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 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.

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.

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.

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.