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Drug Profile

Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections Expert Rev. Clin. Pharmacol. 7(2), 123–135 (2014)

Eric Beresford*1, Donald Biek2, Alena Jandourek2, Yogesh Mawal1, Todd Riccobene1 and H David Friedland2 1 Global Medicines Development, Forest Research Institute, Harborside Financial Center, Plaza V, Jersey City, NJ 07311, USA 2 Cerexa, Inc., 2100 Franklin Street, Suite 900, Oakland, CA 94612, USA *Author for correspondence: Tel.: +1 201 427.8794 Fax: +1 201 604.6937 [email protected]

Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug–drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class. KEYWORDS: ABSSSI • acute bacterial skin and skin structure infections • AWARE • CAPTURE • ceftaroline fosamil • methicillin-resistant Staphylococcus aureus • MRSA

Over the past several decades, the USA has witnessed an epidemic of skin infections [1,2], broadly characterized into two categories, uncomplicated skin and skin structure infections (uSSSI; e.g., simple abscesses, furuncles and limited cellulitis) and complicated skin and skin structure infections (cSSSI; e.g., infected ulcers, infected burns and major abscesses). Skin infections can be life-threatening and may require surgery and hospitalization [3,4]. Skin infections are an increasingly common reason for hospital admissions [1–5] and are associated with significant healthcare costs [4–6]. During 2001–2003, of the 11.6 million outpatients visits for acute bacterial skin and skin structure infections (ABSSSI) in the USA, more than one-half were abscesses and cellulitis related, primarily caused by Staphylococcus aureus, with an estimated outpatient visit rate greater than 400 per 10,000 persons [7]. In 2005, US hospitals had an estimated 478,000 hospitalizations with a diagnosis of S. aureus. Of these, approximately 278,000 hospitalizations were related to methicillin-resistant S. aureus (MRSA). This included people informahealthcare.com

10.1586/17512433.2014.884457

admitted to the hospital for treatment of an infection that was community acquired or occurred outside the hospital (i.e., communityassociated MRSA) [8]. In recent years, US hospitals have experienced a 71% increase in the rate of hospitalizations due to skin infections [1], with an increase in the incidence of communityacquired MRSA infections [2]. Despite a changing epidemiology over the last few years, S. aureus remains the leading causative organism in Canada, the USA and Europe [9]. In Asia, most reports on the epidemiology of MRSA are from developed countries, not due to low actual prevalence, but due to scarce access to diagnostic facilities. The rate of MRSA in all communityassociated S. aureus infections in Asian countries ranges from 2.5 to 39% [10]. Currently, vancomycin, daptomycin, linezolid and sulfamethoxazole-trimethoprim are the antibiotic agents most widely used empirically or when MRSA is a suspected pathogen [11]. These agents, however, have been associated with significant side effects or treatment-limiting toxicities. Reported side effects for vancomycin


2014 Informa UK Ltd

ISSN 1751-2433

123

Drug Profile

Beresford, Biek & Jandourek et al.

Prodrug ceftaroline fosamil

CH3 +

N N O N P O O

O

N N S N

O

S

N

N O-

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O

CH3COOH

S

S

O

H2O

Active metabolite ceftaroline

CH3 N+

N H2N

O

N N S N

O

S

N

N

S

O O

S

O-

Figure 1. Chemical structure of ceftaroline fosamil and active metabolite. Chemically, ceftaroline monoacetate monohydrate is (6R,7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphonoamino)-1,2,4-thiadiazol-3-yl]acetamido}-3-{[4-(1-methylpyridin1-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. Data on file.

include nephrotoxicity (1–21%) [12,13] and ototoxicity [14]; reduced susceptibility of ABSSSI-associated pathogens to vancomycin has also been reported [15–21]. Challenges such as maintaining adequate trough levels for special patient populations, including the obese, diabetic and those with altered renal clearance, require frequent dose modifications. Although indicated for MRSA-related skin infections, linezolid has been associated with myelosuppression, peripheral and optic neuropathy [17–20] and serotonin toxicity [21] and daptomycin has been associated with myalgia and elevations in creatine phosphokinase levels [22]. Vancomycin, linezolid and daptomycin each lack activity against Gram-negative pathogens [22–24], and there are increasing reports of Gram-positive organisms resistant to vancomycin and linezolid [25,26]. Adverse events associated with sulfamethoxazoletrimethoprim in treatment of outpatient infections caused by community-acquired MRSA include hyperkalemia and serum creatinine elevation [27]. Ceftaroline fosamil is a prodrug of the bactericidal broad-spectrum cephalosporin ceftaroline, which received approval for treatment of ABSSSI and communityacquired bacterial pneumonia (CABP) from the US FDA in October 2010 (Teflaro Forest Laboratories. Inc., Jersey City, NJ, USA), and for similar indications in the European Union in TM August 2012 (ZINFORO , AstraZeneca, UK), and has since 124

been approved in several other countries worldwide. In the USA, ceftaroline fosamil is indicated for the treatment of ABSSSI caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: S. aureus (including methicillinsusceptible [MSSA] and MRSA isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca [28,29]. Ceftaroline has also shown antimicrobial activity against multidrug-resistant S. aureus strains with reduced susceptibility to vancomycin and daptomycin [30]. This review examines the pharmacodynamic and pharmacokinetic properties of ceftaroline fosamil, summarizes the efficacy and tolerability of ceftaroline fosamil in the management of patients with ABSSSI and reviews the in vitro antibacterial surveillance program of ceftaroline against bacteria commonly associated with ABSSSI. Chemistry

Ceftaroline is the active metabolite of an N-phosphono prodrug, ceftaroline fosamil. The structure–activity relationship of the ceftaroline molecule has been summarized by Zhanel [31]. This water-soluble compound has a molecular weight of 762 [32]. The prodrug ceftaroline fosamil is converted into bioactive ceftaroline (FIGURE 1) [33,34] in the plasma by phosphatase enzymes, and concentrations of the prodrug are measurable in plasma primarily during intravenous (i.v.) infusion. Hydrolysis of the b-lactam ring occurs to form a microbiologically inactive, open-ring metabolite (ceftaroline M-1). The mean standard deviation (SD) ratio of ceftaroline M-1 area under the plasma concentration curve (AUC) to ceftaroline AUC following a single 600-mg i.v. infusion of ceftaroline fosamil in healthy adults (n = 6) with normal renal function was 28% (3.1%) [28]. Ceftaroline inhibits cell wall biosynthesis in both Grampositive and Gram-negative bacteria through binding to the transpeptidase active site of penicillin-binding proteins (PBPs), which carry out the final steps in cell wall biosynthesis [35–37]. Unlike most b-lactams, however, ceftaroline has a high affinity for modified PBPs, such as PBP2a in MRSA and PBP2x in Streptococcus pneumoniae, providing in vitro antibacterial activity against resistant strains of these bacteria [36,37]. Recent studies, including X-ray crystallography, have shown that ceftaroline is able to bind non-covalently to an allosteric site on PBP2a far removed from the active site, promoting an open conformation of the active site to which ceftaroline can then bind to produce the acyl-enzyme inhibitory complex [38]. Pharmacokinetics & metabolism

The mean pharmacokinetic (PK) parameters of ceftaroline in healthy adults with normal renal function after multiple 1-h i.v. infusions of 600 mg ceftaroline fosamil administered every 12 h are summarized in TABLE 1 [28,39]. The mean half-life (t1/2) of ceftaroline is 2.6 h, apparent total clearance of drug from plasma divided by the fraction metabolized (CL/ƒm) for ceftaroline is 160.07 ± 23.28 ml/min and renal clearance (CLr) of ceftaroline is 118.88 ml/min, suggesting that ceftaroline is Expert Rev. Clin. Pharmacol. 7(2), (2014)

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Ceftaroline fosamil for the treatment of ABSSSI

primarily eliminated by glomerular filtration. Ceftaroline Cmax and AUC values increased in proportion to increases in dose within the dose range of 50–1000 mg, demonstrating an approximately linear PK profile following i.v. infusion. No appreciable accumulation of ceftaroline fosamil is observed following multiple i.v. infusions of 600 mg administered every 12 h for up to 14 days in healthy adults with normal renal function. The median (range) steady-state volume of distribution of ceftaroline in healthy adult males (n = 6) following a single 600 mg i.v. dose of radiolabeled ceftaroline fosamil was 20.3 L (18.3–21.6 L), similar to extracellular fluid volume. Of note, a population PK analysis predicted an approximately 30% higher Vss in ABSSSI patients compared to healthy subjects [40,41]. Following administration of a single dose of 600 mg 14C-labeled ceftaroline fosamil, approximately 88% of total radioactivity was recovered in urine, and 6% in feces within 48 h, demonstrating that urinary excretion was the primary route of elimination of ceftaroline fosamil and its metabolites [28]. Based on in vitro studies, the CYP450 system does not appear to be a significant metabolic pathway for ceftaroline. When incubated with pooled human liver microsomes, ceftaroline was metabolically stable ( MIC). For S. aureus, the %ƒT > MIC associated with bacteriostasis, 1-log kill and 2-log kill were 26, 36 and 51%, respectively. An analysis examining the relationship between drug exposure, as measured by %ƒT > MIC and microbiological response, was carried out using data from microbiologically evaluable ceftaroline fosamil-treated patients with ABSSSI enrolled in two Phase II and two Phase III studies. Univariate analysis based on data from all microbiologically evaluable patients in these studies and from those patients with S. aureus demonstrated significant relationships between %ƒT > MIC and microbiological response. Results of this analysis confirmed that 600 mg every 12 h ceftaroline fosamil provides exposures associated with the upper plateau of the PK/PD relationship for efficacy [43]. To provide support for in vitro susceptibility test interpretive criteria for ceftaroline against S. aureus, as well as dose adjustment recommendations for renal impairment, PK/PD target attainment was evaluated for simulated patients administered ceftaroline fosamil 600 mg every 12 h and simulated patients with renal impairment administered various dosing regimens [40]. Using a previously developed population PK model, Monte Carlo simulation was used to generate ceftaroline plasma concentration profiles for simulated patients with normal renal function or mild, moderate or severe renal impairment, and %ƒT > MIC was calculated for ceftaroline at steady state. Percentages of simulated patients achieving %ƒT > MIC targets for S. aureus based on the murine thigh infection model were calculated by MIC. At an MIC of 125

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Table 2. Percentage of simulated patients with normal renal function achieving %fT > minimum inhibitory concentration targets by minimum inhibitory concentration following administration of ceftaroline fosamil 600 mg every 12 h. MIC (mg/ml)

%fT > MIC ‡26

%fT > MIC ‡36

%fT > MIC ‡51

0.125

100

100

100

0.25

100

100

99.8

0.5

100

99.8

97.1

1

99.7

97.9

76.2

2

95.9

74.5

28.8

4

46.8

14.6

2.15

8

0.65

0

0

16

0

0

0

Data taken from [40].

2 mg/ml, greater than 90% of simulated patients with normal renal function and mild renal impairment dosed with ceftaroline fosamil 600 mg every 12 h, moderate renal impairment dosed with ceftaroline fosamil 400 mg every 12 h and severe renal impairment dosed with ceftaroline fosamil 300 mg every 12 h achieved the %ƒT > MIC target associated with stasis for S. aureus (26%) in the murine thigh infection model (TABLE 2). At an MIC of 1 mg/ml using the same dose regimens, greater than 90% of simulated patients achieved the %ƒT > MIC target associated with 1-log kill for S. aureus (36%) in the murine thigh infection model, and greater than 90% of simulated patients achieved the %ƒT > MIC target associated with 2-log kill of S. aureus (51%) in the murine thigh infection model at an MIC of 0.5 mg/L (TABLE 2). Recommendations for dose adjustments for patients with renal impairment were also supported by the results of these analyses. Clinical studies CANVAS I & II studies

CANVAS (CeftAroliNe Versus vAncomycin in Skin and skin structure infections) 1 and 2 were two identically designed, multinational, multicenter, Phase III, double-blind, randomized controlled non-inferiority clinical studies designed to evaluate the safety and efficacy of ceftaroline fosamil monotherapy compared with vancomycin plus aztreonam therapy (NCT00424190 for CANVAS 1 and NCT00423657 for CANVAS 2) [44,45] in adults with cSSSIs. Patients included in these studies had severe enough infections that required hospitalization and parenteral antimicrobial therapy for 5 days or more. Patients had to have a clinically documented complicated skin infection (e.g., deep or extensive cellulitis, major abscess, wound infection or diabetes mellitus or peripheral vascular disease and cellulitis or abscess in the lower extremity) and three or more signs of infection (e.g., purulent discharge, erythema, heat or localized warmth, pain or tenderness, temperature >38˚C or hypothermia). Patients with 126

severe renal impairment, necrotizing fasciitis, gangrene, diabetic or decubitus ulcers with underlying osteomyelitis, endocarditis or septic arthritis were excluded. Patients were randomized 1:1 to receive ceftaroline fosamil or vancomycin plus aztreonam, and randomization was stratified by country. Ceftaroline fosamil 600 mg i.v. every 12 h and vancomycin 1 g plus aztreonam 1 g i.v. every 12 h days were administered for 5–14 days. Patients with CrCL of 31–50 ml/min received an adjusted dose of ceftaroline fosamil (400 mg i.v. every 12 h); the vancomycin dose was adjusted according to individual hospital guidelines. Aztreonam could be discontinued if no Gram-negative pathogen was identified or suspected. No oral step-down therapy was permitted. The primary objective of the CANVAS studies was to assess the non-inferiority of clinical cure rates in the clinically evaluable (CE) and modified intent-to-treat (MITT) populations at the test-of-cure (TOC) visit, which occurred 8 to 15 days after the last dose of study medication was given. The MITT population included all randomized patients who received any amount of study drug treatment. The microbiologically mMITT population included MITT patients who met clinical disease criteria for cSSSI and had at least one bacterial pathogen isolated from blood or the cSSSI site at baseline. The CE population included MITT patients who met clinical disease criteria for cSSSI, received a prespecified minimum amount of the study drug and for whom outcome information was available. The microbiologically evaluable (ME) population included the CE patients with at least one bacterial pathogen isolated from blood or the cSSSI site at baseline. Clinical cure was defined as complete resolution or improvement of infection such that antimicrobial therapy was no longer warranted. Noninferiority was determined if the lower limit of the 95% CI was above the prospectively defined margin of –10%. Of 1,378 patients enrolled in the two CANVAS studies, 693 patients received ceftaroline fosamil (TABLE 3). The mean age was 47.5 years and the majority of patients were white and 63% were male. At baseline, patients in ceftaroline and comparator groups had similar BMIs (median, 26.9 and 27.4, respectively), rates of diabetes mellitus (17.6 and 17.5%) and bacteremia 4.2 and 3.8%, respectively. Infection types were similar for the two treatment groups, and the most common infections diagnosed were cellulitis, major abscesses and infected wounds/ulcers. Baseline pathogens were similar in both treatment groups, with the most common pathogen isolated being S. aureus (with the proportion of MRSA being 40% in the ceftaroline group and 34% in the comparator group) [46]. The clinical cure rate for the ceftaroline group and comparator group at TOC in the CE population was 91.6 and 92.7% (difference -1.1%; 95% CI: -4.2 to 2.0%) and in the MITT population was 85.9 and 85.5%. Clinical cure rates from the mMITT were ceftaroline 88.7 versus comparator 87% for all S. aureus; ceftaroline 86.6 versus comparator 82.1% for MRSA and ceftaroline 90.2 versus comparator 90.3% for MSSA (TABLE 4). Among the 47 subjects with bacteremia clinical cure Expert Rev. Clin. Pharmacol. 7(2), (2014)

