Comparing probability of target attainment against Staphylococcus aureus for ceftaroline fosamil, vancomycin, daptomycin, linezolid, and ceftriaxone in complicated skin and soft tissue infection using pharmacokinetic/pharmacodynamic models.

For recently licensed antibiotics, such as the cephalosporin ceftaroline fosamil, probability of target attainment (PTA) curves, showing the percentage of patients reaching a predefined pharmacokinetic (PK)/pharmacodynamic (PD) target at different bacterial minimum inhibitory concentrations (MICs), have been used to support and justify dose recommendations across patient populations. However, information on PTA for older antibiotics is limited. A retrospective analysis was conducted to construct PTA curves for 4 antibiotics against Staphylococcus aureus in patients with complicated skin and soft tissue infections (cSSTIs). PK models for vancomycin, linezolid, daptomycin, and ceftriaxone were selected from the literature based on large numbers of subjects with covariates representative of patients in Europe and/or the United States. An existing model was available for ceftaroline fosamil. Standard and high-dosage regimens were used to compare the PTA of each antibiotic at MIC values 0.03 to 64 mg/L for a simulated set of patients with cSSTI caused by S. aureus. These were compared to proportions of S. aureus isolates at each MIC from global surveillance data. Ceftaroline achieved PTAs >99.9% for bacteriostatic and bactericidal targets at the MIC90 (1 mg/L), whereas the comparators failed to achieve PTAs >90%, at bacteriostatic or bactericidal targets, even when clinical doses were increased beyond those recommended. PTA analysis can be used to compare different drugs with the same simulated patient dataset, subject to availability of an appropriate PK model and robust exposure targets. This analysis shows that some antibiotics commonly used to treat cSSTIs may fail to reach high PTAs relative to contemporary MIC90 estimates.

Ceftaroline fosamil therapy in patients with acute bacterial skin and skin-structure infections with systemic inflammatory signs: A retrospective dose comparison across three pivotal trials.

This post-hoc analysis compared the pharmacokinetics and clinical outcomes of ceftaroline fosamil 600 mg every 12 (q12h) versus every 8 hours (q8h) in patients with acute bacterial skin and skin-structure infection (ABSSSI) and signs of sepsis. Clinical outcomes at test-of-cure in patients with ABSSSI and systemic inflammatory signs/systemic inflammatory response syndrome (SIRS) as well as ceftaroline minimum inhibitory concentrations (MICs) against baseline pathogens were compared between the COVERS trial (ceftaroline fosamil 600 mg q8h, 2-h infusion) and the CANVAS 1 and 2 trials (ceftaroline fosamil 600 mg q12h, 1-h infusion). Ceftaroline exposure among patients in COVERS with or without markers of sepsis was compared using population pharmacokinetic modelling. In COVERS, 62% (312/506) and 41% (208/506) of ceftaroline fosamil-treated patients had ≥1 systemic inflammatory sign or SIRS, respectively, compared with 55% (378/693) and 22% (155/693), respectively, in the CANVAS trials. Clinical cure rates for the modified intent-to-treat population in COVERS and CANVAS were similar for ceftaroline fosamil-treated patients with ≥1 sign of sepsis [82% (255/312) and 85% (335/394)] and for those with SIRS [84% (168/199) and 85% (131/155)]. Ceftaroline MIC distributions were similar across trials. Sepsis did not affect predicted individual steady-state ceftaroline exposure. Clinical cure rates in patients with ≥1 systemic inflammatory sign or SIRS were comparable for both ceftaroline fosamil dosage regimens. Pathogen susceptibilities to ceftaroline were similar across trials. Ceftaroline exposure was not affected by disease severity. Ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most ABSSSI patients with sepsis [ClinicalTrials.gov ID: NCT01499277, NCT00424190, NCT00423657].

Ceftaroline fosamil doses and breakpoints for Staphylococcus aureus in complicated skin and soft tissue infections.

Objectives: To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L). Methods: A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT>MIC for stasis, 31% fT>MIC for 1 log10 kill and 35% fT>MIC for 2 log10 kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study. Results: The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L. Conclusions: The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Analysis of Potential ß-Lactam Surrogates To Predict In Vitro Susceptibility and Resistance to Ceftaroline for Clinical Isolates of Enterobacteriaceae.

