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

Shampa Das, Jianguo Li, Joseph Iaconis, Diansong Zhou, Gregory G Stone, Jean Li Yan, David Melnick, Shampa Das, Jianguo Li, Joseph Iaconis, Diansong Zhou, Gregory G Stone, Jean Li Yan, David Melnick

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01499277 NCT01371838 NCT01458743 NCT01612507 NCT01664065.

Figures

Figure 1.
Figure 1.
PTA for 5000 simulated cSSTI patients with normal renal function achieving PK/PD targets for S. aureus by MIC following administration of ceftaroline fosamil 600 mg q12h 1 h iv infusion, overlaid with ceftaroline MIC distributions for S. aureus collected from the 2013 AWARE surveillance study in Europe and the Asia Pacific region. The ceftaroline MIC90 values for all S. aureus isolates and the MRSA subset were 1 mg/L and 2 mg/L in Europe and the Asia Pacific region, respectively.
Figure 2.
Figure 2.
PTA for 5000 simulated cSSTI patients with normal renal function achieving PK/PD targets for S. aureus by MIC following administration of ceftaroline fosamil 600 mg q8h 2 h iv infusion, overlaid with ceftaroline MIC distributions for S. aureus collected from the 2013 AWARE surveillance study in Europe and the Asia Pacific region. The ceftaroline MIC90 values for all S. aureus isolates and the MRSA subset were 1 mg/L and 2 mg/L in Europe and the Asia Pacific region, respectively.

