crossmark

Single- and Repeated-Dose Pharmacokinetics of Ceftaroline in Plasma and Soft Tissues of Healthy Volunteers for Two Different Dosing Regimens of Ceftaroline Fosamil ¨ sterreicher,a Markus Zeitlingera Peter Matzneller,a Edith Lackner,a Heimo Lagler,a,b Beatrix Wulkersdorfer,a Zoe O Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austriaa; Clinical Division of Infectious Diseases and Tropical Medicine, Department of Medicine I, Medical University of Vienna, Vienna, Austriab

Ceftaroline fosamil (CPT-F) is currently approved for use for the treatment of complicated skin and soft tissue infections and community-acquired pneumonia at 600 mg twice daily (q12h), but other dosing regimens are under evaluation. To date, very limited data on the soft tissue pharmacokinetics (PK) of the active compound, ceftaroline (CPT), are available. CPT concentrations in the plasma, muscle, and subcutis of 12 male healthy volunteers were measured by microdialysis after single and repeated intravenous administration of 600 mg CPT-F q12h or three times daily (q8h) in two groups of 6 subjects each. Relevant PK and PK/pharmacodynamic (PD) parameters were calculated and compared between groups. In plasma, the area under the concentration-time curve (AUC) from 0 to 24 h for total CPT and the cumulative percentage of the dosing interval during which the free drug concentrations exceeded the MIC (fTMIC) for unbound CPT for the currently established threshold of 1 mg/liter were significantly higher in the group receiving CPT-F q8h. Exposure to free drug in soft tissues was higher in the group receiving CPT-F q8h, but high interindividual variability in relevant PK parameters was observed. The mean ratios of the AUC from time zero to the end of the dosing interval (AUC0-␶) for free CPT in soft tissues and the AUC0-␶ for the calculated free fraction in plasma at steady state ranged from 0.66 to 0.75. Administration of CPT-F q8h led to higher levels of drug exposure in all investigated compartments. When MIC values above 1 mg/liter were assumed, the calculated fTMIC after dosing q12h was markedly lower than that after dosing q8h. The clinical implications of these differences are discussed in light of recently completed clinical phase III and PK/PD studies.

C

eftaroline fosamil (CPT-F; brand names, Zinforo in Europe and Teflaro in the United States) was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of complicated skin and soft tissue infections (cSSTIs) and community-acquired pneumonia (CAP) in adults. Ceftaroline (CPT) is a cephalosporin antibiotic and acts, like all beta-lactam agents, via inhibition of peptidoglycan synthesis. In contrast to other cephalosporins, CPT is active against some resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-nonsusceptible Streptococcus pneumoniae (PNSP), and is therefore often referred to as a “fifth generation,” or advanced-generation, cephalosporin. CPT-F, a water soluble N-phosphono prodrug, is converted to the active CPT in human plasma, and CPT is further converted into the inactive ring-opened metabolite CPT M-1. Although CPT-F was shown to be effective against both approved indications, CAP and cSSTIs (1–5), precise information regarding the pharmacokinetics (PKs) of CPT in the interstitial space fluid of soft tissues is very limited to date. However, this information is considered to be highly relevant as a key input for PK/pharmacodynamic (PD) calculations and subsequently for the appropriate setting of site-specific susceptibility breakpoints. The currently approved dosing regimen of CPT-F is 600 mg twice daily (q12h). However, it has been discussed that an intensified dosing regimen of 600 mg three times daily (q8h) might be beneficial under certain conditions, as might an extension of the currently approved infusion time of 1 h. Data from clinical trials investigating this modified dosing regimen have recently become available. In patients with cSSTIs, CPT-F at 600 mg q8h as an intravenous infusion over 2 h has shown good efficacy and safety

June 2016 Volume 60 Number 6

compared to those of a vancomycin-aztreonam combination therapy (6, 7). A retrospective analysis of the safety if CPT-F in 527 patients, 75 (14%) of whom were given CPT-F q8h, showed an increased frequency of skin rash and acute kidney failure in the population receiving CPT-F q8h compared to that in the population receiving CPT-F q12h but otherwise similar adverse event rates (8). Still, clinical studies including a direct comparison of both q12h and q8h dosing of CPT-F have not been conducted to date and are very unlikely to be performed on a larger scale in the future. This emphasizes the importance of comparative PK studies as a tool to gain information otherwise difficult to retrieve. In an attempt to anticipate the impacts of different dosing regimens on target site concentrations, this study investigated the PKs of CPT in the plasma and soft tissues of healthy volunteers after q8h administration of 600 mg of CPT-F and compared them to the PKs in the plasma and soft tissues of healthy volunteers after dosing q12h. In addition, two different infusion times were tested:

Received 12 January 2016 Returned for modification 7 February 2016 Accepted 26 March 2016 Accepted manuscript posted online 4 April 2016 Citation Matzneller P, Lackner E, Lagler H, Wulkersdorfer B, O¨sterreicher Z, Zeitlinger M. 2016. Single- and repeated-dose pharmacokinetics of ceftaroline in plasma and soft tissues of healthy volunteers for two different dosing regimens of ceftaroline fosamil. Antimicrob Agents Chemother 60:3617–3625. doi:10.1128/AAC.00097-16. Address correspondence to Markus Zeitlinger, [email protected]. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Antimicrobial Agents and Chemotherapy

aac.asm.org

3617

Matzneller et al.

CPT-F was administered over 1 h to volunteers assigned to the q12h dosing regimen (the q12h group) and over 2 h to volunteers assigned to the q8h dosing regimen (the q8h group). For both dosing regimens, the concentration-time profiles of the active compound, CPT, were assessed after the administration of both single and repeated doses. MATERIALS AND METHODS Materials and substances. CPT-F (Zinforo) and CPT hydrochloride were ¨ sterreich, Vienna, Austria). provided by AstraZeneca (AstraZeneca O Physiological 0.9% saline solution was purchased from Medica Medicare, Kufstein, Austria. All microdialysis (␮D) catheters were purchased from M Dialysis, Stockholm, Sweden. ␮D. The technique of in vivo ␮D, previously described in numerous review articles, has become an established method for the description of tissue pharmacokinetics, especially in the field of drug distribution and metabolism (9–11). In brief, this method is based on the exchange of analytes between the extracellular space fluid (ECF) of the tissue or compartment of interest and the perfusion fluid of a ␮D probe. Only free, i.e., non-protein-bound, substances can diffuse across the semipermeable membrane located at the tip of the ␮D probe and can be collected for subsequent analysis. From the time of insertion onwards, the ␮D probes are constantly perfused with an appropriate perfusion fluid at a defined flow rate, and complete equilibration between the tissue and the probe never occurs. Hence, the analyte concentration that is measured in the collected ␮D sample is just a fraction of the actual concentration in the ECF surrounding the probe. To determine the actual ECF concentration, ␮D probes must be calibrated. In this study, each single probe was calibrated by reverse dialysis, also referred to as retrodialysis (9). The retrodialysis method relies on the fact that the process of diffusion across the semipermeable membrane is quantitatively equal in both directions. This implies that the fraction of the ECF drug concentration which is recovered in the collected ␮D sample, which is referred to as “relative recovery,” can be calculated according to the following equation: relative recovery (in percent) ⫽ 100 ⫺ [100 ⫻ (analyte concentrationout/analyte concentrationin)], where analyte concentrationout is the analyte concentration measured in the collected retrodialysis sample and analyte concentrationin is the analyte concentration in the medium used for perfusion of the ␮D probe during retrodialysis. Accordingly, ECF CPT concentrations were calculated as follows: ECF concentration ⫽ 100 ⫻ (sample concentration/ relative recovery). In this study, the values were individually corrected for each probe; i.e., ECF CPT concentrations were calculated using the relative recovery value determined for each individual ␮D probe during calibration. In vitro ␮D study. Prior to initiation of the clinical part of the study, in vitro ␮D experiments were performed with different concentrations of CPT hydrochloride (0.3, 3, and 30 ␮g/ml). In particular, these investigations addressed the question of whether the relative recovery of CPT in ␮D samples was constant over time, constant over different drug concentrations, and comparable between forward and reverse dialysis. In vivo ␮D study. This prospective, open-label PK study was conducted at the Department of Clinical Pharmacology at the Medical University of Vienna, Vienna, Austria, in accordance with actual International Conference on Harmonization-Good Clinical Practice (ICH-GCP) guidelines and the Declaration of Helsinki. The study was registered under EudraCT number 2012-005134-11, approved by the Ethics Committee of the Medical University of Vienna (reference number 1930/2012), and authorized by the Austrian Agency for Health and Food Safety. Signed informed consent to study participation was obtained from all study subjects before inclusion. All subjects underwent a screening visit which included physical examination; blood sampling for hematology, clinical chemistry, virology, and coagulation tests; as well as electrocardiogram tracing and noninvasive arterial blood pressure measurement. Key inclusion criteria were as follows: male, age between 18 and 50 years, body mass index between 18

3618

aac.asm.org

and 30 kg/m2, no regular concomitant medication within the last 2 weeks prior to the study day, and written informed consent. Key exclusion criteria were a known allergy or hypersensitivity to the study drug and clinically relevant abnormal physical or laboratory findings. A total of 12 male healthy volunteers were enrolled and randomly assigned to two groups of 6 individuals each. Within a time frame of 24 h, CPT-F was administered intravenously every 8 h as a 2-h infusion in the first group (intensified dosing regimen, further referred to here as the q8h regimen) and every 12 h as a 1-h infusion in the second group (the currently approved regimen, further referred to here as the q12h regimen). Blood and microdialysate samples were collected from all subjects at defined time points before and after infusion of the first CPT-F dose and at steady state, i.e., before and after the last dose, for which steady-state conditions can be expected on the basis of the drug’s half-life. At each dosing time point, 600 mg of CPT-F was administered intravenously in 250 ml saline by means of a volumetric pump. In total, over the entire study period, individuals assigned to the q8h group received 4 intravenous doses of CPT-F, whereas those assigned to the q12h group received 3 intravenous doses of CPT-F. Sampling intervals. Sampling intervals were chosen to cover the full dosing interval. In the q8h group, total CPT concentrations in plasma were determined at the baseline and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, and 8 h after drug administration. Unbound CPT concentrations in soft tissues were determined by ␮D over the following time intervals before and after drug administration: ⫺0.5 to 0 (baseline) and 0 to 0.5, 0.5 to 1, 1 to 1.5, 1.5 to 2, 2 to 2.5, 2.5 to 3, 3 to 4, 4 to 5, 5 to 6, and 7 to 8 h. In the q12h group, additional blood draws were performed at 10 and 12 h after drug administration, consistent with the additional ␮D sampling intervals from 9 to 10 and 11 to 12 h, respectively. Microdialysis sampling. Free, non-protein-bound CPT concentrations in muscle and subcutaneous adipose tissue were determined by means of the ␮D technique. In brief, two 63 Microdialysis Catheters with a membrane length of 10 mm and a molecular mass cutoff of 20 kDa (sterilized by beta-radiation and Conformité Européenne [CE] marked according to the Medical Device Directive, 93/42/EEC, of the European Community) were aseptically inserted into one thigh of each volunteer without local anesthesia. One probe was placed into the subcutis, and the second one was placed in muscle tissue. From the times of insertion onwards, all probes were perfused with 0.9% saline solution at a flow rate of 2 ␮l/min by means of a microinfusion pump. The tubes of all ␮D probes were made of polyurethane with a polycarbonate Luer lock connection and a polyarylethersulfone dialysis membrane. Calibration solutions were prepared and stored at ⫺80°C until use. Before removal, all probes were individually calibrated by retrodialysis using CPT hydrochloride at a concentration of 30 ␮g/ml. Sample handling and analysis. At each time point, approximately 6 ml of venous blood for measurement of CPT PK parameters was collected and placed into precooled sodium fluoride-potassium oxalate tubes (Vacuette FX; Greiner Bio-One, Austria). The tubes were carefully flipped upside down 10 times in order to allow mixing of blood and anticoagulant. After collection, the blood samples were immediately placed on ice and within a time period of no longer than 15 min centrifuged at 4°C and 1,500 ⫻ g for 15 min. Then, 2 plasma aliquots of 1 to 2 ml each were transferred into precooled cryovials and immediately (within 15 min from the time of plasma harvesting, i.e., not later than 45 min after blood collection) stored at approximately ⫺80°C. All microdialysate samples were also immediately placed on ice and stored at approximately ⫺80°C within 15 min from the time of collection. All samples remained stored at approximately ⫺80°C until analysis. Sample analysis. Concentrations of CPT were determined in plasma samples treated with sodium fluoride-potassium oxalate as an anticoagulant. CPT and its internal standard deuterated CPT (CPT-d3) were extracted from human plasma by protein precipitation. The supernatant was reconstituted and analyzed using an internally validated liquid chromatography (LC)-tandem mass spectrometry (MS/MS) method. The

Antimicrobial Agents and Chemotherapy

June 2016 Volume 60 Number 6

Pharmacokinetics of Ceftaroline in Healthy Volunteers

range of CPT concentrations for the standard curve, obtained using a plasma sample volume of 50.0 ␮l, was 50.0 to 50,000 ng/ml. Plasma calibration curves were linear over the concentration range of 50 to 50,000 ng/ml (r ⫽ 0.999). Relative standard deviations (RSDs) for interday and intraday precision were within 11% for low-, medium-, and high-quality controls, and bias (accuracy) was ⫾3.3%. The CPT in the microdialysis samples and the internal standard (CPTd3) were processed by dilution and analyzed using an internally validated LC-MS/MS method. The range of CPT concentrations for the standard curve, obtained using a microdialysate sample volume of 50.0 ␮l, was 4.00 to 2,000 ng/ml. Curves for calibration of the CPT concentration in the microdialysate were linear over the concentration range of 4 to 2,000 ng/ml (r ⫽ 0.999). Here, RSDs for interday and intraday precision were within 8% for low-, medium-, and high-quality controls, and bias (accuracy) was ⫾8.0%. PK parameters and statistical analyses. PK parameters were calculated using noncompartmental analysis (NCA) by means of a commercially available computer program (Kinetica, version 3.0; Innaphase, USA). The maximum concentration in plasma (Cmax), the time to the maximum concentration in plasma (Tmax), the terminal elimination halflife (t1/2), and the area under the concentration-time curve (AUC) from time zero to the end of the dosing interval (AUC0 –␶) were calculated from nonfitted data by employing the trapezoidal rule for all compartments. The area under the total CPT concentration-time curve from time zero to 24 h (AUC0 –24) was estimated by multiplying the calculated AUC0 –␶ by 3 (for the q8h group) or by 2 (for the q12h group) as a very conservative estimate. Additionally, total body clearance (CL) and the apparent volume of distribution (V) were calculated for plasma. The cumulative percentage of the dosing interval during which the free drug concentration exceeded the MIC (fTMIC) was calculated according to the equation proposed by Turnidge (12). Independent-samples and related-samples Mann-Whitney U tests were used to compare the distribution of key pharmacokinetic parameters between study groups and between single and repeated doses, respectively. Statistical analysis was performed by means of a commercially available statistical program (IBM SPSS Statistics 22; IBM, Armonk, NY, USA).

RESULTS

In vitro ␮D study. In forward dialysis experiments, the mean ⫾ standard deviation (SD) CPT recovery was 47.4% ⫾ 5.7%. In the reverse dialysis mode, the mean ⫾ SD CPT recovery was 38.5% ⫾ 7.5%. In both the forward and reverse dialysis modes, no clear trends of an increase or a decrease in the amount of CPT recovered over time or between the amount of CPT recovered at the three tested concentrations (0.3, 3, and 30 ␮g/ml, respectively) were observed. In vivo ␮D study. All (n ⫽ 12) subjects (age range, 24 to 50 years; mean body mass index, 23.3 ⫾ 2.7 kg/m2 and 22.2 ⫾ 2.1 kg/m2 for the q8h and q12h groups, respectively) completed the study. CPT-F was well tolerated by all study participants. The only potentially drug-related adverse event was a single episode of mild diarrhea in one subject in the q12h group following study drug administration. One subject in the q8h group reported fatigue with onset before and spontaneous resolution during the study day. The discomfort experienced during microdialysis probe insertion in tissue was well tolerated by all subjects. None of the subjects required any pain medication during the entire study. The permanent positioning of the microdialysis probes in muscle and subcutaneous adipose tissue for a time frame of up to 40 h was also well tolerated by all study participants. No cases of bleeding or infection and no other procedure-related lesions were recorded. The concentration-time profiles of total and unbound CPT in plasma as well as those of only free, i.e., non-protein-bound, CPT

June 2016 Volume 60 Number 6

in the muscle and subcutaneous adipose tissue of healthy volunteers after intravenous administration of CPT-F are shown in Fig. 1. For plasma, where total drug concentrations were measured, unbound drug concentrations were calculated by assuming a plasma protein binding of 20% (13). After the first intravenous administration of 600 mg of CPT-F over 1 h (q12h group), mean CPT concentrations in plasma showed a steep increase before reaching a peak concentration in plasma of 18.1 ⫾ 1.6 mg/liter 1 h after the start of the infusion. Accordingly, in the q8h group, a Cmax of 12.2 ⫾ 2.2 mg/liter was attained after 2 h (P ⫽ 0.002 for the difference in Tmax), and this value was significantly lower than that attained after the 1-h infusion (P ⫽ 0.004). The elimination halflife of active CPT was significantly shorter in the q8h group after both single and repeated administration (P ⫽ 0.009 and 0.004, respectively), whereas the apparent volume of distribution did not show significant changes. The steady-state area under the concentration-time curve from 0 to 24 h (AUC0 –24) for unbound ceftaroline in plasma was significantly higher in the q8h group than the q12h group (109.9 ⫾ 19.4 mg · h/liter versus 81.1 ⫾ 19.4 mg · h/liter, respectively; P ⫽ 0.041). When target organisms with a MIC of 1 mg/liter according to current EUCAST breakpoints (14) were considered, fTMIC was significantly higher in the q8h group than the q12h group (89.4% ⫾ 12.02% versus 70.2% ⫾ 10.8%, respectively; P ⫽ 0.026). Within each dosing group, no significant differences in the values of the key PK parameters of CPT in plasma were observed between single and repeated administration. The levels of unbound CPT were measurable in the soft tissue of all study participants. Mean ␮D probe recovery, determined by retrodialysis, was 23.8% ⫾ 8.8% for muscle and 25.5% ⫾ 8.3% for subcutaneous adipose tissue. The mean steady-state ratios of the AUC from time zero to the end of the dosing interval (AUC0-␶) for unbound CPT in tissue to the AUC0-␶ for unbound drug in plasma (assuming plasma protein binding of 20%) for the q8h and q12h groups were 0.67 ⫾ 0.4 and 0.66 ⫾ 0.2, respectively, for muscle and 0.75 ⫾ 0.3 and 0.75 ⫾ 0.3, respectively, for the subcutis. In skeletal muscle tissue, the pattern of higher and earlier peak concentrations after infusion over 1 h than after infusion over 2 h was substantially confirmed, although differences between groups were mainly descriptive and statistically significant only for Tmax after repeated dosing (1.8 ⫾ 0.5 h in the q12h group and 3.3 ⫾ 1.0 h in the q8h group; P ⫽ 0.004). After a single dose, Cmax values were 5.5 ⫾ 2.4 and 6.1 ⫾ 1.8 mg/liter in the q8h and q12h groups, respectively, and after repeated doses, Cmax values were 6.3 ⫾ 2.8 and 7.1 ⫾ 17 mg/liter in the q8h and q12h groups, respectively. The AUC0 –24 for CPT in muscle showed consistently higher values in the q8h group than in the q12h group (50.9 ⫾ 25.0 versus 39.6 ⫾ 7.1 mg · h/liter, respectively, after a single dose and 69.5 ⫾ 31.6 versus 52.2 ⫾ 18.3 mg · h/liter, respectively, after repeated doses). Here, too, the differences between groups did not reach statistical significance. Of note, within each dosing group, Cmax, AUC0 –24, as well as the mean ratio of the AUC0-␶ for unbound CPT in muscle to the AUC0-␶ for unbound CPT in plasma showed a marked though not statistically significant increase from single to repeated doses. The disposition of CPT observed in subcutaneous tissue was in good overall agreement with that observed in muscle tissue. The shorter infusion time in the q12h group produced shorter times to the peak concentration (1.9 ⫾ 0.4 versus 2.8 ⫾ 0.3 h after a single dose in the q12h and q8h groups, respectively, and 1.8 ⫾ 0.4 versus 1.9 ⫾ 0.4 h after repeated doses in the

Antimicrobial Agents and Chemotherapy

aac.asm.org

3619

Matzneller et al.

FIG 1 Single and repeated dose concentration-time profiles for total (closed symbols) and unbound (open symbols) CPT in the plasma, muscle, and subcutis of healthy volunteers after the intravenous administration of 600 mg CPT-F q12h and q8h. Plasma unbound CPT concentrations after administration q8h (dotted lines) and after administration q12h (dashed lines) were calculated by assuming plasma protein binding of 20%.

q12h and q8h groups, respectively) and higher peak levels (4.8 ⫾ 1.1 and 6.3 ⫾ 1.8 mg/liter after a single dose in the q12h and q8h groups, respectively, as well as 6.8 ⫾ 2.2 and 8.5 ⫾ 1.9 mg/liter after repeated doses in the q8h and q12h groups, respectively). Similar to what was observed in muscle, these differences did not reach statistical significance, except for Tmax after a single dose (P ⫽ 0.004). Calculated AUC0 –24 values for unbound CPT also followed the pattern of a descriptively higher level of drug exposure in the q8h group than the q12h group (47.4 ⫾ 14.2 versus 42.7 ⫾ 12.7 mg · h/liter after a single dose in the q12h and q8h groups, respectively, and 79.6 ⫾ 19.6 versus 59.5 ⫾ 18.2 mg · h/liter after repeated doses in the q8h and q12h groups, respectively). Again, when the differences between the single and repeated CPT-F administration within the single study groups are considered, Cmax, AUC0 –24, and the mean ratio of AUC0-␶ for unbound CPT in the subcutis to AUC0-␶ for unbound CPT in plasma increased consistently after repeated dosing in both groups. Here, the increases in the values of all parameters were statistically significant in both dosing groups (P ⫽ 0.046 for Cmax, 0.028 for AUC0 –24, and 0.028 for subcutis/ plasma AUC0-␶ ratios). The values of the key PK and PK/PD parameters for active CPT in all investigated compartments are summarized in Table 1. Table 2 provides an overview of the values of the key PK parameters for CPT measured in the present study and in two additional recent studies following a single intravenous infusion of 600 mg CPT-F over 1 h.

3620

aac.asm.org

DISCUSSION

CPT-F, one of the most recently developed antimicrobial substances, is currently still searching for a well-defined position among the available treatment options for both labeled indications, i.e., CAP as well as skin and soft tissue infections. Significantly, it is perhaps the drug’s most important and distinguishing feature within the class of beta-lactams, its activity against MRSA, that has been met with the most skepticism. In particular, concerns over the appropriateness of the currently recommended dosage of 600 mg twice daily for the treatment of infections caused by S. aureus isolates with MIC values above the current EUCAST breakpoint of 1 mg/liter (14) have been raised, given that CPT MIC90 values of 2 mg/liter for MRSA have been reported in certain countries within Europe, in Latin America, and in Asia (15–20). These concerns have driven the initiation of additional clinical trials evaluating an increased frequency of administration (every 8 h) and an extension of the duration of the intravenous infusion of the drug from 1 to 2 h as a potential future mode of administration for infections caused by less susceptible organisms. The present study measured the pharmacokinetics of CPT in plasma and soft tissue after a single administration and repeated administration of CPT-F, with the aim of anticipating the pharmacokinetic basis of both of these dosing regimens. The use of microdialysis enabled us to characterize the so far insufficiently described kinetics of unbound, active CPT in the interstitial space

Antimicrobial Agents and Chemotherapy

June 2016 Volume 60 Number 6

Pharmacokinetics of Ceftaroline in Healthy Volunteers

TABLE 1 Values of PK parameters for total and unbound CPT in plasma, muscle, and subcutis after single and repeated administration of CPT-F q12h and q8ha Single administration

Repeated administration

Value for the following group:

Value for the following group:

Compartment and PK parameter

q12h

q8h

P valueb

q12h

q8h

P value

Plasma Cmax (mg/liter) AUC0–24 (mg · h/liter) fCmax (mg/liter) fAUC0–24 (mg · h/liter) Tmax (h) t1/2 (h) V (liters) fTMIC (%)

22.6 ⫾ 2.0 102.65 ⫾ 13.2 18.1 ⫾ 1.6 81.8 ⫾ 10.6 1.0 ⫾ 0.0 2.3 ⫾ 0.5 39.0 ⫾ 8.0 69.9 ⫾ 10.6

15.3 ⫾ 2.7 133.0 ⫾ 17.2 12.2 ⫾ 2.2 103.9 ⫾ 16.1 2.1 ⫾ 0.2 1.7 ⫾ 0.0 32.3 ⫾ 3.6 84.4 ⫾ 4.0

0.004 0.002 0.004 0.015 0.002 0.009 0.310 0.041

22.0 ⫾ 4.0 101.3 ⫾ 24.2 17.6 ⫾ 3.2 81.1 ⫾ 19.4 1.0 ⫾ 0.0 2.3 ⫾ 0.2 40.7 ⫾ 7.3 70.2 ⫾ 10.8

14.7 ⫾ 2.0 137.4 ⫾ 24.3 11.8 ⫾ 1.6 109.9 ⫾ 19.4 2.0 ⫾ 0.0 1.9 ⫾ 0.2 33.6 ⫾ 3.8 89.4 ⫾ 12.0

0.009 0.041 0.009 0.041 0.002 0.004 0.065 0.026

Muscle fCmax (mg/liter) fAUC0–24 (mg · h/liter) Tmax (h) t1/2 (h) fTMIC (%) fAUC0-␶ M/P ratio

6.1 ⫾ 1.8 39.6 ⫾ 7.1 1.9 ⫾ 0.6 2.0 ⫾ 0.3 48.3 ⫾ 7.6 0.50 ⫾ 0.1

5.5 ⫾ 2.4 50.9 ⫾ 25.0 2.4 ⫾ 0.6 1.7 ⫾ 0.1 60.75 ⫾ 10.4 0.49 ⫾ 0.2

0.699 0.699 0.180 0.041 0.041 0.589

7.1 ⫾ 1.7 52.2 ⫾ 18.3 1.8 ⫾ 0.5 2.1 ⫾ 0.4 56.8 ⫾ 13.3 0.66 ⫾ 0.2

6.3 ⫾ 2.8 69.5 ⫾ 31.6 3.3 ⫾ 1.0 2.0 ⫾ 0.8 75.6 ⫾ 19.7 0.67 ⫾ 0.4

0.589 0.485 0.004 0.485 0.132 0.818

Subcutis fCmax (mg/liter) fAUC0–24 (mg · h/liter) Tmax (h) t1/2 (h) fTMIC (%) fAUC0-␶ S/P ratio

6.3 ⫾ 1.8 42.7 ⫾ 12.7 1.9 ⫾ 0.4 2.0 ⫾ 0.3 47.4 ⫾ 8.6 0.53 ⫾ 0.2

4.8 ⫾ 1.1 47.4 ⫾ 14.2 2.8 ⫾ 0.3 2.2 ⫾ 1.3 64.6 ⫾ 22.4 0.47 ⫾ 0.2

0.485 0.589 0.004 0.818 0.065 0.589

8.5 ⫾ 1.9 59.5 ⫾ 18.2 1.8 ⫾ 0.4 1.9 ⫾ 0.4 54.3 ⫾ 11.0 0.75 ⫾ 0.3

6.8 ⫾ 2.2 79.6 ⫾ 19.6 1.9 ⫾ 0.4 1.8 ⫾ 0.5 75.1 ⫾ 17.4 0.75 ⫾ 0.3

0.180 0.132 0.699 0.485 0.026 1.000

a Unbound CPT concentrations in plasma were calculated by assuming plasma protein binding of 20%. Cmax, peak (maximum) total CPT concentration; fCmax, peak unbound (free) CPT concentration; AUC0 –24, area under the concentration-time curve from 0 to 24 h for total CPT; fAUC0 –24, area under the concentration-time curve from time zero to 24 h for unbound (free) CPT; fTMIC, fraction of the dosing interval during which the unbound (free) drug concentrations exceeded the MIC; Tmax, time to the peak concentration; t1//2, half-life; V, apparent volume of distribution; fAUC0-␶ M/P, ratio of the AUC from time zero to the end of the dosing interval for unbound (free) CPT in muscle (M) to the AUC from time zero to the end of the dosing interval for the calculated free fraction of CPT in plasma (P); fAUC0-␶ S/P, ratio of the AUC from time zero to the end of the dosing interval for unbound (free) CPT in the subcutis (S) to the AUC from time zero to the end of the dosing interval for the calculated free fraction of CPT in plasma. Values are shown as means ⫾ standard deviations. b P values show the exact significance.

fluid of muscle and subcutaneous adipose tissue, the target tissue in the case of cSSTIs. As far as plasma is concerned, Table 2 shows that the values of the key PK parameters of CPT after administration q12h (i.e., the currently recommended dosing regimen) were in line with the values from the recent literature (21, 22). In comparison, administration of CPT-F q8h produced significantly higher AUC0 –24 and, more importantly, fTMIC values. This may not be surprising, since, of course, an increase in the dosing frequency or, in other words, shortening of the dosage interval will produce a higher total daily dose and necessarily lead to an increment of exposure. However, it was hypothesized that these differences may have im-

plications for the attainment of target PK/PD indices under specific circumstances, as will be discussed below. For CPT, as for other antibiotics with time-dependent activity, the fraction of the dosing interval during which free (i.e., unbound) drug concentrations exceed the MIC (fTMIC) is the PK/PD index with the best ability to predict clinical efficacy (12, 23, 24). A CPT fTMIC in plasma of 31%, corresponding to a bacterial colony count reduction of 1 log10 step, has been suggested to be the PK/PD target for S. aureus (25, 26). In recent probability-of-target-attainment (PTA) studies, dosing of CPT-F both q12h and q8h has been predicted to safely reach this target, with PTA exceeding 95% for MICs equal to or below 2 mg/liter (27). Results

TABLE 2 Key PK parameters for total CPT in plasma of healthy volunteers after a single intravenous dose of 600 mg CPT fosamil as a 1-h infusiona Study

Age (yr)

BMI (kg/m2)

Male sex (%)

Cmax (mg/liter)

AUC0–12 (mg · h/liter)

AUC0–⬁ (mg · h/liter)

t1/2 (h)

V (liters)

CL (liters)

Riccobene et al. (22) Justo et al. (21) This study

29.3 ⫾ 7.2 34.6 ⫾ 11.6 37.8 ⫾ 7.7

26.1 ⫾ 2.7 24.6 ⫾ 1.8 22.2 ⫾ 2.1

50 87.5 100

27.9 ⫾ 4.3 22.3 ⫾ 5.9 22.6 ⫾ 2.0

51.9 ⫾ 11.8 51.3 ⫾ 6.6

62.2 ⫾ 8.5 53.0 ⫾ 12.3 52.2 ⫾ 7.1

2.5 ⫾ 0.3 2.1 ⫾ 0.3 2.3 ⫾ 0.5

19.7 ⫾ 3.3 36.4 ⫾ 9.7 39.0 ⫾ 8.0

8.7 ⫾ 1.2 12.0 ⫾ 3.3 11.7 ⫾ 1.7

Data (shown as means ⫾ standard deviations) from the present study are compared with values from two recent studies with healthy subjects. BMI, body mass index; Cmax, peak (maximum) concentration; AUC0 –12, area under the concentration-time curve from time zero to 12 h; AUC0 –⬁, area under the concentration-time curve from time zero to infinity; t1/2, half-life; V, apparent volume of distribution; CL, apparent total body clearance.

a

June 2016 Volume 60 Number 6

Antimicrobial Agents and Chemotherapy

aac.asm.org

3621

Matzneller et al.

TABLE 3 Comparison of simulated PTA for PK/PD target of 31% fTMIC for q12h and q8h administration of CPT-F and calculated fTMIC values derived from CPT concentrations in plasma, muscle, and subcutis measured in the present studya q12h group

q8h group fTMIC (%)

fTMIC (%)

MIC (mg/liter)

PTA (%)

Plasma

Muscle

Subcutis

PTA (%)

Plasma

Muscle

Subcutis

1 2 4

100 96.1 49.5

70.2 ⫾ 10.8 50.7 ⫾ 9.0 31.1 ⫾ 7.3

56.8 ⫾ 13.3 39.0 ⫾ 9.8 21.2 ⫾ 6.3

54.3 ⫾ 11.0 38.2 ⫾ 8.5 22.2 ⫾ 6.3

100 100 96.8

89.4 ⫾ 12.0 66.2 ⫾ 9.6 43.0 ⫾ 7.2

75.6 ⫾ 19.7 50.9 ⫾ 13.8 26.2 ⫾ 14.3

75.1 ⫾ 17.4 52.9 ⫾ 11.8 30.8 ⫾ 6.8

a The PTA for the PK/PD target of 31% fTMIC for q12h and q8h administration of CPT-F is according to Li et al. (27). fTMIC, fraction of the dosing interval during which the free drug concentrations exceeded the MIC. Values are shown as means ⫾ standard deviations.

from the present trial generally support these considerations, as the fTMIC values calculated for both dosing regimens, assuming MICs of up to 2 mg/liter, far exceeded the threshold of 31%. Only at a MIC of 4 mg/liter did fTMIC drop to 31.1% after q12h dosing, while q8h administration still provided CPT concentrations above the MIC for 43.0% of the dosing interval. Again, this is in good agreement with the results of the PTA analysis mentioned above, where, with the assumption of MICs of up to 4 mg/liter, the predicted PTA is clearly superior in the q8h dosing scheme (96%) than the q12h dosing scheme (49.5%) (27). An overview of reported PTA values for different MICs and the corresponding fTMIC values calculated in the present study is presented in Table 3. In soft tissues, the microdialysis measurements obtained in this study indicate that consistent amounts of free drug reach the target site, with the steady-state concentrations in the subcutis being slightly superior to those in muscle. In analogy to the findings for plasma, q8h dosing also led to higher levels of drug exposure in soft tissues, as expressed by the higher AUC0 –24 for unbound CPT in both muscle and subcutis. Here, however, differences in the values of key pharmacokinetic parameters between study groups were merely descriptive and did not reach statistical significance. The reasons for this are to be sought mainly in the small sample size and the higher between-subject variability of soft tissue measurements. Measurements of the relative recovery of CPT in soft tissue (23.8% ⫾ 8.8% for muscle and 25.5% ⫾ 8.3% for subcutaneous adipose tissue) showed high between-probe variability. In preliminary in vitro experiments, recovery values were observed to be constant over time and over different CPT concentrations. Also, recovery was comparable between forward and reverse dialysis. The reason for the difference in the magnitude of the loss rates observed between the in vitro experiment (38.5%; see above) and the in vivo experiment (on the order of 25%; see above) remains unclear. However, these discrepancies between the results of the in vitro study and those of the in vivo study are not uncommon for microdialysis studies and highlight the importance of correction of the values for individual probes, i.e., calculation of the actual analyte concentrations in ESF using recovery values obtained from each individual ␮D probe as a correction factor (as was done in the present study). PK/PD parameters are usually referred exclusively to the concentrations in plasma since free drug concentrations in tissue are not readily available for most compounds. Nevertheless, the therapeutic success or failure of an anti-infective agent are determined by target site concentrations, and, ideally, PK/PD indices as well as dosing recommendations should not neglect the tissue penetration of an antibiotic (28). Therefore, fTMIC values were also calculated for muscle and the subcutis on the basis of the free CPT

3622

aac.asm.org

concentrations in soft tissue measured in this study. They are summarized in Table 1 together with the values of the other PK/PD parameters. After both a single dose and repeated doses, the values for the q8h group were clearly superior to those for the q12h group in both compartments. With the assumption of a MIC of 1 mg/liter, calculated steady-state soft tissue fTMIC values in the q12h group were 56.8% ⫾ 13.3% for muscle and 54.3% ⫾ 11.0% for the subcutis. On the other hand, q8h administration provided CPT concentrations above the MIC for 75.6% ⫾ 19.7% and 75.1% ⫾ 17.4% of the dosing interval in muscle and the subcutis, respectively (P ⫽ 0.132 for muscle and 0.026 for the subcutis). Given a MIC of 2 mg/liter, the resulting fTMIC values after repeated q12h administration amounted to 39.0% ⫾ 9.8% and 38.2% ⫾ 8.5% in muscle and the subcutis, respectively, while the fTMIC after q8h dosing still reached values slightly above 50% in both tissues. The numbers discussed above are confirmed graphically in Fig. 2. In the subcutis, the soft tissue with the highest level of CPT exposure, q8h administration continued to provide drug levels above the MIC for a sufficient portion of the dosing interval even when a MIC of 2 mg/liter was assumed, but the CPT concentrations after q12h dosing strikingly dropped below the line defining the MIC before 50% of the dosing interval had elapsed. If an even higher MIC of 4 mg/liter is included in the equation, the fTMIC in the subcutis was 22.2% after q12h dosing, but it was still 30.8% after q8h dosing. Under the same MIC assumption, the values were similar for muscle, with fTMIC values being 21.2% and 26.2% after q12h and q8h dosing, respectively. Considering that soft tissue infections are one of the therapeutic targets of the drug, this rather small difference might become critical when a less susceptible pathogen is treated and, accordingly, suggests that more frequent dosing could be advantageous in specific clinical situations. It should also be kept in mind that to date CPT-F is rarely chosen as a first-line treatment option (8), which implies that patients treated with the drug have already undergone one or more unsuccessful antibiotic treatment courses and, in a considerable portion of the cases, are severely ill. Importantly, hemodynamic alterations in critically ill patients have already been shown to impair the tissue penetration of beta-lactam antibiotics (29) and might constitute an additional obstacle to appropriate target attainment. Taken together, the clinical implications of the marked increase in the level of exposure to CPT observed in the present trial after administration of CPT-F q8h might be limited, if they are set in relation to relevant plasma PK/PD targets. Accordingly, our findings indicate that q12h dosing should be sufficient for the treatment of infections caused by the vast majority of pathogens. Under certain conditions, however, we hypothesize that the

Antimicrobial Agents and Chemotherapy

June 2016 Volume 60 Number 6

Pharmacokinetics of Ceftaroline in Healthy Volunteers

FIG 2 Measured (lines and symbols) and extrapolated (dashed lines) steady-state concentration-time curves for unbound ceftaroline in plasma (a) and the subcutis (b) over 24 h after administration of CPT-F q12h and q8h. Horizontal lines, MICs of 1 mg/liter, 2 mg/liter, and 4 mg/liter. Unbound ceftaroline concentrations in plasma were calculated by assuming plasma protein binding of 20%.

pharmacokinetic advantages of q8h dosing described in this study might indeed have clinical relevance. In disease states like endocarditis or MRSA bacteremia, more aggressive (i.e., q8h) therapy with CPT-F has already been shown to have highly bactericidal activity (i.e., 3-log-unit killing or more) and improved efficacy compared to the q12h dosing scheme (30, 31). Similarly, in immunocompromised patients, in individuals with severely impaired tissue penetration, or in the case of infection caused by organisms with particularly low levels of susceptibility to CPT, a more intensive CPT-F treatment regimen also might be justified for soft tissue infections. In this case, a higher degree of bacterial killing might be required (23) and an fTMIC target of 31% might no longer hold true. For clinicians who face such situations, the present data might serve as an element in favor of q8h dosing of CPT-F. The present data stem from studies with healthy volunteers. Accordingly, demographic characteristics, comedication, and the comorbidities of severely ill patients are not reflected in the findings presented here. The extrapolation of the conclusions from the present trial to clinical practice should therefore be done with caution. Also, as mentioned above, microdialysis measurements in soft tissues were affected by high interindividual variability, which precluded the ability of this study to describe clear statistically significant between-group differences with regard to PKs in soft tissue. In this context, the fact that the two study groups differed by more than one variable (i.e., dosing frequency and duration of infusion) might be seen as a limitation since it prevents a clear interpretation of the observed trends. On the other hand, the results obtained from the studies with the two study groups depict the totality of differences of the dosing regimens, and therefore, these differences might be considered representative of possible

June 2016 Volume 60 Number 6

differences that might also occur in patients when these two regimens are employed. Moreover, the ratio of the AUC0-␶ for CPT in muscle to that for CPT in plasma and the ratio of the AUC0-␶ for CPT in the subcutis to that for CPT in plasma indicate incomplete penetration of unbound drug from plasma into tissue. Only approximately 50% of the calculated free plasma CPT could be recovered in the extracellular space of muscle and subcutis after administration of a single dose of CPT-F. After repeated administration, this percentage improved to approximately 66% for muscle and 75% for subcutis, irrespective of the dosing frequency. Beyond pure accumulation, there are a number of potential explanations for this finding. On the one hand, unbound CPT concentrations in plasma were calculated by assuming a plasma protein binding of 20%, as indicated in the summary of the product characteristics of CPT-F and in a large portion of the available literature. However, higher levels of protein binding of CPT have been described (32). Indeed, the possibility of a level of CPT protein binding above 20% in the present study cannot be excluded and would naturally lead to improved tissue penetration ratios. On the other hand, the unspecific binding of CPT to tissue proteins, previously described in vitro (32), might also have affected the amount of drug recovered in the microdialysis samples. Taken together, the present study was able to provide valuable information on the plasma and, for the first time, soft tissue pharmacokinetics of CPT after the single and repeated administration of CPT-F by two different dosing regimens. The administration of CPT-F at 600 mg q8h led to higher levels of drug exposure in all investigated compartments and showed higher PK/PD target attainment rates than administration q12h. In light of recent clinical and PK/PD data, the clinical relevance of these findings might be

Antimicrobial Agents and Chemotherapy

aac.asm.org

3623

Matzneller et al.

limited, and the q8h dosing regimen might represent a therapeutic option only under specific circumstances. ACKNOWLEDGMENT The design and conduct of the study, analysis of the study data, and opinions, conclusions, and interpretation of the data are the responsibility of the authors.

FUNDING INFORMATION For the conduct of this study, the Medical University of Vienna was supported by an institutional research grant from AstraZeneca.

REFERENCES 1. Corey GR, Wilcox MH, Talbot GH, Thye D, Friedland D, Baculik T. 2010. 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 65(Suppl 4):iv41–iv51. http://dx.doi.org/10.1093/jac/dkq254. 2. File TM, Jr, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley IA, Thye DA. 2011. FOCUS 1: a randomized, double-blinded, multicentre, phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia. J Antimicrob Chemother 66(Suppl 3):iii19 –iii32. http://dx.doi.org/10 .1093/jac/dkr096. 3. Low DE, File TM, Jr, Eckburg PB, Talbot GH, Friedland DH, Lee J, Llorens L, Critchley IA, Thye DA. 2011. 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 66(Suppl 3):iii33–iii44. http://dx.doi.org/10.1093 /jac/dkr097. 4. Wilcox MH, Corey GR, Talbot GH, Thye D, Friedland D, Baculik T. 2010. CANVAS 2: the second phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 65(Suppl 4):iv53–iv65. http://dx.doi.org/10.1093/jac/dkq255. 5. Zhong NS, Sun T, Zhuo C, D’Souza G, Lee SH, Lan NH, Chiang CH, Wilson D, Sun F, Iaconis J, Melnick D. 2015. Ceftaroline fosamil versus ceftriaxone for the treatment of Asian patients with community-acquired pneumonia: a randomised, controlled, double-blind, phase 3, noninferiority with nested superiority trial. Lancet Infect Dis 15:161–171. http://dx.doi.org/10.1016/S1473-3099(14)71018-7. 6. Corey GR, Wilcox M, Gonzalez J, Jandourek A, Wilson D, Friedland HD, Das S, Iaconis JP, Dryden M. 2015. Ceftaroline fosamil (CPT-F) in patients with acute bacterial skin and skin structure infections (ABSSSI) with systemic inflammatory signs: results across 3 pivotal studies using q8h or q12h, abstr L-839. Abstr 55th Intersci Conf Antimicrob Agents Chemother, San Diego, CA. American Society for Microbiology, Washington, DC. 7. Dryden M, Wilson D, Iaconis J, Gonzalez J. 2015. A phase III trial of ceftaroline fosamil 600 mg q8h versus vancomycin plus aztreonam in patients with cSSTI with systemic inflammatory response or underlying comorbidities, abstr O193. Abstr 25th Eur Conf Clin Microbiol Infect Dis, Copenhagen, Denmark. 8. Casapao AM, Davis SL, Barr VO, Klinker KP, Goff DA, Barber KE, Kaye KS, Mynatt RP, Molloy LM, Pogue JM, Rybak MJ. 2014. Large retrospective evaluation of the effectiveness and safety of ceftaroline fosamil therapy. Antimicrob Agents Chemother 58:2541–2546. http://dx.doi .org/10.1128/AAC.02371-13. 9. Chaurasia CS, Muller M, Bashaw ED, Benfeldt E, Bolinder J, Bullock R, Bungay PM, DeLange EC, Derendorf H, Elmquist WF, HammarlundUdenaes M, Joukhadar C, Kellogg DL, Jr, Lunte CE, Nordstrom CH, Rollema H, Sawchuk RJ, Cheung BW, Shah VP, Stahle L, Ungerstedt U, Welty DF, Yeo H. 2007. AAPS-FDA workshop white paper: microdialysis principles, application, and regulatory perspectives. J Clin Pharmacol 47: 589 – 603. http://dx.doi.org/10.1177/0091270006299091. 10. Matzneller P, Brunner M. 2011. Recent advances in clinical microdialysis. TrAC Trends Anal Chem 30:1497–1504. http://dx.doi.org/10.1016/j .trac.2011.06.008. 11. Muller M. 2002. Science, medicine, and the future: microdialysis. BMJ 324:588 –591. http://dx.doi.org/10.1136/bmj.324.7337.588.

3624

aac.asm.org

12. Turnidge JD. 1998. The pharmacodynamics of beta-lactams. Clin Infect Dis 27:10 –22. http://dx.doi.org/10.1086/514622. 13. AstraZeneca. Zinforo. Summary of product characteristics. AstraZeneca, London, United Kingdom. 14. European Committee on Antimicrobial Susceptibility Testing. 2014. Breakpoint tables for interpretation of MICs and zone diameters, version 4.0. 15. Biedenbach DJ, Alm RA, Lahiri SD, Reiszner E, Hoban DJ, Sahm DF, Bouchillon SK, Ambler JE. 2015. In vitro activity of ceftaroline against Staphylococcus aureus isolated in 2012 from Asia-Pacific countries as part of the AWARE Surveillance Program. Antimicrob Agents Chemother 60: 343–347. http://dx.doi.org/10.1128/AAC.01867-15. 16. Biedenbach DJ, Hoban DJ, Reiszner E, Lahiri SD, Alm RA, Sahm DF, Bouchillon SK, Ambler JE. 2015. In vitro activity of ceftaroline against Staphylococcus aureus isolates collected in 2012 from Latin American countries as part of the AWARE Surveillance Program. Antimicrob Agents Chemother 59:7873–7877. http://dx.doi.org/10.1128/AAC.01833-15. 17. Farrell DJ, Flamm RK, Sader HS, Jones RN. 2013. Spectrum and potency of ceftaroline tested against leading pathogens causing skin and soft-tissue infections in Europe (2010). Int J Antimicrob Agents 41:337–342. http: //dx.doi.org/10.1016/j.ijantimicag.2012.12.013. 18. Flamm RK, Sader HS, Jones RN. 2014. Ceftaroline activity tested against contemporary Latin American bacterial pathogens (2011). Braz J Infect Dis 18:187–195. http://dx.doi.org/10.1016/j.bjid.2013.11.005. 19. Flamm RK, Sader HS, Jones RN. 2013. Spectrum and potency of ceftaroline against leading pathogens causing community-acquired respiratory tract and skin and soft tissue infections in Latin America, 2010. Braz J Infect Dis 17:564 –572. http://dx.doi.org/10.1016/j.bjid.2013.02.008. 20. Karlowsky JA, Biedenbach DJ, Bouchillon SK, Iaconis JP, Reiszner E, Sahm DF. 2016. In vitro activity of ceftaroline against bacterial pathogens isolated from skin and soft tissue infections in Europe, Russia and Turkey in 2012: results from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance programme. J Antimicrob Chemother 71:162–169. http://dx.doi.org/10.1093/jac/dkv311. 21. Justo JA, Mayer SM, Pai MP, Soriano MM, Danziger LH, Novak RM, Rodvold KA. 2015. Pharmacokinetics of ceftaroline in normal body weight and obese (classes I, II, and III) healthy adult subjects. Antimicrob Agents Chemother 59:3956 –3965. http://dx.doi.org/10.1128/AAC.00498-15. 22. Riccobene TA, Su SF, Rank D. 2013. 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 57:1496 –1504. http://dx.doi.org/10.1128/AAC.02134-12. 23. Andes D, Craig WA. 2006. Pharmacodynamics of a new cephalosporin, PPI-0903 (TAK-599), active against methicillin-resistant Staphylococcus aureus in murine thigh and lung infection models: identification of an in vivo pharmacokinetic-pharmacodynamic target. Antimicrob Agents Chemother 50:1376 –1383. http://dx.doi.org/10.1128/AAC.50.4.1376-1383 .2006. 24. Andes D, Craig W. 2014. Pharmacodynamics of a new cephalosporin, PPI-0903 (TAK-599), active against methicillin-resistant Staphylococcus aureus in murine thigh and lung infection models: identification of an in vivo pharmacokinetic-pharmacodynamic target. Author correction. Antimicrob Agents Chemother 58:2489. http://dx.doi.org/10.1128/AAC .00134-14. 25. MacGowan AP, Noel AR, Tomaselli S, Bowker KE. 2013. Pharmacodynamics of ceftaroline against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection. Antimicrob Agents Chemother 57: 2451–2456. http://dx.doi.org/10.1128/AAC.01386-12. 26. Singh R, Almutairi M, San Martin M, Chen A, Ambler JE. 2015. Evaluation of ceftaroline pharmacokinetic/pharmacodynamic (PK/PD) target against diverse characterized clinical isolates of Staphylococcus aureus isolates in an in vitro hollow-fibre infection model, abstr O138. Abstr 25th Eur Conf Clin Microbiol Infect Dis, Copenhagen, Denmark. 27. Li J, Singh R, Ambler JE. 2015. Probability of target attainment (PTA) and pharmacokinetic/pharmacodynamic (PK/PD) breakpoint for ceftaroline fosamil 600 mg every 12 h and every 8 h against Staphylococcus aureus, abstr P1384. Abstr 55th Intersci Conf Antimicrob Agents Chemother, San Diego, CA. American Society for Microbiology, Washington, DC. 28. Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. 2008. Tissue concentrations: do we ever learn? J Antimicrob Chemother 61:235–237. http://dx.doi.org/10.1093/jac/dkm476. 29. Joukhadar C, Frossard M, Mayer BX, Brunner M, Klein N, Siostrzonek P, Eichler HG, Muller M. 2001. Impaired target site penetration of beta-

Antimicrobial Agents and Chemotherapy

June 2016 Volume 60 Number 6

Pharmacokinetics of Ceftaroline in Healthy Volunteers

lactams may account for therapeutic failure in patients with septic shock. Crit Care Med 29:385–391. http://dx.doi.org/10.1097/00003246 -200102000-00030. 30. Ho TT, Cadena J, Childs LM, Gonzalez-Velez M, Lewis JS, II. 2012. Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy. J Antimicrob Chemother 67: 1267–1270. http://dx.doi.org/10.1093/jac/dks006. 31. Jacqueline C, Amador G, Batard E, Le Mabecque V, Miegeville AF, Biek D, Caillon J, Potel G. 2011. Comparison of ceftaroline fosamil, dapto-

June 2016 Volume 60 Number 6

mycin and tigecycline in an experimental rabbit endocarditis model caused by methicillin-susceptible, methicillin-resistant and glycopeptideintermediate Staphylococcus aureus. J Antimicrob Chemother 66:863– 866. http://dx.doi.org/10.1093/jac/dkr019. 32. Croisier-Bertin D, Piroth L, Charles PE, Larribeau A, Biek D, Ge Y, Chavanet P. 2011. Ceftaroline versus ceftriaxone in a highly penicillinresistant pneumococcal pneumonia rabbit model using simulated human dosing. Antimicrob Agents Chemother 55:3557–3563. http://dx.doi.org /10.1128/AAC.01773-09.

Antimicrobial Agents and Chemotherapy

aac.asm.org

3625