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Ceftaroline fosamil for the treatment of ABSSSI

rates in the CE population were 84.6% (22 of 26) for ceftaroline versus 100% (21 of 21) for vancomycin plus aztreonam. Four subjects in the ceftaroline-treated bacteremia group were classified as having experienced clinical failure: two due to a treatment-limiting AE leading to withdrawal of study drug (one episode of Clostridium difficile–associated diarrhea and 1 allergic rash), one because of the need for surgical intervention on study day 7 and one due to a resistant co-pathogen (P. aeruginosa) and failure to timely perform surgical intervention. The organisms isolated from these patients were S. aureus (two subjects), one organism from the Streptococcus anginosus group (one patient) and P. aeruginosa plus Morganella morganii as co-pathogens (one patient). Follow-up blood cultures indicated clearance of bacteremia in all four subjects [46]. In 2010, the FDA specified a new primary endpoint for ABSSSI of clinical response at study day 3 instead of at the traditional test of cure [47,48]. Clinical response at day 3 was defined as cessation of infection spread and absence of fever in adult patients with a lesion size of >75 cm2 and either deep and/or extensive cellulitis, major abscess or an infected wound. Using this FDA endpoint in evaluating the integrated CANVAS 1 and 2 study data, the integrated CANVAS 1 and 2 clinical response rates at day 3 were 74.0% (296/400) for ceftaroline and 66.2% (263/397) for vancomycin plus aztreonam (weighted difference, 7.7; 95% CI: 1.3–14.0% [49]. Per-pathogen day 3 response rates were higher for ceftaroline than vancomycin plus aztreonam for common skin pathogens. Most notably, day 3 response rates for S. aureus were 76.4% (188/246) for ceftaroline and 66.1% (156/236) for vancomycin plus aztreonam. Day 3 response rates for MSSA were 71.8% (102/142) for ceftaroline and 60.1% (92/153) for the comparator and for MRSA, response rates were 81.7% (85/104) and 77.4% (65/84) in the vancomycin and aztreonam group, respectively. For S. pyogenes, the response rates were similar between the two groups (53.2 and 57.1%, respectively). In summary, based on the collective data from both CANVAS clinical studies, the efficacy of ceftaroline was found to be non-inferior to combination therapy with vancomycin plus aztreonam in the treatment for adult patients with ABSSSI for each of the predefined primary endpoints, for subgroup analyses, and there was a trend for higher responses at the day 3 for post-hoc analyses suggested by the FDA. CAPTURE study

Clinical Assessment Program and Teflaro Utilization REgistry (CAPTURE) is a multicenter cohort study describing contemporary clinical use of ceftaroline fosamil by review of data from charts of treated patients for infections including ABSSSI in the US. The study was approved by each institution’s ethics committee. Data were collected at participating centers by random selection of patient charts of patients at least 18 years of age at time of treatment with ceftaroline fosamil and included demographic information, disease characteristics, pathogen characteristics, antibiotic use and outcomes. Eligible patients were those who had received ‡2 consecutive doses of ceftaroline fosamil between August 2011 and July informahealthcare.com

Drug Profile

Table 3. CANVAS study patient demographics. Characteristic

CANVAS I and II† Pooled MITT

Population

693

Age (median years; range)

48.0 (18–93)

Male sex (n; %)

444 (64.1)

Race (n; %) White

506 (73.0)

Black or African–American

48 (6.9)

Asian

6 (0.9)

Other/unknown

125 (18.0)

Region of enrollment (n; %) EU

147 (21.2)

Non-EU Europe

187 (27.0)

Latin America

56 (8.1)

USA

303 (43.7) 2

BMI (kg/m ) Median (range)

26.9 (14.1–74.1)

>30 (n; %)

222 (32.0)

Duration of therapy (mean days ± SD)

8.3 ± 3.2

Comorbid conditions (n; %) Diabetes mellitus

122 (17.6)

Peripheral vascular disease

93 (13.4)

Prior antimicrobial therapy

276 (39.8)

Includes patients with surgical procedures performed 24 h before the first dose or randomization and 48 h after the first dose. MITT: Modified intent-to-treat; SD: Standard deviation. † Data taken from [46].

2012 or, following a study protocol amendment, ‡4 consecutive doses of ceftaroline fosamil. Evaluable patients were those who had sufficient information to determine a clinical outcome of either clinical success or clinical failure. Clinical success was defined as clinical cure, with no further need for antibiotic therapy or clinical improvement with a switch to oral antibiotic therapy. Clinical failure was defined as discontinuation of ceftaroline fosamil due to an adverse event or insufficient therapeutic effect and switch to another i.v. antibiotic. In some cases, following a review of information where the patient was confirmed to be improving upon discontinuation of ceftaroline fosamil (with no evidence of failure), patient treatment was deemed as successful. In this study, 1030 patients treated for ABSSSI who were enrolled from August 2011 to February 2013 were included in the evaluable population [50]. Demographics & baseline characteristics

(TABLE 5)

The patient population was predominantly male (53%) and white (65%) [33]. The median age of patients was 59 years 127

Drug Profile

Beresford, Biek & Jandourek et al.

Table 4. CANVAS study clinical cure rate by medical history. Population, type of infection

CANVAS I and II† integrated analysis

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Cure rate (patients cured/ total patients; %) Clinically evaluable

559/610 (91.6)

Microbiologically evaluable

434/468 (92.7)

Clinical diagnosis Cellulitis deep/extensive

213/229 (93.0)

Major abscess

184/202 (91.1)

Infected wound (surgical)

73/84 (86.9)

Infected ulcer

48/53 (90.6)

Underlying comorbidity

Safety & tolerability

Diabetes mellitus

96/110 (87.3)

Peripheral vascular disease

80/90 (88.9)

Methicillin-resistant Staphylococcus aureus pathogen isolated‡

142/152 (93.4)

Methicillin-susceptible S. aureus pathogen isolated‡

212/228 (93.0)

Data taken from [46]. Pathogen isolates identified in microbiologically evaluable population.

† ‡

(range: 18.0–106.0), the mean weight was 97.5 kg and the median BMI was 33.6 kg/m2 (51.2% patients were obese [BMI ‡30 kg/m2]). Comorbidities included diabetes mellitus in 46% and peripheral vascular disease in 17% of patients, and both medical conditions were present in 12% of patients. Types of infections treated included deep/extensive cellulitis in 59% or patients, major abscesses in 19%, infected ulcers in 15% and infected surgical wounds 13%. The most common sites of infection were the leg/thigh (47%) and foot (24%). Antibiotics were given prior to ceftaroline fosamil in 78% of patients, most commonly vancomycin, penicillin and other cephalosporins. Concurrent antibiotics were used in 37% of patients with clindamycin, accounting for the majority of concurrent antibiotic use. The mean treatment duration with ceftaroline fosamil was 6 days (SD ± 5). A bacterial pathogen was isolated in 53% of patients, most commonly S. aureus with MRSA accounting for 24% of pathogens, and MSSA accounting for 11% of pathogens. Clinical outcomes

The overall clinical success rate for patients treated with ceftaroline fosamil was 85% (TABLE 6) [50]. Of note, clinical success was reported in 83% of patients with diabetes mellitus and in 88% of patients with obesity. By infection type, clinical success was 86% in patients with major abscesses, 85% in deep/ extensive cellulitis, 79% in infected surgical wounds and 79% in infected ulcers. For infections due to MRSA and MSSA, the 128

clinical success rates were similar at 80 and 84%, respectively. In patients treated with ceftaroline fosamil as monotherapy, the clinical success rate was 86%. For patients on ceftaroline fosamil who had concurrent antibiotic therapy, the clinical success rate was 84%. In patients infected with MRSA and treated with ceftaroline fosamil monotherapy, the clinical success rate was 83% and in those treated with ceftaroline fosamil and concurrent antibiotics it was 76%. In summary, this data on the contemporary clinical use of ceftaroline fosamil for the treatment of ABSSSI show that it is used in patients with comorbidities including diabetes mellitus, peripheral vascular disease and obesity. Of note is that the percent of patients with diabetes in this observational study is almost twice that reported in the two CANVAS studies. This data further support the clinical utility of ceftaroline fosamil in the clinic.

