilization of chest X-ray findings and no receipt of non-study antibacterial treatment for CABP. at TOC visit (ITT)	240/314 (76.4)	257/324 (79.3)	−2.9 (−9.3, 3.6)
Clinical cure at TOC visit (CE)	200/231 (86.6)	208/238 (87.4)	−0.8 (−6.9, 5.3)

Table 16: Early Clinical Success at Day 3 in Adult Patients with CABP Based on a Post-hoc Analysis of Trial 3
	ZEVTERA n/N (%)	Ceftriaxone ± linezolid n/N (%)	Between-group Difference (%) (two-sided 95% CI) Between-group difference of ZEVTERA minus ceftriaxone ± linezolid. Two-sided 95% CI is based on the Normal approximation to the difference of the two proportions.
Day-3 ITT Population
Clinical Success at Day 3 Clinical success based on improvement in at least two, with no worsening in any, of the following symptoms: pleuritic chest pain, cough, purulent sputum production or respiratory secretion, tachypnea. Seven patients in the ZEVTERA arm and 13 patients in the comparator arm did not report any of these symptoms and were therefore not included in the ITT population for the analysis evaluating early clinical success at Day 3.	218/307 (71.0)	221/311 (71.1)	-0.1% (-7.2, 7.1)
Day-3 modified ITT Population
Clinical Success at Day 3	69/97 (71.1)	60/90 (66.7))	4.5% (−8.8, 17.7)

Table 17: Clinical Cure at Test of Cure Visit and Post-hoc Outcome of Early Clinical Success at Day 3 by Pathogen in Adult CABP Patients in Trial 3
	Clinical Cure at the TOC visit Clinical cure was defined as resolution of signs and symptoms of the infection or improvement to such an extent that no further antimicrobial therapy was necessary and improvement or stabilization of chest X-ray findings. (micro-ITT)		Early Clinical Success at Day 3 Clinical success based on improvement in at least two, with no worsening in any, of the following symptoms: pleuritic chest pain, cough, purulent sputum production or respiratory secretion, tachypnea. (Day 3 micro-ITT)
Pathogen	ZEVTERA n/N (%)	Ceftriaxone ± linezolid n/N (%)	ZEVTERA n/N (%)	Ceftriaxone ± linezolid n/N (%)
Any Gram-positive pathogen	37/48 (77.1)	40/53 (75.5)	36/46 (78.3)	35/52 (67.3)
Staphylococcus aureus	10/14 (71.4)	6/10 (60.0)	10/14 (71.4)	7/10 (70.0)
Methicillin-susceptible	9/12 (75.0)	6/10 (60.0)	8/12 (66.7)	7/10 (70.0)

Streptococcus pneumoniae	29/35 (82.9)	33/41 (80.5)	27/33 (81.8)	27/41 (65.9)
Any Gram-negative pathogen	39/49 (79.6)	43/51 (84.3)	35/49 (71.4)	40/51 (78.4)
Enterobacterales spp.	14/18 (77.8)	11/16 (68.8)	14/18 (77.8)	13/16 (81.3)
Escherichia coli	6/6 (100.0)	1/4 (25.0)	6/6 (100.0)	2/4 (50.0)
Klebsiella pneumoniae	6/8 (75.0)	7/8 (87.5)	7/8 (87.5)	7/8 (87.5)

Haemophilus influenzae	9/10 (90.0)	15/16 (93.8)	4/10 (40.0)	11/16 (68.8)
Haemophilus parainfluenzae	6/9 (66.7)	7/8 (87.5)	8/9 (88.9)	8/8 (100.0)

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.

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