Drug Evaluation
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Pharmacokinetic and pharmacodynamic evaluation of ceftaroline fosamil 1.
Introduction
2.
Mechanism of action
3.
Spectrum of activity
4.
Pharmacokinetics
5.
Pharmacodynamics
6.
Clinical trials
7.
Adverse effects
8.
Conclusion
9.
Expert opinion
Andrew Merker, Larry H Danziger, Keith A Rodvold & Robert C Glowacki† †
University of Illinois at Chicago, College of Pharmacy, Chicago, USA
Introduction: Ceftaroline fosamil is a 5th generation cephalosporin with an in vitro spectrum of activity including Streptococcus agalactiae, penicillinand cephalosporin-resistant S. pneumoniae, S. pyogenes, methicillin-susceptible S. aureus and methicillin-resistant S. aureus, Haemophilus influenzae, Klebsiella oxytoca, K. pneumoniae and Moraxella catarrhalis. It is currently approved by the FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. Areas covered: This review covers the mechanism of action; bacterial resistance; pharmacokinetic characteristics in various patient populations; pharmacodynamic data in animal and in vitro models as well as human studies; efficacy observed in clinical trials for ABSSSI and CABP; and adverse effects. Expert opinion: Ceftaroline provides in vitro bactericidal activity against methicillin-, vancomycin-, daptomycin-, and linezolid-resistant Gram-positive organisms and select Gram-negative pathogens. The pharmacodynamics of ceftaroline is similar to other b-lactam agents. Ceftaroline exhibits a favorable adverse effect profile and is generally well tolerated. There is little data on clinical success of ceftaroline in patients with bacteremia or endocarditis other than what has been published in a small series of case reports. Randomized-control studies are needed to establish clinical outcomes and safety in these patient populations. Keywords: acute bacterial skin and skin structure infections, antibiotic resistance, ceftaroline, community-acquired bacterial pneumonia, methicillin-resistant Staphylococcus aureus Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Antibiotic resistance to Gram-positive organisms has long provided a challenge in determining appropriate antibacterial therapy for patients. Recently, there has been an increase in the incidence of Gram-positive pathogen resistance. This includes Streptococcus pneumoniae that has long been susceptible to penicillin [1,2]. Additionally, there has been a documented increase in the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections [3,4]. The 5th generation cephalosporin, ceftaroline fosamil (Box 1), is a pro-drug that is rapidly hydrolyzed to the active antimicrobial agent ceftaroline. A novel characteristic of ceftaroline over previous cephalosporins include a spectrum of activity against resistant Gram-positive organisms, including penicillin-resistant and cephalosporin-resistant S. pneumoniae as well as MRSA. Ceftaroline was approved by the FDA in 2010 and is indicated for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) [5].
10.1517/17425255.2014.972932 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
1
A. Merker et al.
Box 1. Drug summary Drug name Phase Indications
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Pharmacology description Route of administration Chemical structure
Ceftaroline fosamil Currently available for clinical use Acute bacterial skin and skin structure infections due to: methicillin-susceptible and -resistant Staphylococcus aureus, Streptococcus pyogenes, S. agalactiae, Escherichia coli, Klebsiella pneumoniae, and K. oxytoca Community-acquired bacterial pneumonia due to: S. pneumoniae, methicillin-susceptible S. aureus, Haemophilus influenzae, K. pneumoniae, K. oxytoca, and E. coli Advanced generation bactericidal cephalosporin that targets penicillin-binding proteins IV CH3
CH3 O
N
H N
HO
O
OH
CH3 N H N
P HO
O
N
S
N
S S
O N
N S
O HO
Pivotal trial(s)
2.
Mechanism of action
Ceftaroline exerts its mechanism of action by binding to penicillin-binding proteins (PBPs) in Gram-positive and Gram-negative organisms, thus inhibiting organism cell wall biosynthesis and resulting in bactericidal activity [6]. Ceftaroline has a high binding affinity for common PBP targets for S. pneumoniae (PBP-1a, -2b, and -2x) and S. aureus (PBP-1, -2, -2a, and -3). Ceftaroline was found to have a binding affinity for PBP-2a up to 128 times higher compared to cefotaxime, ceftriaxone, and penicillin G in MRSA isolates [7].
3.
Spectrum of activity
Ceftaroline exhibits in vitro bactericidal activity against Gram-positive and Gram--negative species, including S. pneumoniae, S. aureus, coagulase-negative staphylococcus (CoNS), S. pyogenes, S. agalactiae, Klebsiella pneumoniae, K. oxytoca, Escherichia coli, Moraxella catarrhalis, and Haemophilus influenzae [8-14]. Table 1 includes MIC values for selected Gram-positive and Gram-negative pathogens [8-14]. For penicillin-resistant or cephalosporin-resistant S. pnuemoniae, ceftaroline displays potent antibacterial activity with MIC90 £ 0.5 mg/l [8-10,15-19]. Additionally, ceftaroline demonstrates antimicrobial activity in vitro against antibioticresistant Gram-positive pathogens such as MRSA, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), vancomycin-resistant S. aureus, and daptomycin non-susceptible S. aureus [13,20,21]. The MIC for ceftaroline was £ 1 mg/l for the majority of antibiotic-resistant S. aureus strains and a MIC90 ranging from 0.5 -- 2 mg/l [8-11,13,20,21]. 2
O
CANVAS 1 and 2 [46] FOCUS 1 and 2 [47]
S. aureus isolates from pediatric, adult and elderly patient populations have exhibited susceptibility regardless of methicillin-susceptible S. aureus (MSSA) or MRSA, with MIC90 range from 0.25 -- 1 mg/l [22]. Ceftaroline has displayed minimal antibacterial activity for Enterococcus faecium and E. faecalis, with MIC90 > 8 mg/l [8-12,15,23]. Ceftaroline has shown in vitro antibacterial activity against non-b-lactamase strains of Citrobacter freundii (MIC90 0.25 -- 2 mg/l) and E. coli (MIC90 0.12 -- 1 mg/l). Ceftaroline has no antibacterial activity against Acinetobacter baumannii, Pseudomonas aeruginosa, Morganella morganii or Proteus species (MIC90 > 16 mg/l) [8-12]. Ceftaroline has variable antimicrobial activity against anaerobic organisms. The MIC90 for anaerobic pathogens Bacteroides fragilis (> 32 mg/l), Clostridium difficile (4 mg/l) and Prevotella species (> 32 mg/l) indicate poor antibacterial activity. Ceftaroline has demonstrated antibacterial activity against certain Clostridium species (MIC90 1 mg/l) as well as Proprionbacterium and Peptostreptococcus species (MIC90 0.12 mg/l) [8,15]. There were no bacterial pathogens that developed ceftaroline resistance for strains of penicillin-susceptible and penicillin-resistant S. pneumoniae, MSSA, community-acquired MRSA, MRSA, VISA, and b-lactamase negative H. influenzae. Ceftaroline selected for AmpC inducible strains that were previously derepressed [15,24-26]. The spectrum of activity for ceftaroline primarily includes Gram-positive (staphylococci and streptococci) and nonb-lactamase producing Gram-negative species. Studies of isolates in vitro have documented antimicrobial activity against antibiotic resistant pathogens that include penicillinand cephalosporin-resistant S. pneumoniae, MRSA, VISA,
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
Ceftaroline fosamil
Table 1. Ceftaroline in vitro activity against selected susceptible Gram-positive and -negative isolates. Organism
Total isolates
MIC(mg/l)
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50% Staphylococcus aureus MSSA MRSA Streptococcus pneumoniae PCN-S PCN-R S. agalactiae S. pyogenes Escherichia coli CAZ-S CAZ-R Haemophilus influenzae b-lactamase negative b-lactamase positive Klebsiella pneumoniae CAZ-S CAZ-R Moraxella catarrhalis CAZ-S
Ref.
90%
Range
2042 2677
0.25 0.5 -- 1
0.25 0.5 -- 2
£ 0.03 -- 1 0.12 -- 2
[8-11,14] [8-11,13,14]
4480 375 631 705
£ 0.008 -- £ 0.016 0.12 -- 0.25 0.015 £ 0.008 -- 0.015
0.015 -- 0.12 0.12 -- 0.5 0.015 -- 0.03 0.015
£ £ £ £
0.5 0.5 0.12 0.03
[8-12] [8-10] [9,10,14] [8-10,14]
1810 128
0.06 -- 0.12 > 16
0.12 -- 1 > 16
£ 0.015 -- > 16 0.06 -- > 16
[8-11,14] [9,11]
1761 591
£ 0.008 -- £ 0.016 0.015 -- £ 0.016
0.015 -- 0.06 £ 0.016 -- 0.03
£ 0.008 -- 1 £ 0.008 -- 2
[8-12] [8-10,12]
1004 155
0.06 -- 0.12 > 16
0.25 -- 0.5 > 16
£ 0.008 -- > 16 0.25 -- > 16
[8-11,14] [9,11]
812
0.06 -- 0.12
0.12 -- 0.25
£ 0.008 -- 1
[8,10-12]
0.008 0.008 0.008 0.008
-----
CAZ: Ceftazidime; MRSA: Methicillin-resistant Staphylococcus aureus; MSSA: Methicillin-susceptible Staphylococcus aureus; PCN: Penicillin; R: Resistant; S: Susceptiblet.
hVISA and daptomycin non-susceptible. The rate of resistance development was low for Gram-positive pathogens and H. influenzae; however, ceftaroline can induce AmpCderepressed Enterobacteriaceae. 4.
