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Home , Aztreonam, Cefepime, Cefoxitin, Ceftaroline fosamil, Ceftazidime, Ceftriaxone

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-?

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 caused by a variety of microorganisms, useful activity against -resistant including methicillin-resistant aureus (MRSA). Currently, it is (MRSA) and multidrug-resistant 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, fragilis, and -resis- and skin-structure infections and community- tant Enterobacteriaceae. Its approved indications include acquired bacterial 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 , , and drug-production pipeline, ceftaroline is a step 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 to receive FDA approval in response to this ini- Ceftaroline’s molecular structure was designed to provide tiative. It was followed by (May 2014), tedizolid phosphate (June 2014), orita- enhanced activity against MRSA and multidrug-resistant vancin (August 2014), ceftolozane- S pneumoniae. (December 2014), and - (February 2015). These 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 in treating resistant gram-positive and gram-negative community-acquired pneumonia and at least as effective microorganisms. It is important to understand as plus 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 (eg, difficile ) 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

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■■ AN ERA OF MULTIDRUG-RESISTANT resistance: MICROORGANISMS A continuing problem Increasing rates of 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 (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 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, , , crobial agents with novel mechanisms of ac- of medicine ) 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 , 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

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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 -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 . gram-positive and gram-negative , resistance Enterococcal isolates are intrinsically resis- including (Table 1): in S aureus, tant to cephalosporins. Additionally, cephalo- • Methicillin-susceptible and methicillin- sporins are not active against anaerobic bacte- resistant staphylococci but MRSA quickly • VISA, VRSA, and hVISA ria, except for a subset of structurally unique emerged second-generation cephalosporins, ie, cefo- • Daptomycin-nonsusceptible S aureus tetan and . • Streptococcal species, including penicil- Ceftaroline was synthesized with specific lin-resistant S pneumoniae manipulations of the side chains to provide • Enterobacteriaceae, including enhanced activity against MRSA and multi- pneumoniae, Klebsiella oxytoca, Escherichia drug-resistant S pneumoniae isolates, making it coli, koseri, Citrobacter freun- the first available beta-lactam with this ability. dii, cloacae, Enterobacter aero- genes, Moraxella catarrhalis, Morganella Mechanism of action morganii, and mirabilis. Ceftaroline binds to penicillin-binding pro- Of note, ceftaroline is not active against teins, inhibiting transpeptidation. This inter- Pseudomonas species, species, or action blocks the final stage of . In addition, it is not active synthesis and inhibits bacterial for- against the “atypical” respiratory pathogens mation, ultimately leading to cellular autolysis Mycoplasma pneumoniae, Chlamydophila pneu- and microorganism death. Ceftaroline binds moniae, and Legionella pneumophila.

