AHFS Class:

• Fifth Generation Cephalosporins 8:12.06.20

Generic Name(s):

• Ceftaroline Fosamil

Chemical Name:

• 4-[2-[[(6 R ,7 R )-2-Carboxy-7-[[(2 Z )-(ethoxyimino)[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]thio]-4-thiazolyl]-1-methyl-pyridinium, inner salt, monoacetate, monohydrate

Molecular Formula:

• C₂₂H₂₁N₈O₈PS₄.C₂H₄O₂.H₂O

Ceftaroline is a semisynthetic, fifth generation cephalosporin antibiotic.1,5,6,7,8,27

Community-acquired Pneumonia

Ceftaroline fosamil is used for the treatment of community-acquired bacterial pneumonia (CABP, CAP) caused by susceptible Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible [oxacillin-susceptible] strains only), Haemophilus influenzae , Klebsiella pneumoniae , K. oxytoca , or Escherichia coli in adults and pediatric patients 2 months of age and older.1,3

Initial treatment of CAP generally involves use of an empiric anti-infective regimen based on the most likely pathogens and local susceptibility patterns;30,31 treatment may then be changed (if possible) to provide a more specific regimen (pathogen-directed therapy) based on results of in vitro culture and susceptibility testing.30 The most appropriate empiric regimen varies depending on the severity of illness at the time of presentation, whether outpatient treatment or hospitalization in or out of an intensive care unit (ICU) is indicated, and the presence or absence of cardiopulmonary disease and other modifying factors that increase the risk of certain pathogens (e.g., methicillin-resistant S. aureus [MRSA; also known as oxacillin-resistant S. aureus or ORSA], penicillin-resistant S. pneumoniae , multidrug-resistant S. pneumoniae [MDRSP], enteric gram-negative bacilli, Pseudomonas aeruginosa ).30,31

For information regarding the treatment of CAP, including infections caused by MRSA, the current clinical practice guidelines from the Infectious Diseases Society of America (IDSA) available at [Web] should be consulted.30,31,32

Clinical Experience

Efficacy of ceftaroline fosamil for the treatment of CAP in adults is based on results of 2 randomized, double-blind, active-controlled, phase 3 noninferiority trials in 1231 adults with CAP requiring hospitalization (Pneumonia Outcome Research Team [PORT] risk class III or IV and not admitted to an intensive care unit).1,3 Patients in each trial (Focus 1 and Focus 2) were randomized to receive either ceftaroline fosamil (600 mg given by IV infusion over 1 hour every 12 hours) or ceftriaxone (1 g given by IV infusion over 30 minutes every 24 hours);1,3 patients in the first trial also received oral clarithromycin on the initial day of treatment (500 mg every 12 hours for 2 doses).1,3 Treatment duration was 5-7 days (maximum 7 days);1,3 a switch to oral therapy was not allowed.1,3 Patients with CAP known or suspected to be caused by methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) or caused by an atypical pathogen (e.g., Chlamydophila pneumoniae , Mycoplasma pneumoniae , Legionella ) alone were excluded from the trials.1,3

In the first trial (Focus 1), clinical cure rates at the test-of-cure visit (8-15 days after treatment ended) in the clinically evaluable population were similar for ceftaroline- and ceftriaxone-treated patients (87 and 78%, respectively).1,3 Similarly, clinical cure rates in the second trial (Focus 2) were 82% with ceftaroline and 77% with ceftriaxone.1,3 When results from both adult trials were combined, the overall clinical cure rate in the clinically evaluable population was similar in patients treated with ceftaroline fosamil (84%) compared with those receiving ceftriaxone (78%).3 In addition, when results from both trials were pooled, the 30-day all-cause mortality rate did not differ between treatment groups.1

When results from both adult trials were combined and stratified according to causative organism, the clinical cure rates at the test-of-cure visit in the microbiologically evaluable population that received ceftaroline fosamil were 86% for CAP caused by S. pneumonia , 72% for methicillin-susceptible S. aureus , 83% for H. influenzae , 100% for K. pneumoniae , 83% for K. oxytoca , and 83% for E. coli .1

Skin and Skin Structure Infections

Ceftaroline fosamil is used for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible S. aureus (including MRSA), S. pyogenes (group A β-hemolytic streptococci, GAS), S. agalactiae (group B streptococci, GBS), E. coli , K. pneumoniae , or K. oxytoca in adults and children 2 months of age and older.1,2

