Abstract
This study was conducted to determine the safety, tolerability, and pharmacokinetics of intravenous doses of ceftaroline fosamil administered in combination with the novel non-β-lactam β-lactamase inhibitor avibactam in healthy adults. In the single-dose, open-label arm, 12 subjects received single 1-h intravenous infusions of ceftaroline fosamil alone (600 mg), avibactam alone (600 mg), and ceftaroline fosamil in combination with avibactam (600/600 mg) separated by 5-day washout periods. In the multiple-dose, placebo-controlled, double-blind arm, 48 subjects received intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), 400/400 mg q8h, 900/900 mg q12h, 600/600 mg q8h, or placebo for 10 days. Ceftaroline and avibactam levels in plasma and urine were measured by liquid chromatography coupled with tandem mass spectrometry. No significant differences in systemic exposure of ceftaroline or avibactam were observed when the drugs were administered alone versus concomitantly, indicating that there was no apparent pharmacokinetic interaction between ceftaroline fosamil and avibactam administered as a single dose. No appreciable accumulation of either drug occurred with multiple intravenous doses of ceftaroline fosamil/avibactam, and pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10. Infusions of ceftaroline fosamil/avibactam were well tolerated at total daily doses of up to 1,800 mg of each compound, and all adverse events (AEs) were mild to moderate in severity. Infusion-site reactions were the most common AEs reported with multiple dosing. The pharmacokinetic and safety profiles of ceftaroline fosamil/avibactam demonstrate that the 2 drugs can be administered concomitantly to provide an important broad-spectrum antimicrobial treatment option.
INTRODUCTION
Ceftaroline fosamil, the prodrug of the active metabolite ceftaroline, is a new broad-spectrum parenteral cephalosporin that was approved in 2010 by the United States Food and Drug Administration for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) (1). Ceftaroline fosamil is administered as a 1-h intravenous (IV) infusion of 600 mg every 12 h. The prodrug ceftaroline fosamil is rapidly converted to active ceftaroline in plasma by phosphatase enzymes, and the primary route of elimination for ceftaroline is by renal excretion (2, 3) with an elimination half-life of about 2.6 h. When incubated with pooled human liver microsomes, ceftaroline was metabolically stable (<12% metabolic turnover), indicating that ceftaroline is not a substrate for hepatic CYP450 enzymes (4). In addition, in vitro studies demonstrated that ceftaroline does not inhibit or induce major CYP450 isoenzymes. Population pharmacokinetic analysis did not identify any clinically relevant differences in ceftaroline exposure in patients with ABSSSI or CABP who were taking concomitant medications that are known inhibitors, inducers, or substrates of the cytochrome P450 system; anionic or cationic drugs known to undergo active renal secretion; and vasodilator or vasoconstrictor drugs that may alter renal blood flow (5). Thus, the overall drug-drug interaction potential for ceftaroline can be considered to be low.
Ceftaroline exhibits bactericidal activity against Gram-positive organisms, including methicillin-susceptible and -resistant Staphylococcus aureus (6–11) and Streptococcus pneumoniae (6, 7, 9), in addition to common (non-extended-spectrum-β-lactamase [ESBL]-producing) Gram-negative pathogens (7–9, 12). However, ceftaroline is not active against Gram-negative bacteria producing ESBLs from the TEM, SHV, or CTX-M families, serine carbapenemases (such as KPC), class B metallo-β-lactamases, or class C (AmpC) cephalosporinases (1). As with other β-lactam antimicrobial agents, the time that the unbound plasma concentration of ceftaroline exceeds the MIC of the infectious organism is the pharmacodynamic parameter best correlated with its efficacy (13).
Infections associated with resistant organisms, such as ESBL-producing or multidrug-resistant Gram-negative bacteria, have been associated with high mortality (14). β-Lactams alone provide inadequate coverage against ESBL- and KPC-producing Gram-negative organisms (15). There is, therefore, a pressing need for novel treatments for infections caused by such organisms. Combinations with β-lactamase inhibitors have been effective in extending the coverage of some β-lactams (e.g., amoxicillin-clavulanic acid, piperacillin-tazobactam). However, currently marketed β-lactamase inhibitors provide protection only against class A enzymes.
Avibactam (previously NXL104) is a novel non-β-lactam β-lactamase inhibitor that has little intrinsic activity but is able to protect β-lactams from class A (including ESBLs), class C (AmpC), and some class D β-lactamases (16–21). Like ceftaroline, the primary route of elimination for avibactam is through the kidneys (22) with an elimination half-life of 1.4 to 1.7 h. The addition of avibactam to ceftaroline fosamil extends the antimicrobial spectrum of activity of ceftaroline (14, 15, 23–25). In vitro data have shown the combination to be a promising therapeutic strategy for treating infections associated with resistant strains of Klebsiella pneumoniae and Escherichia coli (e.g., OXA-48 carbapenemase- and CTX-M-15-type ESBL-producing isolates) (14). This combination also demonstrated efficacy in vitro and in animal models of infection against infections caused by Enterobacteriaceae, including strains producing ESBL, KPC, and/or derepressed AmpC enzymes, in addition to penicillin-resistant S. pneumoniae, Haemophilis influenzae, and methicillin-resistant S. aureus (MRSA) (15, 23–25).
This study was conducted to determine the safety, tolerability, and pharmacokinetics of single and multiple IV doses of ceftaroline fosamil and avibactam in healthy adults.
(A preliminary report of these results was presented at the 51st Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 17 to 20 September 2011.)
MATERIALS AND METHODS
Study design and objectives.