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to make it a substrate, inhibitor, or inducer of TABLE 2 the CYP450 system and therefore is Pharmacokinetic profile of ceftaroline fosamil not likely to cause notable CYP450-related drug-drug interactions. Maximum concentration: 27.94 ± 4.34 µg/mL a Like most other beta-lactams, ceftaroline Time to maximum plasma concentration: 1 hour is primarily excreted by the kidneys. Further- more, an estimated 21% of a dose is elimi- Volume of distribution: 20.3 L nated with each intermittent Protein binding: 20% session. Therefore, renal and intermittent hemodialysis dose adjustments are necessary. : No hepatic metabolism; rapidly converted to The estimated elimination half-life is 2.6 active drug, ceftaroline, by plasma phosphatase hours, necessitating dosing two to three times Half-life: 2.6 hours daily, depending on the indication and infec- tious inoculum. : 88% renal, 6% fecal Ceftaroline dosing a After a 600-mg dose (multiple dose and single dose). Ceftaroline is available only in a parenteral Information from references 16 and 17. preparation and is typically given at a dose of 600 mg every 12 hours.10 The intravenous in- Ceftaroline resistance fusion is given over 1 hour. Gram-negative organisms appear to develop The current stability data require recon- resistance to ceftaroline at rates similar to stituted ceftaroline to be used within 6 hours those observed with the other oxyimino-ceph- at room temperature and within 24 hours if alosporins (eg, ceftriaxone). Ceftaroline is in- refrigerated.10 active against gram-negative organisms pro- Ceftaroline requires dosing adjustments ducing extended-spectrum beta-lactamases, for patients with renal insufficiency. Per the including K pneumoniae carbapenemase and manufacturer, renal dosing adjustments are Ceftaroline metallo-beta-lactamases.14 In addition, it in- based on the clearance rate, as esti- fosamil is duces the expression of AmpC beta-lacta- mated by the Cockroft-Gault formula: mases. • Creatinine clearance > 50 mL/min: no typically given Although currently uncommon, resistance dosage adjustment necessary in 600-mg to ceftaroline has also been reported in S au- • Creatinine clearance > 30 to ≤ 50 mL/min: 15 IV doses reus strains. The mechanism of resistance is give 400 mg every 12 hours decreased binding affinity for PBP2a due to • Creatinine clearance ≥ 15 to ≤ 30 mL/min: every 12 hours substitutions on the nonpenicil- give 300 mg every 12 hours lin-binding domains.15 • Creatinine clearance < 15 mL/min or on intermittent dialysis: give 200 mg every 12 Pharmacokinetic profile hours. An understanding of is key Ongoing clinical trials are investigating in optimizing the dose of antimicrobials so a higher-dosing strategy of 600 mg every 8 that the drugs are used most effectively and hours for patients with community-acquired pathogens do not develop resistance to them. bacterial pneumonia at risk of MRSA bacte- Ceftaroline fosamil is a prodrug that, upon 18 intravenous administration, is rapidly con- remia. verted by phosphatase enzymes to its active ■■ CLINICAL TRIALS LEADING moiety, ceftaroline. Its pharmacokinetic pro- file is summarized in Table 2.16,17 Its volume TO CEFTAROLINE’S APPROVAL of distribution is similar to that of the fourth- Ceftaroline was approved for the treatment generation cephalosporin . of community-acquired bacterial pneumonia Ceftaroline is then hydrolyzed into its inac- and acute bacterial skin and skin-structure in- tive metabolite, ceftaroline M-1. It undergoes fections due to susceptible pathogens on the little hepatic metabolism and lacks properties basis of phase 3 comparator trials.

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Community-acquired bacterial pneumonia: The FOCUS 1 and 2 trials TABLE 3 The efficacy and safety of ceftaroline in the Ceftaroline: Clinical cure rates treatment of community-acquired bacterial in community-acquired pneumonia pneumonia was studied in two randomized, double-blind, noninferiority trials, known as Ceftaroline Ceftriaxone Ceftaroline Community-acquired Pneumonia Trial % a % a 19,20 vs Ceftriaxone (FOCUS) 1 and FOCUS 2. FOCUS 119 83.8 77.7 Patients were adults and not critically ill, as was reflected by their being in Pneumonia FOCUS 220 81.3 75.5

Outcomes Research Team (PORT) risk class 21 b III or IV (with class V indicating the high- Integrated analysis 82.6 76.6 est risk of death). Therefore, the results may a Modified intent-to-treat analysis, based on “test-of-cure” assessment conducted 8–15 not be completely applicable to critically ill days after last dose. patients or those not admitted to the hospital. b Statistically significant difference compared with ceftriaxone.

Of note, patients were excluded from the trials FOCUS = Ceftaroline Community-acquired Pneumonia vs Ceftriaxone trial if they had infections known or thought to be due to MRSA or to atypical organisms.21 Base- line characteristics and patient demographics were similar between study groups in both tri- two randomized, double-blind trials: Ceftaro- als. line Versus Vancomycin in Skin and Skin A bacterial pathogen was identified in Structure Infections (CANVAS) 1 and CAN- 26.1% of the patients included in the modified VAS 2.23,24 intent-to-treat analysis of the pooled data of Patients. Adult patients with a diagnosis the trials; the most common pathogens were of community-acquired skin and skin-struc- S pneumoniae, methicillin-sensitive S aureus, ture infections warranting at least 5 days of , K pneumoniae, and E intravenous antimicrobial therapy were in- 21 coli. cluded in the trials. Important protocol exclu- Adjust doses Treatment. Patients received either cef- sions were patients with diabetic foot ulcers, of ceftaroline taroline 600 mg every 12 hours (or a lower decubitus ulcers, burns, ulcers associated with dose based on renal function) or ceftriaxone 1 peripheral vascular disease accompanied by lower in g every 24 hours. In addition, in the FOCUS osteomyelitis, and suspected P aeruginosa in- patients with 1 trial, patients in both treatment groups re- 25 fections. This limits the external validity of renal ceived clarithromycin 500 mg every 12 hours ceftaroline use in the aforementioned exclud- 19 for the first day. ed patient populations. insufficiency Results. In both trials and in the inte- Patients in each treatment group of the grated analysis, ceftaroline was noninferior trials had similar demographic characteristics. 22 to ceftriaxone (Table 3). In the integrated The most common infections were cellulitis, analysis of both trials, compared with the cef- major abscess requiring surgical intervention, triaxone group, the ceftaroline group had a wound infection, and infected ulcer. Bacte- higher clinical cure rate among patients clas- remia was present in 4.2% of patients in the sified as PORT risk class III (86.8% vs 79.2%, ceftaroline group and in 3.8% of patients in weighted treatment difference 12.6%, 95% the vancomycin-aztreonam group. The most confidence interval [CI] 1.3–13.8) and among common pathogen was S aureus. Methicillin patients who had not received prior antibiotic resistance was present in 40% of the ceftaro- treatment (85.5% vs 74.9%, weighted treat- line group and 34% of the control group. 21 ment difference 11.2%, 95% CI 4.5–18.0). Treatment. Patients received either cef- Acute bacterial skin and skin-structure taroline 600 mg every 12 hours or the combi- infections: The CANVAS 1 and 2 trials nation of vancomycin 1 g plus aztreonam 1 g The efficacy and safety of ceftaroline in the given 12 hours, for 5 to 14 days. treatment of complicated acute bacterial skin Results. As assessed at a “test-of-cure” vis- and skin-structure infections was studied in it 8 to 15 days after the last dose of study medi-

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stream infection following ceftaroline therapy. TABLE 4 The dosage was 600 mg every 8 hours, which Ceftaroline: Clinical cure rates in acute is higher than in the manufacturer’s prescrib- bacterial skin and skin-structure infections ing information. Lin et al29 reported using ceftaroline in five Ceftaroline Vancomycin plus a a patients with either possible or probable endo- Study % aztreonam % carditis. Three of the five patients had clinical CANVAS 123 86.6 85.6 cure as defined by resolution or improvement CANVAS 224 85.1 85.5 of all signs and symptoms of infection, and not 29 Integrated analysis25 85.9 85.5 requiring further antimicrobial therapy. More data from clinical trials would be a Modified intent-to-treat analysis, based on “test-of-cure” assessment conducted 8–15 days after last dose. beneficial in defining ceftaroline’s role in treating endocarditis caused by susceptible CANVAS = Ceftaroline Versus Vancomycin in Skin and Skin Structure Infections trial microorganisms. Osteomyelitis In animal studies of osteomyelitis, ceftaroline cation, the efficacy of ceftaroline was similar exhibited activity against MRSA in infected to that of vancomycin-aztreonam, meeting bone and joint fluid. Compared with vanco- the set noninferiority goal (Table 4).25 More- mycin and linezolid, ceftaroline was associat- over, if assessed on day 2 or 3 (a new end point ed with more significant decreases in bacterial recommended by the FDA), the rate of cessa- load in the infected joint fluid, bone marrow, tion of spread and absence of fever and bone.30 was higher in the ceftaroline group than in Lin et al29 gave ceftaroline to two patients the vancomycin-aztreonam group.26 However, with bone and joint infections, both of whom this end point was not in the original trial pro- had received other therapies that had failed. tocol. The doses of ceftaroline were higher than Guidelines on those recommended in the prescribing infor- ■■ CEFTAROLINE FOR OTHER INDICATIONS community- mation; clinical cure was noted in both cases As noted, ceftaroline has been approved for following the switch. acquired treating community-acquired bacterial pneu- These data come from case series, and pneumonia are monia and acute bacterial skin and skin-struc- more study of ceftaroline’s role in the treat- ment of osteomyelitis infections is warranted. being updated ture infections. In addition, it has been used in several studies in animals, and case reports Meningitis of non-FDA approved indications including The use of ceftaroline in meningitis has been endocarditis and osteomyelitis have been pub- studied in rabbits. While ceftaroline penetrat- lished. Clinical trials are evaluating its use in ed into the in only neg- pediatric patients, as well as for community- ligible amounts in healthy rabbits (3% pen- acquired bacterial pneumonia with risk for etration), its penetration improved to 15% in MRSA and for MRSA bacteremia. animals with inflamed meninges. Ceftaroline Endocarditis cerebrospinal fluid levels in inflamed menin- Animal studies have demonstrated ceftaroline ges were sufficient to provide bactericidal ac- to have bactericidal activity against MRSA tivity against penicillin-sensitive and resistant and hVISA in endocarditis.27 S pneumoniae strains as well as K pneumoniae 31,32 A few case series have been published de- and E coli strains. scribing ceftaroline’s use as salvage therapy for persistent MRSA bacteremia and endocardi- ■■ REPORTED ADVERSE EFFECTS tis. For example, Ho et al28 reported using it OF CEFTAROLINE in three patients who had endocarditis as a Overall, ceftaroline was well tolerated in clin- source of their persistent bacteremia. All three ical trials, and its safety profile was similar to patients had resolution of their MRSA blood- those of the comparator agents (ceftriaxone

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and vancomycin-aztreonam). The guidelines on community-acquired As with the other cephalosporins, hyper- pneumonia have not been updated since 2007, sensitivity reactions have been reported with which was before ceftaroline was approved. ceftaroline. In the clinical trials, 3% of pa- However, these guidelines are currently un- tients developed a rash with ceftaroline.33,34 dergoing revision and may provide insight on Patients with a history of beta-lactam ceftaroline’s place in the treatment of commu- were excluded from the trials, so the rate of nity-acquired bacterial pneumonia.36 cross-reactivity with and with oth- Currently, ceftaroline’s routine use for er cephalosporins is unknown. these indications should be balanced by its In the phase 3 clinical trials, gastrointesti- higher cost ($150 for a 600-mg dose) com- nal side effects including (5%), nau- pared with ceftriaxone ($5 for a 1-g dose) or sea (4%), and (2%) were reported vancomycin ($25 for a 1-g dose). The drug’s in with ceftaroline. C difficile-associated diarrhea vitro activity against drug-resistant pneumo- has also been reported.33 cocci and S aureus, including MRSA, hVISA, As with other cephalosporins, ceftaro- and VISA may help fill an unmet need or pro- line can cause a false-positive result on the vide a safer and more tolerable alternative to Coombs test. Approximately 11% of ceftaro- currently available therapies. line-treated patients in phase 3 clinical trials However, ceftaroline’s lack of activity had a positive Coombs test, but hemolytic against P aeruginosa and carbapenem-resistant anemia did not occur in any patients.33,34 Enterobacteriaceae does not meet the pub- Discontinuation of ceftaroline due to an lic health threat needs stemming from these adverse reaction was reported in 2.7% of pa- multidrug-resistant microorganisms. Ongoing tients receiving the drug during phase 3 trials, clinical trials in patients with more serious compared with 3.7% with comparator agents. MRSA infections will provide important in- formation about ceftaroline’s role as an anti- ■■ WHEN SHOULD CEFTAROLINE BE USED MRSA agent. IN DAILY PRACTICE? While the discovery of antimicrobials Ceftaroline has been shown to be at least as ef- has had one of the greatest impacts on medi- fective as ceftriaxone in treating community-ac- cine, continued antibiotic use is threatened quired bacterial pneumonia, and at least as effec- by the emergence of drug-resistant patho- tive as vancomycin-aztreonam in treating acute gens. Therefore, it is as important as ever to bacterial skin and skin-structure infections. The be good stewards of our currently available 2014 Infectious Diseases Society of America’s antimicrobials. Developing usage and dosing guidelines for the diagnosis and management criteria for antimicrobials based on available of skin and soft-tissue infections recommend data and literature is a step forward in op- ceftaroline as an option for for timizing the use of antibiotics—a precious purulent skin and soft-tissue infections.35 medical resource. ■

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