Ceftaroline: A novel cephalosporin with methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae activity

Key Points

Abstract

Resistant Gram-positive infections present serious challenges to patients and providers who care for them. Ceftaroline is a novel advanced-generation cephalosporin with a broad spectrum of activity against many pathogens. Recently, ceftaroline was approved by FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) and community-acquired bacterial pneumonia (CABP). Like other cephalosporins, ceftaroline has predictable pharmacokinetics and is primarily renally excreted, increasing the ease of dosing. Ceftaroline has demonstrated activity against methicillin-resistant Staphylococcus aureus and multidrug-resistant Streptococcus pneumoniae as well as common respiratory Gram-negatives including Haemophilus, Moraxella, and Klebsiella species. During clinical trials, ceftaroline demonstrated noninferiority to vancomycin plus aztreonam for the treatment of complicated skin and skin structure infections (now called ABSSSIs) and ceftriaxone for the treatment of CABP. Ceftaroline was well tolerated in clinical trials with gastrointestinal side effects being the most common adverse event. Ceftaroline's unique spectrum of activity and ease of dosing based on renal function make it a unique addition to the clinician's armamentarium. (Formulary. 2011;46:71–81.)

The prevalence of highly resistant infections, particularly among Gram-positive organisms, continues to increase nationally. Gram-positive organisms are common causes of hospital-acquired and community-acquired infections including acute bacterial skin and skin structure infections (ABSSSIs), pneumonia, and bloodstream infections. The high prevalence of resistant Gram-positive infections raises concern for the availability and need for effective antimicrobial therapy.

Community-acquired bacterial pneumonia (CABP) is most commonly caused by Streptococcus pneumoniae, followed by nontypeable Haemophilus influenzae and Moraxella catarrhalis.⁴ Reports have been increasing about multidrug-resistant S. pneumoniae (MDRSP) infections. Currently, 20% of isolates obtained are multidrug resistant and macrolide resistance has exceeded 35%.^5-6 Multidrug resistance among S. pneumoniae isolates is also of concern. The Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) surveillance study observed that for penicillin-resistant isolates worldwide, coresistance to macrolides was present 72% to 75% of the time.⁷ After the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in 2000, "replacement" serotypes have increased in prevalence, most notably serotype 19A.⁷ It is unknown what will happen to these "replacement" serotypes now that PCV7 has been replaced by a 13-valent vaccine covering the 7 previous serotypes and 1, 3, 5, 6A, 7F, and 19A, as approved by FDA on February 24, 2010.^7,8

Ceftaroline fosamil (PPI-0903), a novel cephalosporin antibiotic with activity against Gram-positive organisms and many common Gram-negative organisms is the first broad-spectrum cephalosporin to target the methicillin-resistant phenotype of S. aureus and MDRSP. A new drug application (NDA) for ceftaroline was submitted to FDA on December 29, 2009, by Cerexa, Inc., a subsidiary of Forest Pharmaceuticals. The drug was approved on October 29, 2010, for the treatment of CABP and for ABSSSIs, formerly known as complicated skin and skin structure infections (cSSSIs).⁹

CHEMISTRY AND PHARMACOLOGY

PHARMACOKINETICS

A double-blind, placebo-controlled multiple-ascending dose study utilizing 3 cohorts (300 mg IV q12h, 600 mg IV q12h, and 800 mg IV q24h) found no accumulation of drug over 14 days for the first 2 cohorts and no accumulation after 7 days in the third cohort.¹³ Ceftaroline is excreted primarily in the urine.¹⁵ Half-life of the drug ranged from 2 hours to 2.5 hours.¹³ In a phase 1 study designed to assess ceftaroline pharmacokinetics in renal impairment, the area under the concentration time curve (AUC) was not affected in mild renal impairment (creatinine clearance [CrCl] 51-80 mL/min) but was almost double when comparing moderate renal impairment (CrCl 31-50 mL/min) to normal renal function (CrCl ≥80 mL/min).¹⁴ Half-life also increased in patients with moderate renal impairment, and the total clearance of the drug decreased as renal function decreased.

Intramuscular (IM) administration has been studied as an alternative route of administering the drug. Compared to IV infusion, the IM injection in laboratory animals provided higher AUC, longer half-life, and a lower maximum concentration in serum (C_max).¹⁷ IM administration in humans produced similar AUC, a longer half-life, and lower C_max when compared to IV infusion.¹⁸ After multiple 600-mg IM injections every 12 hours, the AUC increased by 18% and provided time above the minimum inhibitory concentration (MIC) ranging from 64% to 99% over a range of MICs up to 2 μg/mL.¹⁸ Given the accumulation of drug over time and the favorable time above the MIC, IM administration of ceftaroline may be a suitable alternative route in patients with limited IV access.