References

    1. Bassetti M, Baguneid M, Bouza E. et al. European perspective and update on the management of complicated skin and soft tissue infections due to methicillin-resistant Staphylococcus aureus after more than 10 years of experience with linezolid. Clin Microbiol Infect 2014; 20 Suppl 4: 3–18.
    1. Pfizer. Zinforo 600 mg Powder for Concentrate for Solution for Infusion: Summary of Product Characteristics.2017. .
    1. Allergan. Teflaro™ (Ceftaroline Fosamil) Injection for Intravenous (IV) Use 2016. .
    1. File TM, Low DE, Eckburg PB. et al. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66: iii19–32.
    1. Low DE, File TM, Eckburg PB. et al. FOCUS 2: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 2011; 66: iii33–44.
    1. 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.
    1. Wilcox MH, Corey GR, Talbot GH. et al. 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.
    1. Flamm RK, Sader HS, Jones RN.. Ceftaroline activity tested against contemporary Latin American bacterial pathogens (2011). Braz J Infect Dis 2014; 18: 187–95.
    1. Biedenbach DJ, Alm RA, Lahiri SD. et al. In vitro activity of ceftaroline against Staphylococcus aureus isolated in 2012 from Asia-Pacific countries as part of the AWARE surveillance program. Antimicrob Agents Chemother 2015; 60: 343–7.
    1. Jones RN, Mendes RE, Sader HS.. Ceftaroline activity against pathogens associated with complicated skin and skin structure infections: results from an international surveillance study. J Antimicrob Chemother 2010; 65 Suppl 4: iv17–31.
    1. Dryden M, Zhang Y, Wilson D. et al. 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. J Antimicrob Chemother 2016; 71: 3575–84.
    1. Kahlmeter G. EUCAST proposes to change the definition and usefulness of the susceptibility category ‘Intermediate’. Clin Microbiol Infect 2017; 23: 894–5.
    1. EUCAST. Addendum to Breakpoint Table v 7.1, July 2017.2017. .
    1. Andes D, Craig W.. 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. Erratum in: Antimicrob Agents Chemother 2014; 58: 2489.
    1. Craig WA. Basic pharmacodynamics of antibacterials with clinical applications to the use of β-lactams, glycopeptides, and linezolid. Infect Dis Clin North Am 2003; 17: 479–501.
    1. MacGowan AP, Noel AR, Tomaselli S. et al. Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection. Antimicrob Agents Chemother 2013; 57: 2451.
    1. Singh R, Almutairi M, Alm R. et al. Ceftaroline efficacy against high-MIC clinical Staphylococcus aureus isolates in an in vitro hollow-fibre infection model. J Antimicrob Chemother 2017; 72: 2796–803.
    1. Sunzel M, Learoyd M, Li J. et al. An open-label, non-randomised, phase 1, single-dose study to assess the pharmacokinetics of ceftaroline in patients with end-stage renal disease requiring intermittent haemodialysis. Int J Antimicrob Agents 2015; 46: 682–8.
    1. Talbot GH, Thye D, Das A. et al. Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. Antimicrob Agents Chemother 2007; 51: 3612–6.
    1. Riccobene T, Fang E, Thye D, A single- and multiple-dose study to determine the safety, tolerability, and pharmacokinetics (PK) of ceftaroline (CPT) administered by intramuscular (IM) injection to healthy subjects. In: Abstracts of the 48th ICCAC and 46th IDSA, Washington, DC, USA2008. Abstract A-1888. Washington DC, USA: American Society for Microbiology.
    1. Yang L, Sunzel M, Xu P. et al. Evaluation of the pharmacokinetics and safety of single and multiple ceftaroline fosamil infusions in healthy Chinese and Western subjects. Int J Clin Pharmacol Ther 2015; 53: 681–91.
    1. 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.
    1. . Pharmacokinetics of a Single Dose of Ceftaroline in Subjects 12 to 17 Years of Age Receiving Antibiotic Therapy (NCT00633126). .
    1. Panagiotidis G, Backstrom T, Asker-Hagelberg C. et al. Effect of ceftaroline on normal human intestinal microflora. Antimicrob Agents Chemother 2010; 54: 1811–4.
    1. Riccobene T, Jakate A, Rank D.. A series of pharmacokinetic studies of ceftaroline fosamil in select populations: normal subjects, healthy elderly subjects, and subjects with renal impairment or end-stage renal disease requiring hemodialysis. J Clin Pharmacol 2014; 54: 742–52.
    1. Zhong NS, Sun T, Zhuo C. et al. 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. Lancet Infect Dis 2015; 15: 161–71.
    1. Biedenbach DJ, Iaconis JP, Sahm DF.. Comparative in vitro activities of ceftaroline and ceftriaxone against bacterial pathogens associated with respiratory tract infections: results from the AWARE surveillance study. J Antimicrob Chemother 2016; 71: 3459–64.
    1. Karlowsky JA, Biedenbach DJ, Bouchillon SK. et al. 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. J Antimicrob Chemother 2016; 71: 162–9.
    1. 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. Antimicrob Agents Chemother 2014; 58: 885–91.
    1. Van Wart SA, Forrest A, Khariton T. et al. Population pharmacokinetics of ceftaroline in patients with acute bacterial skin and skin structure infections or community‐acquired bacterial pneumonia. J Clin Pharmacol 2013; 53: 1155–67.
    1. Roberts JA, Abdul-Aziz MH, Lipman J. et al. Individualised antibiotic dosing for patients who are critically ill: challenges and potential solutions. Lancet Infect Dis 2014; 14: 498–509.
    1. Matzneller P, Lackner E, Lagler H. et al. Single- and repeated-dose pharmacokinetics of ceftaroline in plasma and soft tissues of healthy volunteers for two different dosing regimens of ceftaroline fosamil. Antimicrob Agents Chemother 2016; 60: 3617–25.
    1. Castanheira M, Jones RN, Sader HS.. Activity of ceftaroline and comparator agents tested against contemporary Gram-positive and -negative (2011) isolates collected in Europe, Turkey, and Israel. J Chemother 2014; 26: 202–10.
    1. Flamm RK, Sader HS, Farrell DJ. et al. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrob Agents Chemother 2012; 56: 2933–40.
    1. Hackel M, Stone G, Sahm D, Impact of EUCAST ceftaroline breakpoint change on MRSA susceptibility of isolates collected from patients with complicated skin and soft tissue infections. In: Abstracts of the 28th European Congress of Clinical Microbiology and Infectious Diseases, Madrid, Spain2018. Abstract P2503. Basel, Switzerland: European Society of Clinical Microbiology and Infectious Diseases.
    1. Corey G, Wilcox M, Gonzalez J. et al. Ceftaroline fosamil (CPT-F) in patients with acute bacterial skin and skin structure infections (ABSSSI) with systemic inflammatory signs: results across 3 pivotal studies using q8h or q12h. In: Abstracts of the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, 2015. Abstract L-839. Washington DC, USA: American Society for Microbiology.
    1. Zhou D, Dryden M, Gonzalez J. et al. Impact of disease severity on ceftaroline pharmacokinetics in patients with ABSSSI: Phase III COVERS trial. In: Abstracts of the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA, USA, 2015. Abstract A-966. Washington DC, USA: American Society for Microbiology.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren