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

Abstract

Objectives

To describe the pharmacokinetic/pharmacodynamic (PK/PD) modelling and microbiological data that were used to support the recent European approval of ceftaroline fosamil 600 mg q8h by 2 h intravenous (iv) infusion for patients with complicated skin and soft tissue infections (cSSTIs) caused by Staphylococcus aureus with ceftaroline MICs of 2 or 4 mg/L, and the associated EUCAST MIC breakpoint update for q8h dosing (intermediate = 2 mg/L and resistant >2 mg/L).

Methods

A population PK model for ceftaroline and ceftaroline fosamil was developed using PK data from 21 clinical studies. The final model was used to simulate PTA in patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion. PTA was calculated by MIC for S. aureus PK/PD targets derived from preclinical studies (27% fT_>MIC for stasis, 31% fT_>MIC for 1 log₁₀ kill and 35% fT_>MIC for 2 log₁₀ kill) and compared with S. aureus ceftaroline MIC distributions from a 2013 global surveillance study.

Results

The final population PK model based on 951 subjects adequately described ceftaroline and ceftaroline fosamil PK. High PTA (>90%) was predicted for the ceftaroline fosamil 600 mg q12h dosage regimen against S. aureus isolates with ceftaroline MICs ≤2 mg/L. Greater than 90% PTA was predicted for the ceftaroline fosamil 600 mg q8h dosage regimen against S. aureus with ceftaroline MICs ≤4 mg/L.

Conclusions

The approved ceftaroline fosamil dosage regimens for adults and adolescents with cSSTI achieve high PTA against S. aureus at the associated EUCAST breakpoints.

Introduction

Staphylococcus aureus is the most common cause of complicated skin and soft tissue infections (cSSTIs) worldwide.¹ Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, demonstrates in vitro activity against many pathogens commonly implicated in cSSTI, including MSSA and MRSA, Streptococcus pyogenes and non-ESBL-producing Gram-negative species.^2,3

Ceftaroline fosamil is approved in Europe for the treatment of cSSTI and community-acquired pneumonia (CAP), with similar indications in other regions.^2,3 Ceftaroline fosamil is not approved for patients with CAP caused by MRSA,^2,3 as these patients were excluded from the pivotal Phase 3 trials in CAP.^4,5 For adults with cSSTI and normal renal function, ceftaroline fosamil was initially approved at a single dosage of 600 mg q12h by 1 h iv infusion based on data from the Phase 3 CANVAS 1 and 2 studies (NCT00424190 and NCT00423657), which demonstrated the non-inferiority of ceftaroline fosamil 600 mg q12h to vancomycin plus aztreonam.^6,7 Ceftaroline MIC breakpoints for S. aureus of susceptible ≤1 mg/L and resistant >1 mg/L were established by EUCAST for the q12h dosage regimen.

Surveillance data in some regions such as Latin America and the Asia Pacific have reported ceftaroline MIC₉₀ values of 2 mg/L for S. aureus^8,9 and rare S. aureus isolates with ceftaroline MICs of 4 mg/L have also been identified.¹⁰ Therefore, an increased dose of ceftaroline fosamil may be of clinical benefit to treat infections caused by these strains. In the Phase 3 COVERS trial (NCT01499277), an increased total daily ceftaroline fosamil dose and infusion duration (600 mg q8h by 2 h iv infusion) was evaluated in patients with cSSTI and evidence of systemic inflammation and/or underlying comorbidities.¹¹ The higher q8h dose was evaluated to ensure adequate exposure of ceftaroline in severe infections that may be associated with increased clearance of ceftaroline and for infections caused by S. aureus with ceftaroline MICs >2 mg/L. Despite various efforts during COVERS to maximize the number of S. aureus clinical isolates with ceftaroline MICs of ≥2 mg/L, including an MRSA-focused expansion period following the main trial, only one such isolate was identified.¹¹

In the absence of clinical data for the treatment of pathogens with higher MICs, pharmacokinetic/pharmacodynamic (PK/PD) analyses using population PK models in Monte Carlo simulations to determine PTA are important to support dose recommendations and determine clinical breakpoints. The European label for ceftaroline fosamil was recently expanded to recommend an increased dose of 600 mg q8h by 2 h iv infusion for the treatment of patients with cSSTI caused by S. aureus with ceftaroline MICs of 2 or 4 mg/L.² The approval of the q8h dose led EUCAST to introduce an intermediate category of MIC = 2 mg/L for ceftaroline against S. aureus, per EUCAST current practice,¹² and defined the resistant category for the q8h dose as MIC >2 mg/L,¹³ with the breakpoints for the q12h dose remaining unchanged.¹³ This paper describes the PK/PD modelling and microbiological data that were used together with clinical data from COVERS to support updates to the European product labelling for ceftaroline fosamil and associated EUCAST breakpoints.

