CURRENT DRUG THERAPY CME EDUCATIONAL OBJECTIVE: Readers will understand ceftaroline’s place in therapy and optimize its use CREDIT RIANE J. GHAMRAWI, PharmD, BCPS ELIZABETH NEUNER, PharmD SUSAN J. REHM, MD Clinical Pharmacist Specialist, Adult Antimicrobial Infectious Diseases Clinical Specialist, Department of Infectious Disease, Cleveland Clinic; Stewardship Department of Pharmacy, Department of Pharmacy, Cleveland Clinic Clinical Assistant Professor, Cleveland Clinic Lerner University Hospitals Case Medical Center College of Medicine of Case Western Reserve University, Cleveland, OH Ceftaroline fosamil: A super-cephalosporin? ABSTRACT eftaroline fosamil (Teflaro), intro- C duced to the US market in October 2010, Ceftaroline is a broad-spectrum cephalosporin used to is the first beta-lactam agent with clinically treat infections caused by a variety of microorganisms, useful activity against methicillin-resistant including methicillin-resistant Staphylococcus aureus Staphylococcus aureus (MRSA). Currently, it is (MRSA) and multidrug-resistant Streptococcus pneu- approved by the US Food and Drug Admin- moniae. However, it is not active against Pseudomonas istration (FDA) to treat acute bacterial skin aeruginosa, Bacteroides fragilis, and carbapenem-resis- and skin-structure infections and community- tant Enterobacteriaceae. Its approved indications include acquired bacterial pneumonia caused by sus- community-acquired bacterial pneumonia and bacterial ceptible microorganisms. infections of skin and skin structures. It has also been In an era of increasing drug resistance and limited numbers of antimicrobials in the used off-label to treat osteomyelitis, endocarditis, and drug-production pipeline, ceftaroline is a step meningitis caused by ceftaroline-susceptible organisms. forward in fulfilling the Infectious Diseases KEY POINTS Society of America’s “10 × ’20 Initiative” to increase support for drug research and manu- Resistance of S aureus and S pneumoniae to multiple facturing, with the goal of producing 10 new antimicrobial drugs is on the rise, and new agents are antimicrobial drugs by the year 2020.1 Cef- urgently needed. taroline was the first of several antibiotics to receive FDA approval in response to this ini- Ceftaroline’s molecular structure was designed to provide tiative. It was followed by dalbavancin (May 2014), tedizolid phosphate (June 2014), orita- enhanced activity against MRSA and multidrug-resistant vancin (August 2014), ceftolozane-tazobactam S pneumoniae. (December 2014), and ceftazidime-avibactam (February 2015). These antibiotic agents are In clinical trials leading to its approval, ceftaroline was aimed at treating infections caused by drug- found to be at least as effective as ceftriaxone in treating resistant gram-positive and gram-negative community-acquired pneumonia and at least as effective microorganisms. It is important to understand as vancomycin plus aztreonam in treating acute bacterial and optimize the use of these new antibiotic skin and skin-structure infections. agents in order to decrease the risk of emerg- ing antibiotic resistance and superinfections (eg, Clostridium difficile infection) caused by The routine use of ceftaroline for these indications should antibiotic overuse or misuse. be balanced by its higher cost compared with ceftriaxone This article provides an overview of cef- or vancomycin. Ongoing studies should shed more light taroline’s mechanisms of action and resis- on its role in treatment. tance, spectrum of activity, pharmacokinetic properties, adverse effects, and current place in therapy. doi:10.3949/ccjm.82a.14105 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 82 • NUMBER 7 JULY 2015 437 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. CEFTAROLINE FOSAMIL ■ AN ERA OF MULTIDRUG-RESISTANT Streptococcus pneumoniae resistance: MICROORGANISMS A continuing problem Increasing rates of antimicrobial resistance The prevalence of drug resistance in S pneu- threaten the efficacy of antimicrobial drugs moniae has risen since the late 1990s. A 2013 in the daily practice of medicine. The World report from the SENTRY Antimicrobial Sur- veillance Program stated that almost 20% of S Health Organization has labeled antimicrobi- pneumoniae isolates were resistant to amoxicil- al resistance one of the three greatest threats lin-clavulanate, and similar trends have been to human health. Global efforts are under way observed for penicillin (14.8%) and ceftriax- to stimulate development of new antimicro- one (11.7%).6 bial agents and to decrease rates of antimicro- S pneumoniae resistance is acquired through bial resistance. modifications of the penicillin-binding pro- Staphylococcus aureus: teins, namely PBP1a, PBP2b, PBP2x, and, less A threat, even with vancomycin frequently, PBP2a. These modifications lead Between 1998 and 2005, S aureus was one to decreased binding affinity for most beta- 7 of the most common inpatient and outpa- lactams. tient isolates reported by clinical laboratories Clinical impact of multidrug-resistant 2 throughout the United States. S aureus and S pneumoniae Treatment of S aureus infection is compli- In 2011, the US Centers for Disease Control cated by a variety of resistance mechanisms and Prevention reported an estimated 80,000 that have evolved over time. In fact, the first severe MRSA infections and 11,000 MRSA- resistant isolate of S aureus emerged not long related deaths in the United States.8 In the after penicillin’s debut into clinical practice, same report, drug-resistant S pneumoniae was and now the majority of strains are resistant to estimated to be responsible for almost 1.2 mil- penicillin. lion illnesses and 7,000 deaths per year, lead- Methicillin was designed to overcome this ing to upwards of $96 million in related medi- Resistance beta-lactamase resistance and became the cal costs. treatment of choice for penicillin-resistant S While invasive drug-resistant S pneumoni- threatens aureus isolates. However, MRSA isolates soon ae infections usually affect patients at the ex- the efficacy emerged because of the organism’s acquisition tremes of age (under age 5 and over age 65), of penicillin-binding protein PBP2a via the of antimicrobial they have had a serious impact on patients of mecA gene, leading to decreased binding af- all ages.8 drugs in the finity of methicillin.3 In light of the increasing prevalence of daily practice Since then, several agents active against multidrug-resistant organisms, newer antimi- MRSA (vancomycin, daptomycin, linezolid, crobial agents with novel mechanisms of ac- of medicine tigecycline) have been introduced and con- tion are needed. tinue to be widely used. While vancomycin is considered the first-line option for a variety of ■ CEFTAROLINE: A BETA-LACTAM MRSA infections, its use has been threatened WITH ANTI-MRSA ACTIVITY because of the emergence of vancomycin-in- The cephalosporins, a class of beta-lactam an- termediate-resistant S aureus (VISA), S aureus tibiotics, were originally derived from the fun- strains displaying vancomycin heteroresis- gus Cephalosporium (now called Acremonium). tance (hVISA), and vancomycin-resistant S There are now many agents in this class, each aureus (VRSA) strains.4 containing a nucleus consisting of a beta- VISA and hVISA isolates emerged through lactam ring fused to a six-member dihydro- sequential mutations that lead to autolytic ac- thiazine ring, and two side chains that can be tivity and cell-wall thickening. In contrast, modified to affect antibacterial activity and the mechanism of resistance in VRSA is by pharmacokinetic properties. acquisition of the vanA resistance gene, which Cephalosporins are typically categorized alters the binding site of vancomycin from d- into “generations.” With some exceptions, the alanine-d-alanine to d-alanine-d-lactate.5 first- and second-generation agents have good 438 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 82 • NUMBER 7 JULY 2015 Downloaded from www.ccjm.org on September 29, 2021. For personal use only. All other uses require permission. GHAMRAWI AND COLLEAGUES TABLE 1 Antimicrobial activity of ceftaroline fosamil Organism MIC50 (µg/mL) MIC90 (µg/mL) Range Staphylococcus aureus Methicillin-sensitive 0.25 0.25 ≤ 0.03–1 Methicillin-resistant 0.5 1.0 0.12–2 Vancomycin-intermediate 0.5 1.0 0.25–1 Daptomycin-nonsusceptible 0.5 0.55 0.25–1 Coagulase-negative staphylococci Oxacillin-susceptible 0.06 0.12 ≤ 0.03–0.5 Oxacillin-resistant 0.5 0.5 0.06–2 Streptococcus pneumoniae Penicillin-sensitive ≤ 0.008 0.015 ≤ 0.008–0.12 Penicillin-intermediate 0.015 0.06 ≤ 0.008–0.5 Penicillin-resistant 0.12 0.12 ≤ 0.008–0.5 Enterobacteriaceae Ceftazidime-susceptible 0.06 1.0 ≤ 0.03– >16 Ceftazidime-resistant > 16 >16 0.12– >16 MIC50 = the minimum concentration that will inhibit the growth of 50% of organisms MIC90 = the minimum concentration that will inhibit the growth of 90% of organisms Information from references 10–13. activity against gram-positive microorgan- with high affinity to PBP2a and PBP2x, ex- Methicillin isms, including methicillin-susceptible S au- panding its activity to encompass MRSA and reus—but not against MRSA. The third- and penicillin-resistant S pneumoniae isolates.9 was designed fourth-generation cephalosporins have better to overcome gram-negative activity, with many agents hav- Spectrum of activity Ceftaroline has in vitro activity against many beta-lactamase ing activity against the gram-negative bacte- 10–13 rium Pseudomonas aeruginosa. gram-positive and gram-negative