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Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function A. Canut a,b , A. Isla c,d , A. Rodríguez-Gascón c,d,∗ a

Microbiology Service, Hospital Universitario de Álava, Servicio Vasco de Salud Osakidetza, Vitoria-Gasteiz, Spain Instituto de Investigación Sanitaria de Álava (BIOARABA), Servicio Vasco de Salud Osakidetza, Vitoria-Gasteiz, Spain c Pharmacokinetics, Nanotechnology and Gene Therapy Group (PharmaNanoGene), Faculty of Pharmacy, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain d Centro de Investigación Lascaray ikergunea, University of the Basque Country UPV/EHU, Vitoria-Gasteiz, Spain b

a r t i c l e

i n f o

Article history: Received 28 July 2014 Accepted 16 December 2014 Keywords: Ceftaroline fosamil PK/PD Antimicrobial therapy Community-acquired pneumonia Skin and soft-tissue infection

a b s t r a c t In this study, the probability of pharmacokinetic/pharmacodynamic target attainment (PTA) of ceftaroline against clinical isolates causing community-acquired bacterial pneumonia (CABP) and complicated skin and skin-structure infection (cSSSI) in Europe was evaluated. Three dosing regimens were assessed: 600 mg every 12 h (q12 h) as a 1-h infusion (standard dose) or 600 mg every 8 h (q8 h) as a 2-h infusion in virtual patients with normal renal function; and 400 mg q12 h as a 1-h infusion in patients with moderate renal impairment. Pharmacokinetic and microbiological data were obtained from the literature. The PTA and the cumulative fraction of response (CFR) were calculated by Monte Carlo simulation. In patients with normal renal function, the ceftaroline standard dose (600 mg q12 h as a 1-h infusion) can be sufficient to treat CABP due to ceftazidime-susceptible (CAZ-S) Escherichia coli, CAZ-S Klebsiella pneumoniae, meticillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis (CFR > 90%). However, against meticillin-resistant S. aureus (MRSA), the CFR was 72%. In cSSSI, the CFR was also MIC ) [7]. With knowledge of the exposure targets necessary for optimal clinical response, Monte Carlo simulation can be used to combine pharmacokinetic, pharmacodynamic and microbiological data and inform dose selection [8]. The goal of this study was to evaluate the probability of attaining targeted pharmacodynamic exposure of intravenously administered ceftaroline against different clinical isolates causing CABP and cSSSI. Three dosing regimens were evaluated: 600 mg q12 h as a 1-h infusion in simulated patients with normal renal function (standard dose); 400 mg q12 h as a 1-h infusion in simulated patients with moderate renal impairment; and 600 mg every 8 h (q8 h) as a 2h infusion in simulated patients with normal renal function, since in a recent phase 1 clinical trial [9] this dosing regimen was also administered to healthy volunteers. 2. Methods The methodology included the following steps: (i) dosing regimen selection and acquisition of pharmacokinetic data; (ii) microbiological data acquisition; and (iii) Monte Carlo simulation of different i.v. dosing regimens of ceftaroline fosamil in two patient populations, namely patients with normal renal function and patients with moderate renal impairment. Monte Carlo simulation allowed us to estimate the probability of target attainment (PTA), defined as the probability that at least a specific value of a PK/PD index is achieved at a certain MIC, and to calculate the cumulative fraction of response (CFR), defined as the expected

Table 1 Mean ± standard deviation pharmacokinetic parameters of ceftaroline from published studies in patients with normal renal function and in patients with moderate renal impairment [11–13]. Group

V (L)

CL (L/h)

fu

Normal renal function Moderate renal insufficiency

20.39 ± 4.87 20.39 ± 4.87

8.10 ± 1.54 4.44 ± 0.54

0.8 0.8

V, volume of distribution; CL, total body clearance; fu , unbound fraction.

