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5th Generation Cephalosporin Antibiotics
IV broad spectrum cephalosporin antibioticUsed for acute bacterial skin and skin structure infections and community-acquired pneumoniaFirst beta-lactam approved to treat methicillin-resistant S. aureus (MRSA), vancomycin-resistant S. aureus (VRSA), vancomycin-insensitive S. aureus (VISA), and hetero-resistant vancomycin-insensitive S. aureus (hVISA)
Teflaro Intravenous Inj Pwd F/Sol: 400mg, 600mg
600 mg IV every 12 hours for 5 to 14 days. Guidelines suggest ceftaroline as an option for patients with documented or suspected MRSA infections.
400 mg IV every 8 hours or 600 mg IV every 12 hours for 5 to 14 days. Guidelines suggest ceftaroline as an option for patients with documented or suspected MRSA infections.
12 mg/kg/dose IV every 8 hours for 5 to 14 days. Guidelines suggest ceftaroline as an option for patients with documented or suspected MRSA infections.
8 mg/kg/dose IV every 8 hours for 5 to 14 days. Guidelines suggest ceftaroline as an option for patients with documented or suspected MRSA infections.
6 mg/kg/dose IV every 8 hours for 5 to 14 days. Guidelines suggest ceftaroline as an option for patients with documented or suspected MRSA infections.
600 mg IV every 12 hours for at least 5 days.  Guidelines recommend ceftaroline as part of combination therapy for hospitalized patients. FDA-approved labeling recommends a 5- to 7-day treatment course.
400 mg IV every 8 hours or 600 mg IV every 12 hours for 5 to 14 days.
12 mg/kg/dose IV every 8 hours for 5 to 14 days.
8 mg/kg/dose IV every 8 hours for 5 to 14 days.
600 mg IV every 12 hours has been used for other indications. Start within 1 hour of recognition as part of empiric multi-drug therapy. Duration of therapy is generally 7 to 10 days, but may be shorter or longer depending upon patient response, site of infection, and pathogen(s) isolated. Treatment may be narrowed with pathogen identification and/or adequate clinical response.
†Indicates off-label use
1200 mg/day IV.
weighing more than 33 kg: 1200 mg/day IV.weighing 33 kg or less: 36 mg/kg/day IV.
2 years and older weighing more than 33 kg: 1200 mg/day IV.2 years and older weighing 33 kg or less: 36 mg/kg/day IV.younger than 2 years: 24 mg/kg/day IV.
2 to 11 months: 24 mg/kg/day IV.1 month: 18 mg/kg/day IV.
Neonates at least 34 weeks gestational age and 12 days postnatal age: 18 mg/kg/day IV.Neonates at least 34 weeks gestational age and younger than 12 days postnatal age: Safety and efficacy have not been established.Neonates younger than 34 weeks gestational age: Safety and efficacy have not been established.
Ceftaroline does not appear to undergo significant hepatic metabolism; therefore, the systemic clearance is not expected to be significantly affected by hepatic impairment. Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Adult Renal Dosage Adjustment :CrCl more than 50 mL/minute: No dosage adjustment necessary.CrCl 31 to 50 mL/minute: 400 mg IV every 12 hours.CrCl 15 to 30 mL/minute: 300 mg IV every 12 hours.CrCl less than 15 mL/minute: 200 mg IV every 12 hours. Pediatric Renal Dosage Adjustment (Schwartz equation) :CrCl more than 50 mL/minute/1.73m2: No dosage adjustment necessary.CrCl 50 mL/minute/1.73m2 or less: Insufficient information to recommend a dosage regimen. Intermittent hemodialysisCeftaroline is hemodialyzable. Administer 200 mg IV every 12 hours. Administer after hemodialysis on dialysis days.
Administer by intravenous infusion.Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.Ceftaroline solution ranges from clear to dark yellow depending on concentration and storage conditions.
Preparation of InfusionAdd 20 mL of Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection to the ceftaroline 400 mg or 600 mg vial. This will yield an approximate concentration of 20 mg/mL for the 400 mg vials and 30 mg/mL for the 600 mg vials.Mix gently to constitute, then look closely to see that the contents have dissolved completely. Constitution time is less than 2 minutes.Further dilute the vials to a range of 50 mL to 250 mL before infusion. Use the same diluent used for the initial reconstitution, unless the initial diluent was Sterile Water for Injection. If Sterile Water for Injection was used for reconstitution, further dilute with either 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or Lactated Ringer's injection.Preparation of 600 mg dose in 50 mL infusion bag: withdraw 20 mL of diluent from the infusion bag and inject the entire contents of the reconstituted ceftaroline vial into the infusion bag to provide a total volume of 50 mL. The resultant concentration is approximately 12 mg/mL.Preparation of 400 mg dose in 50 mL infusion bag: withdraw 20 mL of diluent from the infusion bag and inject the entire contents of the reconstituted ceftaroline vial into the infusion bag to provide a total volume of 50 mL. The resultant concentration is approximately 8 mg/mL.Preparation of pediatric ceftaroline dose in the 50 mL infusion bag for patients weighing less than 33 kg: the amount of solution withdrawn from the reconstituted ceftaroline vials for dilution in the infusion bag will vary according to the weight and age of the patient; the infusion solution concentration should not exceed 12 mg/mL. Discard unused portion.Do not add ceftaroline to solutions containing other drugs.Storage: When stored in an infusion bag or a 50 to 100 mL Baxter Mini-Bag Plus (containing 0.9% Sodium Chloride Injection), the reconstituted, diluted solution is stable for 6 hours at room temperature or for 24 hours under refrigeration at 2 to 8 degrees C (36 to 46 degrees F). Intermittent IV InfusionFor patients 2 months of age and older, infuse IV over 5 to 60 minutes. For patients younger than 2 months of age, infuse IV over 30 to 60 minutes.Do not mix with or physically add ceftaroline to solutions containing other drugs.
Teflaro:- Store unreconstituted product at room temperature (77 degrees F), excursions of 59 to 86 degrees F permitted
Ceftaroline is contraindicated in patients with known serious hypersensitivity to ceftaroline or other cephalosporin hypersensitivity. Anaphylaxis, anaphylactoid reactions, and serious skin reactions have been reported with ceftaroline use. Cross-reactivity to other beta-lactams is possible; therefore, use with caution in patients with carbapenem hypersensitivity or penicillin hypersensitivity. If an allergic reaction occurs, ceftaroline should be discontinued.
Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including ceftaroline, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.
Ceftaroline does not treat viral infection (e.g., common cold). Prescribing in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria (antimicrobial resistance). Patients should be told to complete the full course of treatment, even if they feel better earlier.
Dosage adjustment is required for ceftaroline in adults with moderate (CrCl 31 to 50 mL/minute) or severe (CrCl 15 to 30 mL/minute) renal impairment and in patients with end-stage renal disease or renal failure (CrCl less than 15 mL/minute), including patients on dialysis. There is insufficient information to recommend a dosage regimen for pediatric patients with CrCl less than 50 mL/minute/1.73 m2. Neurological adverse reactions have been reported in patients with renal impairment who did not receive appropriate dosage adjustment. These reactions were reversible and resolved after discontinuation of ceftaroline or after hemodialysis.
Many cephalosporins have been rarely associated with a fall in prothrombin activity (hypoprothrombinemia). Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated. Cephalosporins that contain the NMTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have been particularly associated with an increased risk for bleeding. Cephalosporins should be used cautiously in patients with a preexisting coagulopathy (e.g., vitamin K deficiency), since these patients may be at a higher risk for these complications. Also, positive direct Coombs' tests have been reported in patients receiving cephalosporins, including ceftaroline. In patients receiving cephalosporins and undergoing hematologic testing, a positive Coombs' test should be considered as possibly being caused by the antibiotic. If anemia develops during or after treatment with ceftaroline, drug-induced hemolytic anemia should be considered.
No overall differences in safety or effectiveness of ceftaroline were observed between the geriatric and younger adults in clinical trials. Ceftaroline is eliminated renally. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities. According to OBRA, use of antibiotics should be limited to confirmed or suspected bacterial infections. Antibiotics are non-selective and may result in the eradication of beneficial microorganisms while promoting the emergence of undesired ones, causing secondary infections such as oral thrush, colitis, or vaginitis. Any antibiotic may cause diarrhea, nausea, vomiting, anorexia, and hypersensitivity reactions.
There are no adequate studies with cefatroline in human pregnancy that informed any drug associated risks. In developmental toxicity studies conducted in animals, no malformations or other adverse developmental effects were observed in offspring of rats exposed to ceftaroline at up to 4 times the maximum recommended human dose (MRHD) during the period of organogenesis through lactation. In rabbits exposed to ceftaroline during organogenesis at doses approximately equal to the MRHD, no drug-induced fetal malformations were observed despite maternal toxicity.
No data is available regarding the presence of ceftaroline in human milk, the effects of ceftaroline on breast-fed infants, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ceftaroline and any potential adverse effects on the breast-fed child from ceftaroline or the underlying maternal condition. The American Academy of Pediatrics (AAP) does suggest that a number of other cephalosporins are compatible with breast-feeding.
hyperkalemia / Delayed / 0-2.0anaphylactic shock / Rapid / 0-2.0bradycardia / Rapid / 0-2.0seizures / Delayed / 0-2.0renal failure (unspecified) / Delayed / 0-2.0agranulocytosis / Delayed / Incidence not knownC. difficile-associated diarrhea / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / 0-3.0constipation / Delayed / 2.0-2.0hepatitis / Delayed / 0-2.0hyperglycemia / Delayed / 0-2.0hypokalemia / Delayed / 2.0-2.0phlebitis / Rapid / 2.0-2.0anemia / Delayed / 0-2.0neutropenia / Delayed / 0-2.0eosinophilia / Delayed / 0-2.0thrombocytopenia / Delayed / 0-2.0palpitations / Early / 0-2.0pseudomembranous colitis / Delayed / 0-2.0leukopenia / Delayed / Incidence not knownencephalopathy / Delayed / Incidence not knownsuperinfection / Delayed / Incidence not known
diarrhea / Early / 5.0-8.0rash / Early / 3.0-7.0vomiting / Early / 2.0-5.0nausea / Early / 3.0-4.0pruritus / Rapid / 0-3.0fever / Early / 0-3.0headache / Early / 0-3.0abdominal pain / Early / 0-2.0urticaria / Rapid / 0-2.0dizziness / Early / 0-2.0
Loop diuretics: (Minor) Nephrotoxicity associated with cephalosporins may be potentiated by concomitant therapy with loop diuretics. Clinicians should be aware that this may occur even in patients with minor or transient renal impairment. Oral Contraceptives: (Moderate) It would be prudent to recommend alternative or additional contraception when oral contraceptives (OCs) are used in conjunction with antibiotics. It was previously thought that antibiotics may decrease the effectiveness of OCs containing estrogens due to stimulation of metabolism or a reduction in enterohepatic circulation via changes in GI flora. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with OCs and antibiotics was reported. It was concluded that the antibiotics ampicillin, ciprofloxacin, clarithromycin, doxycycline, metronidazole, ofloxacin, roxithromycin, temafloxacin, and tetracycline did not alter plasma concentrations of OCs. Antituberculous drugs (e.g., rifampin) were the only agents associated with OC failure and pregnancy. Based on the study results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines, and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, the risk for drug interaction with OCs is less clear, but alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or for newer combined contraceptive deliveries (e.g., patches, rings) are not available. Sodium picosulfate; Magnesium oxide; Anhydrous citric acid: (Major) Prior or concomitant use of antibiotics with sodium picosulfate; magnesium oxide; anhydrous citric acid may reduce efficacy of the bowel preparation as conversion of sodium picosulfate to its active metabolite bis-(p-hydroxy-phenyl)-pyridyl-2-methane (BHPM) is mediated by colonic bacteria. If possible, avoid coadministration. Certain antibiotics (i.e., tetracyclines and quinolones) may chelate with the magnesium in sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Therefore, these antibiotics should be taken at least 2 hours before and not less than 6 hours after the administration of sodium picosulfate; magnesium oxide; anhydrous citric acid solution. Warfarin: (Moderate) The concomitant use of warfarin with many classes of antibiotics, including cephalosporins, may increase the INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Additionally, certain cephalosporins (cefotetan, cefoperazone, cefamandole) are associated with prolongation of the prothrombin time due to the methylthiotetrazole (MTT) side chain at the R2 position, which disturbs the synthesis of vitamin K-dependent clotting factors in the liver. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary.