This study was a single-center, 2-part (parts A and B), phase I study in 60 healthy adult subjects. Part A was a randomized 3-way crossover, open-label, single-dose study in which 12 subjects received each of the following 3 treatments in a randomized sequence: a single 1-h IV infusion of ceftaroline fosamil at 600 mg, a single 1-h IV infusion of avibactam at 600 mg, and a single 1-h infusion of ceftaroline fosamil and avibactam at 600/600 mg. Treatments were separated by 5-day washout periods. Part B was a randomized, double-blind, placebo-controlled, 10-day, multiple-dose study in 48 subjects (9 active/6 placebo subjects per treatment group). Subjects received 1-h IV infusions of ceftaroline fosamil/avibactam at 600/600 mg every 12 h (q12h), ceftaroline fosamil/avibactam at 400/400 mg every 8 h (q8h), ceftaroline fosamil/avibactam at 900/900 mg q12h, ceftaroline fosamil/avibactam at 600/600 mg q8h, or saline placebo on days 2 to 9. On days 1 and 10, subjects received only a single dose of their assigned treatment.
For both parts of this study, ceftaroline fosamil and avibactam were supplied by Cerexa, Inc., Oakland, CA (a wholly owned subsidiary of Forest Laboratories, Inc., New York, NY). Vials of the study drug were reconstituted with the appropriate volumes of sterile water for injection, and the required doses for each treatment were added to normal saline solution to obtain a final infusion volume of 280 ml for all treatments. When ceftaroline fosamil and avibactam were administered concomitantly, reconstituted ceftaroline fosamil and avibactam were added to the same IV infusion bag.
The study protocol was approved by the MDS Pharma Institutional Review Board and complied with the International Conference on Harmonization guidances on General Considerations for Clinical Trials, Nonclinical Safety Studies for the Conduct of Human Clinical Trials for Pharmaceuticals, and Good Clinical Practice: Consolidated Guidance. All subjects provided signed informed consent.
Study populations.
Healthy men and women, between 18 and 45 years of age, were eligible to participate in this study. No subjects with clinically significant abnormal findings on electrocardiogram (ECG), clinical laboratory evaluations, or physical examination were included in the study. The permitted body mass index (BMI) was 18 to 30 kg/m2 inclusive. Female subjects needed to have a negative serum pregnancy test and be using appropriate contraception.
Subjects with hypersensitivity or allergic reaction to any β-lactam antibiotic or β-lactamase inhibitor were excluded from the study. Any clinical condition that might affect the absorption, distribution, biotransformation, or excretion of ceftaroline fosamil or avibactam warranted exclusion from the study, as did previous use of ceftaroline fosamil or avibactam or previous participation in an investigational study of ceftaroline or avibactam.
Pharmacokinetic analysis. (i) Sample collection.
Blood and urine samples were collected at 0 h (predose) and up to 48 h postdose to evaluate the pharmacokinetics of ceftaroline, ceftaroline fosamil, ceftaroline M-1 (a major inactive metabolite arising from hydrolysis of the β-lactam ring of ceftaroline), and avibactam.
For part A, blood samples were collected immediately before (within 15 min) the start of infusion and after the start of study drug infusion at 20, 40, 60, 65, and 75 min and at 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 h for each treatment. Urine samples were collected from −2 to 0 h predose and from 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 h after the start of infusion for each treatment.
For part B, blood samples were collected immediately before (within 15 min of) the start of infusion and after the start of infusion at 20, 40, 60, 65, and 75 min and at 1.5, 2, 3, 4, 6, 8, 12, 18, and 24 h (before the first day 2 study drug administration) on day 1. Additional samples were collected on day 9 predose, immediately before (within 15 min of) the start of infusion for each dose on that day. On day 10, blood was collected immediately before (within 15 min of) the start of infusion and after the start of infusion at 20, 40, 60, 65, and 75 min and at 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 36, and 48 h. Urine samples were collected on day 1 from −2 to 0 h predose and from 0 to 2, 2 to 4, 4 to 8, 8 to 12, and 12 to 24 h after the start of day 1 infusion (and before the first day 2 study drug administration) and on day 10 from −2 to 0 h predose and from 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 h after the start of infusion.
(ii) Plasma and urine concentrations.
Ceftaroline, ceftaroline fosamil, ceftaroline M-1, and avibactam concentrations in plasma and urine were measured using validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) methods. After plasma samples were mixed with internal standard spiking solution, methanol was added to precipitate plasma protein and the supernatant was evaporated to dryness. The analytes (ceftaroline fosamil, ceftaroline, ceftaroline M-1, and avibactam) and their internal standards ([2H3] ceftaroline fosamil, [2H3] ceftaroline, [2H3] ceftaroline M-1, and [13C5, 15N] avibactam) in the reconstituted sample were separated by an Atlantis dC18 column (150 by 2.1 mm, 5-μm particle size) and detected by electrospray ionization (ESI) mass spectrometry with multiple-reaction monitoring (MRM) of positive and negative ions. The MRM in positive mode used precursor → product ions of m/z 685.0 → 208.0, m/z 605.0 → 209.0, m/z 623.1 → 209.0, m/z 688.0 → 211.0, m/z 608.1 → 212.0, and m/z 626.1 → 212.0 to monitor ceftaroline fosamil, ceftaroline, and ceftaroline M-1 and their internal standards, [2H3] ceftaroline fosamil, [2H3] ceftaroline, and [2H3] ceftaroline M-1, respectively. The protonated molecular ions of ceftaroline fosamil, ceftaroline, and ceftaroline M-1 and their corresponding internal standards were the precursor ions for the MRM mode. The MRM in negative mode used precursor → product ions of m/z 264.0 → 95.8 and 270.0 → 95.8 to monitor avibactam and [13C5, 15N] avibactam, respectively. The deprotonated molecular ions of avibactam free acid and [13C5, 15N] avibactam were the precursor ions for the MRM mode. A 3-day validation showed that the method was linear (r2 > 0.99) over the concentration range of 50 to 20,000 ng/ml for ceftaroline fosamil, ceftaroline, ceftaroline M-1, and avibactam. The lower limit of quantification (LLOQ) for all analytes was 50 ng/ml in 25 μl of human plasma with sodium fluoride-potassium oxalate as an anticoagulant. No significant interference was observed in human blank plasma for any of the analytes. The precision (percent coefficient of variation) and accuracy (percent bias) of ceftaroline fosamil plasma standards were within 4.4% and ±2.7%, respectively. The precision and accuracy of ceftaroline plasma standards were within 3.6% and ±3.2%, respectively. The precision and accuracy of ceftaroline M-1 plasma standards were within 4.6% and ±2.2%, respectively. The precision and accuracy of avibactam plasma standards were within 5.8% and ±1.9%, respectively.
