Version May 2024
Note: No dosage adjustment necessary based on body weight (manufacturer’s labeling).
Bloodstream infection (alternative agent) (off-label use): Pathogen-directed therapy for S. aureus, including methicillin-resistant S. aureus:
IV: 500 mg every 6 hours for 8 days, followed by 500 mg every 8 hours thereafter (Holland 2023); treat uncomplicated S. aureus bacteremia for ≥14 days starting from day of first negative blood culture, with longer courses warranted for endocarditis or metastatic sites of infection (IDSA [Mermel 2009]).
Pneumonia:
Community-acquired pneumonia: IV: 500 mg every 8 hours (manufacturer's labeling). Total duration (including oral step-down therapy) is a minimum of 5 days (or 7 days if methicillin-resistant S. aureus [MRSA] is isolated); patients should be clinically stable with normal vital signs prior to discontinuation (IDSA/ATS [Metlay 2019]).
Hospital- acquired pneumonia (alternative agent): As pathogen-directed therapy for MRSA: Note: Not recommended for patients with ventilator-associated pneumonia based on lower cure rate (Awad 2014).
IV: 500 mg every 8 hours (Awad 2014). Duration of therapy varies based on disease severity and response to therapy; treatment is typically given for 7 days (IDSA/ATS [Kalil 2016]).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Altered kidney function: IV:
Note: CrCl should be based on the Cockcroft-Gault formula using actual body weight (manufacturer's labeling).
If recommended dose is 500 mg every 6 hours:
CrCl 50 to 150 mL/minute: No dosage adjustment necessary (Hamed 2020).
CrCl 30 to <50 mL/minute: 500 mg every 8 hours (Hamed 2020).
CrCl <30 mL/minute: 250 mg every 8 hours (Hamed 2020).
If recommended dose is 500 mg every 8 hours:
CrCl 50 to 150 mL/minute: No dosage adjustment necessary (Hamed 2020; manufacturer's labeling).
CrCl 30 to <50 mL/minute: 500 mg every 12 hours (Hamed 2020; manufacturer's labeling).
CrCl <30 mL/minute: 250 mg every 12 hours (Hamed 2020; manufacturer's labeling).
End-stage kidney disease without dialysis: 250 mg every 24 hours (manufacturer's labeling).
Augmented renal clearance (CrCl >150 mL/minute): IV: No dosage adjustment necessary; however, duration of infusion should be extended to 4 hours.
Hemodialysis, intermittent (thrice weekly): Dialyzable (~70% [Torres 2016]): IV: 250 mg every 24 hours (Hamed 2020; manufacturer's labeling).
Peritoneal dialysis: IV: 250 mg every 24 hours (Hamed 2020).
No dosage adjustment necessary.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Endocrine & metabolic: Hyponatremia (≤11%)
1% to 10%:
Cardiovascular: Phlebitis (2% to 3%)
Central nervous system: Headache (≤3%), dizziness (≤1%)
Dermatologic: Skin rash (≤2%)
Gastrointestinal: Nausea (2% to 7%), diarrhea (3% to 6%), vomiting (2% to 6%), dysgeusia (1% to 2%)
Hepatic: Increased serum alanine aminotransferase (≤5%), increased serum aspartate aminotransferase (≤5%)
Hypersensitivity: Hypersensitivity reaction (6%)
Local: Infusion site reaction (7%)
Renal: Increased serum creatinine (1% to 8%)
<1%, postmarketing, and/or case reports: Abdominal pain, agitation, agranulocytosis, anaphylaxis, anemia, anxiety, asthma, Clostridioides difficile colitis, drowsiness, dyspepsia, dyspnea, eosinophilia, fever, hypokalemia, increased lactate dehydrogenase, increased serum alkaline phosphatase, increased serum glucose, increased serum triglycerides, insomnia, leukopenia, muscle spasm, nightmares, panic attack, peripheral edema, pharyngolaryngeal pain, pruritus, renal failure syndrome, seizure, thrombocythemia, thrombocytopenia
Hypersensitivity to ceftobiprole, other cephalosporins, or any component of the formulation; immediate and severe hypersensitivity (eg, anaphylaxis) to any other type of beta-lactams (eg, penicillins or carbapenems)
Concerns related to adverse effects:
• Electrolyte abnormalities: Sodium content should be considered in patients requiring sodium restriction.
• Hemolytic anemia: Seroconversion from a negative to a positive direct Coombs test has been reported. Hemolytic anemia was not reported in clinical studies; however, if anemia develops during or after treatment, consider drug-induced hemolytic anemia.
• Hypersensitivity: [Canadian Boxed Warning]: Anaphylaxis, occasionally fatal, has been reported with use of beta-lactam antibiotics, including ceftobiprole; individuals with prior hypersensitivity reactions to multiple allergens may be at increased risk. Prior to initiating therapy with ceftobiprole, carefully assess patient for prior history of hypersensitivity to cephalosporins, penicillins, or other allergens. Discontinue use immediately with onset of signs/symptoms of allergic reaction and institute supportive emergency measures. Use is contraindicated in patients with a prior anaphylactic reaction to beta-lactam antibiotics. Use caution if initiating therapy in patients with a history of nonsevere hypersensitivity to other beta-lactam drugs.
• Renal toxicity: Reversible renal toxicity was observed in animals receiving high doses and was associated with precipitation of drug-like material in the distal tubules. Clinical significance is unknown; correct hypovolemia to maintain normal urinary output in patients receiving ceftobiprole.
• Superinfection: Use may result in fungal or bacterial superinfection. Clostridioides difficile–associated diarrhea (CDAD) and pseudomembranous colitis have been reported with use; consider this diagnosis in patients who develop diarrhea during or after administration.
Disease-related concerns:
• Renal impairment: Use with caution in patients with renal impairment. Dosage adjustment is required with CrCl <50 mL/minute and prolongation of infusion is recommended in patients with CrCl >150 mL/minute.
• Seizure disorders: Use with caution in patients with a history of seizure or CNS disorder; seizure activity associated with use has most commonly been observed in these patient populations.
Other warnings/precautions:
• Appropriate use: Ceftobiprole is not effective in treatment of ventilator-associated pneumonia (VAP). Clinical efficacy data are limited in multidrug resistant Streptococcus pneumoniae-infected pneumonia patients; not recommended in treatment of hospital-acquired pneumonia (HAP) caused by this pathogen. Ceftobiprole is susceptible to hydrolysis that may be produced by Enterobacteriaceae (eg, extended-spectrum beta-lactamases [ESBLs], serine carbapenemases, class B metallo-beta-lactamases); consider prevalence of Enterobacteriaceae-producing ESBLs when prescribing ceftobiprole.
• Precipitation: May occur when mixed with calcium-containing solutions in the same IV administration line. Do not mix or simultaneously administer ceftobiprole and calcium-containing solutions (except Lactated Ringer's) in the same IV line.
Not available in the United States.
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous:
Zevtera: 500 mg (1 ea)
IV: Administer by IV infusion over 2 hours. Administer over 4 hours in patients with a CrCl >150 mL/minute. Refrigerated infusions should be brought to room temperature prior to administration.
Note: Not approved in the United States.
Pneumonia, community-acquired (CAP) and hospital-acquired (HAP): Treatment of CAP caused by Staphylococcus aureus (including methicillin-resistant S. aureus [MRSA]), Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Haemophilus influenzae; treatment of HAP, excluding ventilator-associated pneumonia (VAP), caused by S. aureus (including MRSA), S. pneumoniae, E. coli, and K. pneumoniae.
Bloodstream infection
Ceftobiprole may be confused with ceftaroline or ceftibuten.
ALERT: Canadian Boxed Warning: Health Canada-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling.
Substrate of OAT1/3
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Aminoglycosides: Cephalosporins may enhance the nephrotoxic effect of Aminoglycosides. Cephalosporins may decrease the serum concentration of Aminoglycosides. Risk C: Monitor therapy
Bacillus clausii: Antibiotics may diminish the therapeutic effect of Bacillus clausii. Management: Bacillus clausii should be taken in between antibiotic doses during concomitant therapy. Risk D: Consider therapy modification
BCG (Intravesical): Antibiotics may diminish the therapeutic effect of BCG (Intravesical). Risk X: Avoid combination
BCG Vaccine (Immunization): Antibiotics may diminish the therapeutic effect of BCG Vaccine (Immunization). Risk C: Monitor therapy
Cholera Vaccine: Antibiotics may diminish the therapeutic effect of Cholera Vaccine. Management: Avoid cholera vaccine in patients receiving systemic antibiotics, and within 14 days following the use of oral or parenteral antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Oral): May diminish the therapeutic effect of Antibiotics. Risk X: Avoid combination
Fecal Microbiota (Live) (Rectal): Antibiotics may diminish the therapeutic effect of Fecal Microbiota (Live) (Rectal). Risk X: Avoid combination
Furosemide: May enhance the nephrotoxic effect of Cephalosporins. Risk C: Monitor therapy
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): Antibiotics may diminish the therapeutic effect of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor therapy
Lactobacillus and Estriol: Antibiotics may diminish the therapeutic effect of Lactobacillus and Estriol. Risk C: Monitor therapy
Probenecid: May increase the serum concentration of Cephalosporins. Risk C: Monitor therapy
Sodium Picosulfate: Antibiotics may diminish the therapeutic effect of Sodium Picosulfate. Management: Consider using an alternative product for bowel cleansing prior to a colonoscopy in patients who have recently used or are concurrently using an antibiotic. Risk D: Consider therapy modification
Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Avoid use of live attenuated typhoid vaccine (Ty21a) in patients being treated with systemic antibacterial agents. Postpone vaccination until 3 days after cessation of antibiotics and avoid starting antibiotics within 3 days of last vaccine dose. Risk D: Consider therapy modification
Vitamin K Antagonists (eg, warfarin): Cephalosporins may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Adverse events were not observed in animal reproduction studies.
It is not known if ceftobiprole is present in breast milk.
Due to the potential for serious adverse reactions in the infant, the manufacturer recommends a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
Renal function; signs/symptoms of hypersensitivity
Prodrug converted in vivo to active drug with bactericidal activity by binding to one or more of the penicillin-binding proteins (PBPs), including PBP2a in methicillin-resistant Staphylococcus aureus (MRSA), PBP2b in Streptococcus pneumoniae (penicillin-intermediate), PBP2x in S. pneumoniae (penicillin resistant), and PBP5 in Enterococcus faecalis.
Note: Ceftobiprole systemic clearance is 40% greater in patients with CrCl >150 mL/minute and Vd is 30% larger.
Distribution: Vdss: 18 L
Protein binding: 16% (concentration independent)
Metabolism: Ceftobiprole medocaril sodium (prodrug) rapidly metabolized by plasma esterases to ceftobiprole (active drug), which undergoes minimal metabolism to an inactive metabolite
Half-life elimination: ~3 hours
Excretion: Urine: 89% (83% as active drug, 5% as inactive metabolite, <1% as unchanged prodrug)
Altered kidney function: Ceftobiprole AUC is 2.5- and 3.3-fold higher in patients with CrCl 30 to <50 mL/minute and CrCl <30 mL/minute, respectively.
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