Ceftaroline:- A new approach to CAP:-
Community Acquired Pneumonia(CAP) is one of the leading infectious cause of death worldwide.1
Streptococcus pneumoniae (S. pneumoniae) and Staphylococcus aureus (S. aureus) including methicillin-sensitive S. aureus (MSSA) are important etiological pathogens.1 Initial therapy for CAP includes β-lactam or β-lactam/macrolide antimicrobials.1 However, antimicrobial resistance among the major pathogens is a cause of concern.3 Ceftaroline fosamil is a broad-spectrum cephalosporin and has proven efficacy and safety against S. aureus CAP.1
This review of article highlights the general properties of ceftaroline fosamil and its clinical efficacy. The CAP remains a critical healthcare concern despite advancements in antibiotic therapy.1 Annually, CAP affects around 5–11 individuals per 1000 population across the world.2 About 20% of these cases require hospitalization.2 In India, the mortality rate among patients with severe pneumonia hospitalized in the intensive care unit is as high as 25%.2 S. pneumoniae is the most common pathogenic bacteria responsible for CAP.4 Staphylococcus aureus and other Gram-negative pathogens may also be involved.4 The initial therapy for CAP mainly includes β-lactam monotherapy or combination therapy of beta-lactam with a macrolide.1 However, emerging resistance against antibiotics is becoming a major concern in the treatment.4
A report suggests that about 20% of S. pneumoniae isolates were resistant to amoxicillin-clavulanate and 14.8% and 11.7% were resistant to penicillin and ceftriaxone (11.7%) respectively.3 S. pneumoniae acquires resistance through modifications at penicillin-binding protein sites.3 On the other hand, the adverse outcomes associated with S. aureus-CAP can be attributed to the ability of S. aureus to adapt and develop antibiotic resistance, structural expression and secretory virulence factors that allow colonization, distribution into host tissues, and breach of the immune system.1 Ineffective initial therapy may lead to adverse outcomes, including mortality and increased expenditure.1 Thus, increasing in multidrug-resistant requires newer antimicrobial agents with a unique mechanism of action.3 Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil exhibits broad-spectrum antimicrobial activity and has proved its efficacy in several clinical trials.1 Therefore, ceftaroline fosamil could be a potential alternative to standard antibiotic CAP regimens.1
Ceftaroline Fosamil: General Characteristics
Mechanism of action
Like other beta-lactam antibiotics, ceftaroline binds to penicillin-binding proteins (PBPs) and causes impaired bacterial cell wall synthesis, cell lysis, and death, thereby exerting its bactericidal effect.1 In addition, ceftaroline has a greater binding affinity for PBPs than other β-lactam antibiotics.1 Spectrum of activity Ceftaroline is a broad-spectrum antibiotic, which has shown in vitro activity against the following pathogens3:
The prodrug ceftaroline fosamil is rapidly converted into active moiety ceftaroline by phosphatase enzymes following intravenous administration.3 Ceftaroline is then hydrolyzed to form its inactive metabolite, ceftaroline M-1. This metabolite undergoes little hepatic metabolism and cannot form a substrate, inhibitor, or inducer of the CYP450 enzyme system.3 Thus, there is less risk of CYP450-related drug-drug interactions.
The table below provides pharmacokinetic parameters of ceftaroline fosamil3:
Gram-negative bacteria develop resistance against ceftaroline at similar rates as observed with ceftriaxone.3 Although uncommon, some studies have observed resistance in S. aureus against ceftaroline strains.3 This resistance is attributed to a decrease in binding affinity for PBP2a as a result of amino acid replacement on the nonpenicillin-binding sites.3
Clinical Trials Leading to Ceftaroline’s Approval
Ceftaroline is approved for the management of CAP of bacterial origin based on the phase 3 comparator trials as follows.3
A Phase III, double-blinded, randomized, multinational, multicenter trial evaluated the non-inferiority of ceftaroline fosamil in clinical cure rates against ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations.4 The study included 613 patients (mean age 61.1 ± 16.5 years) enrolled in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV.4 They were randomized to receive to ceftaroline fosamil 600 mg of intravenously twice daily (n=298) or 1 g of ceftriaxone intravenously once daily (n=308).4 In addition, patients in both groups received clarithromycin 500 mg twice on day 1.4 In addition, patients in both treatment groups received clarithromycin 500 mg every 12 hours for the first day.4