Pharmacokinetics
Ceftaroline fosamil is a pro-drug that is rapidly metabolized to the active antimicrobial agent, ceftaroline. For healthy patients, ceftaroline 600 mg i.v. every 12 h for 14 days resulted in a maximum concentration (Cmax) of 21 mg/l and an area under the curve from time zero to infinity (AUC0 -- ¥) of 56 µg·h/ml [27]. No appreciable accumulation occurs after multiple i.v. doses. In healthy adult males, the median ceftaroline steady-state volume of distribution was 20.3 l (range: 18.3 -- 21.6 l) [5]. The pharmacokinetic profile of ceftaroline is linear and concentrations increase in proportion to increases in the dose. The plasma protein binding of ceftaroline was < 20% at concentrations of 5 mg/l, 20 mg/l and 50 mg/l and tends to decrease as drug concentrations increase (19, 1, and 7%, respectively) [28]. The penetration of ceftaroline into epithelial lining fluid (ELF) at doses of 600 mg every 8 or 12 h for 3 days has been studied in healthy adult patients. The ratio of AUC in ELF to plasma was 21 -- 23% [29]. The hydrolysis of the ceftaroline b-lactam ring results in the formation of the microbiologically inactive metabolite ceftaroline M-1 [5]. There have been no studies to assess dose adjustments in patients with hepatic impairment. However, as ceftaroline undergoes little to no hepatic metabolism,
dose reductions are likely unnecessary. Ceftaroline has negligible metabolism via the CYP system and does not inhibit or induce major CYP enzymes [28]. Therefore, dosing adjustments are probably not necessary when ceftaroline is given concomitantly with potent CYP inhibitors or inducers [5]. The primary route of elimination for ceftaroline is urinary excretion. In healthy patients receiving a single 600 mg i.v. dose, the amount of drug recovered in the urine was 57.03 ± 9.94% (range: 47 -- 71%). The mean elimination t1/2 of the active drug is 2.48 ± 0.30 h with a renal clearance (CLR) of 82.0 ± 16.4 ml/min [30]. Additional information on single- and multiple-dose ceftaroline pharmacokinetics can be found in Table 2 [27,30-32]. The pharmacokinetics of ceftaroline has been studied in varying degrees of creatinine clearance (CrCl), including endstage renal disease (ESRD). For patients with mild (CrCl 50 -- 80 ml/min) and moderate (CrCl 30 -- 50 ml/min) renal impairment, there is an increase in mean AUC0 -- ¥ and t1/2 following a single 600 mg i.v. dose of ceftaroline compared to patients with normal renal function. Patients with severe renal impairment (CrCl < 30 ml/min) or ESRD demonstrated more dramatic changes in AUC0 -- ¥, t1/2 and CLR following a single dose of ceftaroline 400 mg i.v. [32]. For healthy elderly (> 65 years) compared to healthy adults (18 -- 45 years) receiving a single ceftaroline 600 mg i.v. dose, an increased AUC0 -- ¥ (94.1 ± 13.6 vs 70.5 ± 10.1 µg·h/ml) and t1/2 (3.1 ± 0.4 vs 2.2 ± 0.4 h) was demonstrated in the healthy elderly. These observed differences for healthy elderly compared to healthy adults were due to lower mean plasma clearance (95.7 ± 13.4 vs 127.3 ± 15.0 ml/min) and lower
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Table 2. Pharmacokinetic parameters of ceftaroline in healthy adults (18 -- 45 years old). n
Median Tmax (h) (range)
AUC 0 -- ` (mg.h/ml)
Vss(L)
T ½(h)
CL/Fm (ml/min)
CLr (ml/min)
Ref.
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Single dose IV administration 50 mg 6 6 100 mg 6 6 250 mg 6 6 500 mg 6 6 600 mg 11 16 750 mg 6 6 1000 mg 6 6
NA 0.9
3.9 4.0 ± 0.7
NA NA
2.0 2.0 ± 0.2
NA 192.1 ± 38.9
90.0 93.6 ± 25.0
[31] [32]
NA 0.9
6.6 6.7 ± 1.7
NA NA
2.2 2.2 ± 0.4
NA 228.9 ± 49.1
92.0 96.2 ± 29.6
[31] [32]
NA 0.9
22.9 23.4 ± 5.4
NA NA
2.3 2.3 ± 0.3
NA 164.6 ± 39.2
73.4 77.4 ± 27.8
[31] [32]
NA 1.1
44.7 44.8 ± 2.9
NA NA
2.5 2.5 ± 0.3
NA 164.8 ± 10.6
93.7 93.5 ± 14.4
[31] [32]
0.98 (0.97 -- 1.08) 1.0 (0.9 -- 1.1)
62.7 ± 0.3
19.7 ± 3.3
2.4 ± 0.3
144.5 ± 20.1
82.0 ± 16.4
[30]
70.5 ± 10.1
15.8 ± 2.7
2.2 ± 0.4
NA
81.0 ± 23.4
[32]
NA 1.0
56.9 57.6 ± 9.8
NA NA
2.6 2.6 ± 0.3
NA NA
104.9 107.6 ± 26.8
[31] [32]
NA 0.9
80.5 80.9 ± 8.6
NA NA
2.9 2.9 ± 0.1
NA NA
129.2 130.7 ± 21.3
[31] [32]
Multiple dose IV administration (based on after last dose given) 300 mg every 12 h ( 28 doses) 6 0.9 (0.9 -- 1.1) 6 NA 600 mg every 12 h ( 28 doses) 6 0.9 (0.9 -- 1.1) 6 NA 800 mg once daily ( 7 doses) 6 1.1 (0.9 -- 1.1) 6 NA
24.3 ± 3.7 24.0
NA NA
2.6 ± 0.4 2.6
184.9 ± 26.9 183.0
75.3 ± 19.9 NA
[32] [27]
56.3 ± 8.9 56.0
NA NA
2.7 ± 0.4 2.6
160.1 ± 23.3 159.0
118.9 ± 72.8 NA
[32] [27]
74.2 ± 14.2 73.0
NA NA
2.6 ± 0.2 2.6
164.3 ± 35.2 161.0
66.1 ± 20.2 NA
[32] [27]
AUC 0 -- ¥: Area under the curve from time zero to infinity; CL/Fm: Clearance divided by fraction of dose metabolized; CLr: Renal clearance; n: Number of patients; NA: Not applicable; Vss: Volume of distribution at steady state.
mean CLr (54.9 ± 12.7 vs 81.0 ± 23.4 ml/min), respectively. Other pharmacokinetic parameters (Cmax and Vss) were similar between the two groups [32]. Additional pharmacokinetic data on patients based on age and renal function can be found in Table 3 [27,32,33]. As adverse effects of ceftaroline are dose dependent, the elderly and those with poor renal function will be more likely to experience adverse effects as a result of decreased drug clearance. 5.
Pharmacodynamics
Ceftaroline exhibits a bactericidal effect by time-dependent killing. The post-antibiotic effect is longest with S. aureus (0.8 -- 7.2 h) compared to S. pneumoniae (< 1.5 h) and E. coli (< 5.7 h) [34]. The percent of time that the unbound drug level exceeds the MIC (%fT > MIC) has been found to 4
have the most significant impact on bactericidal activity for S. pneumoniae, S. aureus (MSSA and MRSA) and K. pneumoniae in a murine thigh and lung model [34]. The mean % fT > MIC to achieve a bacteriostatic effect after 24 h of initiating ceftaroline for S. pneumoniae, S. aureus (including MSSA and MRSA) and Gram-negative bacilli (E. coli and K. pneumoniae) ranged from 10 -- 40%. In order to achieve a 1-log10 or 2-log10 bacterial killing in these isolates, a % fT > MIC of 20 -- 43% and 28 -- 70% was necessary, respectively [34-36]. A two-compartment, hollow fiber model with MRSA and hVISA isolates (MIC 0.125 -- 2.0 mg/l) found that a %fT > MIC for ceftaroline above 46% achieved bactericidal activity for all strains [37]. A one-compartment in vitro model assessed the pharmacodynamics of ceftaroline against MRSA, hVISA and VISA (MIC 1 mg/l for all isolates) with simulated dosing of ceftaroline 600 mg every 12 h over a
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
Ceftaroline fosamil
Table 3. Pharmacokinetic parameters of single ceftaroline IV doses in different patient populations.
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n
Median Tmax (h) (range)
AUC 0 -- ` (mg.h/ml)
Vss(L)
Healthy elderly -- 600 mg (‡ 65 years) 16 1.0 (0.9 -- 1.1) 94.1 ± 13.6 17.9 ± 3.0 Mild renal impairment -- 600 mg (CrCl 51 -- 80 ml/min) 6 0.9 (0.9 -- 1.3) 92.3 ± 25.3 NA 6 NA 95.0 ± 26.0 NA Moderate renal impairment -- 600 mg (CrCl 31 -- 50 ml/min) 6 1.1 (0.9 -- 1.3) 114.8 ± 14.1 NA 6 NA 120.0 ± 13.0 NA Severe renal impairment -- 400 mg (CrCl # 30 ml/min) 6 1.3 (0.9 -- 1.6) 112.4 ± 20.5 NA ESRD - 400 mg (before hemodialysis) 6 1.0 (1.0 -- 1.1) 92.0 ± 15.9 NA ESRD - 400 mg (after hemodialysis) 6 1.0 (1.0 -- 1.0) 128.6 ± 12.7 NA
T ½(h)
CL/Fm(ml/min)
CLr (ml/min)
Ref.
3.1 ± 0.4
NA
54.9 ± 12.7
[32]
3.7 ± 0.7 3.7 ± 0.7
102.0 ± 28.1 NA
31.2 ± 5.4 64.0 ± 11.0
[32] [33]
4.6 ± 1.1 4.6 ± 1.1
78.0 ± 11.0 NA
20.0 ± 6.3 74.0 ± 9.0
[32] [33]
5.1 ± 1.2
53.6 ± 11.2
11.9 ± 4.3
[32]
6.1 ± 0.8
65.7 ± 12.1
NA
[32]
6.2 ± 0.8
46.2 ± 4.8
NA
[32]
AUC 0 -- ¥ : Area under the curve from time zero to infinity; CL/Fm: Clearance divided by fraction of dose metabolized; CLr: Renal clearance; CrCl: Creatinine clearance; ESRD: End stage renal disease; n: Number of patients; NA: Not applicable; Vss: Volume of distribution at steady state.
Table 4. %fT > MIC to achieve bacteriostatic, 1-log10 and 2-log10 bacterial killing at 24 h after initiation of ceftaroline in in vitro and neutropenic murine models. MIC (mg/l)
Streptococcus pneumoniae* Staphylococcus aureus*, z Staphylococcus aureus*,§ MSSA{ MRSA{ Gram-negative bacilli*,#
0.008 -- 0.12 0.12 -- 1.0 0.125 -- 4.0 0.12 -- 1.0 0.25 -- 2.0 1.0 -- 2.0
%fT > MIC
Ref.
Bacteriostatic effect
1-log killing
2-log killing
39 ± 9 26 ± 8 9.3 26.8 ± 9.6 22.4 ± 8.9 28 ± 9
43 ± 9 33 ± 9 19.3 30.9 ± 11.7 24.8 ± 6.8 41 ± 11
50 ± 10 45 ± 13 70.5 28.2 ± 6.2 27.4 ± 6.2 54 ± 3
[34] [34] [37] [35] [35] [34]
*Neutropenic murine thigh model. z Included MSSA and MRSA strains. § Comprised 4 MSSA and 22 MRSA strains. { In vitro model. # Included E. coli and K. pneumoniae strains. %fT > MIC: Percent time free unbound drug above minimum inhibitory concentration; MRSA: Methicillin-resistant S. aureus; MSSA: Methicillin-susceptible S. aureus.
96-h period. The mean %fT > MIC for all isolates was 61.8 ± 8.5% with a mean decrease in bacterial growth of 3.60 ± 0.6 log10 [38]. The antibiotic activity of human simulated ceftaroline 600 mg i.v. every 12 h has been administered in several animal models including antibiotic-resistant isolates. Using a penicillin-resistant pneumococcal strain in an immunocompetent rabbit pneumonia model, simulated dosing of ceftaroline 600 mg i.v. every 12 h was given over a 48-h period. A ceftaroline %fT > MIC above 40% was associated with total eradication of infection [39]. The same dosing regimen over a 24-h period was used in a neutropenic murine pneumonia model with MSSA (MIC 1.0 mg/l) or MRSA (MIC 0.5 -- 4.0 mg/l). The %fT > MIC ranged from 17 -- 43% and was associated with a 1-log10 bacterial killing effect [40]. Ceftaroline has also been assessed in a rabbit MRSA osteomyelitis and a rabbit E. coli and K. pneumoniae meningitis model.
Both models demonstrated that ceftaroline exhibited bactericidal activity [41,42]. The %fT > MIC associated with bacteriostatic effect and1-log10 and 2-log10 bacterial killing for various isolates from in vitro and a neutropenic murine thigh infection models are found in Table 4 [34,35,37]. Population pharmacokinetic data with ceftaroline 600 mg i.v. every 12 h and %fT > MIC based on results from a murine infection model were used in a Monte Carlo simulation of 2000 patients with varying degrees of renal function to obtain a target attainment analyses. A 1-log10 bacterial killing was demonstrated in 92.4% of S. aureus (MIC 1 mg/l) simulations with %fT > MIC of 36% and in 95.8% of S. pneumoniae (MIC 0.25 mg/l) simulations with % fT > MIC of 44% [43]. Using data collected from Phase III clinical trials, the pharmacodynamics of ceftaroline 600 mg i.v. every 12 h given for 5 days for CABP has been studied. Isolates obtained at baseline included S. pneumoniae,
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Table 5. Ceftaroline target attainment in patients with varying renal function being treated for complicated skin and skin structure infections in a Monte Carlo simulation [45]. MIC (mg/ml)
Probability of target attainment (%)
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T > MIC 30%
T > MIC 40%
T > MIC 50%
Normal renal function -- 600 mg every 12 h 96 h 0.5 100 100 100 1 100 100 96 2 100 90 50 4 71 16 1 CrCl 50 -- 80 ml/min -- 600 mg every 12 h 96 h 0.5 100 100 100 1 100 100 100 2 100 100 94 4 98 66 20 CrCl 30 -- 50 ml/min -- 400 mg every 12 h 96 h 0.5 100 100 100 1 100 100 100 2 100 99 87 4 83 34 6 CrCl: Creatinine clearance; T: Time.
Enterobacteriaceae species and H. influenzae (MIC range £ 0.004 -- 16 mg/l, MIC90 0.5 mg/l). A total of 98.4% of patients attained %fT > MIC of 63.3% [44]. Similarly, data from ceftaroline Phase I and II trials in patients treated for complicated skin and skin tissue infections (cSSSI) with varying degrees of renal function were used in a 4000 patient Monte Carlo simulation to assess the probability of achieving target attainment based on MIC and renal function (Table 5). The results demonstrated that a fT > MIC of 30% was achieved in 71 -- 100% of simulations over a MIC range of 0.5 -- 4 mg/l [45]. Exposure-response analysis supports the recommended dosage regimen of ceftaroline 600 mg i.v. every 12 h in patients with normal renal function. In order to achieve a bactericidal effect (> 1-log10 bacterial killing) with ceftaroline for susceptible pathogens (MIC < 2 mg/l), the fT > MIC of at least 30% is likely necessary. In patients with mild renal impairment (CrCl 30 -- 50 ml/min), ceftaroline 400 mg every 12 h is recommended. For patients with severe (CrCl 15--30 ml/min) renal impairment or ESRD, recommended ceftaroline dosage is 300 mg and 200 mg every 12 h, respectively. Population pharmacokinetic and pharmacodynamic analyses have demonstrated similar %fT > MIC results with the above recommended renal dose adjustments when compared to ceftaroline 600 mg every 12 h in both cSSSI and CABP patient populations [46].
6.