population PTA for a specific drug dose and a specific population of micro-organisms [10]. 2.1. Dosing regimen selection and acquisition of pharmacokinetic data Three dosing regimens were evaluated: i.v. administration of 600 mg ceftaroline q12 h infused over 1 h and 600 mg q8 h infused over 2 h for patients with normal renal function [creatinine clearance (CLCr ) of 80–120 mL/min]; and 400 mg q12 h infused over 1 h for patients with moderate renal impairment (CLCr of 30–50 mL/min). Pharmacokinetic parameters were obtained from published studies [11–13]. Pharmacokinetic studies were identified using PubMed, the National Library of Medicine’s search engine for the Medline® database. Studies were included if they evaluated the selected dosing regimens after multiple-dose administration and provided the mean and standard deviation for the pharmacokinetic parameters of interest for each patient group. Pharmacokinetic parameters (volume of distribution and clearance values and their variability in the different groups of patients) from non-compartmental analysis were selected. Table 1 shows the pharmacokinetic parameters of ceftaroline [total body clearance (CL), volume of distribution (V) and unbound fraction (fu )] used to estimate the fT>MIC . 2.2. Acquisition of microbiological data Susceptibility data for ceftaroline fosamil against pathogens associated with CABP and cSSSI in Europe were obtained from

Table 2 Activity of ceftaroline against bacteria associated with community-acquired bacterial pneumonia isolated in Europe in 2008–2009 [14]. Organism

% of strains inhibited at a ceftaroline MIC (mg/L) of ≤0.008

4

≥8

1.7 1.5 3.9

1.2 1.0 3.1

11.5 2.1 86.7

2.7 3.8

1.5 1.7 1.1

0.6 0.0 2.1

27.5 0.4 96.8

11.0

1.9

0.6

1.3

38.1

53.4 76.7 3.3

19.0 17.8 21.7

18.0

5.8

56.7

18.3

12.3 8.0 61.1

4.9 2.2 36.1

0.2

14.2

0.7

0.015

0.03

0.06

0.125

0.25

0.1 0.1

0.4 0.5

9.0 10.1

31.0 34.9

22.6 25.4

12.2 13.4 2.3

6.3 6.7 3.1

3.9 4.3 0.8

Klebsiella pneumoniae All CAZ-S CAZ-R

0.3 0.4

0.0 0.0

4.8 6.7

30.2 42.1

21.3 29.6

6.6 9.2

4.5 6.3

Enterobacter cloacae

0.6

0.0

0.0

6.5

12.9

27.1

0.5 0.8

3.2 4.7

Escherichia coli All CAZ-S CAZ-R

Staphylococcus aureus All MSSA MRSA Streptococcus pneumoniae All PEN-S PEN-NS

63.0 68.5

Haemophilus influenzae Moraxella catarrhalis

82.8 8.2

10.3 11.2 16.3 7.5

4.5 4.9 0.5 37.3

4.7 5.1 0.5 32.1

0.5

1

2

2.8

MIC, minimum inhibitory concentration; CAZ-S, ceftazidime-susceptible; CAZ-R, ceftazidime-resistant (ESBL phenotype; MIC ≥ 2 mg/L); ESBL, extended-spectrum ␤lactamase; MSSA, meticillin-susceptible S. aureus; MRSA, meticillin-resistant S. aureus; PEN-S, penicillin-susceptible (MIC ≤ 2 mg/L); PEN-NS, penicillin-non-susceptible (MIC ≥ 4 mg/L).

Please cite this article in press as: Canut A, et al. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2014.12.023

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Table 3 Activity of ceftaroline against bacteria associated with complicated skin and skin-structure infections isolated in Europe in 2010 [15]. Organism

% of strains inhibited at a ceftaroline MIC (mg/L) of ≤0.008

Escherichia coli All Non-ESBL phenotype ESBL phenotype

0.015

0.03

0.06

0.125

0.25

0.5

0.6 0.9

7.4 10.6

21.4 30.4

19.2 27.3

7.1 10.1

7.7 11.0

Klebsiella pneumoniae All Non-ESBL phenotype ESBL phenotype ␤-Haemolytic streptococci Group A streptococci Group B streptococci Viridans group streptococci

67.6 99.0 3.5 24.7

28.5 1.0 87.9 19.4

3.6 6.0

27.3 45.8

3.7

0.2

8.5 37.6

11.8

1.1

4.3

1.1

0.3 0.4

11.3 14.7

64.4 82.7 3.9

11.8 2.2 43.5

Staphylococcus aureus All MSSA MRSA

12.9 21.7

5.0 8.4

3.6 6.0

1

4

8

16

32

>32

0.9 0.9 1.0

1.5 0.9 3.1

1.5 0.9 3.1

0.9 0.4 2.1

1.2 4.2

26.0 0.4 86.5

2.9 3.6 1.8

4.3 6.0 1.8

1.4 1.2 1.8

1.4 1.2 1.8

0.7

1.4

35.3

1.8

3.6

87.5

9.6

2.6

41.4

11.2

4.3 6.2

2

MIC, minimum inhibitory concentration; ESBL, extended-spectrum ␤-lactamase; MSSA, meticillin-susceptible S. aureus; MRSA, meticillin-resistant S. aureus.

recently published studies. The bacterial population MIC distribution for isolates associated with CABP collected in 12 European countries were obtained from Jones et al. [14] (Table 2). Data for the bacterial population MIC distribution for isolates associated with cSSSI collected in 19 European countries were obtained from Farrell et al. [15] (Table 3). 2.3. Estimation of fT>MIC and probability of target attainment (PTA) A 10 000-subject Monte Carlo simulation was conducted for each dosing regimen using Oracle® Crystal Ball Fusion Edition v.11.1.1.1.00 (Oracle USA Inc., Redwood City, CA). The percentage of a dosing interval during which the free drug concentration remains above the MIC (fT>MIC ) was calculated for the three dosing regimens (600 mg q12 h, 600 mg q8 h and 400 mg q12 h) over an MIC range of serial two-fold dilutions from 0.008 mg/L to 64 mg/L. A one-compartment pharmacokinetic model was assumed and the following equation was used, valid for i.v. infusions [16]: fT>MIC (%) = [(t2 + tinf ) − t1 ] ×

100 

(1)

where tinf (h) is the infusion time, t1 (h) corresponds to the time at which the drug concentration reaches the MIC during the infusion phase, t2 (h) corresponds to the post-infusion time at which the serum concentration equals the MIC, and  is the dosing interval. Assuming that ceftaroline shows linear pharmacokinetics, t1 and t2 were calculated as follows: t1 =

(MIC − fCmin,ss ) × tinf (fCmax,ss − fCmin,ss )

t2 = Ln

 fC

max,ss

MIC



V × CL

D 1 · (1 − e−(CL/V )·tinf ) · CL · tinf 1 − e−(CL/V )·

fCmin,ss = fCmax,ss · e−(CL/V )·(−tinf )

2.4. Determination of cumulative fraction of response (CFR) The CFR, understood as the expected population PTA for a specific ceftaroline dose and a specific population of micro-organisms, was also calculated. It allowed for an estimation of the proportion of the population achieving a certain PK/PD value, given the Monte Carlo simulation and the MIC distribution of the target microorganism(s) [10]. It is calculated from the following equation: CFR =

n 

PTAi × Fi

(6)

i=1

where i indicates the MIC category ranked from lowest to highest MIC value of a population of micro-organisms, PTAi is the PTA of each MIC category, and F is the fraction of the population of microorganisms at each MIC category.

(2) 3. Results (3)

where fCmin,ss and fCmax,ss were the minimum and maximum serum concentrations of unbound drug (mg/L) at steady state, respectively. Total body clearance (CL), volume of distribution (V), dose (D) and unbound fraction (fu ) were used to estimate fCmax,ss and fCmin,ss according to the following equations: fCmax,ss = fu ·

A log-normal distribution was assumed for CL and V, according to statistical criteria. Unbound fraction, obtained from the literature [13], was included as a fix value [17]. The output consisted of a probability distribution and specific confidence intervals (CIs) over particular fT>MIC and MIC values, according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) approach [18]. Moreover, the PTA, defined as the probability that a specific value of a PK/PD index associated with the efficacy of the antimicrobial treatment is achieved at a certain MIC [10], was estimated. The target was unbound ceftaroline concentrations remaining above the MIC for ≥60% of the dosing interval (fT>MIC > 60%) [1].

(4) (5)

Fig. 1 shows the PTA (fT>MIC > 60%) of ceftaroline in the two patient populations receiving different dosing regimens. On the basis of simulation results and taking into account the target for ceftaroline, 600 mg q12 h covers infections caused by microorganisms with an MIC ≤ 0.5 mg/L (PTA > 90%). In patients with normal renal function receiving ceftaroline 600 mg q8 h as a 2h infusion and in patients with moderate renal failure receiving 400 mg q12 h, micro-organisms with MIC values up to 2 mg/L are also covered. Fig. 2 features the relationship between fT>MIC and MIC for the three different dosing regimens of ceftaroline. The figure shows the total probability function irrespective of the target (EUCAST

Please cite this article in press as: Canut A, et al. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2014.12.023

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100 90 80

PTA (%fT >MIC>60%)

70 60 50 40 30

600 mg q12 h 400 mg q12 h

20

600 mg q8h

10 0 0.008

0.015

0.03

0.06

0.125

0.25

0.5

1

2

4

8

16

32

64

MIC (mg/L) Fig. 1. Probability of target attainment (PTA) (fT>MIC > 60%) of ceftaroline in simulated patients with normal renal function following administration of 600 mg ceftaroline fosamil q12 h (1-h infusion) or 600 mg q8 h (2-h infusion) and in simulated patients with moderate renal impairment following administration of 400 mg q12 h (1-h infusion). fT>MIC > 60%, unbound ceftaroline concentrations remaining above the MIC for ≥60% of the dosing interval; q12 h, every 12 h; q8 h, every 8 h; MIC, minimum inhibitory concentration.

approach). Considering a target of fT>MIC > 60% and on the basis of these results, in patients with normal renal function the MIC value that is supposedly covered with a 1-h infusion of 600 mg q12 h ceftaroline is 0.25 mg/L or 0.125 mg/mL for 95% CI or 99% CI, respectively (corresponding to a PTA of 97.5% and 99.5%) (Fig. 2A). However, if ceftaroline is administered as a 2-h infusion of 600 mg q8 h, the MIC value that ensures a target of fT>MIC > 60% increases to 1 mg/L and 2 mg/L for 99% CI and 95% CI, respectively (Fig. 2B). In patients with moderate renal impairment receiving 400 mg q12 h as a 1-h infusion, the MIC value that ensures the target is also 1 mg/L or 2 mg/L for 99% CI or 95% CI, respectively (Fig. 2C). Table 4 shows the assessment of CFR of ceftaroline against bacteria isolated in CABP. Irrespective of the dosing regimen, CFR values >90% were achieved for penicillin-susceptible and penicillin-non-susceptible S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, meticillin-susceptible S. aureus (MSSA), and ceftazidime-susceptible (CAZ-S) isolates of Escherichia coli and Klebsiella pneumoniae. In simulated patients with normal renal function receiving 600 mg q8 h and in patients with moderate renal insufficiency receiving 400 mg q12 h, a high likelihood of success (CFR = 99%) was also obtained against MRSA. Table 5 shows the assessment of CFR of ceftaroline against bacteria isolated in cSSSIs. The CFR was >90% for non-extended-spectrum ␤-lactamase (ESBL) phenotypes of E. coli and K. pneumoniae, ␤haemolytic streptococci, group A and B streptococci, viridans group streptococci, and S. aureus except MRSA with the dose of 600 mg q12 h. In patients with moderate renal failure, 400 mg q12 h was enough to achieve a CFR of >90% for the same micro-organisms and also for MRSA, as was 600 mg q8 h as a 2-h infusion in the simulated patients with normal renal function.

Table 4 Cumulative fraction of response (CFR) of ceftaroline against bacteria isolated in community-acquired bacterial pneumonia in patients with normal renal function or moderate renal impairment following administration of 600 mg every 12 h (q12 h), 600 mg every 8 h (q8 h) or 400 mg q12 h. Organism

Normal renal function (600 mg q12 h)

Normal renal function (600 mg q8 h)

Moderate renal impairment (400 mg q12 h)

Escherichia coli All CAZ-S CAZ-R

83 94 7

89 98 16

88 97 11

Klebsiella pneumoniae All CAZ-S CAZ-R

69 97 0

73 100 7

72 100 2

Enterobacter cloacae

59

63

62

Staphylococcus aureus All MSSA MRSA

89 97 72

100 100 99

100 100 99

Streptococcus pneumoniae 100 All 100 PEN-S 99 PEN-NS

100 100 100

100 100 100

Haemophilus influenzae Moraxella catarrhalis

100 100

100 100

100 100

CAZ-S, ceftazidime-susceptible; CAZ-R, ceftazidime-resistant (ESBL phenotype; MIC ≥ 2 mg/L); ESBL, extended-spectrum ␤-lactamase; MIC, minimum inhibitory concentration; MSSA, meticillin-susceptible S. aureus; MRSA, meticillin-resistant S. aureus; PEN-S, penicillin-susceptible (MIC ≤ 2 mg/L); PEN-NS, penicillin-nonsusceptible (MIC ≥ 4 mg/L). Dark grey shading indicates CFR ≥ 90%.