Ceftaroline fosamil is one of several anti-infectives that have been recommended for treatment of skin and skin structure infections caused by MRSA, including empiric treatment of surgical site infections in patients at high risk for MRSA (e.g., nasal colonization, prior MRSA infection, recent hospitalization, recent anti-infective therapy).43

For information regarding the treatment of skin and skin structure infections, including infections caused by MRSA, the current IDSA clinical practice guidelines available at [Web] should be consulted.32,43

Clinical Experience

Efficacy of ceftaroline fosamil for the treatment of skin and skin structure infections in adults is based on the results of 2 randomized, double-blind, active-controlled trials in 1396 adults with complicated skin and skin structure infections (e.g., cellulitis, major abscess, infected wound/ulcer/burn).1,2 Patients in each trial (Canvas 1 and Canvas 2) were randomized to receive either ceftaroline fosamil with placebo (600 mg of ceftaroline fosamil given by IV infusion over 1 hour followed by placebo given by IV infusion over 1 hour every 12 hours) or a 2-drug regimen of vancomycin and aztreonam (1 g of vancomycin given by IV infusion over 1 hour followed by 1 g of aztreonam given by IV infusion over 1 hour every 12 hours).1,2 Treatment duration was 5-14 days (mean approximately 8 days); a switch to oral therapy was not allowed.1,2

In the first trial (Canvas 1), clinical cure rates at the test-of-cure visit in the clinically evaluable population for ceftaroline-treated patients were similar to clinical cure rates for vancomycin- and aztreonam-treated patients (91 and 93%, respectively).1 Similarly, the clinical cure rate in the second trial (Canvas 2) was 92% in both treatment groups.1 When results from both adult trials were combined, the overall clinical cure rate in the clinically evaluable population was similar in those treated with ceftaroline fosamil (92%) compared with those treated with vancomycin and aztreonam (93%).2 Of the 693 patients in the modified intent-to-treat population from both trials, 20 patients had S. aureus bacteremia at baseline (11 with methicillin-susceptible strains, 9 with MRSA);1 65% of these patients were clinical responders at study day 3 and 90% were considered clinical success at the test-of-cure visit (8-15 days after treatment ended).1

When results from both adult trials were combined and stratified according to causative organism, the clinical cure rates in the microbiologically evaluable population that received ceftaroline fosamil were 93% for methicillin-susceptible S. aureus , 93% for MRSA, 100% for S. pyogenes , 96% for S. agalactiae , 95% for E. coli , 94% for K. pneumoniae , and 83% for K. oxytoca .1,2

For additional information on the role of parenteral cephalosporins in the treatment of these and other infections, see Uses in the Cephalosporins General Statement 8:12.06.

Administration

Ceftaroline fosamil is administered by IV infusion.1

Ceftaroline fosamil solutions should not be admixed with or added to solutions containing other drugs.1

Reconstitution and Dilution

Ceftaroline fosamil must be reconstituted and further diluted prior to IV infusion.1 Strict aseptic technique must be observed when preparing IV solutions of the drug.1

Single-use vials labeled as containing 400 or 600 mg of ceftaroline fosamil should be reconstituted by adding 20 mL of sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, or lactated Ringer's injection, to provide a solution containing approximately 20 or 30 mg/mL, respectively.1 The vial should be gently mixed;1 reconstitution should be complete in less than 2 minutes.1

Prior to IV administration, the appropriate dose of reconstituted solution must be further diluted in 50-250 mL of an appropriate infusion solution.1 The same diluent should be used for both reconstitution and further dilution unless the drug was reconstituted with sterile water, in which case the dose should be further diluted using any compatible IV solution (e.g., 0.45 or 0.9% sodium chloride injection, 2.5 or 5% dextrose injection, lactated Ringer's injection).1

To prepare a 600-mg dose of ceftaroline fosamil in a 50-mL infusion bag for administration in adults, 20 mL of the diluent should be removed from the infusion bag prior to injecting the entire reconstituted contents of a 600-mg vial of the drug;1 the concentration of the final infusion solution is approximately 12 mg/mL.1

