As with other beta-lactam antimicrobial agents, the time that unbound plasma concentration of ceftaroline exceeds the minimum inhibitory concentration (MIC) of the infecting organism has been shown to best correlate with efficacy in a neutropenic murine thigh infection model with S. aureus and S. pneumoniae.
Exposure-response analysis of Phase 2/3 ABSSSI trials supports the recommended dosage regimen of Teflaro 600 mg every 12 hours by IV infusion over 1 hour. For Phase 3 CABP trials, an exposure-response relationship could not be identified due to the limited range of ceftaroline exposures in the majority of patients.
In a randomized, positive- and placebo-controlled crossover thorough QTc study, 54 healthy subjects were each administered a single dose of Teflaro 1500 mg, placebo, and a positive control by IV infusion over 1 hour. At the 1500 mg dose of Teflaro, no significant effect on QTc interval was detected at peak plasma concentration or at any other time.
The mean pharmacokinetic parameters of ceftaroline in healthy adults (n=6) with normal renal function after single and multiple 1-hour IV infusions of 600 mg ceftaroline fosamil administered every 12 hours are summarized in Table 8. Pharmacokinetic parameters were similar for single and multiple dose administration.
Table 8: Mean (Standard Deviation) Pharmacokinetic Parameters of Ceftaroline IV in Healthy Adults
||Single 600 mg Dose Administered as a 1-Hour Infusion (n=6)
||Multiple 600 mg Doses Administered Every 12 Hours as 1-Hour Infusions for 14 Days (n=6)
|AUC (mcg•h/mL) b
|a Reported as median (range)
b AUC0-∞, for single-dose administration; AUC0-tau, for multiple-dose administration; Cmax, maximum observed concentration; Tmax, time of Cmax; AUC0-∞, area under concentration-time curve from time 0 to infinity; AUC0-tau, area under concentration-time curve over dosing interval (0-12 hours); T1/2, terminal elimination half-life; CL, plasma clearance
The Cmax and AUC of ceftaroline increase approximately in proportion to dose within the single dose range of 50 to 1000 mg. No appreciable accumulation of ceftaroline is observed following multiple IV infusions of 600 mg administered every 12 hours for up to 14 days in healthy adults with normal renal function.
The systemic exposure (AUC), T1/2, and clearance of ceftaroline were similar following administration of 600 mg ceftaroline fosamil in a volume of 50 mL to healthy subjects every 8 hours for 5 days as a 5-minute or 60-minute infusion, and the Tmax of ceftaroline occurred about 5 minutes after the end of the ceftaroline fosamil infusion for both infusion durations. The mean (SD) Cmax of ceftaroline was 32.5 (4.82) mcg/mL for the 5-minute infusion duration (n=11) and 17.4 (3.87) mcg/mL for the 60-minute infusion duration (n=12).
The average binding of ceftaroline to human plasma proteins is approximately 20% and decreases slightly with increasing concentrations over 1-50 mcg/mL (14.5-28.0%). The median (range) steady-state volume of distribution of ceftaroline in healthy adult males (n=6) following a single 600 mg IV dose of radiolabeled ceftaroline fosamil was 20.3 L (18.3-21.6 L), similar to extracellular fluid volume.
Ceftaroline fosamil is the water-soluble prodrug of the bioactive ceftaroline. Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphatase enzyme and concentrations of the prodrug are measurable in plasma primarily during IV infusion. Hydrolysis of the beta-lactam ring of ceftaroline occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1. The mean (SD) plasma ceftaroline M-1 to ceftaroline AUC0-∞ ratio following a single 600 mg IV infusion of ceftaroline fosamil in healthy adults (n=6) with normal renal function is 28% (3.1%).
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.
Ceftaroline and its metabolites are primarily eliminated by the kidneys. Following administration of a single 600 mg IV dose of radiolabeled ceftaroline fosamil to healthy male adults (n=6), approximately 88% of radioactivity was recovered in urine and 6% in feces within 48 hours. Of the radioactivity recovered in urine approximately 64% was excreted as ceftaroline and approximately 2% as ceftaroline M-1. The mean (SD) renal clearance of ceftaroline was 5.56 (0.20) L/h, suggesting that ceftaroline is predominantly eliminated by glomerular filtration.
Patients with Renal Impairment
Following administration of a single 600 mg IV dose of Teflaro, the geometric mean AUC0-∞ of ceftaroline in subjects with mild (CrCl > 50 to ≤ 80 mL/min, n=6) or moderate (CrCl > 30 to ≤ 50 mL/min, n=6) renal impairment was 19% and 52% higher, respectively, compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6). Following administration of a single 400 mg IV dose of Teflaro, the geometric mean AUC0-∞ of ceftaroline in subjects with severe (CrCl ≥ 15 to ≤30 mL/min, n=6) renal impairment was 115% higher compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6). Dosage adjustment is recommended in patients with moderate and severe renal impairment [see Dosage and Administration (2.2)].