SPECTRUM OF ACTIVITY

Ceftaroline also has excellent activity against many common respiratory Gram-negative organisms including Proteus, Morganella, Haemophilus, both non- β-lactamase and β-lactamase producing strains, and Moraxella species. The drug has activity against other Gram-negatives including Klebsiella pneumoniae, Escherichia coli, Citrobacter, Providencia, and Serratia marcescens.²⁰ This wide spectrum of activity becomes clinically relevant as the number of effective antimicrobials against Gram-negative pathogens decreases and the incidence of infections increases.²⁵ Ceftaroline does not have activity against extended-spectrum β-lactamase (ESBL)-producing or AmpC-overexpressing organisms, or Pseudomonas aeruginosa.^20,25,26 When tested in combination with other antibiotics, ceftaroline showed synergy with amikacin, meropenem, and aztreonam against 2 ESBL E. coli and 2 derepressed AmpC Enterobacter cloacae.²⁵ Additionally the compound has little activity against most Acinetobacter spp.²⁶

Anaerobic bacteria are common in many pulmonary infections including aspiration pneumonia, lung abscesses, and empyema.²⁷ Ceftaroline has excellent Gram-positive anaerobic and good activity including Porphyromonas asaccharolytica, Porphyromonas somerae, Fusobacterium spp., Veillonella spp., Finegoldia magna, Parvimonas micra, Actinomyces spp., Propionibacterium acnes, and Propionibacterium avidum.²⁷ There is poor activity against Bacteroides spp. and β-lactamase producing Prevotella isolates.²⁷

PHARMACODYNAMICS

Ceftaroline, like all other cephalosporins, exhibits time-dependent killing. The main pharmacodynamic parameter predicting efficacy for ceftaroline is the percentage of the dosing interval for which free drug concentrations remain above the MIC (%fT>MIC).²⁸ In general, cephalosporins require 30% to 40% and 50% to 70% fT>MIC to achieve bacteriostatic and bactericidal activity, respectively.^28-30 In a murine thigh and lung infection model, the mean %fT>MIC for a 2-log kill was reported for S. aureus (mean ± standard deviation) 45% ± 13%, S. pneumoniae at 50% ± 10%, and for Gram-negative organisms (E. coli and K. pneumoniae) at 54% ± 3%.²⁸

FDA has approved MIC breakpoints for common Gram-positive and Gram-negative organisms. S. aureus, including MRSA isolates from the skin only, with an MIC ≤1 are considered susceptible.⁹ S. pyogenes isolates obtained from the skin with MICs ≤0.015 are also considered susceptible. S. pneumoniae and H. influenzae isolates from the respiratory tract are considered susceptible if MICs are ≤0.25 and 0.12, respectively. Intermediate and resistant breakpoints have yet to be set. Breakpoints for Enterobacteriaceae including E. coli, K. pneumoniae, and Klebsiella oxytoca in both CABP and skin isolates are ≤0.5, 1, and ≥2, for susceptible, intermediate, and resistant, respectively.⁹

CLINICAL TRIALS

One phase 2, randomized, observer-blinded, multinational study was designed to compare the efficacy of ceftaroline to currently recommended therapy for cSSSI.³¹ Patients were included if they were 18 years of age or older, required hospitalization and IV antibiotics for an infection involving deeper soft tissue and/or large surgical intervention, or developed a lower extremity infection with comorbid diabetes mellitus or peripheral vascular disease. Exclusion criteria included β-lactam or vancomycin allergy, a history of red man syndrome or epilepsy, multiple doses of antibiotics 96 hours prior to randomization, suspected P. aeruginosa or anaerobic infection, decubitus ulcers, diabetic foot ulcers, burns, bites, necrotizing fasciitis, AIDS, any significant or life-threatening condition or disease, and pregnancy.³¹

The primary outcome of the study was clinical cure at the test-of-cure (TOC) visit in the clinical modified intent-to-treat (cMITT) population, defined as all subjects who received study drug, had a confirmed diagnosis of cSSSI, and were clinically evaluable (CE). Secondary outcomes included microbiologic cure at TOC visit and relapse at 21 to 28 days following treatment conclusion. Clinical cure was defined as a resolution of all signs and symptoms of the cSSSI or no further need for antimicrobial therapy due to improvement in the infection determined by the blinded investigator. Failure was defined as persistence, incomplete resolution, or worsening of signs and symptoms requiring further antibiotics; unplanned surgical intervention; new signs and symptoms associated with the original or new cSSSI at the same site; requirement of additional antibiotic therapy, or death caused by cSSSI.³¹

Patients were randomly assigned to ceftaroline 600 mg IV every 12 hours given by a 60-minute infusion or standard therapy (vancomycin 1 g IV every 12 hr) in a 2:1 fashion. Aztreonam was added (1 g every 8 hr) when Gram-negative infections were suspected in the standard therapy group. Treatment continued for a total of 7 to 14 days. Clinical assessment was performed daily throughout therapy, 8 to 14 days after the last study dose, and at 21 to 28 days after the last study dose.³¹

Study enrollment included 100 patients, 67 in the ceftaroline arm and 33 in the standard therapy arm. Age (41.6 vs 44 years), male gender (55.2% vs 59.4%), race/ethnicity, and infection type were all similar between each group. The most common infection types were major abscesses (44.8% vs 50%), and deep extensive cellulitis (34.3% vs 37.5%). The majority of bacteria isolated from patients were S. aureus or Streptococci. At the TOC visit, 96.7% of CE patients who received ceftaroline were defined as cured versus 88.9% in the standard therapy group. The cMITT clinical cure rates were 88.1% and 81.3% in the ceftaroline and standard therapy groups, respectively. Microbiologic cure rate for the ceftaroline group was 95.2% versus 85.7% for the standard therapy.³¹

Two phase 3 studies with identical designs and protocols were also performed with ceftaroline compared with standard therapy with vancomycin plus aztreonam in patients with cSSSI.³² Patients were eligible for inclusion if they had cSSSI requiring initial hospitalization or emergency department treatment, unless they could have outpatient antimicrobial therapy, and 5 days or more of IV antibiotics. Patients were randomly assigned to ceftaroline 600 mg IV every 12 hours or vancomycin 1 g every 12 hours adjusted to therapeutic concentrations plus aztreonam (for Gram-negative activity) in a 1:1 fashion. Patients were treated for a total of 5 to 14 days. The primary outcome was clinical cure rate in both the CE and modified intent-to-treat (MITT) populations.³²

At study conclusion, 693 patients received ceftaroline and 685 patients received standard therapy with vancomycin and aztreonam. Clinical cure rates among the CE groups were 91.6% for the ceftaroline arm and 92.7% for the standard therapy arm. The MITT groups demonstrated similar results with 85.9% and 85.5% cure rates in the ceftaroline and standard therapy arms, respectively. Adverse events and discontinuation of drug due to adverse effects were similar between treatment groups. The most common side effects for ceftaroline versus standard therapy group were nausea (5.9% vs 5.1%), headache (5.2% vs 4.5%), diarrhea (4.9% vs 3.8%), and pruritus (3.5% vs 8.2%).³²

Two other phase 3 trials were designed to assess the use of ceftaroline in patients with CABP.³³ These studies were randomized, double-blind, and multicenter, comparing the efficacy and safety of ceftaroline with ceftriaxone. Patients were included if they were hospitalized requiring IV antibiotics with moderate or severe CABP as defined by the Pneumonia Outcomes Research Trial (PORT) risk class III or IV. Patients were randomly assigned in a 1:1 fashion to receive either ceftaroline 600 mg IV every 12 hours by a 60-minute infusion or ceftriaxone 1 g IV every 24 hours for 5 to 7 days. Both arms received adjunctive clarithromycin 500 mg every 12 hours for 2 doses. The primary outcome was noninferiority in the clinical cure rate at the TOC visit for the CE and modified intent-to-treat efficacy (MITTE) groups. MITTE groups met all inclusion criteria, received drug, and had a PORT score of III or IV. CE patients met all the evaluability criteria. Secondary outcomes included microbiologic cure rates at TOC visit and safety.³³

Of the 1,228 patients who were randomly assigned and treated, 614 subjects were randomly assigned to each group. Baseline demographics including age (61 vs 61 years), male gender (62.4% vs 63.9%), comorbid conditions, and PORT classification score were all similar between the ceftaroline and ceftriaxone groups, respectively. Clinical cure rates in the MITTE were similar between each group, 82.6% for ceftaroline and 76.6% for ceftriaxone with a weighted treatment difference of 6% (95% CI, 1.4-10.7). In the CE groups, cure rates were 84.3% and 77.7% for each treatment group. Microbiologic cure rates were also similar between the treatment arms. Ceftaroline exhibited high cure rates (85.5%) against S. pneumoniae, the most common pathogen in CABP. Four MDRSP isolates were identified in the ceftaroline group, all of which were treated successfully, versus 9 identified in the ceftriaxone group, only 2 of which were treated to cure.³³