After the addition of [2H3] ceftaroline fosamil/[2H3] ceftaroline/[2H3] ceftaroline M-1 and [13C5, 15N] avibactam internal standards to urine samples, the samples were diluted with 100 mM ammonium formate-water methanol-isopropyl alcohol. The analytes and their internal standards in the diluted sample were separated by an Atlantis dC18 column (150 by 2.1 mm, 5-μm particle size) and detected by ESI mass spectrometry with MRM of positive and negative ions as described above for plasma samples. A 3-day validation showed that the method was linear (r2 > 0.99) over the concentration range of 0.5 to 50 μg/ml for ceftaroline fosamil, ceftaroline, ceftaroline M-1, and avibactam. The LLOQ for all analytes was 0.5 μg/ml in 50 μl of human urine. No significant interference was observed in human blank urine for any of the analytes. The precision and accuracy of ceftaroline fosamil urine standards were within 3.9% and ±8.9%, respectively. The precision and accuracy of ceftaroline urine standards were within 2.3% and ±5.0%, respectively. The precision and accuracy of ceftaroline M-1 urine standards were within 3.0% and ±2.2%, respectively. The precision and accuracy of avibactam urine standards were within 4.0% and ±1.6%, respectively.
(iii) Pharmacokinetic parameters.
Principal parameters describing the pharmacokinetics of ceftaroline, ceftaroline fosamil, ceftaroline M-1, and avibactam were derived from plasma and urine concentrations using noncompartmental analysis with the software program WinNonlin (version 5.2.1; Pharsight Corp., Mountain View, CA). Concentrations below the limit of quantification were treated as 0 for all pharmacokinetic calculations. The actual sampling times were used in the calculations of pharmacokinetic parameters in this study.
Safety analysis.
Safety assessments, including adverse events (AEs), clinical laboratory measures, vital sign values, ECG parameters, and physical examination findings, were performed throughout the study. Treatment-emergent adverse events (TEAEs) included all AEs that occurred after administration of the first dose of the study drug up to 30 days following the last dose of the study drug. All TEAEs were evaluated by the investigator for severity and relationship to the study drug.
Statistical methods.
This was an exploratory study and was not powered for statistical analysis. Descriptive statistics were calculated for pharmacokinetic parameter estimates. In part A, pharmacokinetic parameters for ceftaroline, ceftaroline fosamil, and ceftaroline M-1 were compared by analysis of variance (ANOVA) using SAS version 9.1.3 (or newer) on a UNIX operating system. A general linear model with sequence, subject within sequence, treatment, and period as factors was used as the basis for the analysis. The pharmacokinetic parameters for ceftaroline, ceftaroline fosamil, and ceftaroline M-1 following administration of ceftaroline fosamil concomitantly with avibactam (test) were compared with the pharmacokinetic parameters for these analytes following administration of ceftaroline fosamil alone (reference). In addition, the pharmacokinetic parameters for avibactam following administration of avibactam concomitantly with ceftaroline fosamil (test) were compared with the pharmacokinetic parameters for avibactam following administration of avibactam alone (reference). Statistical inference was based on log-transformed values for the maximum plasma drug concentration (Cmax) and area under the plasma concentration-time curve (AUC) parameters. Two-sided 90% confidence intervals for the ratio of geometric means of Cmax and AUC between the test and reference treatments were constructed. Times of maximum plasma drug concentration (Tmax) for test and reference were compared using the Wilcoxon signed-rank test. In part B, descriptive statistics were provided for all pharmacokinetic parameters of ceftaroline, ceftaroline fosamil, ceftaroline M-1, and avibactam.
RESULTS
Study population.
Twelve subjects (6 males, 6 females) were enrolled in part A and completed the study. The subject mean age (± standard deviation [SD]) was 29.3 ± 7.2 years (range = 20 to 45 years), and mean weight and BMI were 70.6 ± 10.2 kg and 26.1 ± 2.7 kg/m2, respectively. The majority (91.7%) were Caucasian. Forty-eight subjects (24 males, 24 females) were enrolled in part B and are included in the safety evaluation; 46 completed the study. In part B, the subject mean age (± SD) was 30.7 ± 6.2 years (range = 20 to 45 years). Mean weight and BMI were 71.8 ± 9.5 kg and 25.8 ± 2.6 kg/m2, respectively. Subjects were again mainly (85.4%) Caucasian. Demographics were similar across individual treatment groups within part B.
Pharmacokinetic analysis. (i) Part A—single-dose administration.
The mean ceftaroline plasma concentration-time profiles following a single 1-h IV infusion of 600 mg ceftaroline fosamil or 600/600 mg ceftaroline fosamil/avibactam were comparable (Fig. 1A). Similarly, the mean avibactam plasma concentration-time profiles following a single 1-h IV infusion of 600 mg avibactam or 600/600 mg ceftaroline fosamil/avibactam were comparable (Fig. 1B).
Fig 1.
Mean (± SD) ceftaroline plasma concentration-time profile (n = 12) following a single 1-h intravenous infusion of ceftaroline fosamil administered alone or coadministered with avibactam (A) and mean (± SD) avibactam plasma concentration-time profile (n = 12) following a single 1-h intravenous infusion of avibactam administered alone or coadministered with ceftaroline fosamil (B) in healthy adult subjects.
Pharmacokinetic parameters for ceftaroline and avibactam following single-dose administration alone or in combination are summarized in Tables 1 and 2, respectively. Pharmacokinetic parameters for ceftaroline were unchanged when ceftaroline fosamil was coadministered with avibactam compared with ceftaroline fosamil administered alone (Table 3). Pharmacokinetic parameters of avibactam also were unchanged when it was coadministered with ceftaroline fosamil or administered alone (Table 3). No effect was observed on the formation of ceftaroline M-1 when ceftaroline fosamil was coadministered with avibactam. In addition, the pharmacokinetic parameters for ceftaroline fosamil were similar with and without the coadministration of avibactam, indicating that the conversions of prodrug to active ceftaroline occurred at similar rates.
Table 1.
Pharmacokinetic parameters for ceftaroline following a single 1-h intravenous infusion of ceftaroline fosamil administered alone or coadministered with avibactam in healthy adult subjects
| Parametera | Value forb: |
|
|---|---|---|
| Ceftaroline fosamil 600 mg (n = 11)c | Ceftaroline fosamil/avibactam 600/600 mg (mean ± SD) (n = 12) | |
| Cmax, μg/ml | 27.94 ± 4.34 | 26.88 ± 3.24 |
| AUC0-∞, μg · h/ml | 62.17 ± 8.51 | 60.48 ± 6.46 |
| Median (minimum–maximum) Tmax, h | 0.98 (0.97–1.08) | 0.98 (0.97–1.08) |
| t1/2, h | 2.48 ± 0.30 | 2.51 ± 0.40 |
| Vss, ml | 19,715.8 ± 3,323.2 | 19,809.3 ± 2,918.7 |
| CL, ml/h | 8,671.0 ± 1,204.3 | 8,853.9 ± 961.0 |
| CLr, ml/h | 4,920.0 ± 983.7 | 5,249.8 ± 1,453.8 |
| % dose recovered in urine | 57.03 ± 9.94 | 59.06 ± 13.71 |
AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; CL = apparent total body clearance of drug; CLr = renal clearance of drug; Cmax = maximum plasma drug concentration; Tmax = time of maximum plasma drug concentration; t1/2 = terminal elimination half-life; Vss = apparent volume of distribution at steady state.
Values represent means ± standard deviations except where otherwise indicated.
One subject was excluded because of an aberrant PK profile, possibly resulting from extravascular dosing.
Table 2.
Pharmacokinetic parameters for avibactam following a single 1-h intravenous infusion administered alone or coadministered with ceftaroline fosamil in healthy adult subjects
| Parametera | Value forb: |
|
|---|---|---|
| Avibactam 600 mg (n = 12) | Ceftaroline fosamil/avibactam 600/600 mg (n = 12) | |
| Cmax, μg/ml | 29.71 ± 3.85 | 29.24 ± 3.41 |
| AUC0-∞, μg · h/ml | 52.31 ± 6.03 | 51.77 ± 6.87 |
| Median (minimum–maximum) Tmax, h | 0.97 (0.97–1.08) | 0.98 (0.97–1.083) |
| t1/2, h | 1.68 ± 0.44 | 1.67 ± 0.33 |
| Vss, ml | 16,785.6 ± 2,296.9 | 16,921.5 ± 2,431.9 |
| CL, ml/h | 11,609.4 ± 1,325.8 | 11,780.2 ± 1,593.1 |
| CLr, ml/h | 10,673.9 ± 2,604.1 | 10,276.9 ± 3,070.6 |
| % dose recovered in urine | 93.02 ± 26.96 | 86.78 ± 19.79 |
AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; CL = apparent total body clearance of drug; CLr = renal clearance of drug; Cmax = maximum plasma drug concentration; Tmax = time of maximum plasma drug concentration; T1/2 = terminal elimination half-life; Vss = apparent volume of distribution at steady state.
Values represent means ± standard deviations except where otherwise indicated.
Table 3.
Comparison of pharmacokinetic parameters for ceftaroline and avibactam administered alone or coadministered following a single 1-h intravenous infusion in healthy adult subjects
| Parametera | Ceftaroline |
Avibactam |
||
|---|---|---|---|---|
| Ratio of geometric meansb | 90% CI (P) | Ratio of geometric meansb | 90% CI (P) | |
| Cmax, ng/ml | 0.952 | 0.89, 1.02 (0.196) | 0.986 | 0.95, 1.02 (0.511) |
| AUC0-t, ng · h/ml | 0.976 | 0.94, 1.01 (0.242) | 0.988 | 0.97, 1.01 (0.227) |
| AUC0-∞, ng · h/ml | 0.976 | 0.94, 1.01 (0.250) | 0.988 | 0.97, 1.00 (0.224) |
| t1/2, h | 0.071 | −0.42, 0.47 (0.638) | −0.019 | −0.46, 0.54 (0.791) |
AUC0-t = area under the plasma concentration-time curve from time zero to time t; AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; CI = confidence interval; Cmax = maximum plasma drug concentration; t1/2 = terminal elimination half-life.