Clinical trials
Two Phase III, multi-center, randomized, double-blind trials (CANVAS 1 and 2) have assessed ceftaroline in patients 6
with ABSSSI. Patients received ceftaroline 600 mg every 12 h (n = 693) or vancomycin 1 g every 12 h with aztreonam (n = 685) for 5 -- 14 days. The primary efficacy endpoint was proportion of patients who achieved clinical cure at the end of treatment. Clinical cure rates in the modified intention to treat (MITT) population for ceftaroline (85.9%) and vancomycin/aztreonam (85.5%) were similar [47]. A post-hoc analysis assessing the number of patients who had a lesion ‡ 75 cm2 and either major abscess ‡ 5 cm, erythema, wound infection or deep/extensive cellulitis were assessed for cessation of lesion spread and absence of fever following day 3 of therapy. This response was defined as the exploratory MITT population. Although outcomes at the test-of-cure visit among clinically evaluable and MITT populations were equivalent in the study groups, the exploratory MITT at day 3 was superior in the ceftaroline treated patients. However, by the test-of-cure visit in the exploratory MITT population, the groups were again similar in their treatment responses for ceftaroline and vancomycin/aztreonam (74.0 vs 66.2%, respectively) [5]. Ceftaroline has been compared to ceftriaxone in CABP patients with two Phase III, double-blinded, randomized, multi-center studies (FOCUS 1 and 2). Adult patients were hospitalized (non-intensive care unit patients) for CABP and had a Pneumonia Outcomes Research Team risk class III or IV. Patients received ceftaroline 600 mg every 12 h (n = 580) or ceftriaxone 1000 mg every 24 h (n = 573) for 5 -- 7 days. In patients with a CrCl of 30 -- 50 ml/min, the ceftaroline dose was adjusted to 400 mg every 12 h; those patients with CrCls of £30 ml /min were excluded. Patients enrolled in North America also received clarithromycin 500 mg orally every 12 h for 2 days (FOCUS 1) for therapy directed at atypical pathogens, where this is considered standard of practice. The primary endpoint was clinical cure at 8 -- 15 days following antibiotic therapy. Clinical cure rates for MITT patients were similar for ceftaroline (82.6%) and ceftriaxone (76.6%; -6% difference; 95% CI 1.4 -- 10.7%) [48]. Clinical cure rates were also similar among the various subgroups analyzed, including those with classic versus mixed infection, bacteremia, and receipt of prior antimicrobial therapy. The response rates at day 4 of therapy were studied as part of a post hoc analysis. Patients who achieved improvement in symptoms including cough, dyspnea, pleuritic chest pain or sputum production from baseline and were hemodynamically stable after 4 days of therapy in the ceftaroline and ceftriaxone arms were similar (69.2 vs 60%, respectively) [5]. There have been a series of case reports assessing the administration of ceftaroline as salvage therapy in patients with bacteremia and infective endocarditis. One case series involved six patients with MRSA bacteremia (MIC 0.5 mg/ l) who were administered ceftaroline 600 mg every 8 -- 12 h following failure to clear MRSA after receiving at least 7 days of vancomycin therapy. All six patients cleared the MRSA bacteremia [49]. In another case series, 10 patients with infective endocarditis and failed or ineligible to receive
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Ceftaroline fosamil
vancomycin were administered ceftaroline 800 mg every 8 h (if CrCl < 60 ml/min, then ceftaroline 400 mg every 8 h). Of the 10 patients, six achieved a clinical cure (defined as the resolution of all signs and symptoms of infection that resulted in no further antibiotic therapy being necessary) [50]. More recently, a retrospective analysis of patients receiving ceftaroline for at least 72 h have been reported. A total of 527 patients who received ceftaroline were analyzed, 67% were treated for off-label indications. Clinical success was defined as resolution of all signs and symptoms of infection without any further need for adjustment of ceftaroline therapy. Clinical success was seen in 88% (426/484) of cases. The authors reported that patients treated with ceftaroline for both FDA-approved and non-approved uses had positive outcomes [51]. 7.
Adverse effects
In Phase II and III clinical trials, ceftaroline 600 mg every 12 h was well tolerated overall. Patients with adverse effects to ceftaroline (44.7 -- 61.2%) were similar to vancomycin and aztreonam (47.5 -- 56.3%) and ceftriaxone (45.7%). The most common ceftaroline-related adverse reactions included nausea (2.3 -- 6%), headache (3.4 -- 6%), diarrhea (4.2 -- 4.9%) and insomnia (2.5 -- 6%). Incidence of rash (2.9%) and pruritus (2.2%) were low. Laboratory reported adverse effects secondary to ceftaroline were infrequent, with elevated transaminases (2.2 -- 6%) being most common [47,48,52]. Seroconversion from a negative to a positive direct Coombs’ test result occurred in 120 of 1114 (10.8%) patients receiving ceftaroline in the four pooled Phase III trials [47,48]. Adverse reactions representing hemolytic anemia were not reported in any of the clinical trials. Infusion site reactions were less common with ceftaroline compared to vancomycin [47]. The incidence of serious adverse effects for ceftaroline (4.3 -- 11.3%) was similar to ceftriaxone (11.7%) and vancomycin/aztreonam (4.1%). There were few patients requiring premature drug discontinuation due to adverse events with ceftaroline (3 -- 4.4%) [48,52]. There have been case reports on ceftaroline-induced eosinophilic pneumonia [53,54], leukopenia [55] and neutropenia [56]. Recently, Jain et al. reported their experience in 12 patients who received ceftaroline for the treatment of refractory MRSA and CoNS infections [57]. All patients received ceftaroline after developing intolerance to or failing treatment with other first-line agents. The median duration of therapy in these patients was 22 days. Ceftaroline was discontinued in 9 of 12 patients (75%) as a result of adverse effects. The average age of patients who discontinued ceftaroline was 53 years, had a reported mean body mass index of 29 kg/m2 and had multiple complex comorbidities. The causes for discontinuation of therapy in these patients were hematologic toxicities in seven patients and severe rash in two patients. The authors concluded that when given for unapproved, off-label indications, ceftaroline was associated with a high rate of
discontinuation secondary to adverse events. It seems that as with other cephalosporins, an increase in adverse effects may occur with increasing doses or prolonged therapy. 8.
Conclusion
The 5th generation cephalosporin, ceftaroline, has Grampositive and -negative coverage similar to previous cephalosporin agents but with additional antimicrobial in vitro activity against penicillin- and cephalosporin-resistant S. pneumoniae, MRSA, VISA, hVISA and daptomycin non-susceptible strains. Ceftaroline Gram-negative coverage includes E. coli, H. influenzae, M. catarrhalis, K. oxytoca and K. pneumoniae. Susceptibility studies in vitro have shown ceftaroline bactericidal activity remains active against b-lactamase positive H. influenzae but not for other b-lactamase producing Gram-negative pathogens. Ceftaroline can induce AmpC expression. Dose reductions are recommended in patients with impaired renal function. In the US, ceftaroline is currently indicated for ABSSSI and CABP at a recommended dosage of 600 mg every 12 h in patients with normal renal function. Similar to other cephalosporins, ceftaroline exhibits a favorable adverse effect profile and is generally well tolerated. 9.
Expert opinion
Currently, ceftaroline is FDA indicated in ABSSSI patients with infections due to S. aureus (including MRSA), ceftriaxone-resistant S. pneumoniae, S. pyogenes, S. agalactiae, E. coli, K. pneumoniae and K. oxytoxa. For those patients who have a contraindication or fail therapy with vancomycin, ceftaroline would be a reasonable alternative for first-line therapy in patients with suspected or documented MRSA skin and skin structure infections. For patients with CABP, ceftaroline is indicated by the FDA for S. pneumoniae, S. aureus (MSSA only), H. influenzae, K. pneumoniae, K. oxytoca and E. coli. As there have been no studies evaluating the efficacy of ceftaroline in CABP patients with isolated MRSA, it cannot be recommended at this time. Additionally, in CABP patients, it is not recommended to treat patients with b-lactamase positive H. influenzae with ceftaroline as no human studies have assessed the efficacy with this pathogen. In vitro data have demonstrated susceptibility of ceftaroline against hVISA, VISA and daptomycin non-susceptible organisms. However, there is no data available from human trials. Limited data is available for ceftaroline salvage therapy in bone and joint infections, bacteremia and endocarditis that have demonstrated potential efficacy, but only limited clinical data is available and the appropriate doses still need to be defined. Clinical trials are currently underway to establish the safety and efficacy of ceftaroline in CABP patients with a risk for MRSA, pediatric patients with CABP or cSSSI, patients with S. aureus bacteremia or with persistent MRSA bacteremia, endocarditis and bone and joint infections.
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
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Future research will define the role of ceftaroline in the treatment of these infections.
Declaration of interest RC Glowacki has done research with Cubist. KA Rodvold is a consultant, serves on the speaker bureau and has an investigator-initiated research grant from Forest Laboratories.
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Hiramatsu K, Hanaki H, Ino T, et al. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility. J Antimicrob Chemother 1997;40:135-46 Ceftaroline fosamil [package insert]. Forrest Pharmaceuticals; St. Louis, MO: 2010
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LH Danziger is a speaker for Forest Laboratories, Cubist, Astellas Pharma and Durata Therapeutics, Inc. He is also a consultant for Durata Therapeutics, Inc. and Cubist and has done research with Cubist and Forest Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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Jones RN, Farrell DJ, Mendes RE, Sader HS. Comparative ceftaroline activity tested against pathogens associated with community-acquired pneumonia: results from an international surveillance study. J Antimicrob Chemother 2011;66(3):69-80 Pfaller MA, Farrell DJ, Sader HS, Jones RN. AWARE ceftaroline surveillance program (2008-2010): trends in resistance patterns among Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis in the United States. Clin Infect Dis 2012;55(3):S187-93 Sader HS, Fritsche TR, Jones RN. Antimicrobial activities of ceftaroline and ME1036 tested against clinical strains of community-acquired methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 2008;52(3):1153-5 Pfaller MA, Flamm RK, Sader HS, Jones RN. Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure
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Riccobene TA, Su SF, Rank D. Singleand 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(3):1496-504
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Ge Y, Thye D, Liao S, Talbot G. Pharmacokinetics (PK) of ceftaroline (PPI-0903) in subjects with mild or moderate renal impairment (RI) [abstract A-1939]. 46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); San Francisco, CA; 2006 Andes D, Craig WA. Pharmacodynamics of a new cephalosporin, PPI-0903 (TAK599), active against methicillin-resistant Staphylococcus aureus in murine thigh and lung infection models: identification of an in vivo pharmacokineticpharmacodynamic target. Antimicrob Agents Chemother 2006;50(4):1376-83
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Van War SA, Forest 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(11):1155-67
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Ge Y, Liao S, Thye D, Talbot GH. Ceftaroline (CPT) dose adjustment recommendations for subjects with mild or moderate renal impairment (RI) [abstract A-35]. 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, IL; 2007 Bhavnani SM, Hammel JP, Van Wart SA, et al. Pharmacokinetic-pharmacodynamic analyses for efficacy of ceftaroline fosamil in patients with community-acquired bacterial pneumonia. Antimicrob Agents Chemother 2013;57(12):6348-50 Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, double-blind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skin-structure infection. Clin Infect Dis 2010;51(6):641-50 Clinical trial assessing ceftaroline in complicated skin and skin tissue infection patients File TM, Low DE, Eckburg PB, et al. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, double-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-
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Affiliation Andrew Merker1 PharmD, Larry H Danziger2 PharmD, Keith A Rodvold2 PharmD & Robert C Glowacki†3 PharmD † Author for correspondence 1 HIV PGY2 Resident, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, Chicago, 60612, USA 2 Professor, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, M/C 886, Chciago, 60612, USA 3 Clinical Assistant Professor, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, M/C 886, Chicago, 60612, USA E-mail: [email protected]
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Pharmacokinetic and pharmacodynamic evaluation of ceftaroline fosamil 1.
Introduction
2.
Mechanism of action
3.
Spectrum of activity
4.
Pharmacokinetics
5.
Pharmacodynamics
6.
Clinical trials
7.
Adverse effects
8.
Conclusion
9.
Expert opinion
Andrew Merker, Larry H Danziger, Keith A Rodvold & Robert C Glowacki† †
University of Illinois at Chicago, College of Pharmacy, Chicago, USA
Introduction: Ceftaroline fosamil is a 5th generation cephalosporin with an in vitro spectrum of activity including Streptococcus agalactiae, penicillinand cephalosporin-resistant S. pneumoniae, S. pyogenes, methicillin-susceptible S. aureus and methicillin-resistant S. aureus, Haemophilus influenzae, Klebsiella oxytoca, K. pneumoniae and Moraxella catarrhalis. It is currently approved by the FDA for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. Areas covered: This review covers the mechanism of action; bacterial resistance; pharmacokinetic characteristics in various patient populations; pharmacodynamic data in animal and in vitro models as well as human studies; efficacy observed in clinical trials for ABSSSI and CABP; and adverse effects. Expert opinion: Ceftaroline provides in vitro bactericidal activity against methicillin-, vancomycin-, daptomycin-, and linezolid-resistant Gram-positive organisms and select Gram-negative pathogens. The pharmacodynamics of ceftaroline is similar to other b-lactam agents. Ceftaroline exhibits a favorable adverse effect profile and is generally well tolerated. There is little data on clinical success of ceftaroline in patients with bacteremia or endocarditis other than what has been published in a small series of case reports. Randomized-control studies are needed to establish clinical outcomes and safety in these patient populations. Keywords: acute bacterial skin and skin structure infections, antibiotic resistance, ceftaroline, community-acquired bacterial pneumonia, methicillin-resistant Staphylococcus aureus Expert Opin. Drug Metab. Toxicol. [Early Online]
1.
Introduction
Antibiotic resistance to Gram-positive organisms has long provided a challenge in determining appropriate antibacterial therapy for patients. Recently, there has been an increase in the incidence of Gram-positive pathogen resistance. This includes Streptococcus pneumoniae that has long been susceptible to penicillin [1,2]. Additionally, there has been a documented increase in the incidence of methicillin-resistant Staphylococcus aureus (MRSA) infections [3,4]. The 5th generation cephalosporin, ceftaroline fosamil (Box 1), is a pro-drug that is rapidly hydrolyzed to the active antimicrobial agent ceftaroline. A novel characteristic of ceftaroline over previous cephalosporins include a spectrum of activity against resistant Gram-positive organisms, including penicillin-resistant and cephalosporin-resistant S. pneumoniae as well as MRSA. Ceftaroline was approved by the FDA in 2010 and is indicated for acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) [5].
10.1517/17425255.2014.972932 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 All rights reserved: reproduction in whole or in part not permitted
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A. Merker et al.
Box 1. Drug summary Drug name Phase Indications
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Pharmacology description Route of administration Chemical structure
Ceftaroline fosamil Currently available for clinical use Acute bacterial skin and skin structure infections due to: methicillin-susceptible and -resistant Staphylococcus aureus, Streptococcus pyogenes, S. agalactiae, Escherichia coli, Klebsiella pneumoniae, and K. oxytoca Community-acquired bacterial pneumonia due to: S. pneumoniae, methicillin-susceptible S. aureus, Haemophilus influenzae, K. pneumoniae, K. oxytoca, and E. coli Advanced generation bactericidal cephalosporin that targets penicillin-binding proteins IV CH3
CH3 O
N
H N
HO
O
OH
CH3 N H N
P HO
O
N
S
N
S S
O N
N S
O HO
Pivotal trial(s)
2.
Mechanism of action
Ceftaroline exerts its mechanism of action by binding to penicillin-binding proteins (PBPs) in Gram-positive and Gram-negative organisms, thus inhibiting organism cell wall biosynthesis and resulting in bactericidal activity [6]. Ceftaroline has a high binding affinity for common PBP targets for S. pneumoniae (PBP-1a, -2b, and -2x) and S. aureus (PBP-1, -2, -2a, and -3). Ceftaroline was found to have a binding affinity for PBP-2a up to 128 times higher compared to cefotaxime, ceftriaxone, and penicillin G in MRSA isolates [7].
3.
Spectrum of activity
Ceftaroline exhibits in vitro bactericidal activity against Gram-positive and Gram--negative species, including S. pneumoniae, S. aureus, coagulase-negative staphylococcus (CoNS), S. pyogenes, S. agalactiae, Klebsiella pneumoniae, K. oxytoca, Escherichia coli, Moraxella catarrhalis, and Haemophilus influenzae [8-14]. Table 1 includes MIC values for selected Gram-positive and Gram-negative pathogens [8-14]. For penicillin-resistant or cephalosporin-resistant S. pnuemoniae, ceftaroline displays potent antibacterial activity with MIC90 £ 0.5 mg/l [8-10,15-19]. Additionally, ceftaroline demonstrates antimicrobial activity in vitro against antibioticresistant Gram-positive pathogens such as MRSA, vancomycin-intermediate S. aureus (VISA), heteroresistant VISA (hVISA), vancomycin-resistant S. aureus, and daptomycin non-susceptible S. aureus [13,20,21]. The MIC for ceftaroline was £ 1 mg/l for the majority of antibiotic-resistant S. aureus strains and a MIC90 ranging from 0.5 -- 2 mg/l [8-11,13,20,21]. 2
O
CANVAS 1 and 2 [46] FOCUS 1 and 2 [47]
S. aureus isolates from pediatric, adult and elderly patient populations have exhibited susceptibility regardless of methicillin-susceptible S. aureus (MSSA) or MRSA, with MIC90 range from 0.25 -- 1 mg/l [22]. Ceftaroline has displayed minimal antibacterial activity for Enterococcus faecium and E. faecalis, with MIC90 > 8 mg/l [8-12,15,23]. Ceftaroline has shown in vitro antibacterial activity against non-b-lactamase strains of Citrobacter freundii (MIC90 0.25 -- 2 mg/l) and E. coli (MIC90 0.12 -- 1 mg/l). Ceftaroline has no antibacterial activity against Acinetobacter baumannii, Pseudomonas aeruginosa, Morganella morganii or Proteus species (MIC90 > 16 mg/l) [8-12]. Ceftaroline has variable antimicrobial activity against anaerobic organisms. The MIC90 for anaerobic pathogens Bacteroides fragilis (> 32 mg/l), Clostridium difficile (4 mg/l) and Prevotella species (> 32 mg/l) indicate poor antibacterial activity. Ceftaroline has demonstrated antibacterial activity against certain Clostridium species (MIC90 1 mg/l) as well as Proprionbacterium and Peptostreptococcus species (MIC90 0.12 mg/l) [8,15]. There were no bacterial pathogens that developed ceftaroline resistance for strains of penicillin-susceptible and penicillin-resistant S. pneumoniae, MSSA, community-acquired MRSA, MRSA, VISA, and b-lactamase negative H. influenzae. Ceftaroline selected for AmpC inducible strains that were previously derepressed [15,24-26]. The spectrum of activity for ceftaroline primarily includes Gram-positive (staphylococci and streptococci) and nonb-lactamase producing Gram-negative species. Studies of isolates in vitro have documented antimicrobial activity against antibiotic resistant pathogens that include penicillinand cephalosporin-resistant S. pneumoniae, MRSA, VISA,
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
Ceftaroline fosamil
Table 1. Ceftaroline in vitro activity against selected susceptible Gram-positive and -negative isolates. Organism
Total isolates
MIC(mg/l)
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50% Staphylococcus aureus MSSA MRSA Streptococcus pneumoniae PCN-S PCN-R S. agalactiae S. pyogenes Escherichia coli CAZ-S CAZ-R Haemophilus influenzae b-lactamase negative b-lactamase positive Klebsiella pneumoniae CAZ-S CAZ-R Moraxella catarrhalis CAZ-S
Ref.
90%
Range
2042 2677
0.25 0.5 -- 1
0.25 0.5 -- 2
£ 0.03 -- 1 0.12 -- 2
[8-11,14] [8-11,13,14]
4480 375 631 705
£ 0.008 -- £ 0.016 0.12 -- 0.25 0.015 £ 0.008 -- 0.015
0.015 -- 0.12 0.12 -- 0.5 0.015 -- 0.03 0.015
£ £ £ £
0.5 0.5 0.12 0.03
[8-12] [8-10] [9,10,14] [8-10,14]
1810 128
0.06 -- 0.12 > 16
0.12 -- 1 > 16
£ 0.015 -- > 16 0.06 -- > 16
[8-11,14] [9,11]
1761 591
£ 0.008 -- £ 0.016 0.015 -- £ 0.016
0.015 -- 0.06 £ 0.016 -- 0.03
£ 0.008 -- 1 £ 0.008 -- 2
[8-12] [8-10,12]
1004 155
0.06 -- 0.12 > 16
0.25 -- 0.5 > 16
£ 0.008 -- > 16 0.25 -- > 16
[8-11,14] [9,11]
812
0.06 -- 0.12
0.12 -- 0.25
£ 0.008 -- 1
[8,10-12]
0.008 0.008 0.008 0.008
-----
CAZ: Ceftazidime; MRSA: Methicillin-resistant Staphylococcus aureus; MSSA: Methicillin-susceptible Staphylococcus aureus; PCN: Penicillin; R: Resistant; S: Susceptiblet.
hVISA and daptomycin non-susceptible. The rate of resistance development was low for Gram-positive pathogens and H. influenzae; however, ceftaroline can induce AmpCderepressed Enterobacteriaceae. 4.
Pharmacokinetics
Ceftaroline fosamil is a pro-drug that is rapidly metabolized to the active antimicrobial agent, ceftaroline. For healthy patients, ceftaroline 600 mg i.v. every 12 h for 14 days resulted in a maximum concentration (Cmax) of 21 mg/l and an area under the curve from time zero to infinity (AUC0 -- ¥) of 56 µg·h/ml [27]. No appreciable accumulation occurs after multiple i.v. doses. In healthy adult males, the median ceftaroline steady-state volume of distribution was 20.3 l (range: 18.3 -- 21.6 l) [5]. The pharmacokinetic profile of ceftaroline is linear and concentrations increase in proportion to increases in the dose. The plasma protein binding of ceftaroline was < 20% at concentrations of 5 mg/l, 20 mg/l and 50 mg/l and tends to decrease as drug concentrations increase (19, 1, and 7%, respectively) [28]. The penetration of ceftaroline into epithelial lining fluid (ELF) at doses of 600 mg every 8 or 12 h for 3 days has been studied in healthy adult patients. The ratio of AUC in ELF to plasma was 21 -- 23% [29]. The hydrolysis of the ceftaroline b-lactam ring results in the formation of the microbiologically inactive metabolite ceftaroline M-1 [5]. There have been no studies to assess dose adjustments in patients with hepatic impairment. However, as ceftaroline undergoes little to no hepatic metabolism,
dose reductions are likely unnecessary. Ceftaroline has negligible metabolism via the CYP system and does not inhibit or induce major CYP enzymes [28]. Therefore, dosing adjustments are probably not necessary when ceftaroline is given concomitantly with potent CYP inhibitors or inducers [5]. The primary route of elimination for ceftaroline is urinary excretion. In healthy patients receiving a single 600 mg i.v. dose, the amount of drug recovered in the urine was 57.03 ± 9.94% (range: 47 -- 71%). The mean elimination t1/2 of the active drug is 2.48 ± 0.30 h with a renal clearance (CLR) of 82.0 ± 16.4 ml/min [30]. Additional information on single- and multiple-dose ceftaroline pharmacokinetics can be found in Table 2 [27,30-32]. The pharmacokinetics of ceftaroline has been studied in varying degrees of creatinine clearance (CrCl), including endstage renal disease (ESRD). For patients with mild (CrCl 50 -- 80 ml/min) and moderate (CrCl 30 -- 50 ml/min) renal impairment, there is an increase in mean AUC0 -- ¥ and t1/2 following a single 600 mg i.v. dose of ceftaroline compared to patients with normal renal function. Patients with severe renal impairment (CrCl < 30 ml/min) or ESRD demonstrated more dramatic changes in AUC0 -- ¥, t1/2 and CLR following a single dose of ceftaroline 400 mg i.v. [32]. For healthy elderly (> 65 years) compared to healthy adults (18 -- 45 years) receiving a single ceftaroline 600 mg i.v. dose, an increased AUC0 -- ¥ (94.1 ± 13.6 vs 70.5 ± 10.1 µg·h/ml) and t1/2 (3.1 ± 0.4 vs 2.2 ± 0.4 h) was demonstrated in the healthy elderly. These observed differences for healthy elderly compared to healthy adults were due to lower mean plasma clearance (95.7 ± 13.4 vs 127.3 ± 15.0 ml/min) and lower
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
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Table 2. Pharmacokinetic parameters of ceftaroline in healthy adults (18 -- 45 years old). n
Median Tmax (h) (range)
AUC 0 -- ` (mg.h/ml)
Vss(L)
T ½(h)
CL/Fm (ml/min)
CLr (ml/min)
Ref.
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Single dose IV administration 50 mg 6 6 100 mg 6 6 250 mg 6 6 500 mg 6 6 600 mg 11 16 750 mg 6 6 1000 mg 6 6
NA 0.9
3.9 4.0 ± 0.7
NA NA
2.0 2.0 ± 0.2
NA 192.1 ± 38.9
90.0 93.6 ± 25.0
[31] [32]
NA 0.9
6.6 6.7 ± 1.7
NA NA
2.2 2.2 ± 0.4
NA 228.9 ± 49.1
92.0 96.2 ± 29.6
[31] [32]
NA 0.9
22.9 23.4 ± 5.4
NA NA
2.3 2.3 ± 0.3
NA 164.6 ± 39.2
73.4 77.4 ± 27.8
[31] [32]
NA 1.1
44.7 44.8 ± 2.9
NA NA
2.5 2.5 ± 0.3
NA 164.8 ± 10.6
93.7 93.5 ± 14.4
[31] [32]
0.98 (0.97 -- 1.08) 1.0 (0.9 -- 1.1)
62.7 ± 0.3
19.7 ± 3.3
2.4 ± 0.3
144.5 ± 20.1
82.0 ± 16.4
[30]
70.5 ± 10.1
15.8 ± 2.7
2.2 ± 0.4
NA
81.0 ± 23.4
[32]
NA 1.0
56.9 57.6 ± 9.8
NA NA
2.6 2.6 ± 0.3
NA NA
104.9 107.6 ± 26.8
[31] [32]
NA 0.9
80.5 80.9 ± 8.6
NA NA
2.9 2.9 ± 0.1
NA NA
129.2 130.7 ± 21.3
[31] [32]
Multiple dose IV administration (based on after last dose given) 300 mg every 12 h ( 28 doses) 6 0.9 (0.9 -- 1.1) 6 NA 600 mg every 12 h ( 28 doses) 6 0.9 (0.9 -- 1.1) 6 NA 800 mg once daily ( 7 doses) 6 1.1 (0.9 -- 1.1) 6 NA
24.3 ± 3.7 24.0
NA NA
2.6 ± 0.4 2.6
184.9 ± 26.9 183.0
75.3 ± 19.9 NA
[32] [27]
56.3 ± 8.9 56.0
NA NA
2.7 ± 0.4 2.6
160.1 ± 23.3 159.0
118.9 ± 72.8 NA
[32] [27]
74.2 ± 14.2 73.0
NA NA
2.6 ± 0.2 2.6
164.3 ± 35.2 161.0
66.1 ± 20.2 NA
[32] [27]
AUC 0 -- ¥: Area under the curve from time zero to infinity; CL/Fm: Clearance divided by fraction of dose metabolized; CLr: Renal clearance; n: Number of patients; NA: Not applicable; Vss: Volume of distribution at steady state.
mean CLr (54.9 ± 12.7 vs 81.0 ± 23.4 ml/min), respectively. Other pharmacokinetic parameters (Cmax and Vss) were similar between the two groups [32]. Additional pharmacokinetic data on patients based on age and renal function can be found in Table 3 [27,32,33]. As adverse effects of ceftaroline are dose dependent, the elderly and those with poor renal function will be more likely to experience adverse effects as a result of decreased drug clearance. 5.
Pharmacodynamics
Ceftaroline exhibits a bactericidal effect by time-dependent killing. The post-antibiotic effect is longest with S. aureus (0.8 -- 7.2 h) compared to S. pneumoniae (< 1.5 h) and E. coli (< 5.7 h) [34]. The percent of time that the unbound drug level exceeds the MIC (%fT > MIC) has been found to 4
have the most significant impact on bactericidal activity for S. pneumoniae, S. aureus (MSSA and MRSA) and K. pneumoniae in a murine thigh and lung model [34]. The mean % fT > MIC to achieve a bacteriostatic effect after 24 h of initiating ceftaroline for S. pneumoniae, S. aureus (including MSSA and MRSA) and Gram-negative bacilli (E. coli and K. pneumoniae) ranged from 10 -- 40%. In order to achieve a 1-log10 or 2-log10 bacterial killing in these isolates, a % fT > MIC of 20 -- 43% and 28 -- 70% was necessary, respectively [34-36]. A two-compartment, hollow fiber model with MRSA and hVISA isolates (MIC 0.125 -- 2.0 mg/l) found that a %fT > MIC for ceftaroline above 46% achieved bactericidal activity for all strains [37]. A one-compartment in vitro model assessed the pharmacodynamics of ceftaroline against MRSA, hVISA and VISA (MIC 1 mg/l for all isolates) with simulated dosing of ceftaroline 600 mg every 12 h over a
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
Ceftaroline fosamil
Table 3. Pharmacokinetic parameters of single ceftaroline IV doses in different patient populations.
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n
Median Tmax (h) (range)
AUC 0 -- ` (mg.h/ml)
Vss(L)
Healthy elderly -- 600 mg (‡ 65 years) 16 1.0 (0.9 -- 1.1) 94.1 ± 13.6 17.9 ± 3.0 Mild renal impairment -- 600 mg (CrCl 51 -- 80 ml/min) 6 0.9 (0.9 -- 1.3) 92.3 ± 25.3 NA 6 NA 95.0 ± 26.0 NA Moderate renal impairment -- 600 mg (CrCl 31 -- 50 ml/min) 6 1.1 (0.9 -- 1.3) 114.8 ± 14.1 NA 6 NA 120.0 ± 13.0 NA Severe renal impairment -- 400 mg (CrCl # 30 ml/min) 6 1.3 (0.9 -- 1.6) 112.4 ± 20.5 NA ESRD - 400 mg (before hemodialysis) 6 1.0 (1.0 -- 1.1) 92.0 ± 15.9 NA ESRD - 400 mg (after hemodialysis) 6 1.0 (1.0 -- 1.0) 128.6 ± 12.7 NA
T ½(h)
CL/Fm(ml/min)
CLr (ml/min)
Ref.
3.1 ± 0.4
NA
54.9 ± 12.7
[32]
3.7 ± 0.7 3.7 ± 0.7
102.0 ± 28.1 NA
31.2 ± 5.4 64.0 ± 11.0
[32] [33]
4.6 ± 1.1 4.6 ± 1.1
78.0 ± 11.0 NA
20.0 ± 6.3 74.0 ± 9.0
[32] [33]
5.1 ± 1.2
53.6 ± 11.2
11.9 ± 4.3
[32]
6.1 ± 0.8
65.7 ± 12.1
NA
[32]
6.2 ± 0.8
46.2 ± 4.8
NA
[32]
AUC 0 -- ¥ : Area under the curve from time zero to infinity; CL/Fm: Clearance divided by fraction of dose metabolized; CLr: Renal clearance; CrCl: Creatinine clearance; ESRD: End stage renal disease; n: Number of patients; NA: Not applicable; Vss: Volume of distribution at steady state.
Table 4. %fT > MIC to achieve bacteriostatic, 1-log10 and 2-log10 bacterial killing at 24 h after initiation of ceftaroline in in vitro and neutropenic murine models. MIC (mg/l)
Streptococcus pneumoniae* Staphylococcus aureus*, z Staphylococcus aureus*,§ MSSA{ MRSA{ Gram-negative bacilli*,#
0.008 -- 0.12 0.12 -- 1.0 0.125 -- 4.0 0.12 -- 1.0 0.25 -- 2.0 1.0 -- 2.0
%fT > MIC
Ref.
Bacteriostatic effect
1-log killing
2-log killing
39 ± 9 26 ± 8 9.3 26.8 ± 9.6 22.4 ± 8.9 28 ± 9
43 ± 9 33 ± 9 19.3 30.9 ± 11.7 24.8 ± 6.8 41 ± 11
50 ± 10 45 ± 13 70.5 28.2 ± 6.2 27.4 ± 6.2 54 ± 3
[34] [34] [37] [35] [35] [34]
*Neutropenic murine thigh model. z Included MSSA and MRSA strains. § Comprised 4 MSSA and 22 MRSA strains. { In vitro model. # Included E. coli and K. pneumoniae strains. %fT > MIC: Percent time free unbound drug above minimum inhibitory concentration; MRSA: Methicillin-resistant S. aureus; MSSA: Methicillin-susceptible S. aureus.
96-h period. The mean %fT > MIC for all isolates was 61.8 ± 8.5% with a mean decrease in bacterial growth of 3.60 ± 0.6 log10 [38]. The antibiotic activity of human simulated ceftaroline 600 mg i.v. every 12 h has been administered in several animal models including antibiotic-resistant isolates. Using a penicillin-resistant pneumococcal strain in an immunocompetent rabbit pneumonia model, simulated dosing of ceftaroline 600 mg i.v. every 12 h was given over a 48-h period. A ceftaroline %fT > MIC above 40% was associated with total eradication of infection [39]. The same dosing regimen over a 24-h period was used in a neutropenic murine pneumonia model with MSSA (MIC 1.0 mg/l) or MRSA (MIC 0.5 -- 4.0 mg/l). The %fT > MIC ranged from 17 -- 43% and was associated with a 1-log10 bacterial killing effect [40]. Ceftaroline has also been assessed in a rabbit MRSA osteomyelitis and a rabbit E. coli and K. pneumoniae meningitis model.
Both models demonstrated that ceftaroline exhibited bactericidal activity [41,42]. The %fT > MIC associated with bacteriostatic effect and1-log10 and 2-log10 bacterial killing for various isolates from in vitro and a neutropenic murine thigh infection models are found in Table 4 [34,35,37]. Population pharmacokinetic data with ceftaroline 600 mg i.v. every 12 h and %fT > MIC based on results from a murine infection model were used in a Monte Carlo simulation of 2000 patients with varying degrees of renal function to obtain a target attainment analyses. A 1-log10 bacterial killing was demonstrated in 92.4% of S. aureus (MIC 1 mg/l) simulations with %fT > MIC of 36% and in 95.8% of S. pneumoniae (MIC 0.25 mg/l) simulations with % fT > MIC of 44% [43]. Using data collected from Phase III clinical trials, the pharmacodynamics of ceftaroline 600 mg i.v. every 12 h given for 5 days for CABP has been studied. Isolates obtained at baseline included S. pneumoniae,
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Table 5. Ceftaroline target attainment in patients with varying renal function being treated for complicated skin and skin structure infections in a Monte Carlo simulation [45]. MIC (mg/ml)
Probability of target attainment (%)
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T > MIC 30%
T > MIC 40%
T > MIC 50%
Normal renal function -- 600 mg every 12 h 96 h 0.5 100 100 100 1 100 100 96 2 100 90 50 4 71 16 1 CrCl 50 -- 80 ml/min -- 600 mg every 12 h 96 h 0.5 100 100 100 1 100 100 100 2 100 100 94 4 98 66 20 CrCl 30 -- 50 ml/min -- 400 mg every 12 h 96 h 0.5 100 100 100 1 100 100 100 2 100 99 87 4 83 34 6 CrCl: Creatinine clearance; T: Time.
Enterobacteriaceae species and H. influenzae (MIC range £ 0.004 -- 16 mg/l, MIC90 0.5 mg/l). A total of 98.4% of patients attained %fT > MIC of 63.3% [44]. Similarly, data from ceftaroline Phase I and II trials in patients treated for complicated skin and skin tissue infections (cSSSI) with varying degrees of renal function were used in a 4000 patient Monte Carlo simulation to assess the probability of achieving target attainment based on MIC and renal function (Table 5). The results demonstrated that a fT > MIC of 30% was achieved in 71 -- 100% of simulations over a MIC range of 0.5 -- 4 mg/l [45]. Exposure-response analysis supports the recommended dosage regimen of ceftaroline 600 mg i.v. every 12 h in patients with normal renal function. In order to achieve a bactericidal effect (> 1-log10 bacterial killing) with ceftaroline for susceptible pathogens (MIC < 2 mg/l), the fT > MIC of at least 30% is likely necessary. In patients with mild renal impairment (CrCl 30 -- 50 ml/min), ceftaroline 400 mg every 12 h is recommended. For patients with severe (CrCl 15--30 ml/min) renal impairment or ESRD, recommended ceftaroline dosage is 300 mg and 200 mg every 12 h, respectively. Population pharmacokinetic and pharmacodynamic analyses have demonstrated similar %fT > MIC results with the above recommended renal dose adjustments when compared to ceftaroline 600 mg every 12 h in both cSSSI and CABP patient populations [46].
6.
Clinical trials
Two Phase III, multi-center, randomized, double-blind trials (CANVAS 1 and 2) have assessed ceftaroline in patients 6
with ABSSSI. Patients received ceftaroline 600 mg every 12 h (n = 693) or vancomycin 1 g every 12 h with aztreonam (n = 685) for 5 -- 14 days. The primary efficacy endpoint was proportion of patients who achieved clinical cure at the end of treatment. Clinical cure rates in the modified intention to treat (MITT) population for ceftaroline (85.9%) and vancomycin/aztreonam (85.5%) were similar [47]. A post-hoc analysis assessing the number of patients who had a lesion ‡ 75 cm2 and either major abscess ‡ 5 cm, erythema, wound infection or deep/extensive cellulitis were assessed for cessation of lesion spread and absence of fever following day 3 of therapy. This response was defined as the exploratory MITT population. Although outcomes at the test-of-cure visit among clinically evaluable and MITT populations were equivalent in the study groups, the exploratory MITT at day 3 was superior in the ceftaroline treated patients. However, by the test-of-cure visit in the exploratory MITT population, the groups were again similar in their treatment responses for ceftaroline and vancomycin/aztreonam (74.0 vs 66.2%, respectively) [5]. Ceftaroline has been compared to ceftriaxone in CABP patients with two Phase III, double-blinded, randomized, multi-center studies (FOCUS 1 and 2). Adult patients were hospitalized (non-intensive care unit patients) for CABP and had a Pneumonia Outcomes Research Team risk class III or IV. Patients received ceftaroline 600 mg every 12 h (n = 580) or ceftriaxone 1000 mg every 24 h (n = 573) for 5 -- 7 days. In patients with a CrCl of 30 -- 50 ml/min, the ceftaroline dose was adjusted to 400 mg every 12 h; those patients with CrCls of £30 ml /min were excluded. Patients enrolled in North America also received clarithromycin 500 mg orally every 12 h for 2 days (FOCUS 1) for therapy directed at atypical pathogens, where this is considered standard of practice. The primary endpoint was clinical cure at 8 -- 15 days following antibiotic therapy. Clinical cure rates for MITT patients were similar for ceftaroline (82.6%) and ceftriaxone (76.6%; -6% difference; 95% CI 1.4 -- 10.7%) [48]. Clinical cure rates were also similar among the various subgroups analyzed, including those with classic versus mixed infection, bacteremia, and receipt of prior antimicrobial therapy. The response rates at day 4 of therapy were studied as part of a post hoc analysis. Patients who achieved improvement in symptoms including cough, dyspnea, pleuritic chest pain or sputum production from baseline and were hemodynamically stable after 4 days of therapy in the ceftaroline and ceftriaxone arms were similar (69.2 vs 60%, respectively) [5]. There have been a series of case reports assessing the administration of ceftaroline as salvage therapy in patients with bacteremia and infective endocarditis. One case series involved six patients with MRSA bacteremia (MIC 0.5 mg/ l) who were administered ceftaroline 600 mg every 8 -- 12 h following failure to clear MRSA after receiving at least 7 days of vancomycin therapy. All six patients cleared the MRSA bacteremia [49]. In another case series, 10 patients with infective endocarditis and failed or ineligible to receive
Expert Opin. Drug Metab. Toxicol. (2014) 10(12)
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Ceftaroline fosamil
vancomycin were administered ceftaroline 800 mg every 8 h (if CrCl < 60 ml/min, then ceftaroline 400 mg every 8 h). Of the 10 patients, six achieved a clinical cure (defined as the resolution of all signs and symptoms of infection that resulted in no further antibiotic therapy being necessary) [50]. More recently, a retrospective analysis of patients receiving ceftaroline for at least 72 h have been reported. A total of 527 patients who received ceftaroline were analyzed, 67% were treated for off-label indications. Clinical success was defined as resolution of all signs and symptoms of infection without any further need for adjustment of ceftaroline therapy. Clinical success was seen in 88% (426/484) of cases. The authors reported that patients treated with ceftaroline for both FDA-approved and non-approved uses had positive outcomes [51]. 7.
Adverse effects
In Phase II and III clinical trials, ceftaroline 600 mg every 12 h was well tolerated overall. Patients with adverse effects to ceftaroline (44.7 -- 61.2%) were similar to vancomycin and aztreonam (47.5 -- 56.3%) and ceftriaxone (45.7%). The most common ceftaroline-related adverse reactions included nausea (2.3 -- 6%), headache (3.4 -- 6%), diarrhea (4.2 -- 4.9%) and insomnia (2.5 -- 6%). Incidence of rash (2.9%) and pruritus (2.2%) were low. Laboratory reported adverse effects secondary to ceftaroline were infrequent, with elevated transaminases (2.2 -- 6%) being most common [47,48,52]. Seroconversion from a negative to a positive direct Coombs’ test result occurred in 120 of 1114 (10.8%) patients receiving ceftaroline in the four pooled Phase III trials [47,48]. Adverse reactions representing hemolytic anemia were not reported in any of the clinical trials. Infusion site reactions were less common with ceftaroline compared to vancomycin [47]. The incidence of serious adverse effects for ceftaroline (4.3 -- 11.3%) was similar to ceftriaxone (11.7%) and vancomycin/aztreonam (4.1%). There were few patients requiring premature drug discontinuation due to adverse events with ceftaroline (3 -- 4.4%) [48,52]. There have been case reports on ceftaroline-induced eosinophilic pneumonia [53,54], leukopenia [55] and neutropenia [56]. Recently, Jain et al. reported their experience in 12 patients who received ceftaroline for the treatment of refractory MRSA and CoNS infections [57]. All patients received ceftaroline after developing intolerance to or failing treatment with other first-line agents. The median duration of therapy in these patients was 22 days. Ceftaroline was discontinued in 9 of 12 patients (75%) as a result of adverse effects. The average age of patients who discontinued ceftaroline was 53 years, had a reported mean body mass index of 29 kg/m2 and had multiple complex comorbidities. The causes for discontinuation of therapy in these patients were hematologic toxicities in seven patients and severe rash in two patients. The authors concluded that when given for unapproved, off-label indications, ceftaroline was associated with a high rate of
discontinuation secondary to adverse events. It seems that as with other cephalosporins, an increase in adverse effects may occur with increasing doses or prolonged therapy. 8.
Conclusion
The 5th generation cephalosporin, ceftaroline, has Grampositive and -negative coverage similar to previous cephalosporin agents but with additional antimicrobial in vitro activity against penicillin- and cephalosporin-resistant S. pneumoniae, MRSA, VISA, hVISA and daptomycin non-susceptible strains. Ceftaroline Gram-negative coverage includes E. coli, H. influenzae, M. catarrhalis, K. oxytoca and K. pneumoniae. Susceptibility studies in vitro have shown ceftaroline bactericidal activity remains active against b-lactamase positive H. influenzae but not for other b-lactamase producing Gram-negative pathogens. Ceftaroline can induce AmpC expression. Dose reductions are recommended in patients with impaired renal function. In the US, ceftaroline is currently indicated for ABSSSI and CABP at a recommended dosage of 600 mg every 12 h in patients with normal renal function. Similar to other cephalosporins, ceftaroline exhibits a favorable adverse effect profile and is generally well tolerated. 9.
Expert opinion
Currently, ceftaroline is FDA indicated in ABSSSI patients with infections due to S. aureus (including MRSA), ceftriaxone-resistant S. pneumoniae, S. pyogenes, S. agalactiae, E. coli, K. pneumoniae and K. oxytoxa. For those patients who have a contraindication or fail therapy with vancomycin, ceftaroline would be a reasonable alternative for first-line therapy in patients with suspected or documented MRSA skin and skin structure infections. For patients with CABP, ceftaroline is indicated by the FDA for S. pneumoniae, S. aureus (MSSA only), H. influenzae, K. pneumoniae, K. oxytoca and E. coli. As there have been no studies evaluating the efficacy of ceftaroline in CABP patients with isolated MRSA, it cannot be recommended at this time. Additionally, in CABP patients, it is not recommended to treat patients with b-lactamase positive H. influenzae with ceftaroline as no human studies have assessed the efficacy with this pathogen. In vitro data have demonstrated susceptibility of ceftaroline against hVISA, VISA and daptomycin non-susceptible organisms. However, there is no data available from human trials. Limited data is available for ceftaroline salvage therapy in bone and joint infections, bacteremia and endocarditis that have demonstrated potential efficacy, but only limited clinical data is available and the appropriate doses still need to be defined. Clinical trials are currently underway to establish the safety and efficacy of ceftaroline in CABP patients with a risk for MRSA, pediatric patients with CABP or cSSSI, patients with S. aureus bacteremia or with persistent MRSA bacteremia, endocarditis and bone and joint infections.
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Future research will define the role of ceftaroline in the treatment of these infections.
Declaration of interest RC Glowacki has done research with Cubist. KA Rodvold is a consultant, serves on the speaker bureau and has an investigator-initiated research grant from Forest Laboratories.
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Affiliation Andrew Merker1 PharmD, Larry H Danziger2 PharmD, Keith A Rodvold2 PharmD & Robert C Glowacki†3 PharmD † Author for correspondence 1 HIV PGY2 Resident, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, Chicago, 60612, USA 2 Professor, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, M/C 886, Chciago, 60612, USA 3 Clinical Assistant Professor, University of Illinois at Chicago, College of Pharmacy, 833 South Wood Street, M/C 886, Chicago, 60612, USA E-mail: [email protected]
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