Secondary outcomes include clinical cure in the microbiologically evaluable (ME) and microbiological modified intent-to-treat efficacy (mMITTE) populations at test of cure (TOC) visit and at the end-of-therapy (EOT) visit.4 The results showed that clinical cure rates for ceftaroline fosamil and ceftriaxone in CE population were 86.6% and 78.2% respectively, and in microbiological MITTE population, the cure rates were 83.8% and 77.7% respectively.4 Similarly, clinical cure rates at the end-of-therapy were consistent with the primary results (Table 2).4 Ceftaroline fosamil was well-tolerated and showed comparable and consistent safety profile to ceftriaxone and with the cephalosporin class respectively.4
The study showed that ceftaroline fosamil was effective in hospitalised patients with CAP of PORT risk class III or IV.4
A Phase III, double-blinded, randomized, multinational, multicenter trial was conducted to compare the safety and efficacy of ceftaroline versus ceftriaxone. The study included 627 patients with CAP of PORT risk class III or IV severity.5 The participants were divided into two groups to receive 600 mg of ceftaroline fosamil intravenously twice daily (n=317, mean age 60.6 ± 16.1 years) or 1 g of ceftriaxone intravenously once daily (n=310, mean age 62 ± 14.7 years).5 The clinical cure rates for ceftaroline fosamil were greater compared with ceftriaxone in all evaluated participants (Table 3). Both ceftaroline and ceftriaxone were well-tolerated with comparable safety profiles.5
The study demonstrated high clinical cure rates and microbiological response rates with ceftaroline fosamil compared with ceftriaxone in patients with CAP of PORT risk class III or IV.5
Integrated analysis of FOCUS 1 and FOCUS 2 trial showed that patients receiving ceftaroline had a higher clinical cure rate among patients classified as PORT risk class III (86.8% vs 79.2%, weighted treatment difference 7.5%, 95% [CI] 1.3–13.8), PORT risk class IV (80.2% vs 75.4%, weighted treatment difference 4.7%, 95% [CI] -4.1 to 13.5), and among patients who had not received prior antibiotic treatment (85.8% vs 74.9%, weighted treatment difference 11.2%, 95% CI 4.5–18.0) compared with patients receiving ceftriaxone.6 The analysis also revealed that ceftaroline fosamil was non-inferior to ceftriaxone.6 Additionally, US Food and Drug Administration (FDA) guidelines for the design of non- inferiority CAP trials recommend evaluation of clinical response 72–96 h following initiating therapy (Day 4).7 Therefore, a retrospective post-hoc analysis of day 4 response rates was carried out among 309 patients with moderate-to-severe CAP from FOCUS trials. Overall, day 4 clinical response rate for ceftaroline fosamil was greater compared with ceftriaxone (69.5% vs. 59.4%, (difference 10.1%; 95% confidence interval, -0.6% to 20.6%).7 Similarly, for most common pathogens such as S. pneumoniae (73% vs 56%) and MSSA (58.3% vs. 54.8%) ceftaroline showed higher response rates compared with ceftriaxone.7
Key Takeaway :-
1. Worldwide, the burden of CAP remains substantial with increased morbidity and mortality.
2. In clinical trials, ceftaroline showed similar efficacy compared with ceftriaxone.
3. Ceftaroline also demonstrated a good safety profile and was consistent with the cephalosporin class.
4. Thus, ceftaroline fosamil could be a promising agent for the treatment of CAP.
1. Welte T, Kantecki M, Stone GG, Hammond J. Ceftaroline fosamil as a potential treatment option for Staphylococcus aureus community-acquired pneumonia in adults. Int J Antimicrob Agents. 2019 Oct;54(4):410-422.
2. Mahendra M, Jayaraj BS, Limaye S, Chaya SK, Dhar R, Mahesh PA. Factors influencing severity of community-acquired pneumonia. Lung India. 2018;35(4):284–289.
3. Ghamrawi RJ, Neuner E, Rehm SJ. Ceftaroline fosamil: A super-cephalosporin? Cleve Clin J Med. 2015 Jul;82(7):437-44. 4. File TM Jr, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley IA, Thye DA; FOCUS 1 investigators. 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 Apr;66 Suppl 3:iii19-32.
5. Low DE, File TM Jr, Eckburg PB, Talbot GH, David Friedland H, Lee J, Llorens L, Critchley IA, Thye DA; FOCUS 2 investigators. 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 Apr;66 Suppl 3:iii33-44.
6. File TM Jr, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley I, Thye D. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clin Infect Dis. 2010 Dec 15;51(12):1395-405.
7. Eckburg PB, Friedland HD, Llorens L, Smith A, Witherell GW, Laudano JB, Thye D. Day 4 Clinical Response of Ceftaroline Fosamil Versus Ceftriax- one for Community-Acquired Bacterial Pneumonia. Infect Dis Clin Pract 2012;20:254–60.
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