PPA News



Posted by: Kailynn DeRonde on Feb 15, 2017

About the Author: Kailynn DeRonde, PharmD is a PGY1 Pharmacy Resident at Children’s Hospital Colorado


Infections caused by resistant gram positive bacteria are becoming a growing concern in the pediatric population1.  Limited antimicrobial agents with demonstrated pediatric safety and efficacy2, as well as the presence of methicillin resistant Staphylococcus aureus (MRSA) and cephalosporin and macrolide resistant Streptococcus pneumoniae3, highlight the importance of the development of new agents that can effectively target these bacteria. Ceftaroline fosamil, a fifth generation cephalosporin, was approved by the FDA in May 2016 for the treatment of acute skin and soft tissue infections and community acquired pneumonia in patients 2 months and older2. Ceftaroline’s ability to maintain coverage against MRSA and resistant S. pneumoniae, as well as its favorable pharmacokinetic and safety profile, make this agent a potential therapeutic option for pediatric patients with complex infections.

Upon intravenous administration, ceftaroline fosamil, an inactive prodrug, is converted into the active bactericidal agent ceftaroline, by plasma phosphatases. Through the core structure of the beta-lactam ring, ceftaroline actively targets penicillin binding proteins (PBP), preventing peptidoglycan formation and bacterial wall synthesis through the prevention of the transpeptidation reaction4,5. While mutations in PBP found in both Staphylococcus aureus and Streptococcus pneumoniae confer resistance to other cephalosporines, ceftaroline is able to maintain activity.

MRSA species are positive for the gene mecA which encodes for PBP2a. This mutation in the penicillin binding protein leads to resistance to all beta-lactam antibiotics with the exception of ceftaroline. Ceftaroline binds to an allosteric site on a non-penicillin binding domain of PBP. This leads to a conformational change within the protein that opens the active site on PBP2a and subsequently allows ceftaroline to bind and block the active site5. Similarly, cephalosporin-resistant S. pneumoniae encodes for a mutated PBP, PBP2x. Ceftaroline maintains a strong affinity for PBP2x, 5 allowing for its activity against the otherwise cephalosporin resistant bacteria. In addition to the broad coverage of MRSA and S. pneumoniae, ceftaroline has bactericidal activity against coagulase negative Staphylococcus, alpha-hemolytic streptococcus, and gram negative species including Moraxella catarrhalis, Haemophilus influenza (including beta-lactamase positive isolates), Neisseria gonorrhoeae, and non-extended beta-lactamase producing Escherichia coli and Klebsiella pneumonia1,5.

Current dosing regimens for ceftaroline in the pediatric population are as follows: for infants > 2 months to children < 2 years, 8mg/kg every 8 hours, and for children > 2 years and adolescents <18 years, 12mg/kg/dose every 8 hours if the patient weighs < 33kg, and 400mg every 8 hours or 600mg every 12 hours if the patient weighs >33kg4,6,7. Ceftaroline’s bactericidal activity is dependent upon time above the minimum inhibitory concentration (time>MIC) of the pathogen. A pediatric population pharmacokinetic simulation assessed the ability of published dosing regimens to obtain median values of 36% time >MIC for S. aureus and 44% time>MIC for S. pneumoniae. These time>MIC targets have demonstrated a 1-log kill (90% population reduction) in both respective species3, and are similar to the optimal bacteriostasis time>MIC targets of 26 + 8% for S. aureus and 39 + 9% for S. pneumoniae demonstrated in a murine model of thigh and lung infection8. The authors found favorable results with both the 8 hour and 12 hour regimens. The 8 hour dosing regimen for infants and children less than 2 years old demonstrated >94% target attainment of 36% time> MIC for a MIC of 2 for S. aureus and >99% target attainment of 44% time>MIC for an MIC of 1 for S. pneumonia. The 12 hour dosing regimen for children 12 to <18 years old achieved >90% target attainment of 36% time> MIC for an MIC of 2 for S. aureus and >97% target attainment of 44% time>MIC for an MIC of 1 for S. pneumoniae3.  Additionally, with the published dosing regimens, common adverse effects of ceftaroline include diarrhea, nausea, headache, insomnia, and rash. Serious, but rare reactions include Clostridium difficile, transaminitis, hepatitis, anaphylaxis, and seizures4,5.  These adverse effects are reported to be similar to ceftriaxone5, and overall, ceftaroline is considered to be well tolerated2.