In general, the cephalosporin antibiotics are well-tolerated, and adverse effects are found in general categories including hypersensitivity reactions, gastrointestinal effects, hematologic changes, hepatotoxicity, nephrotoxicity and neurotoxicity. In the four large Phase III studies, ceftaroline fosamil was well-tolerated and the safety did not differ from that would be expected for cephalosporins. Its safety profile was found to be similar to that of the comparator agents used in the clinical trials, ceftriaxone and vancomycin plus aztreonam. In the Phase III studies, rash occurred in 3% of patients and urticaria and anaphylaxis were rare [51]. Overall, approximately 2% of patients without a history of a b-lactam allergy may have a reaction to a cephalosporin and in the ceftaroline fosamil Phase III studies patients with a history of a b-lactam allergy were excluded [52]. Approximately 5% of patients receiving ceftaroline fosamil in the clinical trials developed diarrhea. Since ceftaroline is not excreted by the biliary system, it does not have the colecystitis associated with ceftriaxone. Eosinophilia has been reported in up to 4% of patients treated with a cephalosporin and neutropenia and thrombocytopenia are rare; similar findings were observed with ceftaroline use. A positive Coombs test has also been reported with cephalosporins with varying frequencies, and for ceftaroline this finding was seen in 11% compared with 4% for the comparator agents, and none developed hemolytic anemia. Nephrotoxicity is uncommon with cephalosporins, and less than 1% of patients had a more than 50% decrease in creatinine clearance and none of the renal reactions were attributed to ceftaroline. With regard to neurotoxicity, headache and dizziness are commonly reported and for ceftaroline the rates were less than 5%. Hepatotoxicity is rarely seen with cephalosporins, and in the Phase III studies liver function abnormalities occurred in less than 3% of patients. Discontinuations of treatment with ceftaroline fosamil due to an adverse event occurred in approximately 3% of patients in the Phase III studies. Allergic reactions were the most common reason for discontinuation [51]. Specifically, in the integrated safety summary of CANVAS 1 and CANVAS 2, the incidences of treatment-emergent Expert Rev. Clin. Pharmacol. 7(2), (2014)

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Ceftaroline fosamil for the treatment of ABSSSI

Drug Profile

adverse events were similar between treatment groups [53]. The majority (>75%) of patients in the CANVAS studies had either no or mild adverse events. The adverse events most commonly reported were nausea, headache, diarrhea, pruritus and rash were most commonly reported treatment-emergent adverse events in ceftaroline-treated patients. Pruritus, nausea, headache, diarrhea and increased transaminase levels were the most common among vancomycin plus aztreonam-treated patients. The rate of discontinuation because of adverse events was low in the CANVAS studies (3.0% in the ceftaroline fosamil group and 4.8% in the vancomycin plus aztreonam group). Hypersensitivity reactions resulted in more discontinuations in the vancomycin/aztreonam group than in the ceftaroline fosamil group. Serious adverse events were similar between ceftarolineand vancomycin/aztreonam-treated patients (4.3 vs 4.1%, respectively); none were related to study drug [53]. Nearly all systemic antibacterial agents carry a risk of Clostridium difficile-associated diarrhea, and this occurred in two patients in the ceftaroline fosamil group in the CANVAS studies [46]. Additionally, a study of fecal specimen cultures [54] supports the low impact of ceftaroline on fecal flora. In this study, 12 healthy subjects aged 20 to 41 years received ceftaroline fosamil 600 mg i.v. every 12 h for 7 days and ceftaroline was not found to have a significant impact on the intestinal microflora. In a thorough QTc study, there was no clinically meaningful effect of ceftaroline fosamil on the QTc interval following a single supratherapeutic dose of 1500 mg in healthy subjects [55].

Table 5. CAPTURE study patient demographics.

Microbiology surveillance studies

Includes patients with surgical procedures performed 24 h before the first dose or randomization and 48 h after the first dose. SD: Standard deviation. † Data taken from [50].

In vitro susceptibility

In 2013, the FDA susceptibility interpretive criteria (breakpoints) for ceftaroline were revised in line with those published by Clinical Laboratory Standard Institute (CLSI) [28,56]. CLSI breakpoints for ceftaroline for S. aureus include intermediate and resistant categories and were based in part on PK/PD target attainment and in view of the distributions of wild-type isolates, and a desire to avoid confusion for interpretations by clinical testing laboratories. Breakpoints for streptococci and Haemophilus influenzae were increased relative to the 2010 FDA breakpoints based primarily on PK/PD target attainment considerations and the low MIC values for the wild-type distributions of isolates. FDA/CLSI and European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for ceftaroline are listed in TABLE 7. The in vitro activity of ceftaroline has been monitored against current clinical isolates from across the US and worldwide since 2008 in the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. As a part of this program, clinical isolates (one per patient) from a large number of centers are submitted to a central reference laboratory (JMI Laboratories, North Liberty, IA) for broth microdilution MIC testing with ceftaroline and a large number of comparator agents according to CLSI reference methods, and susceptibilities are assessed according to current breakpoints. The in vitro activities of ceftaroline against clinical isolates obtained in the AWARE informahealthcare.com

Characteristic

CAPTURE† evaluable population

Population

1030

Age (median years; range)

59.0 (18–106)

Male sex (n; %)

551 (53.5)

Race (n; %) White

672 (65.2)

Black or African–American

98 (9.5)

Asian

14 (1.4)

Other/unknown

246 (23.9)

Region of enrollment (n; %) USA

1,030 (100)

BMI (kg/m2) Median (range)

31.1 (12.5–96.3)

>30 (n; %)

527 (51.2)

Duration of therapy (mean days ± SD)

6.0 (4.9)

Comorbid conditions (n; %) Diabetes mellitus

471 (45.7)

Peripheral vascular disease

178 (17.3)

Prior antimicrobial therapy, number (%)

798 (77.5)

program in 2010 from patients with cSSSI infections in the US, the European Union, Israel, Greece and Turkey, the Asia-Pacific region and South Africa, and Latin America are shown in TABLE 8. The in vitro antibacterial activity of ceftaroline against clinical isolates collected from patients with cSSSI from 65 centers located across the US in 2010 is summarized in TABLE 8. Of the 1114 S. aureus isolates tested, 51.5% were oxacillin-(methicillin) resistant (MRSA). Ceftaroline was active against MRSA (MIC90, 1 mg/ml; 99.3% S [susceptible]) and MSSA isolates (MIC90, 0.25 mg/ml; 100.0% S). The highest MIC was 2 mg/ml (0.4% of all S. aureus isolates; data not shown), which is intermediate susceptible according to CLSI/FDA breakpoints. Ceftaroline had potent activity against b-hemolytic streptococci S. pyogenes and S. agalactiae with MIC90 values £0.015 mg/ml (100% S). Ceftaroline is also active against many Gram-negative pathogens, including Enterobacteriaceae common in cSSSI. Ceftaroline is not active against isolates producing ESBL, carbapenemase, metallo-b-lactamase or overexpressing AmpC b-lactamase enzymes. The MIC90 values reflect the percentage of isolates that produce these b-lactamases. For all US E. coli isolates in 2010, the MIC90 was 32 mg/ml (80.3% S), for K. pneumoniae 0.5 mg/ml and for K. oxytoca 8 mg/ml. In 129

Drug Profile

Beresford, Biek & Jandourek et al.