Data represent test/reference ratios where test = ceftaroline fosamil/avibactam and reference = ceftaroline fosamil or avibactam alone. t1/2 data represent differences of arithmetic means.
Nearly 60% of the ceftaroline fosamil dose was excreted in the urine as ceftaroline (Table 1). Ceftaroline fosamil was rapidly converted in plasma to ceftaroline, with concentrations of the prodrug typically measurable for only about 15 min after the end of the infusion; urinary excretion of ceftaroline fosamil was below the limit of quantification. Approximately 6% of the ceftaroline fosamil dose was excreted in the urine as ceftaroline M-1. Between 87% and 93% of avibactam administered was excreted in urine as avibactam (Table 2).
(ii) Part B—multiple-dose administration.
The mean ceftaroline and avibactam plasma concentration-time profiles following multiple daily 1-h IV infusions of ceftaroline fosamil/avibactam were comparable on days 1 and 10 for all treatment groups (Fig. 2 and 3). Steady state was achieved before day 9 for both ceftaroline and avibactam. Pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10 (Tables 4 and 5), suggesting that coadministration of ceftaroline fosamil and avibactam for 10 days did not impact pharmacokinetic parameters of either drug.
Fig 2.
Mean (± SD) ceftaroline (CPT) plasma concentration-time profile on days 1 and 10 following daily 1-h intravenous infusions of ceftaroline fosamil/avibactam (AVI) at 600/600 mg q12h (A), 400/400 mg q8h (B), 900/900 mg q12h (C), and 600/600 mg q8h (D) in healthy adult subjects.
Fig 3.
Mean (± SD) avibactam (AVI) plasma concentration-time profile on days 1 and 10 following daily 1-h intravenous infusions of ceftaroline fosamil/avibactam at 600/600 mg q12h (A), 400/400 mg q8h (B), 900/900 mg q12h (C), and 600 mg/600 mg q8h (D) in healthy adult subjects.
Table 4.
Pharmacokinetic parameters for ceftaroline on days 1 and 10 following daily 1-h intravenous infusions of ceftaroline fosamil/avibactam in healthy adult subjects
| Parametera | Value for ceftaroline fosamil/avibactam at indicated dosesb |
|||||||
|---|---|---|---|---|---|---|---|---|
| 600/600 mg q12h |
400/400 mg q8h |
900/900 mg q12h |
600/600 mg q8h |
|||||
| Day 1 (n = 9) | Day 10 (n = 8c) | Day 1 (n = 9) | Day 10 (n = 9) | Day 1 (n = 9) | Day 10 (n = 9) | Day 1 (n = 9) | Day 10 (n = 8c) | |
| Cmax, μg/ml | 28.84 ± 9.32 | 31.03 ± 7.50 | 19.09 ± 4.97 | 19.21 ± 3.73 | 48.39 ± 10.13 | 47.52 ± 7.30 | 27.30 ± 4.28 | 29.44 ± 4.82 |
| AUC0-τ, μg · h/mld | NA | 65.45 ± 12.46 | NA | 43.62 ± 4.14 | NA | 104.89 ± 16.48 | NA | 65.72 ± 7.59 |
| AUC0-∞, μg · h/ml | 59.61 ± 12.50 | NA | 42.65 ± 3.74 | NA | 100.87 ± 15.87 | NA | 62.01 ± 7.78 | NA |
| Median (minimum–maximum) Tmax, h | 0.98 (0.98–1.08) | 0.98 (0.72–1.08) | 0.98 (0.97–1.00) | 0.98 (0.67–1.08) | 0.98 (0.98–1.08) | 0.98 (0.67–1.08) | 1.0 (0.98–1.05) | 0.98 (0.98–1.08) |
| t1/2, h | 2.54 ± 0.29 | 2.81 ± 0.39 | 2.33 ± 0.31 | 2.48 ± 0.38 | 2.49 ± 0.22 | 2.46 ± 0.30 | 2.48 ± 0.33 | 2.45 ± 0.55 |
| Vss, ml | 21,022.1 ± 5,759.9 | 20,386.0 ± 4,866.6 | 18,865.1 ± 2,783.6 | 18,432.9 ± 2,748.5 | 16,934.3 ± 3,306.7 | 17,240.6 ± 2,789.1 | 19,795.2 ± 3,515.0 | 18,379.0 ± 2,856.6 |
| CL, ml/h | 9,241.3 ± 1,902.3 | 8,100.7 ± 1,536.1 | 8,329.6 ± 630.9 | 7,539.7 ± 626.6 | 8,040.3 ± 1,168.4 | 7,550.4 ± 1,084.7 | 8,654.4 ± 1,001.3 | 7,532.7 ± 865.6 |
| CLr, ml/h | 6,454.2 ± 1,492.8 | 5,461.8 ± 902.4 | 4,582.3 ± 555.1 | 4,829.6 ± 896.1 | 4,138.9 ± 883.3 | 3,961.3 ± 668.5 | 4,074.4 ± 616.6 | 3,846.9 ± 622.8 |
| % dose recovered in urine | 70.78 ± 16.29 | 68.48 ± 12.78 | 55.23 ± 7.56 | 63.80 ± 8.42 | 51.51 ± 8.75 | 52.46 ± 4.38 | 47.00 ± 4.39 | 50.86 ± 3.31 |
AUC0-τ = area under the plasma concentration-time curve during the dosing interval, τ, at steady state; AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; CL = apparent total body clearance of drug; CLr = renal clearance of drug; Cmax = maximum plasma drug concentration; NA = not applicable; Tmax = time of maximum plasma drug concentration; t1/2 = terminal elimination half-life; Vss = apparent volume of distribution at steady state; q8h = every 8 h; q12h = every 12 h.