To prepare a 400-mg dose of ceftaroline fosamil in a 50-mL infusion bag for administration in adults or pediatric patients 2 months of age or older weighing more than 33 kg, 20 mL of the diluent should be removed from the infusion bag prior to injecting the entire reconstituted contents of a 400-mg vial of the drug;1 the concentration of the final infusion solution is approximately 8 mg/mL.1

To prepare a dose in a 50-mL infusion bag for administration in pediatric patients 2 months of age or older weighing 33 kg or less, the amount of diluent to be removed from the infusion bag and the amount of reconstituted solution of drug to be withdrawn from the vial and added to the diluent vary depending on the age and weight of the child.1 The concentration of the final infusion solution for these pediatric patients should not exceed 12 mg/mL.1

Reconstituted and diluted ceftaroline fosamil solutions should appear clear and light to dark yellow, depending on the concentration and storage conditions.1 Final ceftaroline fosamil solutions in the IV infusion bag should be used within 6 hours when stored at room temperature or within 24 hours when stored in the refrigerator at 2-8°C.1 (See Chemistry and Stability: Stability.)

Rate of Administration

IV infusions of ceftaroline fosamil should be given over 5-60 minutes.1

Dosage

Ceftaroline fosamil is commercially available as ceftaroline fosamil monoacetate monohydrate; dosage is expressed in terms of anhydrous ceftaroline fosamil.1

Adult Dosage

Community-acquired Pneumonia

The recommended dosage of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia (CABP, CAP) in adults is 600 mg every 12 hours for 5-7 days.1

The duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress.1

Skin and Skin Structure Infections

The recommended dosage of ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections (ABSSSI) in adults is 600 mg every 12 hours for 5-14 days.1

The duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress.1

Pediatric Dosage

Community-acquired Pneumonia

The recommended dosage of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia in pediatric patients 2 months to less than 2 years of age is 8 mg/kg every 8 hours.1 Pediatric patients 2 years to less than 18 years of age weighing 33 kg or less should receive 12 mg/kg every 8 hours and those 2 years to less than 18 years of age weighing more than 33 kg should receive 400 mg every 8 hours or 600 mg every 12 hours.1

The manufacturer recommends a treatment duration of 5-14 days in pediatric patients;1 the duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress.1

Skin and Skin Structure Infections

The recommended dosage of ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections in pediatric patients 2 months to less than 2 years of age is 8 mg/kg every 8 hours.1 Pediatric patients 2 years to less than 18 years of age weighing 33 kg or less should receive 12 mg/kg every 8 hours and those 2 years to less than 18 years of age weighing more than 33 kg should receive 400 mg every 8 hours or 600 mg every 12 hours.1

The manufacturer recommends a treatment duration of 5-14 days in pediatric patients;1 the duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriologic progress.1

Dosage in Renal and Hepatic Impairment

Dosage of ceftaroline fosamil must be modified according to the degree of renal impairment in adults with creatinine clearances of 50 mL/minute or less, including those undergoing hemodialysis.1 (See Table 1.)

Dosage adjustments are not necessary if ceftaroline fosamil is used in pediatric patients with creatinine clearances greater than 50 mL/minute per 1.73 m².1 Data are insufficient to make dosage recommendations for pediatric patients with creatinine clearances less than 50 mL/minute per 1.73 m².1

Pharmacokinetics of ceftaroline fosamil have not been studied in patients with impaired hepatic function, but hepatic impairment is not expected to have a clinically important effect on systemic clearance of the drug.1

Dosage in Geriatric Patients

Dosage of ceftaroline fosamil should be selected with caution in geriatric patients.1 Dosage adjustments are not required based on age, but may be required based on age-related changes in renal function.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Adverse Effects

Adverse effects reported with ceftaroline fosamil are similar to those reported with other cephalosporins.4,25 (See Cautions in the Cephalosporins General Statement 8:12.06.) Ceftaroline fosamil generally is well tolerated;4,25 serious adverse effects have been reported in up to 7.5% of adults receiving the drug in phase 3 clinical trials and have required discontinuance of the drug in about 3% of patients.1,25

Adverse effects reported in 2% or more of adults receiving ceftaroline fosamil in phase 3 clinical trials include GI effects (diarrhea,1,25 nausea,1,25 vomiting,1 constipation1 ), headache,25 rash,1,25 pruritus,25 hypokalemia,1 increased transaminases,1,25 and phlebitis.1

Precautions and Contraindications

Ceftaroline fosamil shares the toxic potentials of the cephalosporins, and the usual precautions of cephalosporin therapy should be observed.1

Sensitivity Reactions

Serious, sometimes fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving β-lactam antibiotics.1 Anaphylaxis has been reported in some patients receiving ceftaroline fosamil.1

Prior to initiation of ceftaroline fosamil therapy, careful inquiry should be made concerning previous hypersensitivity reactions to ceftaroline, other cephalosporins, penicillins, or carbapenems.1 There is clinical and laboratory evidence of partial cross-sensitivity among β-lactam antibiotics.1,27

Ceftaroline fosamil is contraindicated in patients with known serious hypersensitivity to the drug or other cephalosporins.1 If ceftaroline fosamil is used in patients allergic to penicillin or other β-lactams, the patient should be closely monitored.1

Patients should be advised that allergic reactions, including serious allergic reactions, could occur and that serious reactions require immediate treatment.1

If a hypersensitivity reaction occurs, ceftaroline fosamil should be discontinued and appropriate treatment and supportive measures initiated.1

Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile .1,12,13,14,15,16

C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all systemic anti-infectives, including ceftaroline, and may range in severity from mild diarrhea to fatal colitis.1,12,13,14,15,16C. difficile produces toxins A and B which contribute to the development of CDAD;1,13,12 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.1

CDAD should be considered in the differential diagnosis in patients who develop diarrhea during or after anti-infective therapy.1,12,13,14,15,16 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,12,14,15,16 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically indicated.1,12,13,14,15,16

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact a clinician if severe watery or bloody diarrhea develops.1

Hematologic Effects

Neutropenia,33 leukopenia,1 and agranulocytosis1,34 have been reported in patients receiving ceftaroline fosamil during postmarketing experience.1,33,34

Seroconversion from negative to positive direct antiglobulin (Coombs') test results was reported in about 10-11% of adults receiving ceftaroline fosamil in phase 3 clinical trials compared with about 4-5% of adults receiving comparator anti-infectives.1 In pediatric trials, seroconversion from negative to positive direct antiglobulin (Coombs') test results was reported in about 18% of those receiving ceftaroline fosamil compared with about 3% of those receiving comparator anti-infectives.1 There was no evidence of hemolytic anemia in these adult or pediatric patients.1

Drug-induced hemolytic anemia should be considered in patients who develop anemia during or after treatment with ceftaroline fosamil.1 In such patients, diagnostic studies should be performed and should include a direct antiglobulin test.1 If drug-induced hemolytic anemia is suspected, discontinuance of ceftaroline fosamil should be considered and supportive treatment (e.g., transfusion) should be administered as clinically indicated.1

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of ceftaroline fosamil and other antibacterials, the drug should be used only for the treatment of infections proven or strongly suspected to be caused by susceptible bacteria.1

When selecting or modifying anti-infective therapy, results of culture and in vitro susceptibility testing should be used.1 In the absence of such data, local epidemiology and susceptibility patterns should be considered when selecting anti-infectives for empiric therapy.1

Patients should be advised that antibacterials (including ceftaroline fosamil) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with ceftaroline fosamil or other antibacterials in the future.1

Precautions in Patients with Renal Impairment

Because the area under the concentration-time curve (AUC) and plasma half-life of ceftaroline are increased in patients with renal impairment,1,4 dosage adjustments are recommended for adults with creatinine clearances less than 50 mL/minute, including those undergoing hemodialysis.1 Data are insufficient to date to make dosage recommendations for use of ceftaroline fosamil in pediatric patients with creatinine clearances less than 50 mL/minute per 1.73 m².1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Pediatric Precautions

Safety and efficacy of ceftaroline fosamil have not been established in pediatric patients younger than 2 months of age.1

Safety and efficacy of ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections have been established in pediatric patients 2 months to less than 18 years of age.1 Use of the drug for these indications in this age group is supported by evidence from adequate and well-controlled studies in adults and additional pharmacokinetic and safety data from pediatric trials.1

