Zevtera: Uses, Dosage & Side Effects

What Is Zevtera and What Is It Used For?

Zevtera contains the active substance ceftobiprole, supplied as its water-soluble prodrug ceftobiprole medocaril sodium. Upon intravenous administration, the prodrug is rapidly converted by plasma esterases to the active moiety ceftobiprole. It belongs to the cephalosporin class of antibiotics, which are part of the broader beta-lactam antibiotic family. Cephalosporins are categorized into generations based on their spectrum of antibacterial activity, and ceftobiprole is classified as a fifth-generation cephalosporin due to its exceptional breadth of coverage across both Gram-positive and Gram-negative organisms.

The antibacterial activity of ceftobiprole is mediated through its binding to penicillin-binding proteins (PBPs), which are essential bacterial enzymes involved in the final transpeptidation step of peptidoglycan cell wall synthesis. By inhibiting these enzymes, ceftobiprole disrupts cell wall integrity, leading to osmotic instability and ultimately bacterial cell lysis and death. What distinguishes ceftobiprole from earlier-generation cephalosporins is its remarkable affinity for a broad range of PBPs, including PBP2a in methicillin-resistant Staphylococcus aureus (MRSA) and PBP2x in penicillin-resistant Streptococcus pneumoniae. This high-affinity binding to altered PBPs that confer resistance to other beta-lactams is the molecular basis for ceftobiprole’s activity against these clinically important resistant organisms.

The spectrum of activity of ceftobiprole encompasses a wide range of clinically relevant pathogens commonly encountered in respiratory tract infections. Against Gram-positive organisms, ceftobiprole demonstrates potent bactericidal activity against methicillin-susceptible and methicillin-resistant Staphylococcus aureus (MSSA and MRSA), Streptococcus pneumoniae (including penicillin-intermediate and penicillin-resistant strains), other streptococci, and Enterococcus faecalis (but not E. faecium). Against Gram-negative organisms, it is active against Haemophilus influenzae, Moraxella catarrhalis, Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, and certain other Enterobacterales. Ceftobiprole also has activity against some anaerobic bacteria. It is important to note that ceftobiprole is not active against extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales or Pseudomonas aeruginosa.

Zevtera is specifically indicated for the treatment of pneumonia in the following settings:

• Community-acquired pneumonia (CAP): Pneumonia that develops outside of hospital settings or within 48 hours of hospital admission. CAP is one of the most common infectious diseases worldwide and a leading cause of hospitalization and mortality, particularly among elderly patients and those with comorbidities.
• Hospital-acquired pneumonia (HAP): Pneumonia that develops 48 hours or more after hospital admission and was not incubating at the time of admission. HAP is a serious healthcare-associated infection with significant morbidity and mortality. Importantly, Zevtera is not indicated for ventilator-associated pneumonia (VAP)—pneumonia that develops more than 48 hours after initiation of mechanical ventilation.

The clinical efficacy of ceftobiprole in pneumonia has been established through several pivotal phase III randomized controlled trials. In the TARGET study program for CAP, ceftobiprole demonstrated non-inferiority to ceftriaxone (with or without linezolid) in clinical cure rates, with particularly notable efficacy in the subgroup of patients requiring ICU admission. In HAP trials, ceftobiprole showed non-inferiority to ceftazidime plus linezolid in clinical cure rates for non-ventilator-associated HAP. These trials enrolled diverse patient populations across multiple countries, providing robust evidence for ceftobiprole’s effectiveness in real-world clinical practice.

Zevtera was initially approved by the European Medicines Agency (EMA) and has subsequently received regulatory approvals in numerous countries. It is approved for use across the full age spectrum from neonates (excluding premature infants) through adults, making it a versatile antibiotic option in both adult and pediatric infectious disease practice. The availability of pediatric dosing data and approval distinguishes ceftobiprole from many other newer antibiotics that lack pediatric indications.

What Should You Know Before Taking Zevtera?

Contraindications

Zevtera must not be used in the following situations:

• Hypersensitivity to ceftobiprole medocaril sodium or to any of the excipients (citric acid monohydrate and sodium hydroxide).
• Hypersensitivity to other cephalosporins or other beta-lactam antibiotics.
• History of severe allergic reactions (such as anaphylaxis) to other antibiotics including penicillins or carbapenems.

Cross-reactivity between cephalosporins and penicillins is a well-recognized clinical concern, although the actual incidence of cross-allergy is lower than historically believed. Current evidence suggests that the overall rate of cross-reactivity between penicillins and cephalosporins is approximately 1–2%, significantly lower than the previously cited 10%. Nevertheless, patients with a history of anaphylaxis or other severe immediate-type allergic reactions to any beta-lactam antibiotic should not receive Zevtera due to the potentially life-threatening nature of these reactions.

Warnings and Precautions

Before starting treatment with Zevtera, your healthcare provider should be informed about the following:

• Kidney problems: Ceftobiprole is primarily eliminated through the kidneys. Patients with moderate to severe renal impairment require dose reduction. Your doctor will assess your kidney function through blood tests and adjust the dose accordingly. Patients on hemodialysis also require specific dosing considerations, as ceftobiprole is removed during dialysis.
• History of seizures: Cephalosporin antibiotics, including ceftobiprole, have been associated with seizures, particularly in patients with pre-existing neurological conditions, renal impairment (leading to drug accumulation), or those receiving high doses. If you have a history of epilepsy or other seizure disorders, inform your doctor before starting treatment.
• Diarrhea during treatment: Antibiotic use can disrupt the normal gut microbiome, potentially leading to Clostridioides difficile-associated diarrhea (CDAD), which can range from mild diarrhea to fatal colitis. If you develop diarrhea during or after treatment with Zevtera, inform your doctor immediately. Do not take any anti-diarrheal medication without first consulting your healthcare provider, as this can mask the symptoms of CDAD.
• HIV-positive status or immunosuppression: The efficacy and safety of ceftobiprole have not been extensively studied in severely immunocompromised patients, including those with HIV infection, severe neutropenia, or suppressed bone marrow function. Your doctor will weigh the benefits and risks of treatment in these circumstances.
• Ventilator-associated pneumonia: Zevtera is not suitable for treating pneumonia that develops more than 48 hours after the initiation of mechanical ventilation. If you are started on Zevtera and subsequently require mechanical ventilation, your doctor will reassess whether the medication remains appropriate.
• Calcium-containing IV solutions: Zevtera should not be administered simultaneously with calcium-containing intravenous solutions (except lactated Ringer’s solution for injection) through the same IV line, due to the risk of precipitation.

Children and Adolescents

Zevtera is approved for use in neonates (term, not premature), infants, children, and adolescents for the treatment of pneumonia. Dosing in pediatric patients is calculated based on age and body weight. It is important to note that there is no data available for the use of Zevtera in premature (preterm) infants, and the drug should not be used in this population. Your child’s doctor will determine the appropriate dose and monitor for adverse effects throughout the treatment course.

Pregnancy and Breastfeeding

If you are pregnant, think you may be pregnant, or are planning to become pregnant, inform your doctor before receiving Zevtera. There are limited data on the use of ceftobiprole in pregnant women. Animal reproductive toxicity studies have not indicated direct harmful effects on embryo-fetal development, but as a precaution, Zevtera should only be used during pregnancy when the clinical benefit to the mother clearly outweighs the potential risk to the fetus. Your doctor will carefully evaluate whether alternative antibiotics with more established safety profiles during pregnancy may be appropriate.

It is not known whether ceftobiprole or its metabolites are excreted in human breast milk. A risk to the breastfed newborn or infant cannot be excluded. The decision to continue or discontinue breastfeeding or to continue or discontinue Zevtera treatment should be made in consultation with your healthcare provider, taking into account the benefit of breastfeeding for the child and the benefit of Zevtera treatment for the mother.

Driving and Operating Machinery

Zevtera may cause side effects such as dizziness that could affect your ability to drive vehicles or operate machinery. If you experience dizziness or any other adverse effects that impair your alertness or coordination, you should refrain from driving or operating machinery until these effects have resolved. As Zevtera is typically administered in a hospital setting, this concern is primarily relevant during the post-discharge period.

Sodium Content

Each vial of Zevtera contains approximately 22 mg of sodium, which is equivalent to approximately 1.1% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This should be taken into consideration for patients on a controlled sodium diet, particularly when multiple doses are administered daily. At the standard dosing of 500 mg every 8 hours, the total daily sodium load from Zevtera would be approximately 66 mg.

How Does Zevtera Interact with Other Drugs?

Ceftobiprole has a favorable pharmacokinetic profile that minimizes the potential for drug interactions. The drug is not metabolized by cytochrome P450 (CYP) enzymes and does not significantly induce or inhibit CYP enzymes at therapeutic concentrations. Approximately 83% of the administered dose is excreted unchanged in the urine, with the remainder undergoing hydrolysis of the prodrug and ring-opening of the beta-lactam. These characteristics mean that hepatic drug-drug interactions are unlikely with ceftobiprole.

However, certain interactions should be considered when administering Zevtera:

Always inform your doctor or pharmacist about all medications, supplements, and herbal products you are currently taking. This includes both prescription and over-the-counter medications. While ceftobiprole has a relatively clean interaction profile compared to many other antibiotics, comprehensive medication review remains an important aspect of safe prescribing, particularly in hospitalized patients who are often receiving multiple concurrent medications.

It is worth noting that like other cephalosporins, ceftobiprole may theoretically affect the intestinal flora, which could reduce the reabsorption of estrogens and potentially decrease the effectiveness of combined hormonal oral contraceptives. While this interaction is considered unlikely to be clinically significant with most modern low-dose contraceptives, it is a theoretical concern that some clinicians may wish to discuss with patients.

What Is the Correct Dosage of Zevtera?

Zevtera is administered exclusively as an intravenous infusion by a doctor or nurse in a healthcare facility. The powder for concentrate must first be reconstituted and then further diluted before infusion. The medication cannot be taken orally, and it cannot be given as a bolus (rapid) injection. The 2-hour infusion duration is important for achieving appropriate drug levels and minimizing side effects.

Adults and Adolescents (≥12 years)

For adults, the infusion solution is prepared at a concentration of 2 mg/mL. The reconstituted powder (10 mL) is added to 250 mL of a compatible diluent (0.9% sodium chloride, 5% glucose, or lactated Ringer’s solution). For patients with severe renal impairment, only 5 mL of reconstituted solution is added to 125 mL of diluent to achieve the 250 mg dose.

Children (<12 years)

Pediatric patients under 12 years of age receive a higher concentration infusion solution (4 mg/mL ceftobiprole) compared to adults (2 mg/mL). The volume administered is calculated based on the patient’s body weight. For smaller infants where the required dose does not exceed 200 mg, administration via a 50 mL syringe pump is also possible. Your child’s healthcare team will calculate the appropriate dose and volume based on their individual weight and age.

Elderly Patients

No routine dose adjustment is required for elderly patients solely on the basis of age. However, elderly patients frequently have reduced renal function, and dose adjustments should be guided by actual creatinine clearance values rather than age alone. Your doctor will monitor kidney function through blood tests and adjust the dose of Zevtera as necessary.

Missed Dose

Since Zevtera is administered in a hospital or clinical setting by healthcare professionals, missed doses are uncommon. If you believe a dose has been missed, inform your doctor or nurse immediately. They will determine the appropriate course of action, which may include administering the missed dose as soon as possible and adjusting the timing of subsequent doses to maintain the 8-hour dosing interval.

Overdose

If you suspect that you have received too much Zevtera, contact your doctor or nurse immediately. Symptoms of overdose may include an exacerbation of the known side effects, particularly neurological effects such as seizures. Treatment of ceftobiprole overdose is supportive. Ceftobiprole is partially removed by hemodialysis, which may be considered in severe cases. There is no specific antidote for ceftobiprole.

What Are the Side Effects of Zevtera?

Like all medicines, Zevtera can cause side effects, although not everyone will experience them. The following side effects have been observed with ceftobiprole. The frequencies are defined as: very common (affects more than 1 in 10 people), common (affects up to 1 in 10 people), uncommon (affects up to 1 in 100 people), rare (affects up to 1 in 1,000 people), and not known (frequency cannot be estimated from available data).

Most common side effects of Zevtera are mild to moderate in severity and resolve either during or shortly after the completion of treatment. The incidence and nature of side effects in pediatric patients are generally similar to those observed in adults. If you experience any side effects that concern you, inform your doctor or nurse. You can also report suspected adverse reactions to your national pharmacovigilance authority to help monitor the benefit-risk profile of this medicine.

Some laboratory abnormalities associated with Zevtera use deserve special mention. A positive direct Coombs test has been observed in some patients receiving ceftobiprole. This test detects antibodies that may bind to red blood cells. While a positive Coombs test does not necessarily indicate hemolytic anemia, it is important for your healthcare team to be aware of this potential finding, particularly if blood transfusion or further hematological investigations are needed. Additionally, ceftobiprole may interfere with creatinine assays using the Jaffé method, potentially giving falsely elevated creatinine readings. Enzymatic creatinine assays are not affected and should be used when accurate creatinine measurement is critical.

How Should You Store Zevtera?

Keep Zevtera out of the sight and reach of children. Do not use after the expiry date stated on the carton and vial label after “EXP”. The expiry date refers to the last day of the stated month.

Storage requirements for Zevtera are as follows:

• Unopened vials: Store in a refrigerator at 2–8°C. Keep the vial in the outer carton to protect from light.
• Reconstituted concentrate: After reconstitution with sterile water for injections or 5% glucose solution, the concentrate (50 mg/mL) may be stored at room temperature for up to 1 hour, or refrigerated (2–8°C) for up to 24 hours. It is recommended to dilute immediately after reconstitution.
• Diluted infusion solution (2 mg/mL, adults): Stability varies by diluent. When diluted in 0.9% sodium chloride and protected from light: up to 24 hours at 25°C or 96 hours at 2–8°C. When not protected from light: up to 8 hours at 25°C. Solutions in 5% glucose have shorter stability (12 hours at 25°C protected, 8 hours unprotected). Solutions in lactated Ringer’s must not be refrigerated.
• Diluted infusion solution (4 mg/mL, pediatric): When diluted in 5% glucose: 12 hours at 25°C (unprotected from light) or 24 hours at 2–8°C (protected). When diluted in 0.9% sodium chloride: 8 hours at 25°C or 8 hours at 2–8°C.

Reconstituted and diluted solutions should not be frozen or exposed to direct sunlight. If the infusion solution has been refrigerated, it should be allowed to return to room temperature before administration. The infusion solution does not need to be protected from light during administration. The solution should be clear to slightly opalescent and yellowish in color. Inspect visually for particles before use and discard if particles are visible.

Do not dispose of Zevtera via wastewater or household waste. In hospital settings, unused product or waste material is disposed of in accordance with local pharmaceutical waste regulations.

What Does Zevtera Contain?

The active substance in Zevtera is ceftobiprole. Each vial contains 500 mg of ceftobiprole, supplied as 666.6 mg of the prodrug ceftobiprole medocaril sodium. After reconstitution with 10 mL of sterile water for injections or 5% glucose solution, each milliliter of concentrate contains 50 mg of ceftobiprole (corresponding to 66.7 mg of ceftobiprole medocaril sodium).

The other ingredients (excipients) are:

• Citric acid monohydrate (E330): A buffering agent used to maintain the pH of the solution within an acceptable range for intravenous administration.
• Sodium hydroxide (E524): Used for pH adjustment during the manufacturing process.

Zevtera appears as a white, yellowish to slightly brownish cake, broken cake, or powder in a 20 mL glass vial. It is supplied in packs containing 10 vials. After reconstitution and dilution, the ready-to-use infusion solution should be clear to slightly opalescent and yellowish in color.

Zevtera is manufactured by ACS Dobfar S.p.A. in Verona, Italy, and the marketing authorization holder is Basilea Pharmaceutica Deutschland GmbH, based in Lörrach, Germany. The medicine is approved across the European Economic Area and the United Kingdom under the names Zevtera, Mabelio (France, Italy, Luxembourg), and Adaluzis (Ireland).