Ceftaroline is currently approved for use in acute skin and soft tissue infections6, as well as pneumonia in pediatric patients7. Additionally, ceftaroline has been used off-label with success in complicated MRSA sepsis and osteomyelitis9, and there are several current studies exploring its use in additional indications. Current pediatric studies that are actively recruiting include ceftaroline for treatment of hematogenously acquired Staphylococcus aureus osteomyelitis in children10 and ceftaroline penetration into cerebral spinal fluid in children11.  Conceptually, potential indications in which ceftaroline may be an attractive therapeutic option, albeit off-label, include complicated MRSA community acquired pneumonia with a vancomycin MIC > 2, MRSA septic thrombophlebitis, complex osteomyelitis, skin or soft tissue infection, or abscess if the patient is not tolerating vancomycin, linezolid, or daptomycin (or if infection demonstrates a high vancomycin MIC, includes concurrent pneumonia, etc.), and in immunocompromised patients for line rule-outs to spare vancomycin renal toxicity. It is important to note that these indications may require variable dosing and close monitoring as they are not FDA approved.

Overall, with its favorable pharmacokinetic and side effect profile, activity against MRSA and resistant S. pneumoniae, and potential for therapeutic benefit in complex pediatric infectious diseases, ceftaroline is a novel potential addition to the pediatric pharmacist’s tool box.

 

References:

  1. Sader JS. Mendes RE, Farrell DJ et al. Ceftaroline activity tested against bacterial isolates from pediatric patients; results from the Assessing Worldwide Resistance and Evaluation Program for the United States (2011-2012). Pediatr Infect Dis J. 2014; 33: 837-842. Pharmacotherapy. 2010; 30:375-389.
  2. Yim J, Molloy LM, Newland JG. Use of ceftaroline fosamil in children: review of current knowledge and its application. Infect Dis Ther. 2016: 1-11
  3. Riccobene TA, Khariton T, Knebel W, et al. Population PK modeling and target attainment simulations to support dosing of ceftaroline fosamil in pediatric patients with acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia. Pediatric Pharmacology. 2016; 00:1-11.
  4. Ceftaroline. Children’s Hospital Colorado. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL.  Available at:  http://online.lexi.com.  Accessed January 23, 2017.
  5. Steed ME, Rybak MJ. Ceftaroline: a new cephalosporin with activity against resistant gram-positive pathogens. Pharmacotherapy. 2010; 30: 375-389.
  6. Korczowski B, Antadez T, Giorgobiani M et al. A multicenter, randomized, observer-blinded active controlled study to evaluate the safety and efficacy of ceftaroline versus comparator in pediatric patients with acute bacterial skin and skin structure infections. J Pediatr Pharmacol Ther. 2016; 35:e239-247.
  7. Blumer JL, Ghonghadze T, Cannavino C. A multicenter, randomized, observer-blinded active controlled study to evaluate the safety and effectiveness of ceftaroline compared with ceftriaxone plus vancomycin in pediatric patients with complicated community-acquired bacterial pneumonia. J Pediatr Pharmacol Ther. 2016; 35:760-766.
  8. 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(4):1376–83.
  9. Williams AW, Newman PM, Ocheltree S, et al. Ceftaroline fosamil use in 2 pediatric patients with invasive methicillin-resistant Staphylococcus aureus infections. J Pediatr Pharmacol Ther. 2015; 20:476-480.
  10. ClinicalTrials.gov. Ceftaroline for treatment of hematogenously acquired staphylococcus aureus osteomyelitis in children. ClinicalTrials.gov Identifier NCT02335905.  https://clinicaltrials.gov/ct2/show/NCT02335905?term=Ceftaroline+in+children&rank=1. Accessed January 23, 2017.
  11. ClinicalTrials.gov. Ceftaroline diffusion into cerebrospinal fluid of children. ClinicalTrials.gov Identifier NCT 02600793. https://clinicaltrials.gov/ct2/show/NCT02600793?term=Ceftaroline+in+children&rank=3. Accessed January 23, 2017.