Table 6. CAPTURE study clinical cure rate by medical history. Population, type of infection

CAPTURE† analysis Cure rate (patients cured/total patients; %)

Clinically evaluable

876/1030 (85.0)

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Clinical diagnosis Cellulitis deep/extensive

511/603 (84.7)

Major abscess

168/195 (86.2)

Infected wound (surgical)

103/130 (79.2)

Infected ulcer

123/155 (79.4)

Underlying comorbidity Diabetes mellitus

391/471 (83.0)

Peripheral vascular disease

138/178 (77.5)

Methicillin-resistant Staphylococcus aureus pathogen isolated

199/248 (80.2)

Methicillin-susceptible S. aureus pathogen isolated

96/114 (84.2)

tested, 33.8% were methicillin-resistant. The ceftaroline MIC90 value for all S. aureus was 1 mg/ml (93.4% S), and for MRSA and MSSA it was 2 mg/ml (80.6% S) and 0.25 mg/ml (100% S), respectively. Similar to other regions, the activity of ceftaroline against b-hemolytic streptococci from the Asia Pacific and South Africa is high, with MIC90 values £0.015 mg/ml. The variation in overall MRSA rate ranged from as low as 26.7% in South Africa and 27.8% in Australia to 77.4% in Singapore. When tested against the combined set of MRSA, skin and respiratory isolates from Asia Pacific and South Africa, ceftaroline MIC values ranged from 0.25 to 2 mg/ml (MIC50/90, 1/2 mg/ml). All MRSA isolates were inhibited at a ceftaroline MIC of £2 mg/ml, and 80.6% were inhibited at ceftaroline MIC of £1 mg/ml, the susceptible breakpoint established by CLSI, EUCAST and US-FDA [58]. Activity against Enterobacteriaceae is limited by the frequent occurrence of ESBL-producing isolates in these regions. The MIC90 value for both E. coli and K. pneumoniae is >32 mg/ml with 32 and 62.5% susceptible, respectively. Latin America AWARE surveillance

contrast, the MIC90 of ceftaroline for non-ESBL, non-AmpCoverexpressing isolates in the US of E. coli, K. pneumoniae and K. oxytoca was £0.5 mg/ml with susceptibilities ‡96% (TABLE 8). ESBL-phenotype isolates typically have MIC90 values >16 mg/ml (data not shown). Ceftaroline has little activity against most isolates of P. aeruginosa and A. baumannii.

A total of 623 cSSSI isolates were collected from five countries in Latin America in 2010 in the AWARE program. Of the 370 isolates of S. aureus tested, 50.3% were methicillin-resistant. The MIC90 for all S. aureus was 2 mg/ml (84.6% S) and for MRSA and MSSA it was 2 mg/ml (69.4% S) and 0.25 mg/ml (100% S), respectively (TABLE 8). Ceftaroline was very active against the limited numbers of isolates of b-hemolytic streptococci that were tested (MIC90 values of 0.015 mg/ml). Similar to Enterobacteriaceae from the Asia-Pacific region, isolates of E. coli and K. pneumoniae from Latin America often produced ESBL enzymes and MIC90 values were correspondingly higher (>32 mg/ml), with overall susceptibilities of 55 and 32.8%, respectively.

European AWARE surveillance

Development of resistance

A total of 2263 S. aureus isolates from patients with cSSSI infections collected from 19 countries in Europe and the Middle East in 2010 are reported [57]. Of the 1423 S. aureus isolates, 30.3% were methicillin-resistant (TABLE 8). The ceftaroline MIC90 for all S. aureus was 1 mg/ml (97.4% S according to EUCAST breakpoints) and 100% of isolates were inhibited at £2 mg/ml. Ceftaroline showed potent in vitro activity against both MRSA (MIC902 mg/ml, 88.8% S) and MSSA (MIC900.25 mg/ml, 100% S). Ceftaroline was very active against b-hemolytic streptococci (MIC90 £0.015 mg/ml, 100% S). Activity against E. coli, K. pneumoniae and K. oxytoca was somewhat lower than for US isolates, with MIC90 values >32 mg/ml, reflecting a greater percentage of b-lactamase-producing strains. MIC90 values for the non-ESBL-phenotype isolates were £1 mg/ml, with susceptibilities >88% (TABLE 8).

Spontaneous mutants of S. aureus with MICs elevated by more than four times are not readily selected in vitro (frequencies typically 0.25

£0.5

‡26

Haemophilus influenzae† (CABP isolates only)

£0.5

£0.03

>0.03

£0.5

‡30

Enterobacteriaceae‡

£0.5

£0.5

>0.5

£0.5

1

‡2

I

Disk diffusion zone diameter (mm)

R

S

I

R

S

I

R

>1

£1

2

‡4

‡24

21–23

£20

20–22

£19

1

‡2

‡23

The current absence of resistant isolates precludes defining any results other than ‘Susceptible’. Isolates yielding MIC results other than ‘Susceptible’ should be submitted to a reference laboratory for further testing. ‡ Clinical efficacy was shown for the following Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae and Klebsiella oxytoca. CLSI: Clinical Laboratory Standards Institute; EUCAST: European Committee on Antimicrobial Susceptibility Testing; I: Intermediate; MIC: Minimum inhibitory concentration; R: Resistant; S: Susceptible. Data taken from [28,67]. †

rabbit endocarditis and osteomyelitis using human-simulated exposures of 600 mg ceftaroline fosamil every 12 h against S. aureus isolates, including those resistant or hetero-resistant to vancomycin [61–64]. In a rabbit in vivo endocarditis model comparing ceftaroline to daptomycin and tigecycline against MRSA, ceftaroline was found to be most active against a heterogeneous glycopeptide-intermediate S. aureus strain [61] and was superior to daptomycin in terms of sterilization of the vegetation [63]. The murine thigh model was employed to characterize the in vivo time course of antibacterial activity of ceftaroline against a large number of isolates of S. aureus using ceftaroline-simulating human exposure following dosing with ceftaroline fosamil 600 mg every 12 h and produced a 0.95 to ‡3 log10 colony-forming unit/ml reduction after 24 h against all isolates in the neutropenic thigh infection model, and a reduction in bacterial density was observed at the highest MIC of 4 mg/ml equivalent to an ƒT > MIC exposure of 27.5 [65]. The same mouse thigh infection model simulating 600 mg every 12 h exposures of ceftaroline in humans has also been used in studies of Enterobacteriaceae (E. coli, K. pneumoniae, K. oxytoca), with ceftaroline MICs ranging from 0.25 to 32 mg/ml [66]. In the neutropenic mice model, reductions in bacterial counts of 0.65 to 2.36 log10 colony-forming unit were observed for 18/20 Enterobacteriaceae isolates with MIC values £1 mg/ml. The findings from these animal model studies support the FDA-approved susceptible breakpoints of £1 mg/ml for S. aureus and £0.5 mg/ml for Enterobacteriaceae. Expert commentary

With the significant burden of disease attributable to ABSSSI and the increasing incidence of infections due to informahealthcare.com

MRSA, including community-associated MRSA, it is important to have treatment options. A new antibiotic available to treat these serious infections is ceftaroline fosamil. Ceftaroline has a predictable PK profile and has minimal potential for drug–drug interactions. Because it is primarily eliminated by the kidneys, dosage adjustment of ceftaroline fosamil is warranted in subjects with moderate or severe renal impairment or end-stage renal disease. PK/PD analysis for efficacy of ceftaroline fosamil in patients with ABSSSI demonstrated that %ƒT > MIC was significantly associated with microbiological response. Results of PK/PD target attainment analyses support the current FDA and CLSI in vitro susceptibility test interpretive criteria for ceftaroline against S. aureus and also support recommendations for dose adjustments of ceftaroline fosamil in patients with renal impairment. In the CANVAS 1 and 2 Phase III clinical studies, ceftaroline demonstrated high clinical success rates in treating ABSSSI, and contemporary use of ceftaroline continues to support its role for the treatment of these infections. In the Phase III studies, ceftaroline fosamil was non-inferior compared with vancomycin and aztreonam at test-of-cure and at day 3 for the treatment of ABSSSI. Ceftaroline has demonstrated high clinical success for infections associated with either MRSA or MSSA. Ceftaroline has a safety profile reflective of the cephalosporin class, and few patients discontinued ceftaroline fosamil treatment due to adverse events. Ceftaroline fosamil administered intravenously to adults at a dosage of 600 mg every 12 h was efficacious and well-tolerated for the treatment of ABSSSI. Ceftaroline fosamil provides a monotherapy alternative for the treatment of ABSSSI. 131

132

100 7 100 5 93.9 0.25 33 97.3 0.25 37 Non-ESBL phenotype

Data taken from [68]. ‡ Data on file. § CLSI/FDA 2013 breakpoints [67]. { Data taken from [57]. # EUCAST 2013 breakpoints [69]. APAC: Australia, Hong Kong, China, Korea, Malaysia, Singapore, Thailand and South Africa; CLSI: Clinical Laboratory Standards Institute; ESBL: Extended spectrum beta-lactamase; EU: Belgium, Czech Republic, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Romania, Russia, Slovenia, Spain, Sweden, UK, Ukraine, Greece, Israel and Turkey; LA: Argentina, Brazil, Chile, Columbia, and Mexico; MIC: Minimum inhibitory concentration.

8 100 5 72.1 >32 43 83.7 8 43 Klebsiella oxytoca (all)

†

87.5

95.7 0.12 23 100 0.25 54 88.0 1 83 100 42 Non-ESBL phenotype

0.12

32.8 >32 67 62.5 >32 88 52.5 >32 139 91.5 47 Klebsiella pneumoniae (all)

0.5

98.5 0.25 67 89.6 1 48 90.3 0.5 227 96.4 0.25 55 Non-ESBL phenotype

55.0 >32 120 31.9 >32 138 63.5 >32 323 80.3 66 Escherichia coli (all)

32

100 0.015 34 100 0.03 25 100 0.015 141 100 174 Streptococcus agalactiae

0.015

100 0.015 24 100 £0.008 62 100 £0.008 100 183 Streptococcus pyogenes

£0.008

194

69.4 2 186 80.6 2 211 88.8 2 331 99.3 574 Methicillin-resistant

1

100 0.25 184 100 0.25 413 100 0.25 1092 100 540 Methicillin-susceptible

0.25

84.6 2 370 93.4 1 624 97.4 1 1423 99.6 1114

1

Beresford, Biek & Jandourek et al.

Staphylococcus aureus (all)

%S (EUCAST)# MIC90 (mg/ml) Subjects (n)

MIC90 (mg/ml)

%S (CLSI)§

Subjects (n)

MIC90 (mg/ml)

%S (EUCAST)#

Subjects (n)

MIC90 (mg/ml)

%S (EUCAST)#

Subjects (n)

LA‡ APAC‡ EU‡,{ USA†,‡ Species

Table 8. Activity of ceftaroline against skin isolates from 2010 Assessing Worldwide Antimicrobial Resistance Evaluation surveillance.

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Drug Profile

Five-year view

The increasing number of skin infections poses a significant economic burden on our healthcare system. New outcome measurements established by the Centers for Medicare & Medicaid Services for the purpose of aligning Core Quality Measurements with high-quality health care may penalize institutions for high patient readmission rates within a specific period of time. This is a serious concern for an already financially strained healthcare system. Antimicrobial resistant staphylococcal skin infections, for example, are increasingly becoming a more frequent cause of patient-related hospitalization and hospital readmissions. Serious ABSSSIs will need to be evaluated more thoroughly, and treated, either empirically or as first line, with an antimicrobial agent that is both safe and effective across a broad spectrum of pathogens. Ceftaroline fosamil is the only cephalosporin approved by the FDA for treatment of ABSSSI caused by MRSA and Gram-negative pathogens such as E. coli, K. pneumoniae and K. oxytoca. Antibiotic agents such as vancomycin, daptomycin and linezolid are currently the mostly frequently used antimicrobials for the treatment MRSArelated infections. These agents, however, are often associated with serious side-effects or treatment-limiting toxicities. Over time, frequent misuse, overprescribing and lack of appropriate antimicrobial stewardship has led to increasing lack of activity against both Gram-negative pathogens and resistant Gram-positive pathogens. Isolates of S. aureus with ceftaroline MICs >2 mg/ml (intermediate susceptible according to FDA breakpoints, resistant according to EUCAST) are rare in the USA, but clonal types conferring MIC 2 mg/ml are more common in some other countries. Selection of isolates with MICs increased ‡fourfold occurs with low frequency in vitro for S. aureus. Based on ceftaroline fosamil in vitro studies, minimal potential for drug-drug interactions are apparent. In a post-hoc early treatment response analysis of CANVAS I and II trials, ceftaroline fosamil monotherapy had a numerically higher clinical response than vancomycin/ aztreonam combination therapy on day 3, suggesting that ceftaroline fosamil monotherapy may provide better benefit in the treatment of ABSSSI. Current development of newer antimicrobial agents still remains somewhat limited. Anti-MRSA agents currently in development such as oritavancin and dalbavancin may possibly allow for onedose or even once-weekly dosing while providing broad-spectrum coverage. As with vancomycin and ceftriaxone, clinicians will soon have access to Expert Rev. Clin. Pharmacol. 7(2), (2014)

Ceftaroline fosamil for the treatment of ABSSSI

generic forms of currently branded agents. This places even more emphasis on the appropriate prescribing of antimicrobials, along with closely followed antibiotic stewardship practices, to further prevent the development of multidrug-resistant organisms. Information resource

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www.teflaro.com. This site is intended for US Healthcare Professionals only www.zinforo.com. This site is intended for outside the US Healthcare Professionals

Drug Profile

Financial & competing interests disclosure

E Beresford, Y Mawal and T Riccobene are employees of Forest Research Institute, Inc.; D Biek, A Jandourek and H David Friedland are employees of Cerexa, Inc. Both companies are US subsidiaries of Forest Laboratories, Inc. The authors meet the criteria for authorship as recommended by International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions and were involved at all stages of manuscript development. No writing and editorial assistance was provided by Forest Laboratories, Inc.

Key issues • The USA has witnessed an epidemic of skin and skin structure infections, which can be life-threatening, and may require surgery and hospitalization. Recently, the US FDA has provided guidance on antibiotic development for acute bacterial skin and skin structure infections (ABSSSI). • Ceftaroline fosamil is the only cephalosporin approved by the FDA for treatment of ABSSSI caused by methicillin-resistant Staphylococcus aureus. Ceftaroline fosamil administered intravenously to adults at a dosage of 600 mg every 12 h was efficacious and well-tolerated for the treatment of ABSSSI. Safety and efficacy of ceftaroline fosamil has not been established in children. • Ceftaroline fosamil has demonstrated bactericidal activity against both Gram-positive and Gram-negative pathogens. • Ceftaroline fosamil has minimal potential for drug–drug interactions. • Ceftaroline fosamil provides a monotherapy alternative for the treatment of ABSSSI specifically as a first-line agent.

in hospitalized patients: epidemiology and microbiological, clinical, and economic outcomes. Infect Control Hosp Epidemiol 2007;28:1290-8

References Papers of special note have been highlighted as: • of interest •• of considerable interest 1.