Methods

Ceftaroline PK/PD targets for S. aureus

The duration of time that free drug plasma concentration exceeds the MIC of the target organism (%fT_>MIC) is an established PK/PD index for ceftaroline.^14,15 Ceftaroline S. aureus PK/PD targets were derived from three preclinical models: an in vivo neutropenic murine thigh infection model,¹⁴ an in vitro single-compartment dilutional PK model¹⁶ and an in vitro hollow-fibre model.¹⁷ In total, 24 S. aureus isolates with ceftaroline MICs ranging from 0.12 to 4 mg/L and a wide range of genotypes, including different MLST and staphylococcal cassette chromosome mec (SCCmec) types, and isolates with genetic variations in the PBP2a domain, were assessed in these studies to: (i) include representative clinical isolates with molecular characteristics most widely prevalent in different geographic regions; and (ii) compensate for limited efficacy data on clinical trial isolates with ceftaroline MIC values ≥2 mg/L. The mean %fT_>MIC values across the 24 isolates were used to derive S. aureus PK/PD targets for the PTA analysis of 27% fT_>MIC for stasis, 31% fT_>MIC for 1 log₁₀ kill and 35% fT_>MIC for 2 log₁₀ kill (Table 1).

Table 1.

Summary of preclinical studies used to derive ceftaroline S. aureus PK/PD targets for PTA analysis

Study	PK/PD model	No. of isolates	MIC range (mg/L)	PK/PD target [mean (SD) %fT>MIC at 24 h]
				stasis	1 log10 kill	2 log10 kill
Andes and Craig (2006)14	neutropenic murine thigh infection model	4a	0.12–1	26 (8)	33 (9)	45 (13)
MacGowan et al. (2013)16	in vitro single-compartment dilutional PK model	8b	0.125–2	24.5 (8.9)	27.8 (9.5)	27.7 (5.7)
Singh et al. (2017)17	in vitro hollow-fibre model	12c	2–4	28 (7)	31 (6)	35 (6)
		Total	MIC range	Meand (SD)
		24	0.12–4	26.8 (7.7)	30.7 (8.0)	34.7 (9.4)

^aIncluded two MSSA and two MRSA strains.

^bIncluded four MSSA and four MRSA strains.

^cIncluded 12 molecularly characterized MRSA strains: 10 isolates with one to four mutations in the non-penicillin binding domain (nPBD) or WT characteristics and two isolates with one mutation each in nPBD and PBD. SCCmec types included nine isolates of Type I–II and three isolates of Type III.

^dOverall mean of individual isolates from the three data sources.

Population PK model development

Population PK models of ceftaroline and ceftaroline fosamil were developed and updated with clinical trial data throughout the clinical development programme (see footnote to Table S1, available as Supplementary data at JAC Online). In this analysis, the population PK model dataset comprised data from 21 clinical studies [14 Phase 1 studies in healthy subjects and patients with end-stage renal disease (ESRD), 1 Phase 2 and 3 Phase 3 studies in patients with cSSTI and 3 Phase 3 studies in CAP; Table S1].^{4–7,11,18–26} Ceftaroline fosamil was given as an iv infusion in these studies, apart from in one study in which ceftaroline fosamil was administered intramuscularly.²⁰

First-order conditional estimation with interaction method in NONMEM version 7.2.0 was used to develop the population PK model. Full details of the covariate analysis are provided in the Supplementary Methods. In brief, the previous model (unpublished data; J. Li, S. Das, D. Zhou and N. Al-Huniti) was adapted as the basis to re-evaluate the significance of previously identified significant covariates: age, patient status (healthy volunteers versus patients) and creatinine clearance normalized by body surface area (NCL_CR) on ceftaroline CL and patient status on the central volume of distribution of ceftaroline (V_cc). These covariates were re-evaluated with the pooled dataset by a backward elimination procedure to obtain a full model. The full model was subsequently used as a base model to evaluate the effect of the race and gender covariate on ceftaroline CL and V_cc using a forward selection and backward elimination procedure to obtain the final model. The final model was evaluated by standard goodness-of-fit plots and visual predictive check.

PTA analysis

The final model was used to simulate ceftaroline plasma concentration–time courses in 5000 patients with cSSTI receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or 600 mg q8h by 2 h iv infusion by renal function category (doses adjusted for renal function as described below). Covariates for the PTA simulation (including age, sex, body weight and NCL_CR) were based on patients with cSSTI in one Phase 2 and three Phase 3 studies,^6,7,11,19 and subjects from four renal impairment studies.^18,25 Individual PK parameters were simulated from the population mean PK parameters, associated individual covariates from the multivariate covariate distribution and inter-subject variability from the final model. The residual error was fixed to zero in the simulation of individual ceftaroline time courses. For subjects with normal renal function (CL_CR >80 mL/min), individual covariates of 5000 subjects were sampled with replacement from the baseline covariates in patients included in the final model. For simulations of subjects in renal impairment categories, covariates were simulated from the multivariate covariate distribution and bounded by the appropriate upper and lower limits observed in the dataset. CL_CR values were assumed to follow a uniform distribution within the designated range for each category.

The %fT_>MIC at steady-state was calculated for subjects with normal renal function or mild renal impairment (CL_CR 50–80 mL/min) receiving ceftaroline fosamil 600 mg q12h by 1 h iv infusion or q8h by 2 h iv infusion. Doses were adjusted to 400 mg, 300 mg or 200 mg for simulations of patients with moderate renal impairment (CL_CR 30–50 mL/min), severe renal impairment (CL_CR 15–30 mL/min) and ESRD (CL_CR 5–15 mL/min), respectively.^2,3 An 80% unbound fraction of plasma concentration was applied for calculating %fT_>MIC.^2,3 PTA was calculated as the percentage of 5000 simulated subjects with cSSTI who met the S. aureus PK/PD targets described above at ceftaroline MICs of 0.015, 0.03, 0.06, 0.125, 0.25, 0.5, 1, 2, 4 and 8 mg/L. PTA was also calculated by MIC for non-species-specific %fT_>MIC targets ranging from 10%–100%.

To evaluate whether the doses provided adequate coverage for susceptibility profiles of S. aureus isolates encountered in clinical practice, PTAs were compared with ceftaroline MIC frequency distributions of S. aureus clinical isolates collected during 2013 as part of the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance study in medical centres in Europe and the Asia Pacific region. The methodology used in the AWARE surveillance programme has been published elsewhere; in brief, isolates were tested at a central laboratory using reference CLSI broth microdilution methods and susceptibility was interpreted according to CLSI/EUCAST/FDA breakpoints.^9,27,28

Results

Final population PK model

The final population PK model dataset included 2575 ceftaroline fosamil concentrations and 8174 ceftaroline concentrations from 951 subjects. Demographic covariate data for the final modelling dataset are summarized in Table S2. The dataset comprised 501 male and 450 female subjects with a median age of 50 years (range 12–93 years) and a median body weight of 73 kg (range 40–134 kg). Of the 951 subjects, 267 (28%) were healthy volunteers and 684 (72%) were patients, including 214 patients with CAP, 463 patients with cSSTI and 7 patients with suspected infection. The ceftaroline fosamil and ceftaroline concentration–time courses were simultaneously modelled as two-compartment disposition PK models with an assumption of 100% conversion of ceftaroline fosamil into ceftaroline. As one study included intramuscular delivery of ceftaroline fosamil, a zero-order absorption component of ceftaroline fosamil after intramuscular administration of ceftaroline fosamil was included in the model. The impact of body weight on CL and V of both ceftaroline and ceftaroline fosamil were modelled allometrically.

Age, participant status (patients versus healthy volunteers) and NCL_CR were significant covariates on CL of ceftaroline; participant status was a significant covariate on V_cc. The overall CL of ceftaroline increased as CL_CR increased, and decreased as age increased. Race and gender were not considered significant covariates of ceftaroline CL and V_cc. The final population PK model adequately described observed concentrations of both ceftaroline and ceftaroline fosamil and the covariate relationships in patients with cSSTI, judging from standard goodness-of-fit plots and visual predictive checks showing that simulations from the final model were consistent with the observed data (data not shown). All parameter estimates of the final model exhibited small relative standard errors (Table S3).

Ceftaroline in vitro activity against S. aureus isolates collected in the AWARE 2013 surveillance study

A total of 5380 S. aureus clinical isolates (2815 MRSA) were collected in Europe and 2595 S. aureus isolates (1574 MRSA) were collected in the Asia Pacific region. In Europe, the overall ceftaroline MIC₉₀ against all S. aureus isolates including MRSA was 1 mg/L; in the individual countries, ceftaroline MIC₉₀ values were ≤1 mg/L, except in Italy, Poland, Romania, Russia and Turkey, where a ceftaroline MIC₉₀ of 2 mg/L was reported. In the Asia Pacific region, the ceftaroline MIC₉₀ against all S. aureus isolates including MRSA was 2 mg/L. The ceftaroline MIC₉₀ was ≤2 mg/L in all individual countries, except in Thailand where an MIC₉₀ of 4 mg/L was reported. Isolates with ceftaroline MICs >2 mg/L comprised 9 MRSA isolates collected from Thailand with MICs of 8 mg/L and 33 isolates collected from South Korea (4 isolates) and Thailand (29 isolates) with MICs of 4 mg/L.

PTA by MIC for patients with normal renal function given ceftaroline fosamil 600 mg q12h by 1 h iv infusion

PTAs by MIC for the S. aureus PK/PD targets in 5000 simulated cSSTI patients with normal renal function given ceftaroline fosamil 600 mg q12h by 1 h iv infusion are shown in Table 2. Ceftaroline fosamil 600 mg q12h is predicted to achieve >95% PTA for the 1 log₁₀ kill target (31% fT_>MIC) and >90% PTA for the 2 log₁₀ kill target (35% fT_>MIC) against S. aureus testing with ceftaroline MICs ≤2 mg/L. PTA by MIC overlaid with the AWARE 2013 ceftaroline MIC frequency distribution for S. aureus shows that ceftaroline fosamil 600 mg q12h provides >90% PTA for the MIC distributions of S. aureus isolates with a ceftaroline MIC ≤2 mg/L in both Europe and the Asia Pacific region (Figure 1). For PK/PD targets up to and including 50% fT_>MIC (beyond the 35% fT_>MIC required for 2 log₁₀ kill), >90% PTA was achieved for an MIC of 1 mg/L (Table S4). At a target of 60% fT_>MIC, PTA was 78.7% for an MIC of 1 mg/L.

Table 2.

PTA for 5000 simulated cSSTI patients with normal renal function achieving PK/PD targets for S. aureus by MIC following administration of ceftaroline fosamil 600 mg q12h 1 h iv infusion

Ceftaroline MIC (mg/L)	PTA (%)
	stasis (27% fT>MIC)	1 log10 kill (31% fT>MIC)	2 log10 kill (35% fT>MIC)
0.015	100	100	100
0.03	100	100	100
0.06	100	100	100
0.125	100	100	100
0.25	100	100	100
0.5	100	100	100
1	100	100	100
2	98.9	96.1	92.5
4	66.5	49.5	37.1
8	4.84	2.14	1.04
16	0.04	0	0

Figure 1.

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

PTA by MIC for patients with normal renal function given ceftaroline fosamil 600 mg q8h by 2 h iv infusion

PTAs by MIC for the S. aureus PK/PD targets in 5000 simulated cSSTI patients with normal renal function (CL_CR >80 mL/min) given ceftaroline fosamil 600 mg q8h by 2 h iv infusion are shown in Table 3. Ceftaroline fosamil 600 mg q8h is predicted to achieve >95% PTA for the 1 log₁₀ kill target (31% fT_>MIC) and >90% PTA for the 2 log₁₀ kill target against S. aureus isolates with ceftaroline MICs ≤4 mg/L (Table 3). PTA by MIC overlaid with the AWARE 2013 ceftaroline MIC frequency distributions for S. aureus in Europe and the Asia Pacific region shows that ceftaroline fosamil 600 mg q8h provides >90% PTA for the MIC distribution of S. aureus with ceftaroline MICs ≤4 mg/L in both regions (Figure 2). For an MIC of 2 mg/L, >90% PTA was maintained for targets as high as 60% fT_>MIC (Table S5). At an MIC of 4 mg/L, PTA was 86% for a target of 40% fT_>MIC.

Table 3.

PTA for 5000 simulated cSSTI patients with normal renal function achieving PK/PD targets for S. aureus by MIC following administration of ceftaroline fosamil 600 mg q8h 2 h iv infusion

Ceftaroline MIC (mg/L)	PTA (%)
	stasis (27% fT>MIC)	1 log10 kill (31% fT>MIC)	2 log10 kill (35% fT>MIC)
0.015	100	100	100
0.03	100	100	100
0.06	100	100	100
0.125	100	100	100
0.25	100	100	100
0.5	100	100	100
1	100	100	100
2	100	100	100
4	98.7	96.8	93.6
8	42.9	33.1	23.4
16	0.72	0.38	0.22

Figure 2.

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

PTA by MIC for patients with renal impairment receiving adjusted q12h and q8h doses

Similar PTA analyses were conducted for patients with mild renal impairment receiving ceftaroline fosamil 600 mg q12h or q8h, and in patients with moderate renal impairment, severe renal impairment and ESRD receiving the recommended dosage adjustments.^2,3 PTAs by MIC were generally similar or higher in patients with renal impairment compared with subjects with normal renal function (Tables S6 and S7).

Discussion

Ceftaroline PK/PD targets against S. aureus were initially derived based on a single in vivo study against four S. aureus isolates with ceftaroline MICs ranging from 0.12 to 1 mg/L.¹⁴ The mean (SD) %fT_>MIC values for stasis, 1 log₁₀ kill and 2 log₁₀ kill in that study were 26% (8), 33% (9) and 45% (13). Since then, ceftaroline PK/PD against S. aureus have been evaluated in two further in vitro studies.^16,17 The PK/PD targets for S. aureus used in this analysis were derived from these three studies using 24 isolates with a wider range of ceftaroline MICs (0.12–4 mg/L) and genotypes than in the single in vivo study alone. It is expected that there would be some variation in the PK/PD data obtained from in vitro and in vivo approaches; however, the %fT_>MIC values across the three models were generally in good concordance. Using data from across three different models provides a robust basis to determine the S. aureus PK/PD targets for use in PTA analysis to support dosage recommendations and breakpoint determination, as each model may compensate for limitations in the others. The ceftaroline S. aureus PK/PD targets for stasis, 1 log₁₀ kill and 2 log₁₀ kill were thus better characterized and defined as 27%, 31% and 35% fT_>MIC, respectively.

An early population PK model based on data from 185 healthy subjects and 92 patients with cSSTI was used to support the initial approvals of the ceftaroline fosamil 600 mg q12h dosage regimen.^29,30 The population PK model reported here was based on a more substantial clinical dataset comprising 951 subjects, including 463 patients with cSSTI. Similar to the earlier model,³⁰ age, participant status (patients versus healthy volunteers) and NCL_CR were identified as significant covariates impacting ceftaroline and ceftaroline fosamil PK. Critical illness caused by severe infection can affect antibiotic PK, resulting in low exposures and a higher risk of not achieving PK/PD targets compared with non-critically ill patients.³¹ The inclusion of patient PK data from the COVERS study [which included patients with systemic inflammatory response syndrome (SIRS) and bacteraemia]¹¹ ensured that a broad range of comorbid conditions and disease severity covariates were included in the dataset. This provides reassurance that the PTA estimates from this model will be relevant for patients with more severe infections.

Whilst the susceptible breakpoint for the ceftaroline fosamil 600 mg q12h dose is ≤1 mg/L, high PTA (>90%) was predicted for patients with cSSTI treated with the q12h dosage regimen against S. aureus with ceftaroline MICs up to and including 2 mg/L. Ceftaroline fosamil 600 mg q8h is predicted to achieve high PTA (>90%) for S. aureus MICs up to and including 4 mg/L. Whilst the resistant breakpoint for the ceftaroline fosamil q8h dose is MIC >2 mg/L, both the European label and EUCAST indicate that ceftaroline fosamil 600 mg q8h can be used for the treatment of cSSTI caused by rare S. aureus isolates with MICs of 4 mg/L. For both dosage frequencies, similar or higher PTAs are still achieved in cSSTI patients with renal impairment receiving adjusted doses for renal function compared with patients with normal renal function.

The achievement of therapeutic antibiotic concentrations at the infection site is an important consideration for breakpoint setting and dosing recommendations. In line with the PTA results presented here, comparison of ceftaroline PK following administration of ceftaroline 600 mg q12h or q8h in healthy volunteers found that calculated %fT_>MIC values in the plasma, muscle and subcutis exceeded the S. aureus PK/PD targets for both dosage regimens up to an MIC of 2 mg/L, while the q8h dosage regimen provided %fT_>MIC values ranging from 26.2%–43.0% across the three compartments for an MIC of 4 mg/L.³²

The susceptibility of S. aureus to ceftaroline varies geographically.^8,9,33,34 In the AWARE 2013 surveillance study data presented here, ceftaroline MIC₉₀s of 1 mg/L and 2 mg/L were reported for S. aureus (including MRSA) in Europe and the Asia Pacific region, respectively. Whilst a low frequency of S. aureus isolates were identified with an MIC of 2 mg/L in Europe, ceftaroline MIC₉₀s of 2 mg/L were reported in Italy, Poland, Romania, Russia and Turkey. In the Asia Pacific region there was a much higher frequency of isolates with a ceftaroline MIC of 2 mg/L: in most countries the MIC₉₀ was 2 mg/L, except in Thailand where the MIC₉₀ was 4 mg/L. Ceftaroline 600 mg q12h was shown to provide high PTA across the MIC distributions of real-life S. aureus isolates with ceftaroline MICs ≤2 mg/L, while the ceftaroline 600 mg q8h dosage regimen provides high PTA for S. aureus isolates with ceftaroline MICs ≤4 mg/L.

The effect of the EUCAST MIC breakpoint change on the interpretation of S. aureus susceptibility to ceftaroline was explored in a recent analysis of MRSA isolates from cSSTI patients collected through the AWARE 2015–16 surveillance programme.³⁵ The percentage of isolates categorized as resistant to ceftaroline across Europe, Latin America, Middle East/Africa and the Asia/South Pacific regions decreased from 3.1%–7.6% when using the q12h breakpoints (resistant >1 mg/L) to 0.0%–1.3% when using the q8h breakpoints (intermediate = 2 mg/L, resistant >2 mg/L). This was most notable in the Latin America and Asia/South Pacific regions, where isolates with a ceftaroline MIC of 2 mg/L are more prevalent and are now classified in the intermediate category. These findings indicate that the frequency of S. aureus resistant to ceftaroline (MIC >2 mg/L) remains low globally.

A limitation of this analysis is the lack of clinical outcomes data available for cSSTI caused by S. aureus with high ceftaroline MICs. The results from COVERS demonstrated the non-inferiority of ceftaroline fosamil 600 mg q8h with respect to vancomycin plus aztreonam in patients with cSSTI and no new safety signals were identified.¹¹ Importantly, clinical outcomes in patient subgroups with more severe infection were comparable between COVERS and the CANVAS studies; clinical cure rates in patients with one or more sign of systemic inflammation in the clinically evaluable population were 88.0% (219/249) in COVERS versus 91.1% (308/338) in CANVAS 1 and 2.³⁶ Consistent with this finding, predicted ceftaroline exposures (AUC_ss and C_{max, ss}) were comparable between COVERS patients with and without signs of severe infection, such as high white blood cell count, high C-reactive protein levels and the presence of fever, SIRS or bacteraemia.³⁷ Together with the findings presented here, these data support that ceftaroline fosamil 600 mg q12h is a robust dosage regimen for most patients with cSSTI, with the 600 mg q8h regimen offering an additional treatment option for patients with cSSTI caused by S. aureus with ceftaroline MICs of 2 or 4 mg/L.

Conclusions

S. aureus with ceftaroline MICs of 2–4 mg/L represent the upper end of the MIC distribution and clinical outcomes data are limited for cSSTI caused by S. aureus isolates with high ceftaroline MICs. Population PK modelling based on an extensive patient dataset and using robustly characterized PK/PD targets indicates that ceftaroline fosamil 600 mg q12h achieves >90% PTA against S. aureus at the EUCAST susceptible breakpoint of 1 mg/L as well as for a ceftaroline MIC of 2 mg/L, and that ceftaroline fosamil 600 mg q8h achieves >90% PTA for ceftaroline MICs ≤4 mg/L. These results provide reassurance that the approved ceftaroline fosamil dosage regimens for cSSTI achieve high PTA against S. aureus at the associated EUCAST MIC breakpoints.