Values represent means ± standard deviations except where otherwise indicated.
One subject in the ceftaroline fosamil/avibactam 600/600 mg q12h group and one in the 600/600 mg q8h group withdrew from the study because of adverse events.
τ = 12 h for ceftaroline fosamil/avibactam 600/600 mg q12h and 900/900 mg q12h; τ = 8 h for ceftaroline fosamil/avibactam 400/400 mg q8h and 600/600 mg q8h.
Table 5.
Pharmacokinetic parameters for avibactam on days 1 and 10 following daily 1-h intravenous infusions of ceftaroline fosamil/avibactam in healthy adult subjects
| Parametera | Value for ceftaroline fosamil/avibactam at indicated dosesb |
|||||||
|---|---|---|---|---|---|---|---|---|
| 600/600 mg q12h |
400/400 mg q8h |
900/900 mg q12h |
600/600 mg q8h |
|||||
| Day 1 (n = 9) | Day 10 (n = 8c) | Day 1 (n = 9) | Day 10 (n = 9) | Day 1 (n = 9) | Day 10 (n = 9) | Day 1 (n = 9) | Day 10 (n = 8c) | |
| Cmax, μg/ml | 30.20 ± 8.03 | 31.88 ± 6.87 | 18.48 ± 1.54 | 18.83 ± 2.38 | 48.81 ± 8.69 | 49.81 ± 7.91 | 29.95 ± 4.21 | 31.53 ± 4.69 |
| AUC0-τ, μg · h/mld | NA | 51.96 ± 6.50 | NA | 34.15 ± 3.75 | NA | 87.88 ± 13.66 | NA | 56.75 ± 6.79 |
| AUC0-∞, μg · h/ml | 50.13 ± 7.44 | NA | 34.17 ± 3.77 | NA | 83.84 ± 13.34 | NA | 53.03 ± 6.16 | NA |
| Median (minimum–maximum) Tmax, h | 0.98 (0.72–1.08) | 0.98 (0.72–1.00) | 0.98 (0.97–1.00) | 0.98 (0.98–1.08) | 0.98 (0.98–1.08) | 0.98 (0.67–1.08) | 1.00 (0.98–1.05) | 0.98 (0.98–1.08) |
| t1/2, h | 1.73 ± 0.24 | 1.69 ± 0.29 | 1.72 ± 0.29 | 1.74 ± 0.29 | 1.75 ± 0.31 | 1.82 ± 0.40 | 1.68 ± 0.17 | 1.81 ± 0.37 |
| Vss, ml | 18,539.3 ± 4,924.0 | 17,846.6 ± 4,711.5 | 17,869.2 ± 2,341.9 | 17,993.8 ± 2,792.7 | 15,415.3 ± 2,645.2 | 15,470.8 ± 2,573.5 | 17,158.9 ± 2,823.6 | 16,522.0 ± 3,156.7 |
| CL, ml/h | 12,216.2 ± 1,873.6 | 11,630.0 ± 1,379.5 | 11,833.2 ± 1,297.4 | 11,514.8 ± 1,383.0 | 10,984.9 ± 1,788.8 | 10,381.5 ± 1,507.2 | 11,431.3 ± 1,136.1 | 10,377.9 ± 1,201.9 |
| CLr, ml/h | 12,190.7 ± 2,948.4 | 11,559.9 ± 1,943.6 | 9031.0 ± 1,416.4 | 9982.1 ± 1,676.8 | 9226.4 ± 2,115.9 | 8973.5 ± 1,519.8 | 9206.4 ± 1,570.4 | 8350.4 ± 1,309.0 |
| % dose recovered in urine | 99.73 ± 19.91 | 99.70 ± 13.92 | 76.17 ± 6.94 | 87.49 ± 16.17 | 83.81 ± 11.48 | 86.74 ± 9.82 | 80.32 ± 9.06 | 80.27 ± 5.02 |
AUC0-τ = area under the plasma concentration-time curve during the dosing interval, τ, at steady state; AUC0-∞ = area under the plasma concentration-time curve from time zero to infinity; CL = apparent total body clearance of drug; CLr = renal clearance of drug; Cmax = maximum plasma drug concentration; NA = not applicable; Tmax = time of maximum plasma drug concentration; t1/2 = terminal elimination half-life; Vss = apparent volume of distribution at steady state; q8h = every 8 h; q12h = every 12 h.
Values represent means ± standard deviations except where otherwise indicated.
One patient in the ceftaroline fosamil/avibactam 600/600 mg q12h group and one patient in the 600/600 mg q8h group withdrew from the study because of adverse events.
τ = 12 h for ceftaroline fosamil/avibactam 600/600 mg q12h and 900/900 mg q12h; τ = 8 h for ceftaroline fosamil/avibactam 400/400 mg q8h and 600/600 mg q8h.
No appreciable accumulation was detected for either ceftaroline or avibactam (ratio of day 10 to day 1 area under the curve from time zero to 24 h [AUC0–24]: ceftaroline, 0.93 to 1.41; avibactam, 0.80 to 1.43) when ceftaroline fosamil/avibactam was administered in a q8h or q12h regimen for 10 days. In addition, there was no appreciable accumulation of ceftaroline fosamil or ceftaroline M-1. The mean ratios of day 10 to day 1 AUC0–24 were 0.95 ± 0.23 to 1.56 ± 1.29 for ceftaroline fosamil and 1.14 ± 0.25 to 1.39 ± 0.12 for ceftaroline M-1.