A single 400 mg dose of Teflaro was administered to subjects with ESRD (n=6) either 4 hours prior to or 1 hour after hemodialysis (HD). The geometric mean ceftaroline AUC0-∞ following the post-HD infusion was 167% higher compared to healthy subjects with normal renal function (CrCl > 80 mL/min, n=6). The mean recovery of ceftaroline in the dialysate following a 4-hour HD session was 76.5 mg, or 21.6% of the administered dose. Dosage adjustment is recommended in patients with ESRD (defined as CrCL < 15 mL/min), including patients on HD [see Dosage and Administration (2.2)].
Patients with Hepatic Impairment
The pharmacokinetics of ceftaroline in patients with hepatic impairment have not been established. As ceftaroline does not appear to undergo significant hepatic metabolism, the systemic clearance of ceftaroline is not expected to be significantly affected by hepatic impairment.
Following administration of a single 600 mg IV dose of Teflaro to healthy elderly subjects (≥ 65 years of age, n=16), the geometric mean AUC0-∞ of ceftaroline was ~33% higher compared to healthy young adult subjects (18-45 years of age, n=16). The difference in AUC0-∞ was mainly attributable to age-related changes in renal function. Dosage adjustment for Teflaro in elderly patients should be based on renal function [see Dosage and Administration (2.2)].
The pharmacokinetics of ceftaroline were evaluated in adolescent patients (ages 12 to 17, n=7) with normal renal function following administration of a single 8 mg/kg IV dose of Teflaro (or 600 mg for subjects weighing > 75 kg). The mean plasma clearance and terminal phase volume of distribution for ceftaroline in adolescent subjects were similar to healthy adults (n=6) with normal renal function in a separate study following administration of a single 600 mg IV dose. However, the mean Cmax and AUC0-∞ for ceftaroline in adolescent subjects who received a single 8 mg/kg dose were 10% and 23% less than in healthy adult subjects who received a single 600 mg IV dose. The population pharmacokinetic analyses demonstrated that the pharmacokinetics of ceftaroline in pediatric patients from 2 months to < 18 years of age were similar to those in adult patients after accounting for weight and maturational changes. No clinically significant differences in ceftaroline AUC were predicted in patients from 12 days to 2 months postnatal age and with ≥34 weeks of gestational age compared to adults and pediatric patients 2 months of age and older when given the approved recommended dosage for each patient population [see Adverse Reactions (6), Use in Specific Populations (8.4) and Clinical Studies (14)].
Following administration of a single 600 mg IV dose of Teflaro to healthy elderly males (n=10) and females (n=6) and healthy young adult males (n=6) and females (n=10), the mean Cmax and AUC0-∞ for ceftaroline were similar between males and females, although there was a trend for higher Cmax (17%) and AUC0-∞ (6-15%) in female subjects. Population pharmacokinetic analysis did not identify any significant differences in ceftaroline AUC0-tau based on gender in Phase 2/3 patients with ABSSSI or CABP. No dose adjustment is recommended based on gender.
A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 adult ABSSSI and CABP trials. No significant differences in ceftaroline AUC0-tau was observed across White (n=35), Hispanic (n=34), and Black (n=17) race groups for ABSSSI patients. Patients enrolled in CABP trials were predominantly categorized as White (n=115); thus there were too few patients of other races to draw any conclusions. No dosage adjustment is recommended based on race.
Drug Interactions Studies
No clinical drug-drug interaction studies have been conducted with Teflaro. There is minimal potential for drug-drug interactions between Teflaro and CYP450 substrates, inhibitors, or inducers; drugs known to undergo active renal secretion; and drugs that may alter renal blood flow.
In vitro studies in human liver microsomes indicate that ceftaroline does not inhibit the major cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. In vitro studies in human hepatocytes also demonstrate that ceftaroline and its inactive open-ring metabolite are not inducers of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Therefore, Teflaro is not expected to inhibit or induce the clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner.
Population pharmacokinetic analysis did not identify any clinically relevant differences in ceftaroline exposure (Cmax and AUC0-tau) in Phase 2/3 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.
Mechanism of Action
Ceftaroline is a cephalosporin antibacterial drug with in vitro activity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal against S. aureus due to its affinity for PBP2a and against Streptococcus pneumoniae due to its affinity for PBP2x.
Ceftaroline is not active against Gram-negative bacteria producing extended spectrum beta-lactamases (ESBLs) from the TEM, SHV or CTX-M families, serine carbapenemases (such as KPC), class B metallo-beta-lactamases, or class C (AmpC cephalosporinases). Although cross-resistance may occur, some isolates resistant to other cephalosporins may be susceptible to ceftaroline.
Interaction with Other Antimicrobials
In vitro studies have not demonstrated any antagonism between ceftaroline or other commonly used antibacterial agents (e.g., vancomycin, linezolid, daptomycin, levofloxacin, azithromycin, amikacin, aztreonam, tigecycline, and meropenem).
Ceftaroline has been shown to be active against most of the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)].
Staphylococcus aureus (including methicillin-susceptible and -resistant isolates)
Community-Acquired Bacterial Pneumonia (CABP)
Staphylococcus aureus (methicillin-susceptible isolates only)
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftaroline against isolates of similar genus or organism group. However, the efficacy of ceftaroline in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Susceptibility Test Methods
For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC