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Clinical Therapeutics/Volume 34, Number 4, 2012

New Drug Review

Ceftaroline Fosamil: A Cephalosporin With Activity AgainstMethicillin-Resistant Staphylococcus Aureus

Henry Poon, PharmD, BCPS; Mei H. Chang, BA, PharmD, BCPS; andHoratio B. Fung, PharmD, BCPS

Pharmacy Service, James J. Peters Veterans Affairs Medical Center, Bronx, New York

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ABSTRACTBackground: Ceftaroline is a cephalosporin with ex-

panded gram-positive activity recently approved forclinical uses by the US Food and Drug Administration.

Objective: This article provides an overview of thein vitro and in vivo activities, mechanism of action,pharmacologic and pharmacokinetic properties, clini-cal efficacy, and tolerability of ceftaroline.

Methods: Relevant information was identifiedthrough a search of PubMed (1990–April 2011), EM-BASE (1990–April 2011), International Pharmaceuti-cal Abstracts (1970–April 2011), and Google Scholarusing the key words ceftaroline, PPI-0903, PPI-0903M, T-91825, and TAK-599. A review of the ref-erence lists of identified articles, a search of the USFood and Drug Administration Web site, and postersand abstracts from scientific meetings yielded addi-tional publications.

Results: In vitro, ceftaroline exhibits activity againstmost aerobic gram-positive isolates, common aerobicgram-negative respiratory pathogens, and some gram-positive anaerobes. The MIC range for most Staphylo-coccus aureus isolates, including vancomycin-resistanttrains was between �0.008 and 4 �g/mL. In Phase IIItudies (CANVAS 1 and CANVAS 2), ceftaroline wasound to be noninferior to vancomycin � aztreonamor the treatment of complicated skin and skin-struc-ure infections, with a clinical cure rate of 91.6%mong clinically evaluable patients (ceftaroline versusancomycin � aztreonam: difference, �1.1; 95% CI,

�4.2 to 2.0; P � NS). Ceftaroline’s efficacy has alsobeen assessed for the treatment of community-acquiredpneumonia in 2 Phase III studies (FOCUS 1 and FO-CUS 2) and was equivalent to ceftriaxone, with curerates of 84.3% and 77.7%, respectively, among clini-cally evaluable patients in the combined analysis (cef-
taroline versus ceftriaxone: difference, 6.7; 95% CI,
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1.6 to 11.8). The recommended dosage for patients 18years and older is 600 mg IV every 12 hours. Dosageadjustment is necessary in patients with renal impairment(creatinine clearance �50 mL/min). The pharmacoki-etic properties of ceftaroline in patients with hepatic im-airments are currently unavailable. Ceftaroline ap-eared to be well tolerated generally. The most frequently�3%) reported adverse events were nausea, headaches,iarrhea, pruritus, rash, and insomnia; all were usuallyild to moderate, self-limiting, and of little clinical

ignificance.Conclusions: Ceftaroline is a cephalosporin with

road gram-positive activity, including Methicillin-re-istant S aureus and vancomycin-resistant S aureus. Itsram-negative activity includes common respiratoryathogens and members of the Enterobacteriaceae.linical trials have reported that ceftaroline was non-

nferior to ceftriaxone, and vancomycin � aztreonamor the treatment of community-acquired pneumoniand complicated skin and skin-structure infections,espectively. (Clin Ther. 2012;34:743–765) Publishedy Elsevier HS Journals, Inc.

Key words: ceftaroline, cephalosporin, community-cquired pneumonia, methicillin-resistant Staphylo-occus aureus, skin and skin structure infections.

INTRODUCTIONTreatment of infections caused by drug-resistant gram-positive pathogens continues to pose a challenge as aresult of declines in the development of new antibacte-rial agents because of economic and societal barriers.1

Methicillin-resistant Staphylococcus aureus (MRSA)

Accepted for publication February 22, 2012.doi:10.1016/j.clinthera.2012.02.0250149-2918/$ - see front matter

Published by Elsevier HS Journals, Inc.

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Clinical Therapeutics

has increased in prevalence over time. Health-care–associated MRSA infections in intensive care units inthe United States increased from 2% in 1974 to 64% in2005.2 Between 2003 and 2004, community-associ-ated MRSA (CA-MRSA) accounted for 59.0% (349 of422) to 63.8% (30 of 47) of isolates in patients withbacterial skin and skin structure infections who pre-sented to the emergency department.3,4 In 2005, ap-roximately 20.2% (19,000 of 94,000) of the invasiveases of MRSA infections in the United States resultedn death.5 Drug-resistant Streptococcus pneumoniaeand Streptococcus agalactiae are also increasing inprevalence. Susceptibility testing of 1647 S pneu-moniae isolates from 41 medical centers in the UnitedStates in 2004�2005 indicated that 29.1% were resis-tant to erythromycin.6 The prevalence of erythromycinresistance was 40.0% among 1933 clinical isolates ofgroup B streptococci collected between 2005 and2006.7

A national survey in the United States conductedbetween 2001 and 2003 based on ambulatory-care vis-its for bacterial skin and skin-structure infections re-ported an incidence of 410.7 per 10,000 person-years,with more than half due to cellulitis and abscesses.8

The Infectious Diseases Society of America issued prac-tice guidelines for the diagnosis and management ofskin and skin-structure infections in 2005 and ad-dressed the need for empiric coverage of resistantstrains of bacteria in a variety of skin and soft tissueinfections.9 Clinicians should consider the possibilityof MRSA involvement in patients with established riskfactors for acquiring MRSA, including history of hos-pitalization, history of surgery, residence in a long-term care facility, and colonization with MRSA.4

Based on preliminary data for 2009 from the Na-tional Vital Statistics Reports, influenza and pneu-monia remain the eighth leading cause of death inthe United States.10 Community-acquired pneumo-

ia (CAP) is pneumonia occurring outside of a hos-ital setting or within 48 hours of hospitalization inatients with no prior association (within 14 days)ith any health-care–related facility. An estimated.6 million cases of CAP occur annually in thenited States.11 In a retrospective cohort study of

culture-positive pneumonia based on data collectedfrom 59 US hospitals between 2002 and 2003, Saureus accounted for 25.5% of CAP, with an MRSArate of 8.9%.12 In subsequent multivariate analysis,

positive culture for S aureus was found to be the

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nly factor that correlated with mortality. Although CA-RSA is more likely to be involved in complicated skin

nd skin-structure infections (cSSSIs), CA-MRSA pneu-onia is often fatal, with approximately 15 � higherortality than CA-MRSA SSSIs.13 In addition to MRSA,

he emergence of drug-resistant pneumococcal isolates islso acknowledged as a growing concern in the 2007uidelines for CAP in adults from the Infectious Diseasesociety of America and the American Thoracic Society.14

Clinical failure after treatment with cephalosporins, mac-rolides, or fluoroquinolones has been reported in infec-tions caused by drug-resistant pneumococcal isolates.14

Recent treatment (within the previous 3 months) withantibiotics is likely the most significant risk factor forpneumococcal resistance.14

Historically, MRSA were resistant to �-lactam an-ibiotics, including cephalosporins, because of a struc-ural change in the penicillin-binding protein resultingn a decreased affinity for these antibiotics.15 Vanco-mycin has been the preferred drug for the treatment ofMRSA infections. Nevertheless, a gradual increase inthe MIC among MRSA strains, a phenomenom re-ferred to as “MIC creep,” has been described in somestudies.16–21 The emergence of heteroresistant vanco-mycin-intermediate, vancomycin-intermediate, andvancomycin-resistant strains of S aureus further signalsthat resistance to vancomycin has evolved over time.

Ceftaroline is a cephalosporin with expanded gram-positive activity, including MRSA, that was approvedby the US Food and Drug Administration (FDA) onOctober 29, 2010 for the treatment of acute bacterialSSSIs and community-acquired bacterial pneumo-nia.22,23 Currently, it is the only FDA-approvedephalosporin with activity against multidrug-resis-ant strains of S aureus, including heteroresistantancomycin-intermediate S aureus (hVISA), andancomycin-resistant S aureus (VRSA).24,25 This ar-icle provides an overview of the in vitro and in vivoctivities, mechanism of action, pharmacologic andharmacokinetic properties, clinical efficacy, andolerability of ceftaroline.

METHODSRelevant information pertaining to ceftaroline wasidentified through a search of PubMed (1990–April2011), EMBASE (1990–April 2011), InternationalPharmaceutical Abstracts (1970–April 2011), andGoogle Scholar using the key words ceftaroline, PPI-
0903, PPI-0903M, T-91825, and TAK-599. Limits or
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inclusion and exclusion criteria were not applied inan attempt to retrieve all available information. Areview of the reference lists of identified articles anda search of the FDA Web site yielded additional pub-lications. Posters and abstracts from meetings of theInfectious Diseases Society of America, InterscienceConference on Antimicrobial Agents and Chemo-therapy, and the European Society of Clinical Micro-biology and Infectious Diseases from 2000 to 2010were also consulted.

RESULTSChemical Structure

Ceftaroline fosamil is an N-phosphono prodrug of cef-taroline (Figure).23,26 Ceftaroline is derived from cefozo-ran, a fourth-generation cephalosporin.26 As a free base,

ceftaroline lacks sufficient water solubility (2.3 mg/mL) dueto its zwitterionic properties. The prodrug was devel-oped with the chemical formula (6R,7R)-7-{(2Z)-2-(et-hoxyimino)-2-[5-(phosphonoamino)-1,2,4 thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin-1-ium-4-yl)-1,3-thiazol-2-yl]sulfanyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate monoacetate monohydrate.23 Its empirical for-mula and molecular weight are C22H21N8O8PS4 ·C2H4O2 · H2O and 762.75 daltons, respectively.23 The

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Ceftaroline

Figure. Structural formulas of ceftaroline fosamiland ceftaroline.23,26

-7 acyl moiety contains an alkoxyimino group on the side a

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hain that helps maintain affinity for penicillin-binding pro-ein (PBP) 2a, providing ceftaroline with in vitro activitygainst MRSA.26 The 2-thiazolythio spacer group on an-

other side chain further improves ceftaroline’s activityagainst MRSA.26

Mechanism of ActionSimilar to other �-lactam antibiotics, ceftaroline ex-

rts its effect by binding to PBPs on bacterial cell wallseading to irreversible inhibition of cell-wall synthe-is.26 In addition to the usual PBPs that most cephalo-porins inhibit, ceftaroline also inhibits PBP2a andBP2�.23,27,28 Ceftaroline efficiently forms the inhib-

tory acyl-enzyme intermediate with PBP2a in MRSAk2/Ks � 2.4 � 104 M�1s�1) and PBP2� in penicillin-

resistant S pneumoniae (k2/Ks � 1 � 106 M�1s�1)ith high affinity (MRSA, IC50 [concentration re-uired to inhibit 50% of the PBP] � 0.16 mg/L; Sneumoniae, IC50 � 0.17 mg/L).27,28

In Vitro ActivityThe in vitro activity of ceftaroline has been exam-

ined against clinical isolates worldwide using broth mi-crodilution and agar dilution tests performed accord-ing to the guidelines set forth by the Clinical andLaboratory Standards Institute.24,25,29–41 Ceftarolineexhibits activity against most aerobic gram-positiveisolates, common aerobic gram-negative respiratorypathogens, and some gram-positive anaerobes. Similarto some of older generations of cephalosporins, ceftaro-line is a weak inducer of AmpC �-lactamases when itstherapeutic concentrations fall below the MIC and is vul-nerable to extended-spectrum �-lactamases (ESBL).38,39

Susceptibility break points for ceftaroline have not beenrecommended by the FDA at the time of writing andofficial Clinical and Laboratory Standards Institute breakpoints are pending.

Gram-Positive OrganismsIn vitro activities of ceftaroline against 15,591

clinical isolates of gram-positive aerobic bacteriafrom all over the world, using broth microdilutionmethods, are summarized in Table I.24,25,29 –37 Be-cause ceftaroline was developed specifically for itsenhanced activity against MRSA,26 it was shown to

ave good activity against most of these isolates,ith MIC90 of �2 �g/mL (Table I). The MIC range

for all S aureus isolates, which included isolates ofRSA, VRSA, and daptomycin-nonsusceptible S

ureus, was between �0.008 and 4 �g/mL. Similarly,

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ceftaroline also displayed good activity against streptococciisolates (MIC range, �0.008�2 �g/mL for most isolateslisted), including multidrug-resistant (MDR) strains.Against Enterococcus faecalis, ceftaroline displayed mini-

al in vitro activity, and no activity at all toward En-erococcus faecium regardlesss of the susceptibilityrofiles.24,25,29–37

Gram-Negative OrganismsCeftaroline’s in vitro activity against aerobic

gram-negative pathogens were tested on 7747 differ-ent isolates from different laboratories, research fa-cilities, and hospitals (Table II).24,29,30,33 Ceftaro-ine showed good activity (MIC �0.5 �g/mL)

Table I. In vitro activity of ceftaroline against selecte

Organism No. of Is

Staphylococccus speciesMSSA24,29,30,33 496MRSA24,29,30,33 398CA-MRSA25,29,34 31HA-MRSA29 15hVISA and VISA24,25 12VRSA25 1MS-CoNS24,29,30,33 140Daptomycin NS S aureus25

Streptococcus speciesPCN S S pneumoniae24,29,30 44PCN I S pneumoniae24,30 15PCN R S pneumoniae24,29,30,37 37Cefotaxime R S pneumoniae37 12MDR S pneumoniae24,29,36 16�-hemolytic streptococci24,29,30,33 80Viridans group streptococci24,30,33 31

Enterococcus speciesVancomycin S E faecalis24,29,30,33 145Vancomycin R E faecalis24,30 4Vancomycin S E faecium29,33 27Vancomycin R E faecium24,30 47

CA-MRSA � community-associated MRSA; I � intermediatsistant vancomycin-intermediate S aureus; MDR S pneumoniaand trimethoprim-sulfamethoxazole; MRSA � methicillin-rnegative Staphylococcus; MSSA � methicillin-susceptible S asusceptible; VISA � vancomycin-intermediate S aureus; VRSA

against some of the common gram-negative respira- a

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tory pathogens (eg, Haemophilus influenzae,Moraxella catarrhalis, Neisseria meningitidis, andPasteurella multocida). However, it did not display clin-ically relevant activity against Pseudomonas aeruginosa,Stenotrophomonas maltophilia, or Acinetobacter bauman-nii (MIC90 �64 �g/mL). Ceftaroline also lacked activity forram-negative organisms with extended-spectrum �-lacta-

mases. Importantly, because ceftaroline appears to induceAmpC �-lactamases despite MIC values in susceptiblerange, ceftaroline theoretically should be avoided ingram-negative bacteria known to harbor inducibleAmpC �-lactamases (eg, Serratia, Proteus, Citrobac-er, Morganella, Enterobacter, Providencia, and P

-positive isolates.

s MIC90 (�g/mL) MIC Range (�g/mL)

0.5 �0.008 to 12 0.12 to 41 0.25 to 11 0.5 to 12 0.25 to 40.5 0.12 to 11 �0.008 to 40.55 0.25 to 1

�0.03 �0.008 to 0.250.06 �0.008 to 0.50.25 �0.008 to 0.50.5 0.125 to 20.25 �0.03 to 0.50.03 �0.008 to 0.060.25 �0.008 to 16

16 0.03 to �328 1 to 16

�64 0.25 to �64�32 0.06 to �32

MRSA � health-care–associated MRSA; hVISA � heterore-neumoniae resistant to penicillin, macrolides, lincosamides,

nt S aureus; MS-CoNS � methicillin-susceptible coagulaseNS � nonsusceptible; PCN � penicillin; R � resistant; S �ncomycin-resistant S aureus.

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Anaerobic OrganismsCeftaroline demonstrated good activity (MIC90

�0.5 �g/mL) against gram-positive anaerobes, exceptor Clostridium difficile, and poor activity (MIC90 �32

�g/mL) against gram-negative anaerobic pathogens, inparticular, Bacteroides fragilis.24,40,41 Results of the invitro studies are listed in Table III.24,40,41

PharmacokineticsThe penetration of ceftaroline into possible target

sites of infections has been examined in animal models.After the administration of a single intravenous dose ofceftaroline fosamil 20 mg/kg over 30 minutes in rab-bits, mean (SD) lung tissue and plasma Cmax (maxi-

Table II. In vitro activity of ceftaroline against selecte

Organism No. of Isolat

Acinetobacter baumannii24,29,30 59Citrobacter freundii24,30 50Enterobacter aerogenes29 33Enterobacter cloacae

ESBL–24,29,30 194ESBL�24,30 35

Escherichia coliESBL–24, 29, 30, 33 3661ESBL�24, 30 63

Haemophilus influenza�-lactamase–24,29,30 381�-lactamase�24,30 125

Klebsiella oxytoca29 96Klebsiella pneumonia

ESBL–24,29,30,33 1709ESBL�24,30 66

Moraxella catarrhalis24,30 118Morganella morganii24,30 34Neisseria meningitidis24 10Pasteurella multocida30 22Proteus mirabilis24,29,30,33 351Providencia species24,30 27Pseudomonas aeruginosa24,29 490Serratia marcescens24,29,30 134Stenotrophomonas maltophilia24,29 89

ESBL � extended spectrum �-lactamase.

mum observed concentration) levels taken after the y

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end of infusion were 18.7 (1.2) mg/kg lung and 41 (2.9)mg/L, respectively; penetration of ceftaroline into lungtissue was determined to be 42% (11.2%).43 In an-ther study using a rabbit model, Cottagnoud et alxamined the penetration of ceftaroline into the cere-ral spinal fluid (CSF).44 After intravenous administra-ion of ceftaroline fosamil 40 mg/kg, peak CSF concen-rations were 3.2 mg/L after the first dose and 3.8 mg/Lfter a second dose given 4 hours later. Peak serumevels were approximately 64 mg/L after both dosesnd the mean (SD) CSF penetration of ceftaroline intonflamed meninges was determined to be 14% (5.0%).

Ge et al conducted an ascending single-dose study in6 healthy adult male subjects (age range, 23.7�30.7

m-negative isolates.

MIC90 (�g/mL) MIC Range (�g/mL)

64 0.5 to �640.25 0.06 to 16

16 �0.12 to 32

32 �0.03 to �64�16 0.12 to �16

16 �0.008 to �64�16 2 to �16

�0.06 �0.008 to 10.03 �0.008 to 2

4 �0.12 to �64

�16 �0.008 to �64�16 1 to �16

0.25 �0.016 to 0.516 �0.03 to �16

�0.016 �0.0160.06 �0.008 to 0.064 �0.03 to �16

�16 �0.03 to �16�64 0.25 to �64

16 0.12 to �64�64 32 to �64

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line fosamil was administered 50�1000 mg IV over 60minutes.45 The Cmax and AUC increased proportion-tely with increasing dose. The authors also examinedequential ascending doses of ceftaroline fosamil ad-inistered 300�600 mg IV every 12 hours for 14 daysr 800 mg IV once daily for 7 days in 18 healthy adultale subjects (age range, 24.7�27.8 years; weight

ange, 80.0�83.8 kg).46 Ceftaroline had linear phar-macokinetics with minimal drug accumulation in theplasma (estimated ratio of AUC at steady state on day14 to AUC0�� at day 1 ranged from 0.95 to 1.01) withoth dosing intervals. The pharmacokinetic parame-ers of ceftaroline, administered at the FDA-approveddult dose of 600 mg every 12 hours (n � 6) are sum-

marized in Table IV.46 Based on population pharma-cokinetic analysis of data pooled from Phase I studies,ceftaroline follows a 2-compartment model with par-allel first-order (Klin � 0.342 h�1) and Michaelis-Men-ten (Vmax � 386 mg/h; km � 40.4 mg/L) eliminationathways.47

The mean plasma clearance of the prodrug was ap-proximately 5599 mL/min after single doses45 and themean elimination half-life (t½) after multiple dosingranged 0.15�0.29 hours,46 suggestive of rapid bio-ransformation in plasma to active ceftaroline.

Ceftaroline had low protein binding in plasma�20%) in an in vitro study conducted by Ge et alsing concentrations of ceftaroline ranging from 5 to50 mg/mL in human plasma proteins.48 The same

study also evaluated the stability of ceftaroline in vitroafter a 30-minute incubation in human liver micro-somes and found the percentage of drug remaining to

Table III. In vitro activity of ceftaroline against select

Organism No. of Isolat

Gram-positivesActinomyces species41 13Clostridium difficile24,40 36Clostridium perfringens40,41 20Peptostreptococcus species24,40 39Propionibacterium acnes24,40,41 35

Gram-negativesBacteroides fragilis24,40,41 20Prevotella species24,40,41 16

be at least 88.8%, suggesting ceftaroline is unlikely to

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undergo metabolism via P450 system and unlikely tohave cytochrome-related drug–drug interactions.48

Ceftaroline is primarily excreted in the urine as theactive compound, together with its inactive M-1 me-tabolite. An average of 50.7% of active ceftaroline45,46

and 7.4% of the M-1 metabolite45 can be recovered inhe urine. When ceftaroline was administered at dosesetween 300 mg and 800 mg IV over an hour, the meanlimination half-life ranged from 2.6 to 2.63 hours.46

Individuals with moderate to severe renal impairment,defined as having an estimated creatinine clearance(CrCl) of �50 mL/min, require dosage adjustments

aerobic isolates.

MIC90 (�g/mL) MIC Range (�g/mL)

0.25 �0.008 to 0.258 �0.015 to 80.25 �0.008 to 0.50.5 �0.015 to 80.06 �0.008 to 0.125

�32 4 to �32�32 0.03 to �16

Table IV. Pharmacokinetic parameters of ceftaro-line in healthy adult subjects.46

Parameter* Mean (SD)

Cmax (�g/mL) 21.33 (4.1)Tmax (h) 0.92 (0.92�1.08)AUC0-� (�g·h/mL) 56.25 (8.9)t1⁄2 (h) 2.66 (0.4)Vdss (L) 35.3 (7.4)CLss (L/h) 9.6 (1.4)

CLss � clearance at steady state; Cmax � maximum ob-served concentration; SD � standard deviation; t1⁄2 � ter-minal elimination half-life; Tmax � time of maximum ob-served concentration; � � dosing interval; Vdss �apparent volume of distribution at steady state.*Based on 6 healthy adult subjects who received ceftaro-

line fosamil 600 mg IV every 12 hours over 60 minutesfor 14 days.

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according to package insert information.23,49,50 In aharmacokinetic study in which 12 patients with mildCrCl �50 mL/min to 80 mL/min) or moderate (CrCl30 mL/min to 50 mL/min) renal impairment were

dministered ceftaroline 600 mg IV, a significant cor-elation (R2 � 0.969) was noted between CrCl and theenal clearance of ceftaroline.49 The manufacturer rec-

ommends a 33% dosage reduction to 400 mg IV every12 hours when the CrCl is �30 mL/min to 50 mL/min.23 Patients with severe renal impairment (CrCl�30 mL/min) had a 115% greater ceftaroline exposureand a 67% longer t½.50 The prescribing informationndicates that the dose of ceftaroline should be reducedo 300 mg IV every 12 hours in patients with CrCletween 15 mL/min and 30 mL/min.23 Riccobene et alxamined the effects of hemodialysis on the plasmaharmacokinetic parameters of ceftaroline in 12 adultale patients and reported that 21.6% of the dose was

emoved during a 4-hour session of dialysis, althoughhe type of dialysis filter used was not specified in thebstract.51 According to the New Drug Applicationhat was submitted as part of the application processy the manufacturer, the mean clearance via dialysisas 3.81 � 0.44 L/h,52 leading to the recommendation

of reducing ceftaroline dosage to 200 mg in patientsundergoing hemodialysis, and that the dose be givenafter dialysis sessions.23

Age and sex had no effect on ceftaroline pharmaco-kinetic properties in a study involving 17 healthy el-derly male and female subjects (10 male and 7 females;mean [SD] age, 72.2 [6] years; CrCl � 60 mL/min).53

An independent pharmacokinetic subanalysis of PhaseIII study populations described in the New Drug Ap-plication did not find any significant difference for raceor sex on ceftaroline exposure, and an 18% increase inceftaroline exposure was noted in elderly patients (65years of age or older), although no dosage adjustmentwas recommended.52 Similarly, another populationpharmacokinetics study did not find dosage adjust-ments necessary based on age or body surface area.47

At the time of writing, ceftaroline is currently notindicated for use in the pediatric population,23 al-though Phase IV studies in this population are under-way.52 No pharmacokinetics study of ceftaroline haseen conducted in pregnant females.23 The pharmaco-inetics properties of ceftaroline in patients with he-atic impairment has not been established.23 An in
itro study has shown ceftaroline to be stable in the a
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resence of liver microsomes and is unlikely to be sig-ificantly affected in this population.48

Riccobene et al examined the pharmacokinetic pa-rameters of ceftaroline given intramuscularly at 600mg once or every 12 hours for 5 days in 24 healthyadults (ages 18�45 years) and found this regimen tohave a bioavailability of approximately 100%.54 Intra-

uscular ceftaroline had a pharmacokinetic profilehat was overall comparable with that of the intrave-ous route. At this time, ceftaroline is not indicated forntramuscular administration, although a Phase II clin-cal study using ceftaroline 600 mg administered intra-uscularly every 12 hours has been completed.55

It must be emphasized that much of the informationregarding the pharmacokinetic properties of ceftaro-line was presented in scientific meetings in the form ofabstracts that had not undergone a vigorous peer-re-view process (such as references 43�50, 54).

PharmacodynamicsCeftaroline has been found to have bactericidal ac-

tivity against both gram-positive and gram-negativebacteria. In in vitro56–59 and in vivo animal stud-es,35,58,60,61 ceftaroline has been reported to havetime-dependent activity against gram-positive cocci,including MRSA, as well as some common gram-neg-ative bacteria. Time-kill studies of ceftaroline against avariety of staphylococci reported a reduction in bacte-rial density of �3 log10 CFU/mL within 4�24 hours atoncentrations of �2-fold the MIC.56–58,60 One in

vitro study using 12 clinical strains of S pneumoniae,10 of which were penicillin-resistant, found ceftarolineto have �3 log10 CFU/mL reductions within 24 hoursat concentrations �2-fold the MIC, with 1 penicillin-susceptible strain showing regrowth.59 Bactericidal ac-tivity of ceftaroline against Enterobacteriaceae (eg,Escherichia coli, Klebsiella pneumoniae, Enterobactercloacae, and Serratia marcescens) and common respi-ratory pathogens (eg, Streptococcus pneumoniae and

aemophilus influenzae) was achieved within 8�24ours at concentrations of �2-fold the MIC.56

The post-antibiotic effect of ceftaroline rangedfrom 0.7 to 7.2 hours against most gram-positiveorganisms61,62 and up to 5.7 hours against E coli.62

In one study, the post-antibiotic effect of ceftarolineagainst methicillin-susceptible S aureus (MSSA),MRSA, VISA, hVISA, and VRSA ranged from 0.7 to2.2 hours.61 In another study, the range of post-
ntibiotic effect against strains of MSSA and MRSA
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was 0.8�7.2 hours.62 The post-antibiotic effect ismportant in organisms with elevated MICs, whererug plasma concentrations can fall below the MICuring treatment period. In a murine neutropenichigh infection model with S aureus, S pneumoniae,nd K pneumoniae, the time above MIC (R2 rangedrom 84% to 88%) was the best predictor of efficacys compared with the 24-hour AUC/MIC ratio (R2

ranged from 30% to 82%) and the Cmax/MIC ratio(R2 ranged from 9% to 41%).62 At the recom-

ended dose of 600 mg IV every 12 hours, ceftaro-ine plasma concentrations are expected to exceedhe MICs of most strains of gram-positive organismstudied for �92% of the dosing interval.35,57

The potential for synergistic activity between cef-taroline and tobramycin, as compared with vancomy-cin with tobramycin, was examined against 4 clinicalisolates of hospital-acquired S aureus: MRSA (n � 2),hVISA (n � 1), and VISA (n � 1).63 In this time-killtudy, synergistic activity was observed with the com-ination of ceftaroline and tobramycin against bothRSA strains at 4.8 and 6.1 hours, which was signif-

cantly higher when compared with the combination ofancomycin with tobramycin (P � 0.01 and 0.006,

respectively). Both combinations with tobramycin hadcomparable synergism against hVISA (at 4.5 hours forceftaroline versus 5.1 hours for vancomycin), but neitherhad any appreciable synergy or bactericidal activityagainst the VISA strain. At concentrations below theMIC, the combination of ceftaroline with tobramycinhad greater activity against MRSA when compared withvancomycin plus tobramycin in this in vitro study.63

The activity of ceftaroline in combination with az-treonam, amikacin, cefepime, levofloxacin, mero-penem, tazobactam, or tigecycline has been investi-gated in a time-kill experiment against 10 strains ofgram-negative organisms: P aeruginosa (n � 4), ESBL-producing E coli (n � 2), ESBL-producing K pneu-moniae (n � 2), and AmpC-derepressed E cloacae (n �2).38 Ceftaroline was reported to have synergy, defineds a �2-log CFU/mL decrease between the combina-ion and the most efficient agent alone at 24 hours,hen combined with amikacin (9 strains [90%]), tazo-actam (4 strains [40%]), meropenem (2 strains20%]), and aztreonam (2 strains [20%]). Tazobactamnd meropenem only displayed synergism againstSBL-producing organisms, while aztreonam had syn-rgy against E cloacae alone. The highest synergy rates
ere observed at 24 hours when subinhibitory concen- i
750

rations of ceftaroline were combined with clinicallyelevant, subinhibitory concentrations of amikacin andazobactam. Further studies are warranted to deter-ine the clinical impact of the synergistic activitybserved.

The antibacterial effect of ceftaroline in combina-ion with NXL104, a non��-lactam, �-lactamase in-

hibitor with activity against class-A and class-C �-lac-amases,64 has been studied against various organisms,

including MDR pathogens. Reductions in bacterialdensity of 0.5�5 log10 CFU/mL have been reported inn vitro and murine infection models against ESBL,mpC and K pneumoniae carbapenemase–producing

trains of Enterobacteriaceae.65,66 One in vivo studyreported a �10-fold reduction in ED50 (effective dos-age that results in anti-microbial activity in 50% of thepathogens tested) against AmpC-producing E cloacaeand ESBL-producing K pneumoniae as compared withceftaroline alone.67 Pharmacodynamic studies of thecombination in murine infection models have foundcomparable activity against ESBL, AmpC, and K pneu-moniae carbapenemase–producing gram-negative bac-teria with that of ceftaroline against susceptible patho-gens.67,68 Enhanced activity against anaerobicrganisms was not noted.69 These results suggest that

the spectrum of ceftaroline can be extended to includeMDR gram-negative organisms when combined withNXL104. Phase I studies in humans are currently un-derway,70 with plans to introduce combined therapywith NXL104 to cover ESBLs and AmpC-producingpathogens.

The effects of ceftaroline 600 mg IV every 12hours for 6 days on human intestinal microflora hasbeen examined in 12 healthy adults (6 male; ages20�41 years).71 Fecal concentrations of ceftaroline

ere not detected during the entire study period.nterococci and Candida albicans were within nor-

mal limits and concentrations of Enterobacteriaceaespecies did not change significantly up to 14 days(P � 0.05). Moderate reductions of 2.1 log10 CFU/geces and 1.7 log10 CFU/g feces were seen in Bifido-

bacterium species and lactobacilli, respectively, al-though no effect on Bacteroides strains were noted.There was an increase in Clostridium species of 2log10 CFU/g feces by day 7, although this was con-idered clinically insignificant. The investigatorsoncluded that ceftaroline did not have a significant
mpact on human intestinal microflora.71
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ResistanceThe potential for ceftaroline to select for resistant

mutants was assessed with 5 strains of S pneumoniae (3penicillin-susceptible, 1 penicillin-intermediate, and 1penicillin-resistant), 5 strains of S aureus (VRSA,VISA, hVISA, CA-MRSA, and MSSA), 3 strains of Syogenes, and 2 strains of E faecalis (1 vancomycin-

susceptible and 1 vancomycin-resistant).72 After 20 to50 serial passages through subinhibitory drug concen-trations, ceftaroline produced 1 clone each of vanco-mycin-susceptible and vancomycin-resistant E faecaliswith MICs elevated to 8-fold that of the parents. Cef-taroline also yielded clones with MICs increased 2- to4-fold that of the parent isolates from each of the othergram-positive bacteria but no mutants with �4-foldincrease in MIC were identified and ceftaroline main-tained low MICs against all these organisms (MICs0.004�2 �g/mL). The same authors also examined thepotential for resistant mutant selection using strains ofH influenza (n � 3) and M catarrhalis (n � 1) in aeparate study.73 No mutant with increased MICs re-ulted, aside from 1 strain of H influenzae, which hadn increase from 0.06 �g/mL to 1 �g/mL.73

The ability of ceftaroline to induce expression ofAmpC enzymes were also explored in strains of E clo-acae (n � 4), Citrobacter freundii (n � 2), Morganella

organii (n � 2), Proteus vulgaris (n � 2), and S marc-scens (n � 2).39 At concentrations at or below the

IC, ceftaroline had induction ratios �5, but wasound to have induction ratios of up to 68.9 at 4 to6 � the MIC. Ceftaroline weakly induced AmpC at orelow the MIC and stronger induction seen at higherICs did not appear to be clinically significant.39

Efficacy in Animal ModelsCeftaroline has been studied in multiple animal

models of infection.43,44,58,60,62,74–78 In a neutropenicurine thigh model of infection caused by S pneu-oniae, MRSA, and E coli, ceftaroline resulted in de-

reases in viable cells (mean [SD]) ranging from 2.20.15] log CFU/thigh to 4.6 [0.21] log CFU/thigh for Sneumonia, and 1.2 [0.28] log CFU/thigh to 2.0 [0.61]

og CFU/thigh for S aureus and E coli; P values notrovided).62 Ceftaroline was also compared with lin-zolid and vancomycin in another murine model ofhigh muscle infection induced by MRSA.58 Reduction

in bacterial concentration of thigh muscle with ceftaro-line was comparable to linezolid with both resulting in
�3 log10 CFU/thigh reductions (P � 0.01 versus con-
April 2012

rols) and was associated with a greater reduction inacterial load when compared with vancomycin,hich only had �1 log10 CFU/thigh reductions (P �

.01).The efficacy of ceftaroline was assessed in the treat-

ent of pneumonia based on findings from variousnimal models.58,62,74 In a neutropenic murine model

of MRSA pneumonia, ceftaroline reduced bacterialburden in homogenized pulmonary tissues by �3 log10

CFU/lung when compared with vancomycin and lin-ezolid, which had no detectable effect by day 3 whentreatment was initiated 24 hours after onset of infec-tion (P � 0.01).58 Ceftaroline was compared witheftriaxone in a rabbit model of pneumonia induced bypneumoniae of varying susceptibilities to penicillin.74

Against penicillin-susceptible and intermediate strainsof S pneumoniae, bacterial killing did not differ signif-icantly based on bacterial counts in lung tissue at theend of study (mean [SD], 1.0 [0.0] log CFU/g lungtissue; P values not provided). However, against peni-illin-resistant strains, ceftaroline was found to haveignificantly lower pulmonary bacterial burden com-ared with ceftriaxone (1.1 [0.2] log10 CFU/g versus

6.2 [1.4] log10 CFU/g; P � 0.01) or intramuscularly at5 mg/kg (2.3 [0.9] log10 CFU/g versus 6.2 [1.4] log10

CFU/g; P � 0.05) and at 20 mg/kg (1.08 [0.16] log10

CFU/g versus 6.2 [1.4] log10 CFU/g; P � 0.01).Based on findings from a murine model, ceftaroline

might have a role in the management of bacteremiacaused by MRSA.58 Against 4 clinical isolates of MRSA,eftaroline (ED50, 1.08�4.81 mg/kg) was deemed equiv-

alent to linezolid (ED50, 2.71�3.73 mg/kg), and moreeffective than vancomycin (ED50, 3.06�8.39 mg/kg), tei-oplanin (ED50, 4.53�38.7 mg/kg), and arbekacin

(ED50, 2.19�24.9 mg/kg). P values not provided.58

In rabbit models of meningitis, penetration of cef-taroline into meninges was approximately 15% for in-flamed meninges and 3% for noninflamed menin-ges.44,75 In one study, significantly higher bactericidalactivity with ceftaroline compared with ceftriaxoneagainst penicillin-susceptible S pneumoniae (mean[SD] reduction of 6.35 [0.47] log10 CFU/mL CSF ver-us 5.54 [0.98] log10 CFU/mL CSF, respectively; P �.03), as well as to the combination of ceftriaxone withancomycin against penicillin-resistant S pneumoniae5.54 [0.61] versus 4.65 [1.0]; P � 0.003) was noted inhe CSF.44 Another study reported similar findings

when comparing bacterial killing of ceftaroline to
cefepime against K pneumoniae (5.61 [1.08] log10
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CFU/mL CSF versus 3.54 [0.94] log10 CFU/mL CSF,respectively; P � 0.01).75

Ceftaroline appears to be an effective agent for en-docarditis caused by S aureus based on studies con-ducted in rabbits.60,76,77 Against MSSA, MRSA, and

ISA strains, ceftaroline had complete sterilization ofortic valve vegetations (24 of 24 [100%]) comparedith 73.9% for daptomycin and 0% for tigecycline (Palues not provided).76 Similarly in a second experi-

ment, ceftaroline achieved vegetation sterilization in18 of 20 (90%) rabbits with MRSA endocarditis whengiven at dosages of 20�40 mg/kg as compared with 6of 10 (60%) for teicoplanin (P values not provided).77

A third trial involving strains of MRSA and hVISAreported 75% (15 of 20) sterilizations with ceftaroline,36% (4 of 11) with vancomycin and 0% (0 of 15) withlinezolid (P values not provided).60

The efficacy of ceftaroline against linezolid and van-comycin was evaluated in a rabbit model of acute os-teomyelitis induced by MRSA and VISA.78 Reductionof MRSA titers in the joint fluid were significantly lesswith ceftaroline as compared with linezolid or vanco-mycin (mean [SD] 1.98 [1.0] versus 0.77 [1.39] versus0.19 [1.19], respectively; P � 0.05). Against VISA, cef-aroline had a numerically greater reduction of bacte-ia in joint fluid compared with vancomycin (1.550.52] versus 0.68 [0.34]; P values not provided) andas found to be significantly greater in femoral bonearrow compared with vancomycin (2.02 [0.93] ver-

us 0.41 [0.43], respectively; P �0.01). Mortality ratesfor ceftaroline, vancomycin, and linezolid were, re-spectively, 17%, 17%, and 39% for MRSA, and 0%,27%, and 0% for VISA.78

Clinical EfficacyClinical Studies

Ceftaroline was assessed in the treatment of cSSSIscaused by gram-positive bacteria in 1 Phase II79 and 2hase III clinical trials (CANVAS 180 and CANVAS

281). Its efficacy in the treatment of CAP was studied in2 Phase III clinical trials (FOCUS 182 and FOCUS 270).The findings from these trials are summarized inTable V.70,79–84 A randomized, open-label, parallel-group, Phase II clinical study of the efficacy of ceftaro-line given intramuscularly compared with linezolidwith or without aztreonam in the treatment of cSSSIshas been completed.84,85 At the time of literaturesearch, no information on this trial was published or
presented in scientific meetings. Patients are currently
752

being recruited for Phase I86 and Phase II87 studies ofceftaroline in combination with NXL104.

cSSSIsIn a randomized, single-blind, active-controlled,

parallel-group Phase II trial79 conducted at 15 centersin the United States, South America, South Africa, andRussia, the efficacy and tolerability of ceftaroline wascompared with standard therapy of cSSSIs. Eligible pa-tients were 18 years of age or older with cSSSI (eg,major abscess, deep or extensive cellulitis, or infectedsurgical or trauma wound) requiring initial hospital-ization and intravenous antimicrobials. Patients wereexcluded if they had ischemic ulcers due to peripheralvascular disease, decubitus ulcers, diabetic foot ulcersfor �7 days, third-degree burns, burns involving �5%f the body surface, human or animal bites, necrotizingasciitis, or anaerobic or pseudomonal infection. Pa-ients were also excluded if they had hypersensitivity to

�-lactam agents or vancomycin, history of red mansyndrome, were pregnant or had epilepsy, AIDS, orany significant or life-threatening condition, or re-ceived �1 dose of a non–study antibiotic within 4 daysbefore enrollment unless there was clear evidence offailure. A total of 100 patients participated in the studyand were randomly assigned in a 2:1 ratio to receiveeither ceftaroline 600 mg IV q12h (n � 67) or standardtreatment with vancomycin 1 g IV q12h alone or incombination with aztreonam 1 g IV q8h (n � 33) for7�14 days (up to 21 days allowed for severe infectionsrequiring extended therapy). Vancomycin wasswitched to a penicillinase-resistant penicillin (eg, clox-acillin) within the first 72 hours of treatment based onresults of baseline cultures. Dosage adjustment of van-comycin based on serum concentrations or institu-tional protocols were not specifically mentioned. Therewere no significant differences in demographic charac-teristics between the 2 arms. The majority of patientswere male (55.2%, ceftaroline; 59.4% standard treat-ment) and mean age was 42.8 years (ceftaroline, 41.6years; standard treatment, 44.0 years). The most com-mon diagnosis was a major abscess (46.5%), followedby deep or extensive cellulitis (35.4%), wound infec-tions (8.1%), and lower extremity cSSSI (4.0%). A sin-gle pathogen was isolated in 80.8% of the patients; themost commonly isolated organisms were S aureus(51.1%) and nonenterococcal streptococci (26.1%),with gram-negative bacteria making up only 5.7% of
cultures. Mean duration of treatment was 7.8 days
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H. Poon et al.

(0.4�19.5 days) for ceftaroline and 8.0 days(2.0�20.5 days) for standard therapy. A total of 7patients in the standard therapy arm were given ad-junctive aztreonam for a mean of 5.1 days (1.0�12.1days) and only 1 patient had vancomycin replaced withcloxacillin. The number of patients who had surgicalinterventions was not available. Overall, there did notappear to be a significant difference in clinical efficacybetween ceftaroline and standard treatment of cSSSIs,although only descriptive statistics were performed. Ofthe 99 patients, 88 were considered to be clinicallyevaluable (88.9%). At the test-of-cure (TOC) assess-ment of this population, conducted 8�14 days afteradministration of the last dose of study medication, 59patients (96.7%) in the ceftaroline group and 24 pa-

Table V. Treatment-emergent adverse events reporterequiring intervention.

Adverse Events

CANV

Ceftaroline(n � 692)

Any TAE 309 (44.7)Serious AE 30 (4.3)Discontinuation of treatmentdue to an AE 21 (3.0)TAE

Diarrhea 34 (4.9)Headache 36 (5.2)Nausea 41 (5.9)Insomnia 17 (2.5)Pruritis 24 (3.5)*Hypokalemia 10 (1.4)Rash 22 (3.2)Vomiting 20 (2.9)Constipation 18 (2.6)Phlebitis ND1Transaminases 15 (2.2)Generalized pruritis 15 (2.2)Dizziness 14 (2.0)Hypertension NDPyrexia 9 (1.3)

AE � adverse events; CANVAS � 2 Phase III clinical trials ofIII clinical trials of community-acquired pneumonia; ND �*P � 0.05 �2 with Yates correction factor (current authors’

tients (88.9%) in the standard treatment group had

April 2012

achieved a clinical cure, which was defined as resolu-tion of all signs and symptoms of the cSSSI or improve-ment to the extent requiring no further antimicrobialtherapy. The microbiological response also did not ap-pear to be significantly different between both groups;microbiological eradication was achieved in 40 of 42patients (95.2%) in the ceftaroline group and 18 of 21patients (85.7%) in the standard treatment group. Ad-verse events associated with treatment were reported in41 of 67 (61.2%) and 18 of 32 (56.3%) patients whoreceived ceftaroline and standard treatment, respec-tively. Apparently, more patients in the standard treat-ment group than in the ceftaroline group reported uri-nary crystals (15.6% versus 9.0%), elevated alanineaminotransferase (12.5% versus 6.0%), elevated as-

2% of patients in the CANVAS88 and FOCUS89 trials

and 2 FOCUS 1 and 2

ncomycin andeonam (n � 686)

Ceftaroline(n � 613)

Ceftriaxone(n � 615)

326 (47.5) 288 (47.0) 281 (45.7)28 (4.1) 69 (11.3) 72 (11.7)

33 (4.8) 27 (4.4) 25 (4.1)

26 (3.8) 26 (4.2) 16 (2.6)31 (4.5) 21 (3.4)* 9 (1.5)*35 (5.1) 14 (2.3) 14 (2.3)17 (2.5) 19 (3.1) 14 (2.3)56 (8.2)* ND ND15 (2.2) 14 (2.3) 15 (2.4)17 (2.5) ND ND18 (2.6) ND ND18 (2.6) ND ND

ND 17 (2.8) 13 (2.1)25 (3.6) ND ND19 (2.8) ND ND

8 (1.2) ND NDND 14 (2.3) 16 (2.6)

16 (2.3) ND ND

licated skin and skin structure infections; FOCUS � 2 Phasefined; TAE � treatment-emergent adverse events.tatistical analysis).

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rash (6.3% versus 1.5%), whereas nausea was morefrequently reported in the ceftaroline arm (6% versus0%). Two patients in the ceftaroline arm and 1 patientin the standard treatment arm discontinued study med-ications due to an adverse event. The effectiveness andtolerability of ceftaroline at a dosage of 600 mg IVq12h did not appear different from those of standardtreatment for cSSSI.79

Two Phase III, multinational, randomized, double-blind, active-controlled, parallel-group clinical trials ofidentical design (CANVAS 180 and CANVAS 281)ompared the effectiveness and tolerability of ceftaro-ine with the combination of vancomycin and aztreo-am in patients with cSSSIs. The CANVAS studiesere of a noninferiority design with a prespecified mar-in of equivalence set at �10%. Corey et al83 reported

results of the combined analysis of the CANVAS 1 and2 studies. Patients were recruited from 111 centers in14 countries between February 2007 and December2007.80,81 Both studies had a primary end point ofnoninferiority to vancomycin � aztreonam in cure rateamong clinically evaluable patients at the TOC visit(scheduled 8�15 days after the last dose of study med-ication). Eligible patients were 18 years of age or olderwith cSSSI (deep or extensive cellulitis, major abscessrequiring drainage, infected wound or ulcer, or in-fected burn) requiring initial hospitalization or treat-ment in emergency department, had �3 clinical signsof infection and requiring �5 days of intravenous an-timicrobial therapy. Patients were excluded if they hadosteomyelitis, gangrene, necrotizing fasciitis, decubitusulcers, diabetic foot ulcers, ulcers associated with pe-ripheral vascular disease, third-degree burn, burns cov-ering �5% of body surface, known Pseudomonal oranaerobic infection, required concomitant antimicro-bial therapy or high-dose corticosteroids, received �24hours of antimicrobial therapy within 96 hours prioror had a CrCl �30 mL/min. A total of 1378 patientswere randomized in a 1:1 ratio to receive ceftaroline600 mg IV q12h (n � 693) or vancomycin 1 g IVq12h � aztreonam 1 g IV q12h (n � 685) for 5�14days. Individualized vancomycin dosing based on se-rum concentrations was permitted. The baseline demo-graphic characteristics of the patients were not signifi-cantly different between the 2 groups. The majority ofpatients were men (64.1%, ceftaroline; 61.2%, vanco-mycin � aztreonam) and white (73.0%, ceftaroline;74.7%; vancomycin � aztreonam). Median age was
48 years in both groups (range, 18�93 years, ceftaro-
754

line; range, 18�96 years, vancomycin � aztreonam).The proportion of patients who were older than 75years of age (ceftaroline, 7.8%; vancomycin �aztreonam, 7.3%), diabetic (ceftaroline, 17.6%;vancomycin � aztreonam, 17.5%), and having mild tomoderate renal impairment (ceftaroline, 3.3%; vanco-mycin � aztreonam, 3.8%) were also not significantlydifferent. Of note, 97 patients (13.9%) who rec-eived ceftaroline and 108 (15.8%) who receivedvancomycin � aztreonam underwent 1 or more surgi-cal procedure involving the primary infection site. Theproportions of patients with incision and drainage ofan abscess or surgical debridement were not signifi-cantly different between the ceftaroline and vancomy-cin � aztreonam groups (11.1% [77 of 693] versus11.7% [80 of 685]). The most common diagnosis wasdeep or extensive cellulitis (ceftaroline, 35.9%; vanco-mycin � aztreonam, 39.9%) followed by abscess (cef-taroline, 34.3%, vancomycin � aztreonam, 34.2%),wound infection (ceftaroline, 14.7%; vancomycin �aztreonam, 12.0%), and infected ulcer (ceftaroline7.8%; vancomycin � aztreonam, 7.6%). At baseline, apathogen was isolated from 76.1% (1049 of 1378) ofthe patients, and the most commonly isolated organ-isms were S aureus (ceftaroline, 78.7% [425 of 540];vancomycin � aztreonam, 78.4% [409 of 522]), othergram-positive bacteria, such as enterococci andstreptococci (ceftaroline, 25.4% [137 of 540];vancomycin � aztreonam, 27.9% [146 of 522]), andgram-negative organisms (ceftaroline, 19.6% [106 of540]; vancomycin � aztreonam, 19.7% [103 of 522]).Median durations of therapy were 7 days in theCANVAS 1 study and 6.5 days in the CANVAS 2 studyfor both groups.83 Cure rates in clinically evaluableatients at the TOC visit were 91.1% (288 of 316) inhe ceftaroline group versus 93.3% (280 of 300) in theancomycin with aztreonam group in the CANVAS 1tudy (difference, �2.2; 95% CI, �6.6 to 2.1; P �S),80 and 92.2% (271 of 294) in the ceftaroline group

ersus 92.1% (269 of 292) in the vancomycin withztreonam group in the CANVAS 2 study (difference,.1; 95% CI �4.4 to 4.5; P � NS).81 In the combined

analysis, there were no significant differences in curerates between the treatment arms. At the TOC visit,cure was reported in 595 of 693 (85.9%) patients inthe ceftaroline group and 586 of 685 (85.5%) in thevancomycin � aztreonam group (difference, �0.3;95% CI, �3.4 to 4.0; P � NS). Among clinically evalu-
able patients, 91.6% (559 of 610) receiving ceftaroline
Volume 34 Number 4

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H. Poon et al.

and 92.7% (549 of 592) receiving vancomycin � az-treonam had achieved a cure (difference, �1.1; 95%CI, �4.2 to 2.0; P � NS). The microbiological re-sponse was not significantly different between cef-taroline and vancomycin � aztreonam groups. Inclinically evaluable patients who had a positive cul-ture at baseline, microbiological eradication wasachieved in 92.7% (434 of 468) of patients in theceftaroline group and 94.4% (421 of 446) of pa-tients in the vancomycin � aztreonam group (differ-ence, �1.7; 95% CI, �4.9 to 1.6; P � NS). In sub-group analyses of microbiologically evaluablepatients, there did not appear to be any difference inclinical cure rates between ceftaroline and vancomy-cin � aztreonam in patients infected with gram-pos-itive pathogens only (93.8% [348 of 371] versus94.3% [330 of 350]; difference, �0.5, 95% CI, �4.1to 3.1), mixed gram-positive and gram-negativepathogens (90.5% [57 of 63] versus 93.1% [67 of72]; difference, �2.6; 95% CI, �13.4 to 7.2) orpolymicrobial infection (91.9% [125 of 136] versus96.4% [134 of 139]; difference, �4.2; 95% CI,�10.5 to 1.5). However, in microbiologically evalu-able patients infected with gram-negative organismsalone, cure rate was significantly less with ceftaro-line compared with vancomycin � aztreonam85.3% [29 of 34] versus 100% [24 of 24]; differ-nce, �15.6, 95% CI, �31.6 to �1.2).83 In 274

patients who were infected with MRSA at baseline,the clinical cure rate appeared to be similar (ceftaro-line, 93.4%; vancomycin � aztreonam, 94.3%), al-though statistical analyses of the differences werenot provided. Adverse events were reported in 158 of692 (22.8%) patients who received ceftaroline and181 or 686 (26.4%) patients who received vancomy-cin � aztreonam. A total of 54 patients discontinuedtudy medication due to an adverse event and ap-eared to be numerically lower in the ceftarolineroup as compared with vancomycin � aztreonam21 [3.0%] versus 33 [4.8%]. The incidence andature of adverse events in the CANVAS 1 andANVAS 2 studies are described in detail in thedverse Events section. Ceftaroline appeared to beell tolerated with the incidence and profile of ad-erse events similar to those of comparators. Thenvestigators concluded that the efficacy of ceftaro-ine noninferior to that of vancomycin � aztreonam
n the treatment of patients with cSSSI.83 e
April 2012

CAPTwo Phase III, multinational, randomized, double-

blind, active-controlled clinical trials (FOCUS 182 andOCUS 270) of similar noninferiority design compared

the efficacy and tolerability of ceftaroline and ceftriax-one in the treatment of CAP. The prespecified marginfor noninferiority was �10%. Results of the combinedanalysis of both studies were reported by File et al.84

Eligible patients were adults aged 18 years or olderhospitalized with radiographically confirmed CAP of�7 days duration, with �3 clinical signs, and a Pneu-monia Outcomes Research Team risk class III or IV.Patients were excluded if they were admitted to theintensive care unit, had Pneumonia Outcomes Re-search Team risk class of I, II or V, had radiographicchanges of noninfectious etiology, or had suspected orknown infection with MRSA or atypical or hospital-acquired pathogens. They were also excluded if theyhad CrCl �30 mL/min, aminotransferase concentra-tions were �10 � the upper limit of normal (ULN),absolute neutrophil count �500 cells/mm3, HIV infec-ion with AIDS, or chronic systemic corticosteroids of40 mg prednisone equivalent. Previous antimicrobial

herapy for CAP within 96 hours was not allowed un-ess it was a single dose of a short-acting agent. Bothtudies were methodically identical, with the exceptionhat all patients in FOCUS 1 were required to receive4 hours of adjunctive macrolide therapy to recruitatients from North America.82,84 A total of 1240 pa-

tients were randomized in a 1:1 ratio to receive ceftaro-line 600 mg IV q12h (n � 621) or ceftriaxone 1 g IV24h (n � 619) for 5�7 days. Renal adjustment ofeftaroline dosage was done by unblinded pharma-ists. Sputum and blood specimens for culture wereollected at baseline. The primary end point of thetudies was noninferiority of ceftaroline comparedith ceftriaxone in the cure rate of clinically evaluablend modified intent-to-treat efficacy (MITTE) popula-ions at the TOC. There were no significant differencesn the demographic characteristics between the 2ooled ceftaroline and ceftriaxone groups, respec-ively. Mean ages of patients were 60.8 years and 61.6ears in the ceftaroline and ceftriaxone groups, respec-ively. About two thirds of the patients were male (cef-aroline, 62.4%; ceftriaxone, 63.9%) and the majorityf patients were Caucasian (ceftaroline, 92.8%; ceftri-xone, 92.8%) from the European continent (ceftaro-ine, 81.0%; ceftriaxone, 80.9%). Structural lung dis-
ase was present in about a quarter of patients
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(ceftaroline, 27.6%; ceftriaxone, 25.7%) and abouthalf the patients had mild or moderate renal impair-ment (ceftaroline, 49.5%; ceftriaxone, 48.0%). Atbaseline, a pathogen was isolated from 26.9% (333 of1240) of patients, with the most commonly isolatedorganism being S pneumoniae (ceftaroline, 20.7% [69of 333]; ceftriaxone, 21.0% [70 of 333]) followed by Saureus (ceftaroline, 7.5% [25 of 333]; ceftriaxone,9.0% [30 of 333]).84,88 Overall, 88.0% (293 of 333) ofpatients had CAP caused by a typical pathogen, and12.0% (40 of 333) of patients had mixed infectioncaused by both typical and atypical organisms; patientsinfected with solely atypical organisms were excludedfrom analysis.84,88 Mean duration of therapy was 6.5ays for both treatment groups. Overall, ceftarolineas found to have an equivalent clinical cure rate com-ared with ceftriaxone for both clinically evaluable84.3% [387 of 459] versus 77.7% [349 of 449]; dif-erence, 6.7; 95% CI, 1.6�11.8) and MITTE patients82.6% [479 of 580] versus 76.6% [439 of 573]; dif-erence, 6.0; 95% CI, 1.4�10.7) in the combined anal-sis of the FOCUS 1 and 2 studies.84 At the TOC eval-ation conducted 8�15 days after the last dose oftudy medication, the clinical cure rates in clinicallyvaluable patients were 86.6% (194 of 224) in the cef-aroline group versus 78.2% (183 of 234) in the ceftri-xone group in the FOCUS 1 study (difference, 8.4;5% CI, 1.4 to 15.4),82 and 82.1% (193 of 235) in theeftaroline group versus 77.2% (166 of 215) in theeftriaxone group in the FOCUS 2 study (difference,.9; 95% CI, �2.5 to 12.5).70 For MITTE patients,

clinical cure rates were 83.8% (244 of 291) in the cef-taroline group versus 77.7% (233 of 300) in the ceftri-axone group in the FOCUS 1 study (difference, 6.2;95% CI, �0.2 to 12.6),82 and 81.3% (235 of 289) inhe ceftaroline group versus 75.5% (206 of 273) in theeftriaxone group in the FOCUS 2 study (difference,.9; 95% CI, �1.0 to 12.7).70 In subgroup analyses ofITTE patients, ceftaroline was found to have numer-

cally higher cure rates versus ceftriaxone for patientsnfected with S pneumoniae (85.5% [59 of 69] versus8.6% [48 of 70]), MDR (resistant to �2 classes ofntimicrobials) S pneumoniae (100% [4 of 4] versus2.2% [2 of 9]) and S aureus (72.0% [18 of 25] versus0.0% [18 of 30]), as well as K pneumoniae (93.3%

[14 of 15] versus 76.9% [10 of 13]) and E coli (83.3%[10 of 12] versus 69.2% [9 of 13]).84 The investigatorsostulate that the difference in MIC90 values between

ceftaroline and ceftriaxone for S pneumoniae (�0.015

756

versus 1 �g/mL, respectively) and S aureus (0.25 versus4 �g/mL, respectively) might have contributed to thedifferences seen in microbiological cure rates in thesepathogens.84,88 The single-day course of macrolidetherapy in FOCUS 1 patients was not considered tohave any meaningful impact. There were no apparentdifferences in cure rates between different age groupsor those with renal impairment. Among clinicallyevaluable patients with PORT risk class III, ceftarolinehad significantly higher clinical cure rates comparedwith ceftriaxone (86.8% [249 of 287] versus 79.2%[217 of 274]; difference, 7.5; 95% CI, 1.3�13.8). Pa-tients who did not receive any prior antimicrobial ther-apy also appeared to have higher cure rates with cef-taroline versus ceftriaxone (85.8% [235 of 274] versus74.9% [191 of 255]; difference, 11.2; 95% CI,4.5�18.0). Adverse events were reported in 47.0%(288 of 613) of patients on ceftaroline and 45.7% (281of 615) of patients on ceftriaxone. Of these, 183 of 288(63.5%) in the ceftaroline group and 188 of 281(66.9%) in the ceftriaxone group were considered to betreatment emergent. A total of 52 patients discontin-ued study medication because of an adverse event (27[4.4%] in the ceftaroline group and 25 [4.1%] in theceftriaxone group; P � NS). The incidence and natureof adverse events in the FOCUS 1 and FOCUS 2 trialsare described in detail in the Adverse Events section.The authors conclude that the efficacy and tolerabilityof ceftaroline is comparable to that of ceftriaxone.84

Adverse EventsThe tolerability data submitted to the FDA as part

of the approval process for ceftaroline consisted ofpooled information from 275 patients who received asingle or multiple twice daily dose(s) of 50�2000 mgof ceftaroline in clinical pharmacology studies, and1367 patients who received multiple twice daily dosesof 400�600 mg of ceftaroline in efficacy and tolerabil-ity studies.85 Treatment-emergent adverse eventsTAE) that occurred in �2% of patients in 4 PhaseII efficacy and tolerability trials (ie, CANVAS 1,ANVAS 2, FOCUS 1, and FOCUS 2) are listed inable V.89,90 Because ceftaroline was approved in01023 and the tolerability data were obtained from

�1700 patients who received the drug in clinical trials,the true nature and prevalence of adverse events withceftaroline remain to be determined. To date, no addi-tional adverse events have been reported in post-mar-
keting surveillances.
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Overall, data pooled from the clinical pharmacol-ogy studies reveal the incidence of TAE was 38.6% (91of 236) for ceftaroline versus 32.1% (25 of 78) forplacebo, with discontinuations due to TAE occurringin 1.7% (n � 4) of ceftaroline patients and 1.3% (n �1) of placebo patients.85 The most common TAE seen

ith ceftaroline in the pooled data was nausea10.2%), followed by headache (8.5%), vomiting3.4%), dizziness (3.0%), abnormal urine color3.0%), and urine discoloration (3.0%). In a 2-parthase I clinical pharmacology study designed to delin-ate the pharmacokinetic profile of ceftaroline, 48ealthy male subjects were randomly assigned to re-eive a single intravenous dose of the drug at 50�1000g or placebo45 and 18 healthy male subjects were

andomly assigned to receive multiple twice-dailyoses of the drug at 300�800 mg IV q12h or pla-ebo.46 Overall, 40.7% (22 of 54) patients on ceftaro-ine and 50% (9 of 18) of patients on placebo reportedt least 1 adverse event, all of which were deemed to beild to moderate and resolved without intervention.he most common adverse event reported in the single-ose study was headache (11%),45 while in the multi-le-dose study, arm bruising was the most commonceftaroline, 28%; placebo, 50%), followed by urineiscoloration, which only occurred in patients receiv-

ng ceftaroline 600 mg IV q12h (n � 6), and rash (cef-aroline, 22.2%; placebo, 0.0%).46 Likewise, Phase Itudies in patients with varying degrees of renal impair-ent reported mild or moderate, self-limiting adverse

vents occurring in 66.7% (4 of 6) of patients withild,49 moderate,49 and severe50 renal dysfunction,

which did not appear to be different from their respec-tive comparator placebo groups, with the most com-mon adverse event being nausea (n � 3), followed bydizziness (n � 2) and headache (n � 2).49,50 In 6 adult

ales on hemodialysis, the incidence of adverse eventsith ceftaroline was 33.3% (2 of 6) as compared with6.7% (1 of 6) in normal renal function, although thexact nature of the adverse events was not specified.51

When ceftaroline was given as a single-dose of 600 mgIV in an age-stratified study, the incidence of mild tomoderate TAE was 23.5% (4 of 17) in healthy subjectsaged 65 years and older and 6.3% (1 of 16) in subjectsaged 18�45 years, with headache being the most com-monly reported (n � 3).53

The effect of ceftaroline on the QTc interval hasbeen explored in a randomized, double-blind, placebo-
controlled crossover study involving 54 patients (27 c
April 2012

male, 27 female; median age 24 years).85 Patients wereassigned to receive, in a random sequence, ceftaroline1500 mg IV (n � 54), moxifloxacin 400 mg IV (n � 53;positive control as moxifloxacin is known to prolongthe QTc interval), and placebo (n � 54). The durationof washout periods between receiving each study med-ication was not specified. Mean prolongation in theQTc interval, corrected based on baseline QT-RRslope, was 1.6 msec with the supratherapeutic dose ofceftaroline and 19.2 msec with moxifloxacin. Treat-ment-emergent adverse events were seen in 37% (20 of54) of patients on ceftaroline, 36% (19 of 53) of pa-tients on moxifloxacin, and 20% (11 of 54) of patientson placebo, with most being noted as mild in severity.The most common adverse event reported in the cef-taroline group was nausea (n � 11), followed by der-matitis (n � 4), diarrhea (n � 3), abdominal pain (n �3), and headache (n � 3). Ceftaroline was found tohave minimal impact on QTc interval, given that themean difference compared with placebo was �10msec.85

A total of 692 patients with cSSSIs received �1 doseof ceftaroline at the approved dosage (600 mg IV q12h)in the CANVAS trials.83 Of these patients, 309(44.7%) experienced �1 TAE and 4.3% experienced�1 serious adverse event, both of which did not appearto be different when compared with vancomycin �aztreonam (47.5% and 4.1%, respectively).89 The

AEs most frequently (�2%) reported with ceftaro-ine and vancomycin � aztreonam use were nausea5.9% versus 5.1%, respectively; P � NS), headache

(5.2% versus 4.5%; P � NS), diarrhea (4.9% versus3.8%; P � NS), pruritus (3.5% versus 8.2%; P �0.05), rash (3.2% versus 2.5%; P � NS), vomiting(2.9% versus 2.6%; P � NS), constipation (2.6% ver-sus 2.6%; P � NS), insomnia (2.5% versus 2.5%; P �NS), increased transaminases (2.2% versus 3.6%;P � NS), and generalized pruritus (2.2% versus 2.8%;P � NS) (Table V). The proportion of patients whohad serum creatinine concentrations increased by �1.5mg/dL and �50% above the baseline did not appear tobe different between the ceftaroline group and vanco-mycin � aztreonam group (0.9% versus 2.1%; P �NS).89 Three patients (0.4%) in the vancomycin � az-reonam group experienced acute renal failure as op-osed to 1 patient (0.1%) in the ceftaroline group,lthough the latter had an additional patient not in-luded, as the occurrence was not specified as acute or
hronic. At least 1 hepatic adverse event occurred in
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2.7% of patients with ceftaroline and 4.2% with van-comycin � aztreonam, most of which consisted of in-creased transaminases.89 Transaminase elevation

5 � the ULN occurred in 4 patients on ceftarolinend in 10 patients on vancomycin � aztreonam, withhe only hepatic failure seen in the latter group. Ad-erse events with ceftaroline in patients treated forSSSI were mainly gastrointestinal, mild to moderate,nd generally self-limiting. Serious adverse events oc-urred in 30 patients with ceftaroline, of which 4 wereetermined to be related to the study medication (ie,ypersensitivity, C. difficile colitis, anaphylactoid reac-ion, and anaphylactic shock).85 Rates of discontinua-ion due to adverse events were 3.0% with ceftarolinend 4.8% with vancomycin � aztreonam (P � NS). Aotal of 3 deaths were reported in the ceftaroline groupersus none with vancomycin � aztreonam; theseeaths were deemed to be unrelated to study medica-ions.85 Nevertheless, the overall safety profile of cef-aroline appeared to be comparable with that of van-omcyin � aztreonam in patients with cSSSI.89

There was a total of 613 patients with CAP whoreceived �1 dose of ceftaroline 600 mg IV q12h in theFOCUS 1 and 2 studies.90 Two hundred and eighty-ight patients experienced �1 TAE. The TAEs mostrequently (�2%) reported with ceftaroline and ceftri-xone were diarrhea (4.2% versus 2.6%, respectively;� NS), headache (3.4% versus 1.5%; P � 0.05), and

nsomnia (3.1% versus 2.3%; P � NS) followed byhlebitis (2.8% versus 2.1%; P � NS), hypokalemia2.3% versus 2.4%; P � NS), and hypertension (2.3%ersus 2.6%; P � NS) (Table VI). The number of pa-ients with an elevated serum creatinine �1.5 mg/dLnd �50% increase above the baseline did not appearo be different between ceftaroline and ceftriaxone2.0% versus 1.7%; P � NS).90 There were �1 hepatic

TAE reported in 2.3% (14 of 613) of patients on cef-taroline and 2.9% (18 of 615) of patients on ceftriax-one, the predominant TAE being increased transami-nases.90 Incidence of increase in transaminases �5 �the ULN appeared comparable between the ceftaro-line and ceftriaxone groups (1.4% versus 1.2%, re-spectively; P � NS). For patients being treated for

AP, adverse events with ceftaroline were mainlyastrointestinal or neurological, mild to moderate,nd generally reversible. Serious adverse events oc-urred in 69 patients on ceftaroline and 72 patientsn ceftriaxone, although only 3 of these were judged
o be related to ceftaroline: unknown sudden death,
758

ncreased transaminases �10 � ULN and general-ized tonic-clonic seizures.85 Although there were 15deaths (2.4%) in the ceftaroline group and 12 deaths(1.9%) in the ceftriaxone group, only 1 death in eachgroup was deemed related to the study medication.One death occurred in an elderly female patientwithout any cardiovascular disease and on ceftaro-line who died of sudden death and another occurredin a male patient with a reported history of alcoholabuse on ceftriaxone who went into hepatic failurewith resultant multiorgan disorder.85 Overall, thesafety and tolerability profiles of ceftaroline appearto be similar to those of ceftriaxone in patients withCAP.

A review of literature did not identify any studies orcase reports of ceftaroline in pregnant women. A mu-rine model of early pregnancy did not identify any ma-ternal or fetal toxicity with doses up to 8 � the humanequivalent of 600 mg IV q12h.85 In a rabbit reproduc-tive study during early pregnancy, spontaneous abor-tions and an increased incidence of angulated hyoidalae, a common skeletal variant in rabbits, was re-ported with doses similar to those used in humans.85

As a result, ceftaroline has been labeled pregnancy cat-egory B and should only be used in pregnant womanonly if the benefits to the patient outweigh the potentialrisks to the fetus.23 Although the distribution of cef-aroline in human breast milk is not known, caution isarranted in nursing mothers receiving ceftaroline.23

Drug InteractionsAlthough a search of the literature did not identify

any data on drug–drug interaction for ceftaroline fos-amil, information from pharmacokinetic studies pro-vide some data regarding its drug-interaction poten-tial. The pharmacokinetic properties of ceftarolinewere studied in healthy adult subjects45,46 and invitro.48 Ceftaroline was found to have linear pharma-cokinetic properties with minimal plasma accumula-tion, low protein binding (�20%) in plasma, and min-imal metabolism via the cytochrome P450 pathway(�88.8% of drug remaining after a 30-minute incuba-tion). These data suggest that there is no appreciableaccumulation of ceftaroline after multiple administra-tions, ceftaroline is minimally affected by plasma pro-tein binding, and there is minimal potential for drug–drug interaction with substrates of the cytochrome
P450 pathway.
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Dosage and AdministrationCeftaroline fosamil is available in powder formula-

tion as a 400-mg single-dose vial and a 600-mg single-dose vial. The recommended dosage for patients 18years of age and older is 600 mg administered intrave-nously over 60 minutes every 12 hours. For treatmentof cSSSI, the recommended duration of therapy is5�14 days, and for treatment of CAP, the recom-mended duration is 5�7 days.23 Dosage adjustment isnecessary in patients with renal impairment (CrCl �50mL/min).23,49,50 In patients with a CrCl between �30mL/min and 50 mL/min, the recommended dosage reg-imen is 400 mg IV over 60 minutes every 12 hours.23

For patients with a CrCl between 15 mL/min and 30mL/min, the recommended dosage regimen is 300 mgIV over 60 minutes every 12 hours.23 For patients withnd-stage renal disease, including those receiving he-odialysis, the recommended dose of ceftaroline fos-

mil is 200 mg IV over 60 minutes every 12 hours, andf applicable, administered after hemodialysis on he-odialysis days.23 The pharmacokinetic properties of

eftaroline in patients with hepatic impairment has noteen studied; however, an in vitro study has showneftaroline to be stable in the presence of liver micro-omes and unlikely to be significantly affected in thisopulation.23,48 Although clinical studies in the pedi-

atric population are underway, ceftaroline is currentlynot indicated for use in pediatric patients.23,52 Theharmacokinetic properties of ceftaroline in pregnantemales has not been studied in humans and is cur-ently labeled pregnancy category B and, therefore, ithould only be used in this population if the benefitsutweigh the potential risk.23 Ceftaroline should alsoe cautioned in nursing women as it is not knownhether the drug is excreted in breast milk.23 No dose

djustment is warranted on the basis of age, sex, orace; however, dosage adjustments should be made forlderly patients with a decline in renal function (CrCl50 mL/min).23,47,52,53

Pharmacoeconomic ConsiderationsA search of the literature did not identify any pub-

lished pharmacoeconomic studies for ceftaroline. An-timicrobial agents with comparable spectrum of activ-ity to ceftaroline include ampicillin and sulbactam,ceftriaxone, tigecycline, trimethoprim and sulfame-thoxazole, and aztreonam in combination with dapto-mycin, linezolid, telavancin, or vancomycin. All of
these agents provide coverage against gram-positive t
April 2012

and gram-negative pathogens, with some also provid-ing adequate anaerobic coverage as well (ampicillinand sulbactam and tigecycline). The 2011 averagewholesale prices (in US$) for a 10-day intravenouscourse of each agent for a 70-kg patient with normalrenal function are listed in Table VI.91 The acquisitionost for a 10-day course of ceftaroline fosamil$984.00) is comparable with a 10-day course of van-omycin � aztreonam ($834.80) and vancomycin �mpicillin and sulbactam ($827.60), but approxi-ately $700 more than vancomycin � ceftriaxone.hen compared with those with broad gram-positive

overage, ceftaroline fosamil costs $845.20 more thanancomycin, but approximately $700 to $2000 lesshan tigecycline, telavancin, linezolid, and daptomy-in. For an agent with excellent in vitro activity againstram-positive pathogens (please refer to section on Initro Activity of Gram-Positive Organisms), with the

xception of the enterococci species, ceftaroline is com-arably cheaper than tigecycline, telavancin, linezolid,nd daptomycin. Although ceftaroline is more costlyhan vancomycin, it does not require some of the ther-peutic drug monitoring necessary for vancomycinherapy in select situations (eg, elevated MIC of docu-ented pathogen, fluctuation in renal function, serious

llness or complicated infections, and prolonged coursef therapy),92 hence evading costs associated with dos-

age changes based on peak and trough concentrations.Pharmacoeconomic studies are needed to determinewhether ceftaroline fosamil is cost effective when com-pared with other antimicrobial agents.

DISCUSSIONCeftaroline fosamil is a cephalosporin developed specifi-cally for its enhanced activity against gram-positivepathogens.26–28 It has demonstrated good in vitro activ-ty against most gram-positive isolates including drug-esistant strains of S aureus and S pneumoniae.24,25,29–37

Ceftaroline’s gram-negative coverage includes commonrespiratory pathogens24,29,30,33 and members of the En-erobacteriaceae.56 Time-kill analyses found that ceftaro-ine is rapidly bactericidal against a variety of S aureusnd S pneumoniae isolates, achieving a reduction of �3og10 CFU/mL within 4�24 hours.56–58,60 The bacteri-cidal activity of ceftaroline against Enterobacteriaceae (Ecoli, K pneumoniae, E cloacae, and S marcescens) andome common respiratory pathogens (S pneumoniae and

influenzae) were achieved within 8�24 hours.56 Cef-
aroline lacks adequate anaerobic and atypical coverage,
759

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and does not have activity against P aeruginosa, ESBL, orAmpC-producing pathogens, limiting its utility as amonotherapy agent for health-care–associated infections.

In Phase III studies (CANVAS 1 and CANVAS 2),80,81

ceftaroline was found to be noninferior to the combi-nation of vancomycin and aztreonam, with a clinicalcure rate of 91.6% among clinically evaluable patientsfor the treatment of cSSSIs (ceftaroline versus vanco-mycin and aztreonam: difference, �1.1; 95% CI, �4.2to 2.0; P � NS).83 Ceftaroline’s efficacy has also beenassessed for the treatment of CAP in 2 Phase III studies(FOCUS 1 and FOCUS 2)70,82 and was equivalent toceftriaxone, with cure rates of 84.3% and 77.7%, re-spectively, in the clinically evaluable populations (cef-taroline versus ceftriaxone: difference, 6.7; 95% CI,1.6 to 11.8) in the combined analysis.84 It should benoted that in these studies, patients infected withMRSA or atypical pathogens alone were excludedfrom participation, which might limit ceftaroline’s us-age in certain regions where practice guidelines14 rec-ommend coverage of atypical organisms (eg, Chla-mydia pneumoniae, Mycoplasma pneumoniae, and

Table VI. Average wholesale price of selected antimiccourses.90

Drug Name

Ampicillin/sulbactam (generic) 3Aztreonam (generic) 1Ceftaroline fosamil* 6Ceftriaxone (generic) 1Daptomycin† 4Linezolid‡ 6Telavancin§ 1Tigecycline� 1

qTrimethoprim/sulfamethoxazole (generic) 8

dVancomycin (generic) 1

AWP � average wholesale price; IV � intravenous; TMP � t*Trademark: Teflaro® (Forest Pharmaceuticals, Inc., St Lou†Trademark: Cubicin® (Cubist Pharmaceuticals Inc., Lexing‡Trademark: Zyvox® (Pfizer Inc., New York, NY).§Trademark: Vibativ® (Theravance Inc., South San Francisco�Trademark:Tygacil® (Wyeth Pharmaceuticals Inc., Philadel

Legionella pneumophila). Due to ceftaroline’s limited

760

efficacy against atypical organisms, it is the authors’opinion that the addition of another agent with atypi-cal coverage, such as macrolides, would need to beconsidered for these regions.

Tolerability of ceftaroline fosamil was evaluatedbased on 4 Phase III clinical trials and the adverse eventprofile was generally similar to those of the compara-tors. The most frequently (�3%) reported adverseevents were nausea, headaches, diarrhea, pruritus,rash, and insomnia, all usually mild to moderate, self-limiting, and of little clinical significance.83,84

Overall, ceftaroline in theory is a good alternativefor critically ill patients with MRSA infections whorequire a rapidly (�3 log10 CFU/mL reduction in bac-erial density within 4 to 24 hours)56–58,60 bacterio-idal agent. It has shown to have adequate in vitroctivity against hVISA, VISA, and VRSA. In a neutro-enic murine model of MRSA pneumonia, ceftarolineeduced bacterial burden by �3 log10 CFU/lung whennitiated 24 hours after onset of infection as comparedith vancomycin and linezolid, which had no detect-ble effect by day 3 (P � 0.01).58 Our review has a few

l agents compared with ceftaroline fosamil for 10-day

RegimenAcquisition Cost

(AWP, 2011 US$)

q6h � 10 d 688.80q12h � 10 d 696.00g IV q12h � 10 d 984.00q24h � 10 d 109.20g IV q24h � 10 d 2915.20

g IV q12h � 10 d 2402.00/kg IV q24h � 10 d 2044.20g load IV then 50 mg IV

10 d1729.20

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limitations. Limits, inclusion criteria, and exclusion

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criteria were not applied during our attempt to retrieveall available information on ceftaroline, therefore, thiswas not a systematic search. As such, only publisheddata were retrieved, allowing for publication bias. Allpublished trials discussed were sponsored by the man-ufacturer, introducing more potential for bias. Therewere no published studies on drug–drug interaction orpharmacoeconomics of ceftaroline; therefore, the dis-cussion on drug interactions was theoretical based onpharmacokinetic properties of ceftaroline fosamil andthe discussion on cost considerations was based on acomparison of selected antimicrobial agents.

CONCLUSIONSCeftaroline is a cephalosporin with broad gram-posi-tive activity, including MRSA and VRSA. Its gram-negative activity includes common respiratory patho-gens and members of the Enterobacteriaceae. Clinicaltrials have reported that ceftaroline was noninferior toceftriaxone and vancomycin � aztreonam for thetreatment of CAP and cSSSIs, respectively. In an era ofincreasing bacterial resistance, ceftaroline is a welcomeaddition to our armamentarium as a bactericidal agentfor the treatment of difficult S aureus infections.

ACKNOWLEDGMENTSAll authors contributed equally to the literature search,data interpretation, figure creation, and writing of themanuscript.

CONFLICT OF INTERESTThe authors have indicated that they have no conflictsof interest regarding the content of this article.

REFERENCES1. Spellberg B, Powers JH, Brass EP, et al. Trends in antimicro-

bial drug development: implications for the future. ClinInfect Dis. 2004;28:1279–1286.

2. Klevens RM, Edwards JR, Tenover FC, et al. Changes in theepidemiology of Staphylococcus aureus in intensive care unitsin US hospitals, 1992–2003. Clin Infect Dis. 2006;42:389–391.

3. Moran GJ, Amii RN, Abrahamian FM, Talan DA. Methicillin-resistant Staphylococcus aureus in community-acquired skininfections. Emerg Infect Dis. 2005;11:928–930.

4. Moran GJ, Krishnadasan A, Gorwitz RJ, et al. Methicillin-resistant S. aureus infections among patients in theemergency department. N Engl J Med. 2006;355:666 –
674.
April 2012

5. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicil-lin-resistant Staphylococcus aureus infections in the UnitesStates. JAMA. 2007;298:1763–1771.

6. Richter SS, Heilmann KP, Dohrn CL, et al. Changingepidemiology of antimicrobial-resistant Streptococcus pneu-moniae in the United States, 2004–2005. Clin Infect Dis.2009;48:e23–e33.

7. Skoff TH, Farley MM, Petit S, et al. Increasing burden ofinvasive Group B streptococcal disease in nonpregnantadults, 1990–2007. Clin Infect Dis. 2009;49:85–92.

8. McCaig LF, McDonald LC, Mandal S, Jernigan DB.Staphylococcus aureus-associated skin and soft tissue infec-tions in ambulatory care. Emerg Infect Dis. 2006;12:1715–1723.

9. Stevens DL, Bisno AL, Chambers HF, et al. Practiceguidelines for the diagnosis and management of skin andsoft-tissue infections. Clin Infect Dis. 2005;41:1373–1406.

0. Kochanek KD, Xu JQ, Murphy SL, et al. Deaths: preliminarydata for 2009. In: National Vital Statistics Reports. Hyattsville,Md: National Center for Health Statistics; 2011;59:41–69.

1. Niederman MS. Community-acquired pneumonia: man-agement controversies, part 1; practical recommendationsfrom the latest guidelines. J Respir Dis. 2002;23:10–17.

2. Kollef MH, Shorr A, Tabak YP, et al. Epidemiology andoutcomes of health-care-associated pneumonia: resultsfrom a large US database of culture-positive pneumonia.Chest. 2005;128:3854–3862.

3. Moore CL, Hingwe A, Donabedian SM, et al. Comparativeevaluation of epidemiology and outcomes of methicillin-resistant Staphylococcus aureus (MRSA) USA300 infectionscausing community- and healthcare-associated infections.Int J Antimicrob Agents. 2009;34:148–155.

4. Mandell LA, Wunderink RG, Anzueto A, et al. InfectiousDiseases Society of America/American Thoracic Societyconsensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44(Suppl 2):S27–S72.

5. Lim D, Strynadka NC. Structural basis for the beta lactamresistance of PBP2a from methicillin-resistant Staphylococ-cus aureus. Nat Struct Biol. 2002;9:870–876.

6. Steinkraus G, White R, Friedrich L. Vancomycin MIC creepin non-vancomycin-intermediate Staphylococcus aureus(VISA), vancomycin-susceptible clinical methicillin-resis-tant S. aureus (MRSA) blood isolates from 2001–05. JAntimicrob Chemother. 2007;60:788–794.

7. Hiramatsu K, Hanaki H, Ino T, et al. Methicillin-resistantStaphylococcus aureus clinical strain with reduced vancomy-cin susceptibility. J Antimicrob Chemother. 1997;40:135–136.

8. Hiramatsu K. Vancomycin-resistant Staphylococcus aureus: anew model of antibiotic resistance. Lancet Infect Dis. 2001;1:
147–155.
761


19. Tenover FC, Biddle JW, LancasterMV. Increasing resistance to vanco-mycin and other glycopeptides inStaphylococcus aureus. Emerg Infect Dis.2001;7:327–332.

20. Centers for Disease Control andPrevention. Vancomycin-resistantStaphylococcus aureus—Pennsylvania,2002. MMWR Morb Mortal Wkly Rep.2002;51:902.

21. Wang G, Hindler JF, Ward KW,Bruckner DA. Increased vancomycinMICs for Staphylococcus aureus clinicalisolates from a university hospitalduring a 5-year period. J Clin Micro-biol. 2006;44:3883–3886.

22. US Department of Health and Hu-man Services. NDA 200327. NDAapproval. http://www.accessdata.fda.gov/drugsatfda_docs/applet-ter/2010/200327s000ltr.pdf. Ac-cessed April 30, 2011.

23. Teflaro [package insert]. St Louis,Mo: Forest Laboratories, Inc; 2011.http://www.frx.com/pi/teflaro_pi.pdf. Accessed April 30, 2011.

24. Sader HS, Fritsche TR, Kaniga K, etal. Antimicrobial activity and spec-trum of PPI-0903M (T-91825), anovel cephalosporin, tested againsta worldwide collection of clinicalstrains. Antimicrob Agents Chemother.2005;49:3501–3512.

25. Saravolatz L, Pawlak J. Johnson L. Invitro activity of ceftaroline againstcommunity-associated methicillin-resistant, vancomycin-intermediate,vancomycin-resistant, and daptomy-cin-nonsusceptible Staphylococcus au-reus isolates. Antimicrob Agents Che-mother. 2010;54:3027–3030.

26. Ishikawa T, Matsunaga N, TawadaH, et al. TAK-599, a novel N-phos-phono type prodrug of anti-MRSAcephalosporin T-91825: synthesis,physicochemical and pharmacolog-ical properties. Bioorg Med Chem.2003;11:2427–2437.

27. Villegas-Estrada A, Lee M, Hesek D,et al. Co-opting the cell wall infighting methicillin-resistant Staphy-lococcus aureus: potent inhibition of
PBP 2a by two anti-MRSA beta-
762

lactam antibiotics. J Am Chem Soc.2008;130:9212–9213.

28. Moisan H, Pruneau M, Malouin F.Binding of ceftaroline to penicillin-binding proteins of Staphylococcus au-reus and Streptococcus pneumoniae. JAntimicrob Chemother. 2010;65:713–716.

29. Karlowsky JA, Adam HJ, DecorbyMR, et al. In vitro activity of ceftaro-line against gram-positive and gram-negative pathogens isolated from pa-tients attending Canadian hospitalsin 2009. Antimicrob Agents Chemother.2011;55:2837–2846.

30. Ge Y, Biek D, Talbot GH, Sahm DF.In vitro profiling of ceftarolineagainst a collection of recent bacte-rial clinical isolates from across theUnited States. Antimicrob Agents Che-mother. 2008;52:3398–3407.

31. Morrissey I, Ge Y, Janes R. Activity ofthe new cephalosporin ceftarolineagainst bacteraemia isolates frompatients with community-acquiredpneumonia. Int J Antimicrob Agents.2009;33:515–519.

32. Brown SD, Traczewski MM. In vitroantimicrobial activity of a new ceph-alosporin, ceftaroline, and determi-nation of quality control ranges forMIC testing. Antimicrob Agents Che-mother. 2009;53:1271–1274.

33. Jones RN, Mendes RE, Sader HS.Ceftaroline activity against patho-gens associated with complicatedskin and skin structure infections:results from an international surveil-lance study. J Antimicrob Chemother.2010;65:iv17–iv31.

34. Sader HS, Fritsche TR, Jones RN.Antimicrobial activities of ceftaro-line and ME1036 tested against clini-cal strains of community-acquiredmethicillin-resistant Staphylococcus au-reus. Antimicrob Agents Chemother.2008;52:1153–1155.

35. Zhanel GG, Rossnagel E, Nichol K,et al. Ceftaroline pharmacodynamicsactivity versus community-associatedand healthcare-associated methicillin-resistant Staphylococcus aureus, heterore-
sistant vancomycin-intermediate S. au-
reus, vancomycin-intermediate S. aureusandvancomycin-resistantS.aureususinganinvitromodel. JAntimicrobChemother.2011;66:1301–1305.

36. Jacobs MR, Good CE, Windau AR,et al. Activity of ceftaroline againstrecent emerging serotypes of Strepto-coccus pneumoniae in the UnitedStates. Antimicrob Agents Chemother.2010;54:2716–2719.

37. McGee L, Biek D, Ge Y, et al. In vitroevaluation of the antimicrobial activ-ity of ceftaroline against cephalospo-rin-resistant isolates of Streptococcuspneumoniae. Antimicrob Agents Chemo-ther. 2009;53:552–556.

38. Vidaillac C, Leonard SN, Sader HS,et al. In vitro activity of ceftarolinealone and in combination againstclinical isolates of resistant gram-negative pathogens, including beta-lactamase-producing Enterobacteri-aceae and Pseudomonas aeruginosa.Antimicrob Agents Chemother. 2009;53:2360–2366.

39. Mushtaq S, Livermore DM. AmpCinduction by ceftaroline. J AntimicrobChemother. 2010;65:586–588.

40. Snydman DR, Jacobus NV, McDer-mott LA. In vitro activity of ceftaro-line against a broad spectrum ofrecent clinical anaerobic isolates.Antimicrob Agents Chemother. 2011;55:421–425.

41. Citron DM, Tyrrell KL, Merriam CV,Goldstein EJ. In vitro activity ofceftaroline against 623 diversestrains of anaerobic bacteria. Antimi-crob Agents Chemother. 2010;54:1627–1632.

42. Fung HB, Kuczynski S, Finch DA,Ramos L. Current issues in gram-negative resistance: extended-spec-trum beta-lactamases and induciblebeta-lactamases. J Pharm Pract.2001;14:6–17.

43. Jacqueline C, Caillon J, Miegeville AF,et al. Penetration of ceftaroline (PPI-0903),anewcephalosporin, into lungtissues: measurement of plasma andlungtissueconcentrationsafterashortIV infusion in the rabbit. Abstract
presented at: 46th Interscience Con-
Volume 34 Number 4

http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/200327s000ltr.pdf



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http://www.frx.com/pi/teflaro_pi.pdf

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4

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5

5

5

5

5

5

5

5

5

6

H. Poon et al.

ference on Antimicrobial Agents andChemotherapy; September 27�30,2006; San Francisco, Calif. AbstractA�1938.

4. Cottagnoud P, Acosta F, Biek D, et al.Efficacy of ceftaroline fosamil againstpenicillin-sensitiveand-resistantStrep-tococcus pneumoniae in an experimentalrabbitmeningitismodel.Abstractpre-sented at: 50th Interscience Confer-ence on Antimicrobial Agents andChemotherapy; September 13�14,2010;Boston,Mass.AbstractB�702.

5. Ge Y, Redman R, Floren L, et al.Single-dose pharmacokinetics (PK)of ceftaroline (PPI-0903) in healthysubjects. Abstract presented at: 46thInterscience Conference on Antimi-crobial Agents and Chemotherapy;September 27�30, 2006; San Fran-cisco, Calif. Abstract A�1936.

6. Ge Y, Redman R, Floren L, et al. Thepharmacokinetics (PK) and safety ofceftaroline (PPI-0903) in healthysubjects receiving multiple-dose in-travenous (IV) infusions. Abstractpresented at: 46th Interscience Con-ference on Antimicrobial Agents andChemotherapy; September 27�30,2006; San Francisco, Calif. AbstractA�1937.

7. Van Wart SA, Forrest A, BhavnaniSM, et al. Population pharmacoki-netics of ceftaroline in healthy andrenally impaired subjects. Abstractpresented at: 49th Interscience Con-ference on Antimicrobial Agents andChemotherapy; September 12�15,2009; San Francisco, Calif. AbstractA1�004.

8. Ge Y, Hubbel A. In vitro evaluation ofplasma protein binding and meta-bolic stability of ceftaroline (PPI-0903M). Abstract presented at: 46thInterscienceConferenceonAntimicro-bial Agents and Chemotherapy; Sep-tember 27�30, 2006; San Francisco,Calif. Abstract A�1935.

9. Ge Y, Thye D, Liao S, Talbot GH.Pharmacokinetics (PK) of ceftaroline(PPI-0903) in subjects with mild ormoderate renal impairment (RI). Ab-
stract presented at: 46th Interscience
April 2012

Conference on Antimicrobial Agentsand Chemotherapy; September 27�

30, 2006; San Francisco, Calif.Abstract A�1939.

0. Riccobene T, Fang E, Thye D. Anopen-label pharmacokinetic (PK),safety, and tolerability study of singleintravenous (IV) doses of ceftaroline(CPT) in subjects with normal renalfunction or severe renal impairment.Abstract presented at: 49th Inter-science Conference on AntimicrobialAgents and Chemotherapy; Septem-ber 12�15, 2009; San Francisco,Calif. Abstract A1�003.

1. Riccobene T, Jakate A, Rank D, ThyeD. An open-label pharmacokinetic,safety and tolerability study of single-dose intravenous ceftaroline in sub-jects with end-stage renal disease onintermittent haemodialysis. Clin Mi-crobiol Infect. 2009;15(Suppl s4):S407.

2. Clinical pharmacology and biophar-maceutics review(s), Teflaro (ceftaro-line fosamil) injection drug approvalpackage (Application number: 200327). Bethesda, Md: Center for DrugEvaluation and Research, US Foodand Drug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200327Orig1s000ClinPharmR.pdf. Accessed April30, 2011.

3. Riccobene T, Jakate A, Rank D, ThyeD. Open-label pharmacokinetic,safety, and tolerability study of singleintravenous doses of ceftaroline inhealthy elderly and healthy youngadult subjects. Abstract presentedat: 2009 Midyear Clinical Meetingof the American Society of Health-System Pharmacists; December6�10, 2009; Las Vegas, NV. Ab-stract 3�161.

4. Riccobene T, Fang E, Thye D. A single-and multiple-dose study to determinethesafety, tolerability,andpharmaco-kinetics (PK) of ceftaroline (CPT) ad-ministered by intramuscular (IM) in-jection to healthy subjects. Abstractpresented at: 48th Interscience Con-
ference on Antimicrobial Agents and
Chemotherapy/46th Annual Meetingof the Infectious Diseases Society ofAmerica; October 25�28, 2008;Washington, DC. Abstract A�1888.

5. ClinicalTrials.gov. Efficacy andsafety of ceftaroline versus lin-ezolid in subjects with compli-cated skin and skin structure infec-tions. http://clinicaltrials.gov/ct2/show/NCT00633152?term�

ceftaroline&rank�3. AccessedApril 30, 2011.

6. Jones RN, Fritsche TR, Ge Y, et al.Evaluation of PPI-090M (T91825).,a novel cephalosporin: bactericidalactivity, effects of modifying in vitrotesting parameters and optimiza-tion of disc diffusion tests. J Anti-microb Chemother. 2005;56:1047–1052.

7. Vidaillac C, Leonard SN, Rybak MJ.In vitro activity of ceftaroline againstmethicillin-resistant Staphylococcus au-reus and heterogeneous vancomycin-intermediate S. aureus in a hollowfiber model. Antimicrob Agents Che-mother. 2009;53(11):4712–4717.

8. Iizawa Y, Nagai J, Ishikawa T, et al. InvitroantimicrobialactivityofT-91825,a novel anti-MRSA cephalosporin,and in vivo anti-MRSA activity of itsprodrug, TAK-599. J Infect Chemother.2004;10:146–156.

9. Sader HS, Moet G, Fritsche TR, JonesRN. Evaluation of the bactericidalactivity of the novel cephalosporinceftaroline(PPI-0903M)comparedtoceftriaxone against Streptococcus pneu-moniae. Abstract presented at: 46thInterscienceConferenceonAntimicro-bial Agents and Chemotherapy; Sep-tember 27�30, 2006; San Francisco,Calif. Abstract E�0121.

0. Jacqueline C, Caillon J, Le Ma-becque V, et al. In vivo efficacy ofceftaroline (PPI-0903), a new broad-spectrum cephalosporin, comparedwith linezolidandvancomycinagainstmethicillin-resistant and vancomycin-intermediate Staphylococcus aureus in arabbit endocarditis model. AntimicrobAgents Chemother. 2007;51:3397–
3400.
763

http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200327Orig1s000ClinPharmR.pdf




http://clinicaltrials.gov/ct2/show/NCT00633152?term=ceftaroline%26rank=3



http://ClinicalTrials.gov

6

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7

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7

7

7

8

8


61. Pankuch, GA, Appelbaum PC. Post-antibiotic effect of ceftaroline againstgram-positive organisms. AntimicrobAgents Chemother. 2009;53:4537–4539.

62. Andes D, Craig WA. Pharmacody-namics of a new cephalosporin, PPI-0903 (TAK-599), active againstmethicillin-resistant Staphylococcus au-reus in murine thigh and lung infec-tion models: identification of an invivo pharmacokinetic-pharmacod-ynamic target. Antimicrob Agents Che-mother. 2006;50:1376–1383.

63. Vidaillac C, Leonard SN, Rybak MJ.In vitro evaluation of ceftarolinealone and in combination with to-bramycin against hospital-acquiredmeticillin-resistant Staphylococcus au-reus (HA-MRSA) isolates. Int J Antimi-crob Agents. 2010;35:527–530.

64. Bonnefoy A, Dupuis-Hamelin C,Steier V, et al. In vitro activity ofAVE1330A, an innovative broad-spectrum non-beta-lactam beta-lactamase inhibitor. J Antimicrob Che-mother. 2004;54:410–417.

65. Bowker K, Noel A, Elliott H, et al.Comparison of the antibacterial ef-fects of two dosing regimens ofceftaroline in combination withNXL104 against Enterobacteriaceae.Abstract presented at: 50th Inter-science Conference on Antimicro-bial Agents and Chemotherapy; Sep-tember 12-15, 2010; Boston, MA.Abstract A1�1377.

66. Craig WA, Andes DR. Pharmacody-namics (PD) of ceftaroline (CPT) fos-amilplus1:1and2:1ratiosofNXL104(NXL) against Enterobacteriaceae(ENT) containing ESBLs and carbap-enemases (KPCs) in neutropenicmouse thighs. Abstract presented at:50th Interscience Conference on Anti-microbial Agents and Chemotherapy;September 12�15, 2010; Boston,MA. Abstract A1�1387.

7. Levasseur P, Girard A-M, Williams G, etal. In vivo antibacterial efficacy of cef-taroline (CPT) combined with the beta-lactamaseinhibitorNXL104inamurine
septicemia model. Abstract presented
764

at: 49th Interscience Conference onAntimicrobial Agents and Chemo-therapy; September 12�15, 2009; SanFrancisco,Calif.AbstractB�1339a.

8. Wiskirchen DE, Crandon JL, Fur-tado GH, et al. In vivo efficacy of ahuman-simulated regimen of cef-taroline fosamil combined withNXL104 (CXL) against ESBL- andnon-ESBL-producing Enterobact-eriaceae. Antimicrob Agents Chemother.2011;55:3220–3225.

69. Credito K, Ednie LM, AppelbaumPC. Comparative time-kill analysisof ceftaroline (CPT) with and with-out NXL104 (NXL) against anaer-obes. Abstract presented at: 50thInterscience Conference on Antimi-crobial Agents and Chemotherapy;September 12�15, 2010; Boston,MA. Abstract A1�1396.

70. Low DE, File TM Jr, Eckburg PB, etal. FOCUS 2: a randomized, double-blinded, multicentre, Phase III trialof the efficacy and safety of ceftaro-line fosamil versus ceftriaxone incommunity-acquired pneumonia. JAntimicrob Chemother. 2011;66:iii33–iii44.

71. Panagiotidis G, Bäckström T, Asker-Hagelberg C, et al. Effect of ceftaro-line on normal human intestinalmicroflora. Antimicrob Agents Che-mother. 2010;54:1811–1814.

72. Clark C, Kosowska-Shick K, McGheeP, Appelbaum P. Multistep resistancedevelopment studies of ceftaroline(CPT) with Streptococcus pneumoniae,Streptococcus pyogenes, staphylococci,and enterococci. Abstract presentedat: 50th Interscience Conference onAntimicrobial Agents and Chemo-therapy; September 12�15, 2010;Boston MA. Abstract E�813.

73. Clark C, Kosowska-Shick K, McGheeP, Appelbaum P. Multistep resistancedevelopment studies of ceftaroline(CPT) with Haemophilus influenzae andMoraxella catarrhalis. Abstract pre-sented at: 50th Interscience Confer-ence on Antimicrobial Agents andChemotherapy; September 12�15,
2010; Boston, MA. Abstract E�814.
4. Croisier-Bertin D, Piroth L, CharlesPE, et al. Ceftaroline vs ceftriaxonein a highly penicillin-resistant pneu-mococcal pneumonia model. ClinMicrobiol Infect. 2009;15(Suppl s4):S81.

5. Cottagnoud P, Stucki A, Accosta F,et al. Ceftaroline is superior tocefepime against a Klebsiella pneu-moniae strain an experimental rabbitmeningitis model. Clin Microbiol In-fect. 2010;16(Suppl s2):S4565.

6. Jacqueline C, Amador G, Batard E,et al. Comparison of ceftaroline fos-amil, daptomycin and tigecycline inan experimental rabbit endocarditismodel caused by methicillin-suscep-tible, methicillin-resistant and glyco-peptide-intermediate Staphylococcusaureus. J Antimicrob Chemother. 2011;66:863–866.

7. Jacqueline C, Caillon J, Batard E, etal. Evaluation of the in vivo efficacyof intramuscularly administered cef-taroline fosamil, a novel cephalospo-rin, against a methicillin-resistantStaphylococcus aureus strain in a rabbitendocarditis model. J Antimicrob Che-mother. 2010;65:2264–2265.

8. Jacqueline C, Amador G, Caillon J,et al. Efficacy of the new cephalospo-rin ceftaroline in the treatment ofexperimental methicillin-resistantStaphylococcus aureus acute osteomy-elitis. J Antimicrob Chemother. 2010;65:1749–1752.

9. Talbot GH, Thye D, Das A, Ge Y.Phase 2 study of ceftaroline versusstandardtherapy intreatmentofcom-plicated skin and skin structure infec-tions. Antimicrob Agents Chemother.2007;51:3612–3616.

0. Corey GR, Wilcox MH, Talbot GH,et al. CANVAS 1: the first Phase III,randomized, double-blind studyevaluating ceftaroline fosamil forthe treatment of patients with com-plicated skin and skin structure infec-tions. J Antimicrob Chemother. 2010;65:iv41–iv51.

1. Wilcox MH, Corey GR, Talbot GH,et al. CANVAS 2: the second Phase
III, randomized, double-blind study
Volume 34 Number 4

JB. Integrated safety summary of 66:82–98.

v

H. Poon et al.

evaluating ceftaroline fosamil forthe treatment of patients withcomplicated skin and skin structureinfections. J Antimicrob Chemother.2010;65:iv53–iv 65.

82. File TM Jr, Low DE, Eckburg PB, etal. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial ofthe efficacy and safety of ceftarolinefosamil versus ceftriaxone in commu-nity-acquired pneumonia. J AntimicrobChemother. 2011;66:iii19–iii32.

83. Corey GR, Wilcox M, Talbot GH, etal. Integrated analysis of CANVAS 1and 2: phase 3, multicenter, ran-domized, double-blind studies toevaluate the safety and efficacy ofceftaroline versus vancomycin plusaztreonam in complicated skin andskin-structure infection. Clin InfectDis. 2010;51:641–650.

84. File TM Jr, Low DE, Eckburg PB, et al.Integrated analysis of FOCUS 1 andFOCUS2:randomized,double-blinded,multicenter phase 3 trials of the efficacyand safety of ceftaroline fosamil versusceftriaxoneinpatientswithcommunity-acquired pneumonia. Clin Infect Dis.2010;51:1395–1405.

85. Medical review(s), Teflaro (ceftaro-line fosamil) injection drug approvalpackage (Application number:200327). Center for Drug Evalua-tion and Research, US Food andDrug Administration. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200327Orig1s000MedR.pdf. Accessed April 30, 2011.

86. ClinicalTrials.gov. A single-centre,randomised, double-blind, placebo-controlled, four way crossover phaseI study to investigate the effect onQT/QTc interval of ceftazidime NXL104 or ceftaroline fosamil NXL104,compared with placebo, using moxi-floxacin (Avelox®) as a positive con-trol, in healthy male volunteers.http://clinicaltrials.gov/ct2/show/NCT01290900?term�ceftaroline&rank�4. Accessed April 30, 2011.

87. ClinicalTrials.gov. Comparativestudy of coadministered ceftaro-
line fosamil and NXL 104 vs intrave- b
April 2012

nous doripenem in adult subjectswith complicated urinary tractinfections. http://clinicaltrials.gov/ct2/show/NCT01281462?term�

ceftaroline&rank�5. Accessed April30, 2011.

88. Critchley IA, Eckburg PB, JandourekA, et al. Review of ceftaroline fos-amil microbiology: integrated FO-CUS studies. J Antimicrob Chemother.2011;66:iii45–iii51.

89. Corrado ML. Integrated safety sum-mary of CANVAS 1 and 2 trials: PhaseIII, randomized, double-blind studiesevaluating ceftaroline fosamil for thetreatment of patients with compli-cated skin and skin structure infec-tions. J Antimicrob Chemother. 2010;65:iv67–iv 71.

90. Rank DR, Friedland HD, Laudano

ridge Road (119) Bronx, NY 10468. E

FOCUS 1 and FOCUS 2 trials: PhaseIII randomized, double-blind studiesevaluating ceftaroline fosamil forthe treatment of patients withcommunity-acquired pneumonia. JAntimicrob Chemother. 2011;66:iii53–iii59.

91. 2011 Drug Topics Red Book. Montvale,NJ: Thomson Medical Economics;2011.

92. Rybak M, Lomaestro B, RotschaferJC, et al. Therapeutic monitoringof vancomycin in adult patients: aconsensus review of the AmericanSociety of Health-System Pharma-cists, the Infectious Diseases Soci-ety of America, and the Society ofInfectious Diseases Pharmacists.Am J Health Syst Pharm. 2009;

Address correspondence to: Henry Poon, PharmD, BCPS, Pharmacy Ser-ice, James J. Peters Veterans Affairs Medical Center, 130 West Kings-

-mail: [email protected]

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