Ceftaroline fosamil was approved by the United States Food and Drug Administration in 2010 and by the European Medicines Agency in 2012. As of April 2017, only one commercial antimicrobial susceptibility testing device offered a Gram-negative panel that included ceftaroline. This circumstance is unfortunate, as many clinical microbiology laboratories rely solely on commercial devices to generate in vitro antimicrobial susceptibility testing results for common bacterial pathogens. In lieu of device-based testing of clinical isolates of Enterobacteriaceae, laboratories wishing to test ceftaroline must either opt for disk diffusion testing or use a gradient strip; however, both alternatives interrupt laboratory workflow and require additional labor and expense. Identification of a reliable surrogate ß-lactam to predict in vitro susceptibility to ceftaroline may offer another interim solution as laboratories await availability of ceftaroline for testing on their commercial devices. We tested six ß-lactams (aztreonam, ceftazidime, ceftriaxone, cefotaxime, cefoxitin, and cefpodoxime) as potential surrogates for ceftaroline against a collection of 543 clinical isolates of Enterobacteriaceae selected to approximate the distribution of ceftaroline MICs observed in AWARE global surveillance studies conducted in 2013. All six potential surrogates generated very major error rates of 16.3% to 56.6%, far exceeding the accepted limit of 1.5% set by the Clinical and Laboratory Standards Institute (CLSI) and the United States Food and Drug Administration (FDA) Center for Devices and Radiological Health. Failure to identify a reliable surrogate to predict in vitro susceptibility and resistance to ceftaroline for clinical isolates of Enterobacteriaceae underscores the need for expedited addition of newer antimicrobial agents to commercial antimicrobial susceptibility testing devices.

A Phase III, randomized, controlled, non-inferiority trial of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in patients with complicated skin and soft tissue infection with systemic inflammatory response or underlying comorbidities.

OBJECTIVES: Increasing the ceftaroline fosamil dose beyond 600 mg every 12 h may provide additional benefit for patients with complicated skin and soft tissue infections (cSSTIs) with severe inflammation and/or reduced pathogen susceptibility. A Phase III multicentre, randomized trial evaluated the safety and efficacy of ceftaroline fosamil 600 mg every 8 h in this setting. METHODS: Adult patients with cSSTI and systemic inflammation or comorbidities were randomized 2:1 to intravenous ceftaroline fosamil (600 mg every 8 h) or vancomycin (15 mg/kg every 12 h) plus aztreonam (1 g every 8 h) for 5-14 days. Clinical cure was assessed at the test of cure (TOC) visit (8-15 days after the final dose) in the modified ITT (MITT) and clinically evaluable (CE) populations. Non-inferiority was defined as a lower limit of the 95% CI around the treatment difference greater than -10%. An MRSA-focused expansion period was initiated after completion of the main study. Clinicaltrials.gov registration numbers NCT01499277 and NCT02202135. RESULTS: Clinical cure rates at TOC demonstrated non-inferiority of ceftaroline fosamil 600 mg every 8 h versus vancomycin plus aztreonam in the MITT and CE populations: 396/506 (78.3%) versus 202/255 (79.2%) patients (difference -1.0%, 95% CI -6.9, 5.4) and 342/395 (86.6%) versus 180/211 (85.3%) patients (difference 1.3%, 95% CI -4.3, 7.5), respectively. In the expansion period, 3/4 (75%) patients treated with ceftaroline fosamil were cured at TOC. The frequency of adverse events was similar between groups. CONCLUSIONS: Ceftaroline fosamil 600 mg every 8 h was effective for cSSTI patients with evidence of systemic inflammation and/or comorbidities. No new safety signals were identified.

In vitro activity of Ceftaroline against bacterial pathogens isolated from patients with skin and soft tissue and respiratory tract infections in African and Middle Eastern countries: AWARE global surveillance program 2012-2014.

The objective of this report was to document antimicrobial susceptibility testing surveillance data for ceftaroline and comparative agents from the AWARE (Assessing Worldwide Antimicrobial Resistance Evaluation) global surveillance program for bacterial pathogens causing skin and soft tissue and respiratory tract infections in African and Middle Eastern countries from 2012 through 2014. Pathogen identities were confirmed by MALDI-TOF and antimicrobial susceptibility testing performed by CLSI broth microdilution methodology in a central laboratory. All methicillin-susceptible Staphylococcus aureus (MSSA) (n= 923; MIC90, 0.25 µg/mL) and 91.8% of methicillin-resistant S. aureus (MRSA) (n= 1161; MIC90, 1 µg/mL) tested were susceptible to ceftaroline. The maximum ceftaroline MIC observed for isolates of MRSA was 2 µg/mL. All Streptococcus pyogenes (n= 174; MIC90, 0.008 µg/mL), Streptococcus agalactiae (n= 44; MIC90, 0.015 µg/mL), Streptococcus pneumoniae (n= 351; MIC90, 0.25 µg/mL), and Haemophilus influenzae (n= 84; MIC90, ≤0.015 µg/mL) were susceptible to ceftaroline. Rates of susceptibility to ceftaroline among ESBL-negative Escherichia coli (n= 338), Klebsiella pneumoniae (n= 241), and Klebsiella oxytoca (n= 97) were 89.1% (MIC90, 1 µg/mL), 94.2% (MIC90, 0.5 µg/mL), and 99.0% (MIC90, 0.5 µg/mL), respectively.

Multi-center and multi-method evaluation of in vitro activities of ceftaroline against S. aureus.

This five-site study was performed to assess the reproducibility of ceftaroline MIC and disk results for Staphylococcus aureus. Three commercial broth microdilution, three gradient diffusion and ceftaroline 5µg disk diffusion methods were compared to a reference broth microdilution method against challenge isolates (n = 41) and isolates collected at four European sites (n = 30/site). For four MIC methods (Sensititre and three gradient diffusion methods), 99.0% of consolidated MIC results were within +/- 1 dilution of the reference MIC. Categorical agreement rates based on EUCAST breakpoints for the challenge isolates were 75.6-100% and for disk testing were 78.0-92.7%. There was no clear distinction between isolates with MIC results of 1 and 2mg/L with regard to variation in MIC or molecular genotyping results. The addition of an intermediate category for isolates with MIC results of 2mg/L would help to identify these isolates as borderline susceptible/non-susceptible isolates.

Ceftaroline fosamil versus ceftriaxone for the treatment of community-acquired pneumonia: individual patient data meta-analysis of randomized controlled trials.

BACKGROUND: We conducted a meta-analysis of clinical trials of adults hospitalized with pneumonia outcomes research team (PORT) risk class 3-4 community-acquired pneumonia (CAP) receiving ceftaroline fosamil versus ceftriaxone. METHODS: Three Phase III trials (clinicaltrials.gov registration numbers NCT00621504, NCT00509106 and NCT01371838) including 1916 hospitalized patients with CAP randomized 1:1 to empirical ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (1-2 g every 24 h) for 5-7 days were included in the meta-analysis. Primary outcome was clinical response at the test-of-cure visit (8-15 days after end of treatment) in the PORT risk class 3-4 modified ITT (MITT) and clinically evaluable (CE) populations. Data were tested for heterogeneity (χ(2) test) and, if not significant, results were pooled and OR and 95% CI constructed. A logistic regression analysis assessed factors impacting cure rate and treatment interactions. RESULTS: Clinical cure rates in each trial consistently favoured ceftaroline fosamil versus ceftriaxone, with no evidence of heterogeneity. In the meta-analysis, ceftaroline fosamil was superior to ceftriaxone in the MITT (OR: 1.66; 95% CI 1.34, 2.06; P < 0.001) and CE (OR: 1.65; 95% CI 1.26, 2.16; P < 0.001) populations. Results were consistent across various patient- and disease-related factors including patients' age and PORT score. Prior antimicrobial use within 96 h of starting study treatment was associated with diminished differences in cure rates between treatments. CONCLUSIONS: Ceftaroline fosamil was superior to ceftriaxone for empirical treatment of adults hospitalized with CAP. Receipt of prior antimicrobial therapy appeared to diminish the observed treatment effect.

In vitro activity of ceftaroline against bacterial pathogens isolated from skin and soft tissue infections in Europe, Russia and Turkey in 2012: results from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programme.

OBJECTIVES: The objective of this study was to analyse antimicrobial susceptibility testing data generated by the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) global surveillance programme for pathogens causing skin and soft tissue infections (SSTIs) in European countries in 2012. METHODS: Confirmation of pathogen identity by MALDI-TOF and antimicrobial susceptibility testing following the CLSI broth microdilution method were performed by a central laboratory. RESULTS: Using CLSI breakpoint criteria, ceftaroline was active against MSSA (n = 1116; MIC90, 0.25 mg/L; 99.8% susceptible), MRSA (n = 1467; MIC90, 1 mg/L; 92.2% susceptible) and Streptococcus pyogenes (n = 312; MIC90, 0.008 mg/L; 100% susceptible). By CLSI interpretative criteria, two S. aureus isolates (2/2583, 0.08%) were ceftaroline resistant (MIC, ≥4 mg/L) and 114 isolates (114/2583, 4.4%) were ceftaroline intermediate (2 mg/L). By EUCAST interpretative criteria (MIC, >1 mg/L), 4.5% (116/2583) of S. aureus isolates were ceftaroline resistant. Most ceftaroline-non-susceptible isolates (81.0%, 94/116) were from Russia, Turkey, Italy and Hungary. Ceftaroline susceptibility was equal to or exceeded 99% for S. aureus isolates submitted by 7 of 17 countries. Against Escherichia coli (n = 349), Klebsiella pneumoniae (n = 215), Klebsiella oxytoca (n = 74) and Proteus mirabilis (n = 121), ceftaroline activity was dependent upon ESBL production. For ESBL-negative E. coli, K. pneumoniae, K. oxytoca and P. mirabilis, 87.5% (MIC90, 1 mg/L), 92.3% (MIC90, 0.5 mg/L), 93.2% (MIC90, 0.5 mg/L) and 85.1% (MIC90, 2 mg/L) of isolates were susceptible to ceftaroline, respectively. CONCLUSIONS: Ceftaroline demonstrated potent in vitro activity against a contemporary collection of bacterial pathogens from patients with SSTIs in European countries, Russia and Turkey. Surveillance programmes such as AWARE are essential to global efforts to improve antimicrobial stewardship.

Activity of ceftaroline and comparators against pathogens isolated from skin and soft tissue infections in Latin America - results of AWARE surveillance 2012

ABSTRACT As part of the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program in 2012 the in vitro activity of ceftaroline and relevant comparator antimicrobials was evaluated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Venezuela) against pathogens isolated from patients with hospital associated skin and soft tissue infections (SSTIs). The study documented that ceftaroline was highly active (MIC90 0.25 mg/L/% susceptible 100%) against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MIC90 2 mg/L/% susceptible 83.3%) and ß-hemolytic streptococci (MIC90 0.008-0.015 mg/L/% susceptible 100%). The activity of ceftaroline against selected species of Enterobacteriaceae was dependent upon the presence or absence of extended-spectrum ß-lactamases (ESBLs). Against ESBL screen-negativeEscherichia coli, Klebsiella pneumoniae, andKlebsiella oxytoca the MIC90 and percent susceptible for ceftaroline were (0.5 mg/L/94.1%), (0.5 mg/L/99.0%) and (0.5 mg/L/91.5%), respectively. Ceftaroline demonstrated potent activity against a recent collection of pathogens associated with SSTI in six Latin American countries in 2012.

Activity of ceftaroline and comparators against pathogens isolated from skin and soft tissue infections in Latin America - results of AWARE surveillance 2012.

As part of the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program in 2012 the in vitro activity of ceftaroline and relevant comparator antimicrobials was evaluated in six Latin American countries (Argentina, Brazil, Chile, Colombia, Mexico and Venezuela) against pathogens isolated from patients with hospital associated skin and soft tissue infections (SSTIs). The study documented that ceftaroline was highly active (MIC90 0.25mg/L/% susceptible 100%) against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus (MIC90 2mg/L/% susceptible 83.3%) and ß-hemolytic streptococci (MIC90 0.008-0.015mg/L/% susceptible 100%). The activity of ceftaroline against selected species of Enterobacteriaceae was dependent upon the presence or absence of extended-spectrum ß-lactamases (ESBLs). Against ESBL screen-negative Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca the MIC90 and percent susceptible for ceftaroline were (0.5mg/L/94.1%), (0.5mg/L/99.0%) and (0.5mg/L/91.5%), respectively. Ceftaroline demonstrated potent activity against a recent collection of pathogens associated with SSTI in six Latin American countries in 2012.

Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial.

BACKGROUND: Ceftriaxone with or without a macrolide antibiotic is a recommended treatment for patients with community-acquired pneumonia requiring hospital admission and intravenous antibiotic treatment. We aimed to assess the efficacy and safety of ceftaroline fosamil compared with ceftriaxone in the treatment of Asian patients admitted to hospital with community-acquired pneumonia. METHODS: In this international, randomised, controlled, double-blind, phase 3, non-inferiority with nested superiority trial, adult Asian patients with Pneumonia Outcomes Research Team (PORT) risk class III-IV acute community-acquired pneumonia were randomly assigned (1:1) to receive intravenous ceftaroline fosamil (600 mg every 12 h) or ceftriaxone (2 g every 24 h) for 5-7 days. Patients were randomly assigned via centralised telephone and web-based system; patients and treating clinicians were masked to treatment allocation. Investigators who did study assessments remained masked to treatment allocation until completion of the study. The primary endpoint was clinical cure at the test-of-cure visit (8-15 days after last dose of study drug) in the clinically evaluable population. Non-inferiority of ceftaroline fosamil was defined as a lower limit of the two-sided 95% CI for the difference in the proportion of patients clinically cured of -10% or higher; if non-inferiority was achieved, superiority was to be concluded if the lower limit of the 95% CI was greater than 0%. This trial is registered with ClinicalTrials.gov, number NCT01371838. FINDINGS: Between Dec 13, 2011, and April 26, 2013, 847 patients were enrolled at 64 centres in China, India, South Korea, Taiwan, and Vietnam, of whom 771 were randomly assigned and 764 received study treatment. In the clinically evaluable population (n=498) 217 (84%) of 258 patients in the ceftaroline fosamil group and 178 (74%) of 240 patients in the ceftriaxone group were clinically cured at the test-of-cure visit (difference 9·9%, 95% CI 2·8-17·1). The superiority of ceftaroline fosamil was consistent across all preplanned patient subgroup analyses (split by age 65 years, age 75 years, sex, PORT risk class, and previous antibiotic use) apart from patients younger than 65 years. The frequency of adverse events was similar between treatment groups and the safety results for ceftaroline fosamil were consistent with the cephalosporin class and previous clinical trial data. INTERPRETATION: Ceftaroline fosamil 600 mg given every 12 h was superior to ceftriaxone 2 g given every 24 h for the treatment of Asian patients with PORT III-IV community-acquired pneumonia. These data suggest that ceftaroline fosamil should be regarded as an alternative to ceftriaxone in empirical treatment regimens for this patient population. FUNDING: AstraZeneca.

Analysis of Staphylococcus aureus clinical isolates with reduced susceptibility to ceftaroline: an epidemiological and structural perspective.

OBJECTIVES: Ceftaroline, approved in Europe in 2012, has activity against methicillin-resistant Staphylococcus aureus (MRSA), with MIC90 values of 1-2 mg/L depending on geographical location. During a global 2010 surveillance programme, conducted prior to the European launch, 4 S. aureus isolates, out of 8037 tested, possessing ceftaroline MIC values of >2 mg/L were identified. The objective of this study was to characterize these four isolates to elucidate the mechanism of ceftaroline resistance. METHODS: MIC determinations were performed using broth microdilution and whole genome sequencing was performed to enable sequence-based analyses. RESULTS: The only changes in proteins known to be required for full expression of methicillin resistance that correlated with the ceftaroline MIC were in penicillin-binding protein 2a (PBP2a). Isolates with a ceftaroline MIC of 2 mg/L had a Glu239Lys mutation in the non-penicillin-binding domain whereas the four isolates with ceftaroline MIC values of 8 mg/L carried an additional Glu447Lys mutation in the penicillin-binding domain. The impact of these mutations was analysed using the known X-ray structure of S. aureus PBP2a and a model for ceftaroline resistance proposed. Analysis of the core genomes showed that the isolates with reduced susceptibility to ceftaroline were epidemiologically related. CONCLUSIONS: Mutations in PBP2a can affect the activity of ceftaroline against MRSA. Although a rare event, based on surveillance studies, it appears a first-step change in the non-penicillin-binding domain together with a second-step in the penicillin-binding domain may result in elevation of the ceftaroline MIC to >2 mg/L.