4. Discussion Using Monte Carlo simulation, in the present study we have evaluated the probability of PK/PD target attainment by MIC as well as the CFR of ceftaroline in simulated patients with normal renal

function receiving ceftaroline fosamil 600 mg q12 h as a 1-h infusion or 600 mg q8 h as a 2-h infusion, and in simulated patients with moderate renal failure receiving ceftaroline fosamil 400 mg q12 h as a 1-h infusion.

Please cite this article in press as: Canut A, et al. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2014.12.023

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(A) 100

5

mean 600 mg q12h

90

lower 99%CI 600 mg q12h

80

lower 95% CI 600 mg q12h

70

%fT>MIC

60 50 40 30 20 10 0 0.008 0.015

0.03

0.06

0.125

0.25

0.5

1

2

4

8

16

32

64

2

4

8

16

32

64

2

4

8

16

32

64

MIC (mg/L)

(B)

100 90 80 70

%fT>MIC

60 50 40

Mean 600 mg q8h 30

lower 99% CI 600 mg q8h 20

lower 95% CI 600 mg q8h

10 0 0.008 0.015

0.03

0.06 0.125

0.25

0.5

1

MIC (mg/L)

(C)

100 90 80

%fT>MIC

70 60 50 40

Mean 400 mg q12h 30 20

Lower 99% CI 400 mg q12h Lower 95% CI 400 mg q12h

10 0 0.008 0.015

0.03

0.06 0.125

0.25

0.5

1

MIC (mg/L) Fig. 2. Relationship between fT>MIC and MIC for ceftaroline in two different patient populations: (A) patients with normal renal function receiving 600 mg q12 h as a 1-h intravenous (i.v.) infusion; (B) patients with normal renal function receiving 600 mg q8 h as a 2-h i.v. infusion; and (C) patients with moderate renal impairment receiving 400 mg q12 h as a 1-h i.v. infusion. fT>MIC , fraction of time during the dosing interval for which the free drug concentration remains above the MIC for the infecting pathogen(s); MIC, minimum inhibitory concentration; q12 h, every 12 h; q8 h, every 8 h; CI, confidence interval.

Please cite this article in press as: Canut A, et al. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2014.12.023

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Table 5 Cumulative fraction of response (CFR) of ceftaroline against bacteria isolated in complicated skin and skin-structure infections in patients with normal renal function or moderate renal impairment following administration of 600 mg every 12 h (q12 h), 600 mg every 8 h (q8 h) or 400 mg q12 h. Organism

Normal renal function (600 mg q12 h)

Normal renal function (600 mg q8 h)

Moderate renal impairment (400 mg q12 h)

Escherichia coli All Non-ESBL phenotype ESBL phenotype

64 94 0

68 98 3

68 98 2

Klebsiella pneumoniae All Non-ESBL phenotype ESBL phenotype

53 92 2

61 98 5

60 98 4

100

100

100

100 100 100

100 100 100

100 100 100

93 98 79

100 100 100

100 100 100

␤-Haemolytic streptococci Group A streptococci Group B streptococci Viridans group streptococci Staphylococcus aureus All MSSA MRSA

ESBL, extended-spectrum ␤-lactamase; MSSA, meticillin-susceptible S. aureus; MRSA, meticillin-resistant S. aureus. Dark grey shading indicates CFR ≥ 90%.

The efficacy of an antimicrobial drug depends on the relationship between the MIC of the micro-organism and the exposure of the micro-organism to the agent in the patient. The best PK/PD index to predict the efficacy of ceftaroline is the percentage of the time for which the free serum concentration is above the MIC (fT>MIC ) [19]. The bacteriostatic effect of ceftaroline is achieved when unbound drug concentrations exceed the MIC for 30% of the dosing interval (fT>MIC > 30%) for Gram-negative bacilli. Maximum organism kill (bactericidal activity) is achieved at fT>MIC > 50% and fT>MIC > 60% for staphylococci and Gram-negative bacilli, respectively [1]. For the present study, a unique PK/PD target (fT>MIC > 60%) was chosen, irrespective of the micro-organism. This target, quite conservative, was selected because of the severity of these infections, especially CABP due to MRSA. The recommended dosing regimen of ceftaroline in patients with normal renal function is 600 mg q12 h as a 1-h infusion for 5–7 days for the treatment of CABP and for 5–14 days for cSSSI [1]. This dosing regimen has been shown to be well tolerated, with a favourable safety profile consistent with the cephalosporin class [20,21]. Recently, Sunzel et al. [9] carried out a phase 1 clinical trial in which healthy adult volunteers received ceftaroline fosamil either 600 mg q12 h as a 1-h infusion or 600 mg q8 h as a 2-h infusion. In that study, ceftaroline exhibited linear and time-independent pharmacokinetics with little accumulation after q12 h or q8 h multiple-dose administration. Moreover, plasma concentrations suggested than the 600 mg 2-h infusion q8 h could improve the time above the MIC for ceftaroline time-dependent effects on pathogens with higher MICs. This conclusion is in line with the results of the current study. Actually, for the standard dose (600 mg q12 h as a 1-h infusion), the MIC value at which the percentage of simulated patients who achieved fT>MIC > 60% exceeded 90% was 0.5 mg/L (Fig. 1). In simulated patients with normal renal function receiving 600 mg q8 h as a 2-h infusion, the target was attained with MIC values up to 2 mg/L. Therefore, this study confirms that this new dosing regimen improves the time above the MIC. In fact, one of the proposed options to maintain sufficient drug concentration (higher than the MIC value) throughout the dosing interval when prescribing time-dependent antibiotics is to increase the frequency of

administration [22]. Finally, in patients with moderate renal impairment receiving 400 mg q12 h as a 1-h infusion, the maximum MIC value that allowed achievement of the target (fT>MIC > 60%) was 2 mg/L. EUCAST clinical breakpoints for ceftaroline are 0.25 mg/L, 0.5 mg/L and 1 mg/L for S. pneumoniae, Enterobacteriaceae and S. aureus, respectively [23]. However, Clinical and Laboratory Standards Institute (CLSI) susceptibility breakpoints are 0.5 mg/L and 1 mg/L for S. pneumoniae and S. aureus, respectively [24]. PK/PD breakpoints are species-independent and dosagedependent, and although there are differences in the assessment approach in comparison with CLSI and EUCAST, breakpoints are similar. Despite the accepted level of PTA being 90%, it is not yet well defined and different values (99%, 95% or 90%) have been used [16]. If 90% is used, this means that 10% of the population infected with a micro-organism that has the MIC used to determine the PK/PD index would probably not be covered [16]. In order to decrease the risk of underexposure when considering a PTA of 90%, the EUCAST approach considers the total probability function irrespective of the target. In this way, the values for the mean of the population and the confidence intervals are displayed as a function of the MIC [16]. Over the years, EUCAST has included both the 95% CI and 99% CI, corresponding to a PTA of 97.5% and 99.5%, and has used the MIC values that resulted from these PTAs as the initial values for setting the PK/PD breakpoints [16]. Taking into account the EUCAST approach and the results of the current simulations (Fig. 2), the PK/PD breakpoint of ceftaroline in patients with normal renal function was lower (0.25 mg/L and 0.125 mg/L for 95% CI and 99% CI, respectively) if the patients received the drug as a 1-h infusion q12 h than if ceftaroline was administered as a 2-h infusion q8 h (2 mg/L and 1 mg/L for 95% CI and 99% CI, respectively). Slight differences were observed in the fT>MIC values in simulated patients with moderate renal insufficiency who received 400 mg q12 h and in patients with normal renal function receiving 600 mg q8 h. However, the PK/PD breakpoints were the same (1 mg/L and 2 mg/L considering 99% CI or 95% CI, respectively). Ceftaroline fosamil has been approved for the treatment of CABP and cSSSI. According to the PK/PD analysis and in patients with normal renal function, the ceftaroline standard dose may be sufficient to treat CABP when the infection is due to CAZ-S E. coli, CAZ-S K. pneumoniae, MSSA, S. pneumoniae, H. influenzae and M. catarrhalis (CFR ≥ 90%) (Table 4). Although ceftaroline is considered the unique cephalosporin with activity against MRSA, in the current study it leads to a probability of treatment success against this pathogen of only 72% when the standard dose was simulated. This is due to the current susceptibility of MRSA strains in Europe, where 25% of the isolates have an MIC ≤0.5 mg/L, 57% of isolates have an MIC of 1 mg/L and 18% of the isolates have an MIC of 2 mg/L. On the basis of PTA values, with the standard dose (600 mg q12 h), infections caused by micro-organisms with an MIC ≤0.5 mg/L are covered (PTA ≥ 90%); however, the PTA decreases to 75% if the MIC is 1 mg/L and to MIC . On the basis of the current results, CFR values for S. pneumoniae and H. influenzae were 100% in CABP; however, CFR values for Enterobacteriaceae were lower

Please cite this article in press as: Canut A, et al. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2014.12.023

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(83%, 69% and 59% for E. coli, K. pneumoniae and Enterobacter cloacae, respectively). These values of CFR obtained in the current study may explain the clinical and microbiological success rates obtained in the phase 3 trial. In spite of that, it is important to take into account that the mentioned study was carried out in the USA, whereas in the current study susceptibility data of European isolates were used. Differences in susceptibility patterns among geographical areas may exist [25]. Regarding cSSSI, administration of ceftaroline fosamil (600 mg q12 h as a 1-h infusion) was associated with a high probability of treatment success when the infection was due to non-ESBL phenotypes of E. coli and K. pneumoniae, streptococci and MSSA (CFR ≥ 90%) (Table 5). Although ceftaroline presented activity against MRSA (Table 3), the probability of treatment success against this pathogen was 50% of the isolates have MIC ≥ 1 mg/mL. When the dosing regimens of 600 mg q8 h in patients with normal renal function and 400 mg q12 h in patients with moderate renal insufficiency were simulated, the treatment provided a probability of treatment success of 100% in CABP and cSSSI infections caused by MRSA. Normally, exposure of antimicrobials that are eliminated mainly in urine, such as cephalosporins, is higher in patients with renal insufficiency than in patients with normal renal function [26,27] and therefore the probability to reach the pharmacodynamic target significantly increases. This means that patients with normal renal function have more risk of underdosage. If ceftaroline is administered q8 h as a 2-h infusion in patients with normal renal function, the CFR against MRSA increases to 99%, as in patients with moderate renal failure. Observing the data in Tables 4 and 5, we can conclude that, globally, CFR values in patients with normal renal function receiving ceftaroline q8 h and in patients with moderate renal failure are comparable. 5. Conclusions The results obtained in this PK/PD study suggest that in patients with normal renal function, ceftaroline 600 mg q8 h as a 2-h infusion may be a better option than the standard dose of 600 mg q12 as a 1-h infusion, especially if the infection rate by MRSA is high. In patients with moderate renal insufficiency, 400 mg q12 h as a 1-h infusion provides a high probability of treatment success (CFR values of ca. 100%) for most micro-organisms causing CABP and cSSSIs, including MRSA and penicillin-non-susceptible S. pneumoniae. Funding: This work was supported by the Department of Education, Universities and Research (IT341-10), Basque Government, Spain. Competing interests: None declared. Ethical approval: Not required. References [1] Kaushik D, Rathi S, Jain A. Ceftaroline: a comprehensive update. Int J Antimicrob Agents 2011;37:389–95. [2] Keel RA, Crandon JL, Nicolau DP. Efficacy of human simulated exposures of ceftaroline administered at 600 milligrams every 12 hours against phenotypically diverse Staphylococcus aureus isolates. Antimicrob Agents Chemother 2011;55:4028–32. [3] Saravolatz LD, Stein GE, Johnson LB. Ceftaroline: a novel cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2011;52:1156–63. [4] US Food and Drug Administration. Ceftaroline fosamil for the treatment of community-acquired bacterial pneumonia and complicated skin and skin structure infection. In: FDA Briefing Document for Anti-infective Drugs Advisory Committee Meeting. 2010. http://www.fda.gov/downloads/ AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AntiInfectiveDrugsAdvisoryCommittee/UCM224656.pdf [accessed 20.01.15].

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[5] Samtani MN, Flamm R, Kaniga K, Nandy P. Pharmacokinetic– pharmacodynamic-model-guided doripenem dosing in critically ill patients. Antimicrob Agents Chemother 2010;54:2360–4. [6] Bhavnani SM, Hammel JP, Van Wart SA, Rubino CM, Reynolds DK, Forrest A, et al. Pharmacokinetic–pharmacodynamic analyses for efficacy of ceftaroline fosamil in patients with community-acquired bacterial pneumonia. Antimicrob Agents Chemother 2013;57:6348–50. [7] Drusano GL. Antimicrobial pharmacodynamics: critical interactions of ‘bug and drug’. Nat Rev Microbiol 2004;2:289–300. [8] Lodise TP, Drusano GL. Use of pharmacokinetic/pharmacodynamic systems analyses to inform dose selection of tedizolid phosphate. Clin Infect Dis 2014;58(Suppl. 1):S28–34. [9] Sunzel M, Kujacic M, Boadhurst H, Li J, Edeki T. Phase I, randomized singleand multiple-dose study of ceftaroline fosamil 600 mg every 12 h (60-min infusion) and every 8 h (120-min infusion). In: 24th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID). Basel, Switzerland: European Society of Clinical Microbiology and Infectious Diseases; 2014 [Poster 1737]. [10] Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: an update. J Antimicrob Chemother 2005;55:601–7. [11] 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. [12] Ge Y, Thye D, Liao S, Talbot G. Pharmacokinetics (PK) of ceftaroline (PPI-0903) in subjects with mild or moderate renal impairment (RI). In: 46th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: ASM Press; 2006 [Poster A-1939]. [13] Poon H, Chang MH, Fung HB. Ceftaroline fosamil: a cephalosporin with activity against methicillin-resistant Staphylococcus aureus. Clin Ther 2012;34: 743–65. [14] Jones RN, Farrell DJ, Mendes RE, Sader SH. Comparative ceftaroline activity tested against pathogens associated with community-acquired pneumonia: results from an international surveillance study. J Antimicrob Chemother 2011;66(Suppl. 3):iii69–80. [15] Farrell DJ, Flamm RK, Sader HS, Jones RN. Spectrum and potency of ceftaroline tested against leading pathogens causing skin and soft-tissue infections in Europe (2010). Int J Antimicrob Agents 2013;41:337–42. [16] Asín E, Isla A, Canut A, Rodríguez-Gascón A. Comparison of antimicrobial pharmacokinetic/pharmacodynamic breakpoints with EUCAST and CLSI clinical breakpoints for Gram-positive bacteria. Int J Antimicrob Agents 2012;40:313–22. [17] Owens Jr RC, Bhavnani SM, Ambrose PG. Assessment of pharmacokinetic– pharmacodynamic target attainment of gemifloxacin against Streptococcus pneumoniae. Diagn Microbiol Infect Dis 2005;51:45–9. [18] Mouton JW, Brown DF, Apfalter P, Cantón R, Giske CG, Ivanova M, et al. The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach. Clin Microbiol Infect 2012;18:E37–45. [19] Andes D, Craig WA. Pharmacodynamics of a new cephalosporin, PPI0903 (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. [20] Corey GR, Wilcox MH, Talbot GH, Thye D, Friedland D, Baculik T. 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. [21] Low DE, File Jr TM, Eckburg PB, Talbot GH, David Friedland H, Lee J, 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(Suppl. 3): iii33–44. [22] Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med 2013;39: 2070–82. [23] European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for interpretation of MICs and zone diameters. Version 4.0; 2014. http://www.eucast.org [accessed 20.01.15]. [24] Clinical and Laboratory Standard Institute. Performance standards for antimicrobial susceptibility testing; twenty-fourth informational supplement. Document M100-S24. Wayne, PA: CLSI; 2014. [25] Canut A, Isla A, Betriu C, Gascón AR. Pharmacokinetic–pharmacodynamic evaluation of daptomycin, tigecycline, and linezolid versus vancomycin for the treatment of MRSA infections in four western European countries. Eur J Clin Microbiol Infect Dis 2012;31:2227–35. [26] Asín-Prieto E, Rodríguez-Gascón A, Trocóniz IF, Soraluce A, Maynar J, SánchezIzquierdo JÁ, et al. Population pharmacokinetics of piperacillin and tazobactam in critically ill patients undergoing continuous renal replacement therapy: application to pharmacokinetic/pharmacodynamic analysis. J Antimicrob Chemother 2014;69:180–9. [27] Isla A, Trocóniz IF, de Tejada IL, Vázquez S, Canut A, López JM, et al. Population pharmacokinetics of prophylactic cefoxitin in patients undergoing colorectal surgery. Eur J Clin Pharmacol 2012;68:735–45.

Please cite this article in press as: Canut A, et al. Pharmacokinetic/pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function. Int J Antimicrob Agents (2015), http://dx.doi.org/10.1016/j.ijantimicag.2014.12.023

pharmacodynamic analysis to evaluate ceftaroline fosamil dosing regimens for the treatment of community-acquired bacterial pneumonia and complicated skin and skin-structure infections in patients with normal and impaired renal function.

In this study, the probability of pharmacokinetic/pharmacodynamic target attainment (PTA) of ceftaroline against clinical isolates causing community-a...
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