Data indicate that clinical cure rates reported with ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections in children 2 months to less than 18 years of age are similar to clinical cure rates reported in adults 18 years of age or older.1 In addition, adverse effects reported with ceftaroline fosamil in pediatric trials are similar to those reported in adult trials.1 Adverse effects reported in 3% or more of children 2 months to less than 18 years of age receiving ceftaroline fosamil in clinical trials include GI effects (diarrhea,1 nausea,1 vomiting1 ), pyrexia,1 and rash.1

Geriatric Precautions

In phase 3 trials evaluating ceftaroline fosamil for the treatment community-acquired bacterial pneumonia or acute bacterial skin and skin structure infections in adults, about 31% of patients were 65 years of age or older and no overall differences in efficacy or safety relative to younger adults were observed.1

Ceftaroline is substantially eliminated by the kidneys, and the risk of adverse effects may be greater in those with impaired renal function.1 Because geriatric patients are more likely to have reduced renal function, dosage should be selected with caution and monitoring of renal function should be considered.1 Dosage adjustments in geriatric patients should be based on renal function.1 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

In vivo and in vitro studies evaluating ceftaroline fosamil have not shown evidence of mutagenicity.1 Although ceftaroline fosamil and ceftaroline were clastogenic in the absence of metabolic activation in an in vitro chromosomal aberration assay, this did not occur in the presence of metabolic activation.1

Long-term animal studies have not been performed to date to evaluate the carcinogenic potential of ceftaroline fosamil.1

Pregnancy, Fertility, and Lactation

Pregnancy

Adequate data are not available regarding use of ceftaroline fosamil in pregnant women.1

Animal studies in rats using ceftaroline fosamil dosages up to 4 times the maximum recommended human dosage (MRHD) or in rabbits using dosages up to approximately equal to the MRHD have not revealed evidence of fetal harm.1

Fertility

There was no evidence of impaired fertility in male or female rats receiving ceftaroline fosamil dosages approximately 4 times higher than the MRHD based on body surface area.1

Lactation

It is not known whether ceftaroline is distributed into human milk;1 possible effects of the drug on a breast-fed infant or on milk production are unknown.1

Benefits of breast-feeding and the importance of ceftaroline fosamil to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.1

No formal drug interaction studies have been performed to date using ceftaroline fosamil.1 Interactions are unlikely between ceftaroline fosamil and drugs that are cytochrome P-450 (CYP) substrates, inhibitors, or inducers or drugs that undergo active renal secretion or alter renal blood flow.1

In vitro, ceftaroline does not inhibit CYP isoenzymes 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4/5.1 Therefore, pharmacokinetic interactions with drugs metabolized by these isoenzymes are unlikely.1

Aminoglycosides

In vitro, the antibacterial effects of ceftaroline and amikacin were synergistic against Escherichia coli and Klebsiella pneumoniae that produce extended-spectrum β-lactamases (ESBL-producing), AmpC-derepressed Enterobacter cloacae , and Pseudomonas aeruginosa ;22 there was no evidence of antagonism between the drugs.1,22

Aztreonam

In vitro, the antibacterial effects of ceftaroline and aztreonam were indifferent against ESBL-producing E. coli and K. pneumoniae , AmpC-derepressed E. cloacae , and Ps. aeruginosa ;22 there was no evidence of synergism or antagonism between the drugs.1,22

Carbapenems

In vitro, the antibacterial effects of ceftaroline and meropenem were synergistic against ESBL-producing E. coli and indifferent against ESBL-producing K. pneumoniae , AmpC-derepressed E. cloacae , and Ps. aeruginosa ;22 there was no evidence of antagonism between the drugs.1,22

Other Anti-infectives

To date, there has been no in vitro evidence of antagonism between ceftaroline and azithromycin, daptomycin, levofloxacin, linezolid, tigecycline, or vancomycin.1

Warfarin

Increased prothrombin time (PT) and elevated international normalized ratio (INR) have been reported when ceftaroline fosamil was initiated in a patient receiving a stable warfarin dosage.35

Mechanism of Action

Ceftaroline usually is bactericidal in action.1,4,17,22 Like other cephalosporins, the antibacterial activity of the drug results from inhibition of mucopeptide synthesis in the bacterial cell wall.1 For information on the mechanism of action of cephalosporins, see Mechanism of Action in the Cephalosporins General Statement 8:12.06.

Studies evaluating the binding of ceftaroline to penicillin-binding proteins (PBPs), the target enzymes of β-lactam antibiotics, indicate that ceftaroline has high affinity for PBPs 1, 2, 2a, and 3 of Staphylococcus aureus .4,24,26 High affinity for PBP2a appears to be associated with bactericidal activity against methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus , ORSA).1,4,24,26 Ceftaroline also has high affinity for PBPs 1a, 1b, 2a, 2b, 2x, and 3 of Streptococcus pneumoniae .1,24,26 Penicillin resistance in S. pneumoniae appears to involve PBP 2b, 2x, and 1a.24

For most susceptible bacteria, the minimum bactericidal concentration (MBC) of ceftaroline is only 1-4 times higher than the minimum inhibitory concentration (MIC).4,17

Spectrum

Based on its spectrum of activity, ceftaroline is classified as a fifth generation cephalosporin.5,6,7,8,27 For information on the classification of cephalosporins and closely related β-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.

Like third and fourth generation cephalosporins, fifth generation cephalosporins have an expanded spectrum of activity that includes both gram-positive and gram-negative bacteria.4,5,6,7,17,21,27 However, unlike first, second, third, and fourth generation cephalosporins, fifth generation cephalosporins have activity against methicillin-resistant Staphylococcus aureus (MRSA; also known as oxacillin-resistant S. aureus , ORSA).4,5,6,7,17,27

In Vitro Susceptibility Testing

For information on interpreting results of in vitro susceptibility testing (disk susceptibility tests, dilution susceptibility tests) when ceftaroline susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), see Spectrum: In Vitro Susceptibility Testing, in the Cephalosporins General Statement 8:12.06.

Gram-positive Aerobic Bacteria

Ceftaroline is active in vitro against S. aureus , including MRSA, vancomycin-resistant S. aureus [VRSA], and daptomycin-nonsusceptible S. aureus .4,17,21,24,27 The drug also is active in vitro against coagulase-negative staphylococci (e.g., S. epidermidis ), including methicillin-resistant (oxacillin-resistant) strains.4,21,27 The MIC₉₀ of ceftaroline reported for methicillin-susceptible (oxacillin-susceptible) S. aureus is 0.25 mcg/mL,4,21,37,41,42 and the MIC₉₀ of the drug reported for MRSA is 1-2 mcg/mL.4,17,21,37,39,41,42

Ceftaroline is active in vitro against Streptococcus pneumoniae , including penicillin-resistant S. pneumoniae and multidrug-resistant S. pneumoniae (MDRSP).1,4,18,19,20,21,24,27 The MIC₉₀ of the drug is 0.015-0.12 mcg/mL for penicillin-susceptible S. pneumoniae and 0.12-0.25 mcg/mL for penicillin-resistant and multidrug-resistant strains.4,18,20,21,27

Ceftaroline is active in vitro against S. pyogenes (group A β-hemolytic streptococci, GAS),1,4,21,27,42 S. agalactiae (group B streptococci, GBS),1,21,27,42 viridans streptococci,4,21,27 and S. dysgalactiae .1,42 The MIC₉₀ of the drug reported for S. pyogenes and S. agalactiae is 0.03 mcg/mL or less.4,21,27,42

Ceftaroline has only limited activity against Enterococcus .4,21 Some strains of Enterococcus faecalis are inhibited in vitro by ceftaroline concentrations of 2-4 mcg/mL, but E. faecium are resistant to the drug.21

Gram-negative Aerobic Bacteria

Ceftaroline is active in vitro against many Enterobacteriaceae, including some Citrobacter freundii ,1,21,27,42 C. koseri ,1 Enterobacter aerogenes ,1,27,42 E. cloacae ,1,21,27,42 Escherichia coli ,1,21,27,42 Klebsiella pneumoniae ,1,21,27,42 K. oxytoca ,1,42 Morganella morganii ,1,21,42 and Proteus mirabilis .1,21,27,42 The MIC₉₀ of ceftaroline for most susceptible Enterobacteriaceae is 0.25-1 mcg/mL.4,21,27 However, the MIC₉₀ of the drug has been reported to be 4 mcg/mL or higher for many Enterobacteriaceae, including P. mirabilis ,4,21,42 C. freundii (ceftazidime-nonsusceptible strains),4,21,42 M. morganii ,4,21,42 and Serratia .4,21 Providencia and Acinetobacter usually are resistant.21 The activity of ceftaroline against gram-negative bacteria is similar to that reported with third generation cephalosporins.4,27 Ceftaroline is not active against Enterobacteriaceae that produce extended-spectrum β-lactamases (ESBL-producing), AmpC cephalosporinases, metallo-β-lactamases, or serine carbapenemases.1,4,21,27

Ceftaroline is active in vitro against β-lactamase-producing and non-β-lactamase-producing Haemophilus influenzae ,1,4,21,27 H. parainfluenzae ,1 and Moraxella catarrhalis ,1,4,21,27 and the MIC₉₀ reported for most of these organisms is 0.015-0.25 mcg/mL.4,21 The MIC₉₀ of ceftaroline reported for Neisseria gonorrhoeae and N. meningitidis is 0.004-0.25 mcg/mL.4,27

The MIC₉₀ of ceftaroline reported for Pasteurella multocida is 0.06 mcg/mL.21 In vitro studies indicate that Acinetobacter is resistant to ceftaroline.21

Ceftaroline is not active against Pseudomonas aeruginosa .4,27

Anaerobic Bacteria

Ceftaroline has some in vitro activity against anaerobic bacteria.23 The MIC₉₀ of ceftaroline reported for some gram-positive anaerobic bacteria, including Actinomyces , Eubacterium , Lactobacillus , Clostridium , Peptostreptococcus , and Propionibacterium , has been 0.06-4 mcg/mL.23 The MIC₉₀ of ceftaroline reported for some gram-negative anaerobic bacteria, including Fusobacterium , Porphyromonas , and Veillonella , has been 0.03-0.5 mcg/mL.23 In vitro studies indicate that Bacteroides and Prevotella are resistant to ceftaroline.4,23,27

Resistance

Methicillin-resistant Staphylococcus aureus (MRSA; also known as oxacillin-resistant S. aureus , ORSA) with reduced susceptibility or resistance to ceftaroline have been produced in vitro40 and have been reported in clinical isolates.37,38,39,41 Although resistance to ceftaroline in MRSA generally is associated with modifications in the mec A-encoded penicillin-binding protein 2a (PBP2a), other mechanisms of resistance may also be involved.37,38,40,41

Gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs) from the TEM, SHV or CTX-M families, AmpC cephalosporinases, class B metallo-β-lactamases, or serine carbapenemases (such as KPC) are resistant to ceftaroline.1,4,21,27

Although cross-resistance may occur between ceftaroline and other cephalosporins, some bacteria resistant to other cephalosporins may be susceptible to ceftaroline.1

Pharmacokinetics

Absorption

Ceftaroline is administered as ceftaroline fosamil, a prodrug that is inactive until converted in vivo to ceftaroline by a plasma phosphatase.1,4

Peak plasma concentrations and area under the concentration-time curve (AUC) of ceftaroline in healthy adults increase approximately in proportion to dose following single IV doses of 50-1000 mg of ceftaroline fosamil.1

There is no appreciable accumulation of ceftaroline when 600-mg doses of ceftaroline fosamil are given by IV infusion over 1 hour every 12 hours for up to 14 days in adults with normal renal function.1

In healthy adults receiving ceftaroline fosamil in a dosage of 600 mg given by IV infusion over 1 hour every 12 hours for 14 days, peak plasma concentrations of ceftaroline average 21.3 mcg/mL and the median time to peak plasma concentrations is 0.9 hours.1

When 600-mg doses of ceftaroline fosamil in 50 mL of compatible infusion solution were given by IV infusion over 5 or 60 minutes every 8 hours for 5 days in healthy adults, mean peak plasma concentrations of ceftaroline were 32.5 mcg/mL after the 5-minute infusions and 17.4 mcg/mL after the 60-minute infusion;1 the time to peak plasma concentrations (about 5 minutes after the end of the infusion) and AUC were similar for both infusion rates.1

In healthy adolescents 12-17 years of age, peak plasma concentrations and AUC after a single 8-mg/kg IV dose (600 mg in those weighing more than 75 kg) are 10 and 23% lower, respectively, compared with healthy adults who received a single 600-mg IV dose.1

Distribution

The steady-state volume of distribution of ceftaroline in healthy adults following a single 600-mg IV dose of ceftaroline fosamil is 20.3 L and is similar to extracellular fluid volume.1

Ceftaroline is approximately 20% bound to plasma proteins.1 Protein binding decreases slightly with increasing ceftaroline concentrations exceeding 1-50 mcg/mL.1

Limited data are available regarding tissue distribution of ceftaroline; animal data indicate that the drug is distributed into kidneys, skin, and lungs.4,9

It is not known whether ceftaroline is distributed into milk.1

Elimination

Ceftaroline fosamil is rapidly converted in vivo to ceftaroline by a plasma phosphatase, principally during IV infusion.1,4 In addition, the β-lactam ring of ceftaroline is hydrolyzed to an inactive, open-ring metabolite (ceftaroline M-1).1

Ceftaroline is not a substrate of cytochrome P-450 (CYP) isoenzymes.1

Ceftaroline and its metabolites are principally eliminated in urine by glomerular filtration.1 Following a single 600-mg IV dose of ceftaroline fosamil, approximately 88% is eliminated in urine (approximately 64% as unchanged drug and 2% as ceftaroline M-1) and 6% is eliminated in feces within 48 hours.1

The terminal elimination half-life of ceftaroline is 2.7 hours in healthy adults receiving ceftaroline fosamil in a dosage of 600 mg given by IV infusion over 1 hour every 12 hours for 14 days.1 When 600-mg doses of ceftaroline fosamil in 50 mL of compatible infusion solution were given by IV infusion over 5 or 60 minutes every 8 hours for 5 days in healthy adults, the terminal elimination half-life of ceftaroline was similar for both infusion rates.1

The pharmacokinetics of ceftaroline in pediatric patients 2 months to less than 18 years of age are similar to the pharmacokinetics reported in adults.1

The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established.1

In adults with renal impairment, the AUC and plasma half-life of ceftaroline are increased.1,4

Ceftaroline is removed by hemodialysis.1 In adults with end-stage renal disease who received 400 mg of ceftaroline fosamil, 76.5 mg of the drug (approximately 21.6% of the dose) was recovered in the dialysate following a 4-hour hemodialysis session started 4 hours after the dose.1

Chemistry and Stability

Chemistry

Ceftaroline is a semisynthetic cephalosporin antibiotic.1,4 Ceftaroline is structurally similar to parenteral third and fourth generation cephalosporins (e.g., cefepime, cefotaxime, ceftazidime, ceftriaxone).4 Like many third and fourth generation drugs, ceftaroline contains a 1,2,4-thiadiazole ring that enhances antibacterial activity against gram-negative bacteria and an oxime group that contributes to stability in the presence of β-lactamases.4 Unlike other commercially available cephalosporins, ceftaroline contains a 1,3-thiazole ring linked to the 3-position of the cephem ring by a sulfur which appears to contribute to activity against methicillin-resistant Staphylococcus aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA).4

Ceftaroline is commercially available for parenteral use as ceftaroline fosamil monoacetate monohydrate;1 potency is expressed in terms of anhydrous ceftaroline fosamil.1 Ceftaroline fosamil is a prodrug that is inactive until converted in vivo to ceftaroline by a plasma phosphatase.1,4 Commercially available ceftaroline fosamil powder for IV infusion is a pale yellowish-white to light yellow powder.1 Each vial of the drug also contains l-arginine as an excipient.1,9 When reconstituted as directed, ceftaroline fosamil solutions have a pH of 4.8-6.5.1 Depending on the concentration and storage conditions, ceftaroline fosamil solutions are clear, light to dark yellow.1

Stability

Ceftaroline fosamil powder for IV infusion should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1

Following reconstitution and dilution, ceftaroline fosamil solutions in IV infusion bags should be used within 6 hours when stored at room temperature or within 24 hours when refrigerated at 2-8°C.1 Stability testing indicates that ceftaroline fosamil solutions containing 4-12 mg/mL diluted in 50- or 100-mL infusion bags containing 0.9% sodium chloride (Baxter Mini-Bag Plus containers) may be stored for up to 6 hours at room temperature or for up to 24 hours at 2-8°C.1,36

Additional Information

For further information on chemistry, mechanism of action, spectrum, resistance, uses, cautions, acute toxicity, drug interactions, or laboratory test interferences of cephalosporins, see the Cephalosporins General Statement 8:12.06.

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