Hersh AL, Chambers HF, Maselli JH, et al. National trends in ambulatory visits and antibiotic prescribing for skin and soft-tissue infections. Arch Intern Med 2008;168: 1585-91

2.

Edelsberg J, Taneja C, Zervos M, et al. Trends in US hospital admissions for skin and soft tissue infections. Emerg Infect Dis 2009;15:1516-8

3.

Ho VP, Eachempati SR, Barie PS. Surgical infections of skin and soft tissue. In: Britt LD, Peitzman AB, Barie PS, Jurkovich JJ, editors. Acute care surgery. Lippincott, Williams and Wilkins, Philadelphia, PA, USA;2012. p.589-604

4.

5.

6.

Hatoum HT, Akhras KS, Lin SJ. The attributable clinical and economic burden of skin and skin structure infections in hospitalized patients: a matched cohort study. Diagn Microbiol Infect Dis 2009;64: 305-10 Zervos MJ, Freeman K, Vo L, et al. Epidemiology and outcomes of complicated skin and soft-tissue infections in hospitalized patients. J Clin Microbiol 2012;50:238-45 Lipsky BA, Weigelt JA, Gupta V, et al. Skin, soft-tissue, bone, and joint infections

informahealthcare.com

7.

8.

McCaig LF, McDonald LC, Mandal S, et al. Staphylococcus aureus-associated skin and soft tissue infections in ambulatory care. Emerg Infect Dis 2006;12:1715-23 Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999-2005. Emerg Infect Dis 2007;13:1840-6

13.

Hazlewood KA, Brouse SD, Pitcher WD, Hall RG. Vancomycin-associated nephrotoxicity: grave concern or death by character assassination? Am J Med 2010;123:e1-7.Review

14.

Forouzesh A, Moise PA, Sakoulas G. Vancomycin ototoxicity: a reevaluation in an era of increasing doses. Antimicrob Agents Chemother 2009;53:483-6

15.

Hiramatsu K. The emergence of Staphylococcus aureus with reduced susceptibility to vancomycin in Japan. Am J Med 1998;104(Suppl 5A):7S-10S

9.

Jacqueline C, Caillon J, Boutoille D. Management of MRSA/GISA, VISA Endocarditis. Curr Infect Dis Rep 2013;15: 329-34

16.

Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant Staphylococcus aureus in the United States, 2002-2006. Clin Infect Dis 2008;46:668-74

10.

Chuang YY, Huang YC. Molecular epidemiology of community-associated methicillin-resistant Staphylococcus aureus in Asia. Lancet Infect Dis 2013;13: 698-708

17.

Abena P, Mathieux V, Scheiff J, et al. Linezolid and reversible myelosuppression. JAMA 2001;286:1973

18.

Bressler A, Zimmer S, Gilmore J, Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 2004;4:528-31

19.

Lodise TP, Graves J, Evans A, et al. Relationship between vancomycin MIC and failure among patients with methicillinresistant Staphylococcus aureus bacteremia treated with vancomycin. Antimicrob Agents Chemother 2008;52:3315-20

11.

12.

Anstead GM, Cadena J, Javeri H. Treatment of infections due to resistant Staphylococcus aureus. Methods Mol Biol 2014;1085:259-309 Wong-Beringer A, Joo J, Tse E, Beringer P. Vancomycin-associated nephrotoxicity: a critical appraisal of risk with high-dose therapy. Int J Antimicrob Agents 2011;37: 95-101

133

Drug Profile 20.

Rucker J, Hamilton S, Bardenstein D, et al. Linezolid-associated toxic optic neuropathy. Neurology 2006;66:595-8

21.

Lawrence KR, Gillman PK. Serotonin toxicity associated with the use of Linezolid: a review of post-marketing data. Clin Infect Dis 2006;42:1578-83.Review

22.

Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Michigan University on 11/13/14 For personal use only.

Beresford, Biek & Jandourek et al.

US FDA. Cubicin (daptomycin) Prescribing information 2012. Available from: www.cubist.com/downloads/ PrescribingInformation.pdf [Last accessed 15 August 2013]

23.

Stevens DL, Dotter B, Madaras-Kelly K. A review of linezolid: the first oxazolidinone antibiotic. Expert Rev Anti-infective Ther 2004;2:51-9

24.

Kaye KS, Engemann JJ, Fraimow HS, et al. Pathogens resistant to antimicrobial agents: epidemiology, molecular mechanisms, and clinical management. Infect Dis Clin N Am 2004;18:467-511

25.

26.

27.

28.

Jabe´s D, Brunati C, Candiani G, et al. Efficacy of the new antibiotic NAI-107 in experimental infections induced by multidrug-resistant Gram-positive pathogens. Antimicrob Agents Chemother 2011;55:1671-6

31.

Zhanel GG, Sniezek G, Schweizer F, et al. Ceftaroline: a novel broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Drugs 2009;69:809-31

32.

Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2011;52:1156-63

33.

Ishikawa T, Matsunaga N, Tawada H, et al. TAK-599, a novel-phosphono type prodrug of anti-MRSA cephalosporin T-91825: synthesis, physicochemical and pharmacological properties. Bioorg Med Chem 2003;11:2427-37

34.

Lodise TP, Low DE. Ceftaroline fosamil in the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. Drugs 2012;72:1473-93

35.

Villegas-Estrada A, Lee M, Hesek D, et al. Co-opting the cell wall in fighting methicillin-resistant Staphylococcus aureus: potent inhibition of PBP 2a by two antiMRSA beta-lactam antibiotics. J Am Chem Soc 2008;130:9212-13

Rybak JM, Barber KE, Rybak MJ. Current and prospective treatments for multidrugresistant gram-positive infections. Expert Opin Pharmacother 2013;14:1919-32. Review

36.

Gentry CA, Nguyen AT. An evaluation of hyperkalemia and serum creatinine elevation associated with different dosage levels of outpatient trimethoprim-sulfamethoxazole with and without concomitant medications. Ann Pharmacotherapy 2013. [Epub ahead of print]

37.

Moisan H, Pruneau M, Malouin F. Binding of ceftaroline to penicillin-binding proteins of Staphylococcus aureus and Streptococcus pneumoniae. J Antimicrob Chemother 2010;65:713-16

38.

Otero LH, Rojas-Altuve A, Llarrull LI, et al. How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci USA 2013;110:16808-13

US FDA. TeflaroTM (ceftaroline fosamil) package insert. Forest Pharmaceuticals, Inc. Updated July 2013. Available from: www. frx.com/pi/teflaro_pi.pdf [Last accessed 10 July 2013]

•

Ceftaroline fosamil US package insert

29.

EMEA. Teflaro Zinforo summary of product characteristics 2012. Available from: www.ema.europa.eu/docs/en_GB/ document_library/EPAR_-_Public_ assessment_report/human/002252/ WC500132587.pdf [Last accessed 25 June 2013]

•

Ceftaroline fosamil Europe package insert

30.

Saravolatz L, Pawlak J, Johnson L. In vitro activity of ceftaroline against communityassociated methicillin-resistant, vancomycinintermediate, vancomycin-resistant, and daptomycin-non-susceptible Staphylococcus

134

Antimicrob Agents Chemother 2013; In press

aureus isolates. Antimicrob Agents Chemother 2010;54:3027-30

Kosowska-Shick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other beta-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother 2010;54:1670-7

39.

Riccobene TA, Su SF, Rank D. Single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics of ceftaroline fosamil in combination with avibactam in healthy subjects. Antimicrob Agents Chemother 2013;57:1496-504

40.

