Teflaro™ (ceftaroline fosamil) is indicated for the treatment of patients with the following infections caused by susceptible isolates of the designated microorganisms.
Acute Bacterial Skin and Skin Structure Infections
Teflaro is indicated for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Staphylococcus aureus (including methicillin-susceptible and -resistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.
Community-Acquired Bacterial Pneumonia
Teflaro is indicated for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilus influenzae, Klebsiella pneumoniae, Klebsiella oxytoca, and Escherichia coli.
Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of Teflaro and other antibacterial drugs, Teflaro should be used to treat only ABSSSI or CABP that are proven or strongly suspected to be caused by susceptible bacteria. Appropriate specimens for microbiological examination should be obtained in order to isolate and identify the causative pathogens and to determine their susceptibility to ceftaroline. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
2. DOSAGE AND ADMINISTRATION
Recommended Dosage
The recommended dosage of Teflaro is 600 mg administered every 12 hours by intravenous (IV) infusion over 1 hour in patients ≥ 18 years of age. The duration of therapy should be guided by the severity and site of infection and the patient's clinical and bacteriological progress.
The recommended dosage and administration by infection is described in Table 1.
Table 1: Dosage of Teflaro by Infection
| Infection |
Dosage |
Frequency |
Infusion Time
(hours) |
Recommended Duration of Total Antimicrobial Treatment |
|---|
| Acute Bacterial Skin and Skin Structure Infection (ABSSSI) |
600 mg |
Every 12 hours |
1 |
5-14 days |
| Community-Acquired Bacterial Pneumonia (CABP) |
600 mg |
Every 12 hours |
1 |
5-7 days |
Patients with Renal Impairment
Table 2: Dosage of Teflaro in Patients with Renal Impairment
| Estimated CrCla (mL/min) |
Recommended Dosage Regimen for Teflaro |
|---|
a Creatinine clearance (CrCl) estimated using the Cockcroft-Gault formula.
|
b End-stage renal disease is defined as CrCl < 15 mL/min.
|
c Teflaro is hemodialyzable; thus Teflaro should be administered after hemodialysis on hemodialysis days.
|
| > 50 |
No dosage adjustment necessary |
| > 30 to ≤ 50 |
400 mg IV (over 1 hour) every 12 hours |
| ≥ 15 to ≤ 30 |
300 mg IV (over 1 hour) every 12 hours |
End-stage renal disease,
including hemodialysisb |
200 mg IV (over 1 hour) every 12 hoursc |
Preparation of Solutions
Aseptic technique must be followed in preparing the infusion solution. The contents of Teflaro vial should be constituted with 20 mL Sterile Water for Injection, USP. The preparation of Teflaro solutions is summarized in Table 3.
Table 3: Preparation of Teflaro for Intravenous Use
Dosage Strength
(mg) |
Volume of Diluent To Be Added
(mL) |
Approximate Ceftaroline fosamil Concentration
(mg/mL) |
Amount to Be Withdrawn |
|---|
| 400 |
20 |
20 |
Total Volume |
| 600 |
20 |
30 |
Total Volume |
The constituted solution must be further diluted in 250 mL before infusion. Appropriate infusion solutions include: 0.9% Sodium Chloride Injection, USP (normal saline); 5% Dextrose Injection, USP; 2.5% Dextrose Injection, USP, and 0.45% Sodium Chloride Injection, USP; or Lactated Ringer's Injection, USP. The resulting solution should be administered over approximately 1 hour.
Constitution time is less than 2 minutes. Mix gently to constitute and check to see that the contents have dissolved completely. Parenteral drug products should be inspected visually for particulate matter prior to administration.
The color of Teflaro infusion solutions ranges from clear, light to dark yellow depending on the concentration and storage conditions. When stored as recommended, the product potency is not affected.
Studies have shown that the constituted solution in the infusion bag should be used within 6 hours when stored at room temperature or within 24 hours when stored under refrigeration at 2 to 8º C (36 to 46º F).
The compatibility of Teflaro with other drugs has not been established. Teflaro should not be mixed with or physically added to solutions containing other drugs.
3. DOSAGE FORMS AND STRENGTHS
Teflaro is supplied in single-use, clear glass vials containing either 600 mg or 400 mg of sterile ceftaroline fosamil powder.
4. CONTRAINDICATIONS
Teflaro is contraindicated in patients with known serious hypersensitivity to ceftaroline or other members of the cephalosporin class. Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.
5. WARNINGS AND PRECAUTIONS
Hypersensitivity Reactions
Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterials. Before therapy with Teflaro is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. If this product is to be given to a penicillin- or other beta-lactam-allergic patient, caution should be exercised because cross sensitivity among beta-lactam antibacterial agents has been clearly established.
If an allergic reaction to Teflaro occurs, the drug should be discontinued. Serious acute hypersensitivity (anaphylactic) reactions require emergency treatment with epinephrine and other emergency measures, that may include airway management, oxygen, intravenous fluids, antihistamines, corticosteroids, and vasopressors as clinically indicated.
Clostridium difficile-associated Diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Teflaro, and may range in severity from mild diarrhea to fatal colitis.
Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.
C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.
If CDAD is suspected or confirmed, antibacterials not directed against C. difficile should be discontinued, if possible. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated [see Adverse Reactions (6.3)].
Direct Coombs' Test Seroconversion
Seroconversion from a negative to a positive direct Coombs' test result occurred in 120/1114 (10.8%) of patients receiving Teflaro and 49/1116 (4.4%) of patients receiving comparator drugs in the four pooled Phase 3 trials.
In the pooled Phase 3 CABP trials, 51/520 (9.8%) of Teflaro-treated patients compared to 24/534 (4.5%) of ceftriaxone-treated patients seroconverted from a negative to a positive direct Coombs' test result. No adverse reactions representing hemolytic anemia were reported in any treatment group.
If anemia develops during or after treatment with Teflaro, drug-induced hemolytic anemia should be considered. Diagnostic studies including a direct Coombs' test, should be performed. If drug-induced hemolytic anemia is suspected, discontinuation of Teflaro should be considered and supportive care should be administered to the patient (i.e. transfusion) if clinically indicated.
Development of Drug-Resistant Bacteria
Prescribing Teflaro in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.
6. ADVERSE REACTIONS
The following serious events are described in greater detail in the Warnings and Precautions section
- Hypersensitivity reactions [see Warnings and Precautions (5.1)]
- Clostridium difficile-associated diarrhea [see Warnings and Precautions (5.2)]
- Direct Coombs' test seroconversion [see Warnings and Precautions (5.3)]
Adverse Reactions from Clinical Trials
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be compared directly to rates from clinical trials of another drug and may not reflect rates observed in practice.
Teflaro was evaluated in four controlled comparative Phase 3 clinical trials (two in ABSSSI and two in CABP) which included 1300 adult patients treated with Teflaro (600 mg administered by IV over 1 hour every 12h) and 1297 patients treated with comparator (vancomycin plus aztreonam or ceftriaxone) for a treatment period up to 21 days. The median age of patients treated with Teflaro was 54 years, ranging between 18 and 99 years old. Patients treated with Teflaro were predominantly male (63%) and Caucasian (82%).
Serious Adverse Events and Adverse Events Leading to Discontinuation
In the four pooled Phase 3 clinical trials, serious adverse events occurred in 98/1300 (7.5%) of patients receiving Teflaro and 100/1297 (7.7%) of patients receiving comparator drugs. The most common SAEs in both the Teflaro and comparator treatment groups were in the respiratory and infection system organ classes (SOC). Treatment discontinuation due to adverse events occurred in 35/1300 (2.7%) of patients receiving Teflaro and 48/1297 (3.7%) of patients receiving comparator drugs with the most common adverse events leading to discontinuation being hypersensitivity for both treatment groups at a rate of 0.3% in the Teflaro group and 0.5% in comparator group.
Most Common Adverse Reactions
No adverse reactions occurred in greater than 5% of patients receiving Teflaro. The most common adverse reactions occurring in > 2% of patients receiving Teflaro in the pooled phase 3 clinical trials were diarrhea, nausea, and rash.
Table 4 lists adverse reactions occurring in ≥ 2% of patients receiving Teflaro in the pooled Phase 3 clinical trials.
Table 4: Adverse Reactions Occurring in ≥ 2% of Patients Receiving Teflaro in the Pooled Phase 3 Clinical Trials
System Organ Class/
Preferred Term |
Pooled Phase 3 Clinical Trials
(four trials, two in ABSSSI and two in CABP) |
|---|
Teflaro
(N=1300) |
Pooled Comparatorsa
(N=1297) |
|---|
a Comparators included vancomycin 1 gram IV every 12h plus aztreonam 1 gram IV every 12h in the Phase 3 ABSSSI trials, and ceftriaxone 1 gram IV every 24h in the Phase 3 CABP trials.
|
| Gastrointestinal disorders |
| Diarrhea |
5 % |
3 % |
| Nausea |
4 % |
4 % |
| Constipation |
2 % |
2 % |
| Vomiting |
2 % |
2 % |
| Investigations |
| Increased transaminases |
2% |
3 % |
| Metabolism and nutrition disorders |
| Hypokalemia |
2 % |
3 % |
| Skin and subcutaneous tissue disorders |
| Rash |
3% |
2% |
| Vascular disorders |
| Phlebitis |
2% |
1% |
Other Adverse Reactions Observed During Clinical Trials of Teflaro
Following is a list of additional adverse reactions reported by the 1740 patients who received Teflaro in any clinical trial with incidences less than 2%. Events are categorized by System Organ Class.
Blood and lymphatic system disorders - Anemia, Eosinophilia, Neutropenia, Thrombocytopenia
Cardiac disorders - Bradycardia, Palpitations
Gastrointestinal disorders - Abdominal pain
General disorders and administration site conditions - Pyrexia
Hepatobiliary disorders - Hepatitis
Immune system disorders - Hypersensitivity, Anaphylaxis
Infections and infestations - Clostridium difficile colitis
Metabolism and nutrition disorders - Hyperglycemia, Hyperkalemia
Nervous system disorders - Dizziness, Convulsion
Renal and urinary disorders - Renal failure
Skin and subcutaneous tissue disorders - Urticaria
7. DRUG INTERACTIONS
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 [see Clinical Pharmacology (12.3)].
8. USE IN SPECIFIC POPULATIONS
Pregnancy
Category B
Developmental toxicity studies performed with ceftaroline fosamil in rats at IV doses up to 300 mg/kg demonstrated no maternal toxicity and no effects on the fetus. A separate toxicokinetic study showed that ceftaroline exposure in rats (based on AUC) at this dose level was approximately 8 times the exposure in humans given 600 mg every 12 hours. There were no drug-induced malformations in the offspring of rabbits given IV doses of 25, 50, and 100 mg/kg, despite maternal toxicity. Signs of maternal toxicity appeared secondary to the sensitivity of the rabbit gastrointestinal system to broad-spectrum antibacterials and included changes in fecal output in all groups and dose-related reductions in body weight gain and food consumption at ≥ 50 mg/kg; these were associated with an increase in spontaneous abortion at 50 and 100 mg/kg. The highest dose was also associated with maternal moribundity and mortality. An increased incidence of a common rabbit skeletal variation, angulated hyoid alae, was also observed at the maternally toxic doses of 50 and 100 mg/kg. A separate toxicokinetic study showed that ceftaroline exposure in rabbits (based on AUC) was approximately 0.8 times the exposure in humans given 600 mg every 12 hours at 25 mg/kg and 1.5 times the human exposure at 50 mg/kg.
Ceftaroline fosamil did not affect the postnatal development or reproductive performance of the offspring of rats given IV doses up to 450 mg/kg/day. Results from a toxicokinetic study conducted in pregnant rats with doses up to 300 mg/kg suggest that exposure was ≥ 8 times the exposure in humans given 600 mg every 12 hours.
There are no adequate and well-controlled trials in pregnant women. Teflaro should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether ceftaroline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Teflaro is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Of the 1300 patients treated with Teflaro in the Phase 3 ABSSSI and CABP trials, 397 (30.5%) were ≥ 65 years of age. The clinical cure rates in the Teflaro group (Clinically Evaluable [CE] Population) were similar in patients ≥ 65 years of age compared with patients < 65 years of age in both the ABSSSI and CABP trials.
The adverse event profiles in patients ≥ 65 years of age and in patients < 65 years of age were similar. The percentage of patients in the Teflaro group who had at least one adverse event was 52.4% in patients ≥ 65 years of age and 42.8% in patients < 65 years of age for the two indications combined.
Ceftaroline is excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group and it may be useful to monitor renal function. Elderly subjects had greater ceftaroline exposure relative to non-elderly subjects when administered the same single dose of Teflaro. However, higher exposure in elderly subjects was mainly attributed to age-related changes in renal function. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
Patients with Renal Impairment
Dosage adjustment is required in patients with moderate (CrCl > 30 to ≤ 50 mL/min) or severe (CrCl ≥ 15 to ≤ 30 mL/min) renal impairment and in patients with end-stage renal disease (ESRD – defined as CrCl < 15 mL/min), including patients on hemodialysis (HD) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].
10. OVERDOSAGE
In the event of overdose, Teflaro should be discontinued and general supportive treatment given.
Ceftaroline can be removed by hemodialysis. In subjects with ESRD administered 400 mg of Teflaro, the mean total recovery of ceftaroline in the dialysate following a 4-hour hemodialysis session started 4 hours after dosing was 76.5 mg (21.6% of the dose). However, no information is available on the use of hemodialysis to treat overdosage [see Clinical Pharmacology (12.3)].
11. DESCRIPTION
Teflaro is a sterile, semi-synthetic, broad-spectrum, prodrug antibacterial of cephalosporin class of beta-lactams (β-lactams). Chemically, the prodrug, ceftaroline fosamil monoacetate monohydrate is (6R,7R) - 7 - {(2Z) - 2 - (ethoxyimino) - 2 - [5 - (phosphonoamino) - 1,2,4 - thiadiazol - 3 - yl]acetamido} - 3 - {[4 - (1 - methylpyridin - 1 - ium - 4 - yl) - 1,3 - thiazol - 2 - yl]sulfanyl} - 8 - oxo - 5 - thia - 1 - azabicyclo[4.2.0]oct - 2 - ene - 2 - carboxylate monoacetate monohydrate. Its molecular weight is 762.75. The empirical formula is C22H21N8O8PS4.C2H4O2.H2O.
Figure 1: Chemical structure of ceftaroline fosamil
Teflaro vials contain either 600 mg or 400 mg of anhydrous ceftaroline fosamil. The powder for injection is formulated from ceftaroline fosamil monoacetate monohydrate, a pale yellowish-white to light yellow sterile powder. All references to ceftaroline activity are expressed in terms of the prodrug, ceftaroline fosamil. The powder is constituted for IV injection [see Dosage and Administration (2.3)].
Each vial of Teflaro contains ceftaroline fosamil and L-arginine, which results in a constituted solution at pH 4.8 to 6.5.
12. CLINICAL PHARMACOLOGY
Ceftaroline fosamil is the water-soluble prodrug of the bioactive ceftaroline [see Clinical Pharmacology (12.3)].
Mechanism of Action
Ceftaroline is an antibacterial drug [see Clinical Pharmacology (12.4)].
Pharmacodynamics
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.
Cardiac Electrophysiology
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.
Pharmacokinetics
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 5. Pharmacokinetic parameters were similar for single and multiple dose administration.
Table 5: Mean (Standard Deviation) Pharmacokinetic Parameters of Ceftaroline IV in Healthy Adults
| Parameter |
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) |
|---|
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
|
| Cmax (mcg/mL) |
19.0 (0.71) |
21.3 (4.10) |
| Tmax (h)a |
1.00 (0.92-1.25) |
0.92 (0.92-1.08) |
| AUC (mcg•h/mL) b |
56.8 (9.31) |
56.3 (8.90) |
| T1/2 (h) |
1.60 (0.38) |
2.66 (0.40) |
| CL (L/h) |
9.58 (1.85) |
9.60 (1.40) |
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.
Distribution
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.
Metabolism
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.
Excretion
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.
Specific Populations
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)].
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.
Geriatric Patients
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)].
Pediatric Patients
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) 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.
Gender
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.
Race
A population pharmacokinetic analysis was performed to evaluate the impact of race on the pharmacokinetics of ceftaroline using data from Phase 2/3 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
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.
Microbiology
Mode of Action
Ceftaroline is a cephalosporin 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.
Mechanisms of Resistance
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).
Cross-Resistance
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)].
Skin Infections
Gram-positive bacteria
Staphylococcus aureus (including methicillin-susceptible and -resistant isolates)
Streptococcus pyogenes
Streptococcus agalactiae
Gram-negative bacteria
Escherichia coli
Klebsiella pneumoniae
Klebsiella oxytoca
Community-Acquired Bacterial Pneumonia (CABP)
Gram-positive bacteria
Streptococcus pneumoniae
Staphylococcus aureus (methicillin-susceptible isolates only)
Gram-negative bacteria
Haemophilus influenzae
Klebsiella pneumoniae
Klebsiella oxytoca
Escherichia coli
The following in vitro data are available, but their clinical significance is unknown. Ceftaroline exhibits in vitro MICs of 1 mcg/mL or less against most (≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of Teflaro in treating clinical infections due to these bacteria have not been established in adequate and well-controlled clinical trials.
Gram-positive bacteria
Streptococcus dysgalactiae
Gram-negative bacteria
Citrobacter koseri
Citrobacter freundii
Enterobacter cloacae
Enterobacter aerogenes
Moraxella catarrhalis
Morganella morganii
Proteus mirabilis
Haemophilus parainfluenzae
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,3, (broth, and/or agar). Broth dilution MICs need to be read within 18 hours due to degradation of ceftaroline activity by 24 hours. The MIC values should be interpreted according to the criteria in Table 6.
Diffusion Techniques
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method. This procedure uses paper disks impregnated with 30 mcg of ceftaroline to test the susceptibility of bacteria to ceftaroline. The disk diffusion interpretive criteria are provided in Table 6.
Table 6: Susceptibility Interpretive Criteria for Ceftaroline
| Pathogen and Isolate Source |
Minimum Inhibitory Concentrations
(mcg/mL) |
Disk Diffusion Zone Diameter (mm) |
|---|
| S |
I |
R |
S |
I |
R |
|---|
S = susceptible, I = intermediate, R = resistant
|
NOTE: Clinical efficacy of Teflaro to treat lower respiratory infections such as community-acquired bacterial pneumonia due to MRSA has not been studied in adequate and well controlled trials (See “Clinical Trials” section 14)
|
a The current absence of resistant isolates precludes defining any results other than “Susceptible.” Isolates yielding MIC results other than “Susceptible” should be submitted to a reference laboratory for further testing.
|
b Clinical efficacy was shown for the following Enterobacteriaceae: Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.
|
| Staphylococcus aureus (includes methicillin-resistant isolates - skin isolates only) -See NOTE below |
≤ 1a |
— |
— |
≥ 24 |
— |
— |
Streptococcus agalactiae a
(skin isolates only) |
≤ 0.03 |
— |
— |
≥ 26 |
— |
— |
Streptococcus pyogenes a
(skin isolates only) |
≤ 0.015 |
— |
— |
≥ 24 |
— |
— |
| Streptococcus pneumoniae a (CABP isolates only) |
≤ 0.25 |
— |
— |
≥ 27 |
— |
— |
Haemophilus influenzae
(CABP isolates only) |
≤ 0.12 |
— |
— |
≥ 33 |
— |
— |
Enterobacteriaceae b
(CABP and skin isolates) |
≤ 0.5 |
1 |
≥ 2 |
≥ 23 |
20-22 |
≤ 19 |
A report of “Susceptible” indicates that the antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.
Quality Control
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test.1, 2, 3 Standard ceftaro