Between 47% and 71% of the ceftaroline fosamil dose was excreted in urine as ceftaroline, and the percentages of the dose recovered in urine were similar on days 1 and 10 for each treatment group. Urinary excretion of ceftaroline fosamil was below the limit of quantification. Approximately 7% of the ceftaroline fosamil dose was excreted in the urine as ceftaroline M-1 on day 1 and 8% on day 10. Between 76% and 100% of avibactam was excreted in urine as avibactam, and the percentages of the dose recovered in urine were similar on days 1 and 10 for each treatment group.
Safety and tolerability.
Infusions of ceftaroline fosamil, avibactam, and ceftaroline fosamil/avibactam were well tolerated. No serious AEs or deaths occurred during the study. The majority of TEAEs were mild in severity, with only 1 TEAE and 5 TEAEs in parts A and B, respectively, being categorized as moderate. Twelve TEAEs were reported by 7 of 12 (58.3%) subjects in part A, with the most common being headache (reported by 4 subjects). No substantial differences in the number or type of TEAEs were observed for ceftaroline fosamil and avibactam when either was administered alone or coadministered. Of the 12 TEAEs, 7 were considered related to treatment and are detailed in Table 6.
Table 6.
Treatment-emergent adverse events in part A considered to be related to study drug
| Adverse event (system organ class) |
n (%) of events (12 subjects) for study drug dose |
||
|---|---|---|---|
| Ceftaroline fosamil 600 mg | Avibactam 600 mg | Ceftaroline fosamil/avibactam 600/600 mg | |
| At least 1 related TEAEa | 1 (8.3) | 2 (16.7) | 3 (25) |
| Gastrointestinal system disorders | 0 | 0 | 2 (16.7) |
| Diarrhea | 1 (8.3) | ||
| Dry mouth | 1 (8.3) | ||
| General disorders and administration-site condition | 1 (8.3) | 0 | 0 |
| Feeling hot | 1 (8.3) | ||
| Nervous system disorders | 0 | 2 (16.7) | 1 (8.3) |
| Headache | 1 (8.3) | 1 (8.3) | |
| Dizziness | 1 (8.3) | ||
| Tremor | 1 (8.3) | ||
TEAE, treatment-emergent adverse event.
In part B, 307 TEAEs were reported by 46 of 48 (95.8%) subjects. More than 94% of subjects receiving ceftaroline fosamil/avibactam and 100% of those receiving saline placebo had at least 1 TEAE. In all groups, including the saline placebo group, the most common TEAE represented mild infusion-site reactions, including infusion-site pain, erythema, edema, induration, and warmth. Of the 307 TEAEs in part B, 176 (57.3%) were categorized as related to treatment. A greater incidence of related TEAEs of infusion-site reactions, headache, rash (generalized), and pruritus (generalized) was observed in the treatment groups receiving ceftaroline fosamil/avibactam in 1,800/1,800-mg daily doses compared to those receiving 1,200/1,200-mg daily doses. Table 7 presents the per-subject incidence of related TEAEs that occurred in two or more subjects by treatment group and summarizes the individual related TEAEs, counting each one only once for a given subject.
Table 7.
Treatment-emergent adverse events in part B considered to be related to study drug that occurred in more than 1 subject
| Adverse event (system organ class) |
n (%) of events for study drug dose |
|||||
|---|---|---|---|---|---|---|
| Ceftaroline fosamil/avibactam |
Placebo |
|||||
| 600/600 mg q12h (9 subjects) | 400/400 mg q8h (9 subjects) | 900/900 mg q12h (9 subjects) | 600/600 mg q8h (9 subjects) | q12h (6 subjects) | q8h (6 subjects) | |
| At least 1 related TEAEa | 6 (66.7) | 7 (77.8) | 7 (77.8) | 9 (100) | 3 (50) | 3 (50) |
| Gastrointestinal disorders | ||||||
| Nausea | 1 (11.1) | 2 (22.2) | 1 (11.1) | 1 (16.7) | ||
| Diarrhea | 1 (11.1) | 3 (33.3) | 1 (11.1) | 1 (16.7) | ||
| Vomiting | 1 (11.1) | 1 (11.1) | 1 (11.1) | |||
| General disorders and administration-site condition | ||||||
| Infusion-site erythema | 4 (44.4) | 5 (55.6) | 7 (77.8) | 8 (88.9) | 3 (50) | 2 (33.3) |
| Infusion-site induration | 4 (44.4) | 3 (33.3) | 1 (11.1) | 1 (16.7) | ||
| Infusion-site edema | 1 (11.1) | 5 (55.6) | 3 (33.3) | |||
| Infusion-site pain | 2 (22.2) | 2 (22.2) | 4 (44.4) | 5 (55.6) | 2 (33.3) | |
| Pain | 2 (22.2) | 1 (11.1) | ||||
| Chest discomfort | 1 (11.1) | 1 (11.1) | 1 (11.1) | |||
| Infusion-site warmth | 1 (11.1) | 1 (11.1) | ||||
| Feeling hot | 1 (11.1) | 2 (22.2) | ||||
| Pyrexia | 1 (11.1) | 1 (11.1) | ||||
| Investigation | ||||||
| Neutrophil count decreased | 1 (11.1) | 1 (16.7) | ||||
| Musculoskeletal and connective-tissue disorders | ||||||
| Arthralgia | 1 (11.1) | 1 (11.1) | ||||
| Nervous system disorders | ||||||
| Headache | 3 (33.3) | 2 (22.2) | 1 (16.7) | |||
| Respiratory, thoracic, and mediastinal disorders | ||||||
| Oropharyngeal pain | 1 (11.1) | 1 (11.1) | ||||
| Skin and subcutaneous tissue disorders | ||||||
| Pruritus (generalized) | 1 (11.1) | 3 (33.3) | 2 (22.2) | |||
| Rash (generalized) | 1 (11.1) | 2 (22.2) | 3 (33.3) | 3 (33.3) | ||
| Pruritus | 2 (22.2) | 1 (11.1) | ||||
TEAE, treatment-emergent adverse event.
There were no discontinuations because of a TEAE in part A. There were 2 (5.6%) discontinuations in part B after 9 days of ceftaroline fosamil/avibactam administration because of TEAEs. One subject received ceftaroline fosamil/avibactam at 600/600 mg q12h, and the other received ceftaroline fosamil/avibactam at 600/600 mg q8h. The subject on the q12h regimen experienced a mild, generalized rash on day 8 and discontinued treatment with the study drug on day 9 after the morning dose. Her rash improved significantly within the first 24 to 48 h after discontinuation and resolved 6 days after stopping treatment. The subject on the q8h regimen experienced generalized rash and pruritus, diaphoresis, fever, and tachycardia on day 9, which were classified as mild to moderate, and treatment with the study drug was discontinued. His symptoms, with the exception of pruritus and rash, resolved within approximately 15 h. The pruritus and rash improved significantly within the first 24 to 48 h and resolved in approximately 4 days.
No laboratory abnormalities in part A were considered clinically significant by the investigator. There was 1 subject in part B with a low neutrophil count, which was considered clinically significant and was associated with a TEAE of “neutrophil count decreased.” No abnormal vital sign values or ECG measurements were observed in part A subjects. No abnormal ECG measurements were observed in part B subjects. Ten subjects (16.7% of subjects receiving study drug, 33% of subjects receiving placebo) in part B had abnormal vital sign values, which were not considered clinically significant by the investigator.
DISCUSSION
There were no significant differences in systemic exposure of ceftaroline or avibactam when they were administered individually or in combination. Therefore, there does not appear to be a pharmacokinetic interaction between ceftaroline fosamil and avibactam when these drugs are administered concomitantly. The prodrug ceftaroline fosamil was rapidly converted into active ceftaroline at similar rates following administration of a single dose of ceftaroline fosamil alone or in combination with a single dose of avibactam, and no effect was observed on the formation of ceftaroline M-1 when ceftaroline fosamil was coadministered with avibactam. Pharmacokinetic parameters for ceftaroline, ceftaroline M-1, and avibactam were comparable to those from previous studies (1–3, 22, 26, 27) in healthy subjects.
Coadministration of ceftaroline fosamil and avibactam for 10 days did not impact the pharmacokinetics of either drug. Following concomitant administration of multiple doses of ceftaroline fosamil and avibactam as a 1-hour IV infusion either q8h or q12h for 10 days, steady state was achieved prior to day 9, and no appreciable accumulation occurred when study drugs were administered at total daily doses of up to 1,800 mg of each compound in q8h or q12h regimens. These observations are consistent with the relatively short half-lives of both drugs. The pharmacokinetic parameters for ceftaroline and avibactam were similar on days 1 and 10 in this study. In addition, the pharmacokinetic parameters for ceftaroline were similar to those seen in a previous multiple-dose study (3) in healthy subjects.
No serious AEs were reported in the study. There were no discontinuations due to TEAEs in part A. Two (5.6%) subjects (one in the 600/600-mg q12h treatment group and one in the 600/600-mg q8h treatment group) who received study drug in part B withdrew because of TEAEs representing rash. All TEAEs were considered mild to moderate in severity. Headache was the most frequently reported TEAE in part A. In part B, the most frequently reported TEAEs in the active treatment and saline placebo groups were infusion-site reactions. Although the numbers of subjects in each treatment group were small, a possible dose response was observed, with a greater incidence of related TEAEs of infusion-site reactions, headache, rash (generalized), and pruritus (generalized) being observed in the groups receiving ceftaroline fosamil/avibactam 1,800/1,800-mg daily doses than in those receiving 1,200/1,200-mg daily doses. There were no clinically significant changes in ECG measurements. No laboratory abnormalities in part A were considered clinically significant by the investigator. There was 1 subject in part B with a low neutrophil count that was considered clinically significant and was associated with a TEAE. Although a possible dose response was observed for infusion-site reactions, headache, rash (generalized), and pruritus (generalized) in subjects receiving 10 days of ceftaroline fosamil/avibactam, ceftaroline fosamil, and avibactam were generally safe and well tolerated when administered in combination for 10 days either q12h or q8h at total daily doses of up to 1,800 mg of each compound in healthy subjects.
These data provide strong evidence in support of the coadministration of ceftaroline fosamil with avibactam. In addition, based on preclinical data, the doses used in the present study are expected to achieve exposures that have clinical utility for treating resistant Gram-negative organisms. For example, Wiskirchen et al. (15) demonstrated in vivo using a neutropenic mouse thigh infection model that doses of ceftaroline fosamil/avibactam given to simulate free-drug exposures of ceftaroline and avibactam in humans following administration of 600/600 mg ceftaroline fosamil/avibactam q8h were efficacious against ESBL- and KPC-producing Enterobacteriaceae isolates, with MICs of up to 1 mg/liter.
Overall, the pharmacokinetic and safety profiles of the ceftaroline fosamil/avibactam combination, along with its antimicrobial activity in vitro and in preclinical models of infection, suggest that it has the potential to be an important addition to the limited antimicrobial treatment options available, providing broad-spectrum coverage that includes resistant Gram-negative organisms.
ACKNOWLEDGMENTS
This study was supported by Forest Laboratories, Inc. Forest Laboratories, Inc., was involved in the design, collection, analysis, interpretation of data, and decision to present these results.
Scientific Therapeutics Information, Inc., provided editorial assistance, which was funded by Forest Research Institute, Inc.
Footnotes
Published ahead of print 7 January 2013
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