Van Wart SA, Ambrose PG, Rubino CM, et al. Pharmacokinetic pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.

41.

Van Wart SA, Forrest A, Khariton T, et al. Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or communityacquired bacterial pneumonia. J Clin Pharmacol 2013;53:1155-67

42.

Andes D, Craig WA. Pharmacodynamics of a new cephalosporin, PPI-0903 (TAK-599), active against methicillin-resistant Staphylococcus aureus in murine thigh and lung infection models: identification of an in vivo pharmacokinetic–pharmacodynamic target. Antimicrob Agents Chemother 2006;50:1376-83

43.

Bhavnani SM, Hammel JP, Van Wart SA, et al. Pharmacokinetic-pharmacodynamic analysis for efficacy of ceftaroline fosamil in patients with complicated skin and skin structure infections (Abstract A2-552). 51st Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2011

44.

Corey GR, Wilcox MH, Talbot GH, et al. CANVAS 1: the first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010; 65(Suppl 4):iv41-51

••

Pivotal study I demonstrating efficacy of ceftaroline fosamil for treatment of ABSSSI.

45.

Wilcox MH, Corey GR, Talbot GH, et al. CANVAS 2 investigators. CANVAS 2: the second Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010;65(Suppl 4): iv53-65

••

Pivotal study II demonstrating efficacy of ceftaroline fosamil for treatment of ABSSSI.

46.

Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, doubleblind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010;51:641-50

••

Integrated analysis of pivotal trial of ceftaroline fosamil for treatment of ABSSSI

47.

US FDA. US Food and Drug Administration, Guidance for Industry: non-Inferiority Clinical Trials. US Food and

Expert Rev. Clin. Pharmacol. 7(2), (2014)

Ceftaroline fosamil for the treatment of ABSSSI

Drug Administration. March 2010. Available from: www.fda.gov/downloads/ Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ UCM202140.pdf [last accessed 10 July 2013]

Expert Review of Clinical Pharmacology Downloaded from informahealthcare.com by Michigan University on 11/13/14 For personal use only.

48.

49.

50.

US FDA. US Food and Drug Administration, Guidance for Industry: acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment. October 2013. Available from: www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatory Information/Guidances/UCM071185.pdf [last accessed 21 November 2013] Friedland HD, O’Neal T, Biek D, et al. CANVAS 1 and 2: analysis of clinical response at day 3 in two phase 3 trials of ceftaroline fosamil versus vancomycin plus aztreonam in treatment of acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 2012;56: 2231-6 Ramani A, Bagheri F, Vazquez J, et al. Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections (ABSSSI) including treatment of methicillin-resistant Staphylococcus aureus (MRSA): experience from the CAPTURE Study (Abstract K-188). 53rd Interscience Conference on Antimicrobial Agents and Chemotherapy; 2013

••

Data supporting the clinical utility of ceftaroline fosamil in the clinic.

51.

File TM Jr, Wilcox MH, Stein GE. Summary of ceftaroline fosamil clinical trial studies and clinical safety. Clin Infect Dis 2012;55(Suppl 3):S173-80

••

Safety and tolerability of ceftaroline fosamil treatment.

52.

Kelkar PS, Li JT. Cephalosporin allergy. N Engl J Med 2001;345:804-9

53.

Corrado ML. Integrated safety summary of CANVAS 1 and 2 trials: Phase III, randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010;65(Suppl 4):iv67-71

54.

Panagiotidis G, Ba¨ckstro¨m T, Asker-Hagelberg C, et al. Effect of ceftaroline on normal human intestinal

informahealthcare.com

acute osteomyelitis. J Antimicrob Chemother 2010;65:1749-52

microflora. Antimicrob Agents Chemother 2010;54:1811-14 55.

Riccobene TA, Rekeda L, Rank D, et al. Evaluation of the effect of a supratherapeutic dose of intravenous ceftaroline fosamil on the corrected QT interval. Antimicrobial Agents Chemother 2013;57:1777-83

56.

Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing; twentythird information supplement. CLSI document M100-S23. Wayne, PA, USA. 2013

57.

Farrell DJ, Flamm RK, Sader HS, et al. Spectrum and potency of ceftaroline tested against leading pathogens causing skin and soft-tissue infections in Europe (2010). Int J Antimicrob Agents 2013;41:337-42

58.

Sader HS, Flamm RK, Jones RN. Antimicrobial activity of ceftaroline and comparator agents tested against bacterial isolates causing skin and soft tissue infections and community-acquired respiratory tract infections isolated from the Asia-Pacific region and South Africa (2010). Diagn Microbiol Infect Dis 2013;76:61-8

59.

60.

61.

62.

Mushtaq S, Warner M, Ge Y, et al. In vitro activity of ceftaroline (PPI-0903M, T-91825) against bacteria with defined resistance mechanisms and phenotypes. J Antimicrob Chemother 2007;60:300-11 Clark C, McGhee P, Appelbaum PC, Kosowska-Shick K. Multistep resistance development studies of ceftaroline in gram-positive and -negative bacteria. Antimicrob Agents Chemother 2011;55: 2344-51 Jacqueline C, Caillon J, Le Mabecque V, et al. In vivo efficacy of ceftaroline (PPI0903), a new broad-spectrum cephalosporin, compared with linezolid and vancomycin against methicillin-resistant and vancomycin-intermediate Staphylococcus aureus in a rabbit endocarditis model. Antimicrob Agents Chemother 2007;51: 3397-400 Jacqueline C, Amador G, Caillon J, et al. Efficacy of the new cephalosporin ceftaroline in the treatment of experimental methicillin-resistant Staphylococcus aureus

Drug Profile

63.

Jacqueline C, Amador G, Batard E, et al. Comparison of ceftaroline fosamil, daptomycin and tigecycline in an experimental rabbit endocarditis model caused by methicillin-susceptible, methicillin-resistant and glycopeptideintermediate Staphylococcus aureus. J Antimicrob Chemother 2011;66:863-6

64.

Jacqueline C, Caillon J, Le Mabecque V, et al. In vivo activity of a novel anti-methicillin-resistant Staphylococcus aureus cephalosporin, ceftaroline, against vancomycin-susceptible and -resistant Enterococcus faecalis strains in a rabbit endocarditis model: a comparative study with linezolid and vancomycin. Antimicrob Agents Chemother 2009;53:5300-2

65.

Keel RA, Crandon JL, Nicolau DP. Efficacy of human simulated exposures of ceftaroline administered at 600 milligrams every 12 hours against phenotypically diverse Staphylococcus aureus isolates. Antimicrob Agents Chemother 2011;55:4028-32

66.

Housman ST, Keel RA, Crandon JL, et al. Efficacy of human simulated exposures of ceftaroline against phenotypically diverse enterobacteriaceae isolates. Antimicrob Agents Chemother 2012;56:2576-80

67.

FDA breakpoints. Available from: www. accessdata.fda.gov/drugsatfda_docs/label/ 2013/200327s009lbl.pdf [Last accessed 10 July 2013

68.

Sader HS, Farrell DJ, Jones RN. Antimicrobial activity and spectrum of the novel cephalosporin ceftaroline tested against bacterial isolates causing skin and skin structure infections in usa medical centers (Abstract 592). Infectious Diseases Society of America (IDSA) 49th Annual Meeting; 20-23 October 2011; Boston, MA, USA. Available from: www.jmilabs. com/data/posters/IDSA2011%5C592.pdf [Last accessed 10 July 2013]

69.

EUCAST breakpoint. Available from: www. eucast.org/fileadmin/src/media/PDFs/ EUCAST_files/Breakpoint_tables/ Breakpoint_table_v_3.1.pdf [Last accessed 17 December 2013]

135