Overall, these phase 3 studies demonstrated noninferior efficacy against ceftriaxone. Ceftaroline had high efficacy against S. pneumoniae, particularly MDRSP, with minimal side effects limiting its use in clinical practice. When data from both trials were combined, a 6.7% higher clinical cure rate was seen with ceftaroline versus ceftriaxone in the CE group.³³

ADVERSE EVENTS

Multiple clinical studies have demonstrated ceftaroline is well tolerated with few adverse events.^31–33 The percentage of patients who discontinued study medication due to adverse events in combined results from 2 phase 3 trials was similar between ceftaroline and ceftriaxone at 4.4% and 4.1%, respectively.³³ Rates of adverse events were similar to other treatment arms including vancomycin and ceftriaxone. One study reported the following adverse events and their rate of incidence when ceftaroline was compared with vancomycin as increases in creatinine phosphokinase (7.5% vs 6.3%), elevated alanine aminotransferase (6% vs 12.5%), elevated aspartate transaminase (6% vs 9.4%), headache (6% vs 6.3%), insomnia (6% vs 6.3%), nausea (6% vs 0%), and rash (1.5% vs 6.3%).³¹

DRUG INTERACTIONS

Ceftaroline has a low probability of causing major drug-drug interactions. It is primarily eliminated renally and does not go through hepatic metabolism.¹⁵ There are currently no published drug-drug interaction studies or presentations related to ceftaroline.

DOSING AND ADMINISTRATION

The proposed dosing regimen for ceftaroline in patients with normal renal function (CrCl >80 mL/min) is 600 mg IV every 12 hours administered as a 60-minute infusion. This dose has been used in multiple clinical studies and proven to be noninferior compared with vancomycin in cSSSI and ceftriaxone for the treatment of CABP.^31–33 Ceftaroline is excreted renally, so dose adjustment is needed in patients with renal impairment. In patients with mild renal impairment (CrCl >50 to ≤80 mL/min) pharmacokinetic parameters did not change enough to warrant dose adjustment. Patients with moderate renal function (CrCl >30 to ≤50 mL/min) and severe renal function (CrCl >15 to ≤30 mL/min) should receive 400 mg IV every 12 hours and 300 mg IV every 12 hours, respectively, both as a 60-minute infusion due to the increase in AUC.^9,34 This decrease in dose still maintains the same simulated percent time above the MIC as a normal dose in a healthy volunteer.³⁴ Dosage adjustment is further needed in patients with end-stage renal disease (CrCl <15 mL/min), including those on hemodialysis. It is recommended that these patients receive 200 mg IV every 12 hours.^9,35 It is possible a dosage reduction and an increase in the interval between doses is needed as the AUC was 115% higher in patients with severe renal impairment and the half-life was extended to 5.05 hours (vs 3.02 hr) from subjects with normal renal function.³⁶

FORMULARY CONSIDERATIONS

Ceftaroline is a novel, advanced generation cephalosporin with unique activity against Gram-positive organisms (particularly MRSA and MDRSP) and many common respiratory Gram-negative pathogens. Ceftaroline follows predictable pharmacokinetics as an IV infusion as well as an IM injection. Clinical studies have demonstrated noninferiority to standard therapies (vancomycin/aztreonam) in the treatment of cSSSIs (now referred to as ABSSSIs) and ceftriaxone in the treatment of CABP. No drug interactions studies have been performed, but such results are expected to be similar to other cephalosporins in having minimal interactions. The convenience of twice-daily dosing combined with the unique coverage of multidrug-resistant Gram-positive pathogens make this first anti-MRSA β-lactam an attractive addition to our antibacterial armamentarium for the treatment of ABSSSIs and CABP.

Dr Housman is a fellow at the Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Conn. Dr Kuti is associate director, clinical and economic studies, the Center for Anti-Infective Research and Development, Hartford Hospital. Dr Nicolau is director at the Center for Anti-Infective Research and Development; and coordinator for research, Department of Medicine, Division of Infectious Diseases and Pharmacy, Hartford Hospital.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.

In each issue, the "Focus on" feature reviews a newly approved or investigational drug of interest to pharmacy and therapeutics committee members. The column is coordinated by Robert A. Quercia, MS, RPh, medical editor, Department of Pharmacy Services, University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and adjunct associate professor, University of Connecticut School of Pharmacy, Storrs, Conn; and by Craig I. Coleman, PharmD, associate professor of pharmacy practice, University of Connecticut School of Pharmacy, and director, Pharmacoeconomics and Outcomes Studies Group, Hartford Hospital.

EDITORS' NOTE: The clinical information provided in "Focus on" articles is as current as possible. Due to regularly emerging data on developmental or newly approved drug therapies, articles include information published or presented and available to the author up until the time of the manuscript submission.

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