Ceftaroline is a bactericidal cephalosporin antibiotic with in vitro activity against gram-positive and gram-negative bacteria. Bactericidal action due to the inhibition of cell wall synthesis is mediated through binding to essential penicillin-binding proteins (PBPs). Activity against S. aureus is due to its affinity for PBP2a, and activity against S. pneumoniae is due to its affinity for PBP2x. Ceftaroline also exhibits activity against vancomycin-resistant S. aureus (VRSA), vancomycin-insensitive S. aureus (VISA), and hetero-resistant vancomycin-insensitive S. aureus (hVISA). Ceftaroline is not active against gram-negative bacteria that produce extended-spectrum beta-lactamases (ESBLs) from the TEM, SHV, or CTX-M families; serine carbapenemases (i.e., KPC); class B metallo-beta-lactamases; or class C (AmpC) cephalosporinases.   Beta-lactams, including ceftaroline, exhibit concentration-independent or time-dependent killing.  In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T above the MIC).      This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Cephalosporins require free drug concentrations to be above the MIC for 35% to 40% of the dosing interval for bacteriostatic activity and 60% to 70% of the dosing interval for bactericidal activity.   The post-antibiotic effect (PAE) appears to be minimal for S. pneumoniae and E. coli, but longer for S. aureus (0.8 to 7.2 hours). The susceptibility interpretive criteria for ceftaroline are delineated by pathogen. The MICs are defined for beta-hemolytic streptococci, S. pneumoniae, and H. influenzae as susceptible at 0.5 mcg/mL or less (based on a dosage of 600 mg IV every 12 hours). The MICs are defined for Enterobacterales as susceptible at 0.5 mcg/mL or less, intermediate at 1 mcg/mL, and resistant at 2 mcg/mL or more (based on a dosage of 600 mg IV every 12 hours). The Clinical and Laboratory Standards Institute (CLSI) and the FDA differ on MIC interpretation for S. aureus (including MRSA). For S. aureus, the MICs are defined by the FDA as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more. However, the MICs for S. aureus are defined by CLSI as susceptible at 1 mcg/mL or less (based on a dose of 600 mg IV every 12 hours), susceptible-dose dependent (SDD) at 2 to 4 mcg/mL (based on a dose of 600 mg IV every 8 hours over 2 hours), and resistant at 8 mcg/mL or more.  The potential to develop resistance to ceftaroline appears to be greater for gram-negative organisms as single-step mutations. Decreased drug permeability and increased drug efflux may be mechanisms of resistance; however, production of beta-lactamases that hydrolyze ceftaroline may be the biggest contributor to resistance. 
Ceftaroline is administered intravenously. The average protein binding is approximately 20% and decreases slightly with increasing concentrations over 1 to 50 mcg/mL (14.5% to 28%). The median steady-state volume of distribution in healthy adult males (n = 6) after a single 600 mg IV dose was 20.3 L (18.3 to 21.6 L), similar to extracellular fluid volume. Ceftaroline fosamil is converted into bioactive ceftaroline in plasma by a phosphate enzyme. Hydrolysis of the beta-lactam ring occurs to form the microbiologically inactive, open-ring metabolite ceftaroline M-1. Ceftaroline is not a substrate for hepatic CYP450 enzymes. Ceftaroline and its metabolites are primarily eliminated renally. In a clinical study of 6 healthy male adults, approximately 88% of radiolabeled drug was recovered in the urine and 6% in the feces within 48 hours. Of the radioactivity recovered in the urine, approximately 64% was excreted as ceftaroline and approximately 2% as ceftaroline M-1. The mean renal clearance of ceftaroline was 4.45 (SD 0.20) L/hour, suggesting that it is predominantly eliminated by glomerular filtration. In a pharmacokinetic study, the half-life was 1.6 hours (SD 0.38) after a single 600 mg IV dose and 2.66 hours (SD 0.4) after multiple 600 mg IV doses given twice daily for 14 days. After a single IV dose, the clearance rate was 9.58 L/hour (SD 1.85). After multiple IV doses, the clearance rate was 9.6 L/hour (SD 1.4). Affected cytochrome P450 isoenzymes: noneIn vitro studies in human liver microsomes indicate that ceftaroline does not inhibit the cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Additionally, in vitro human hepatocyte studies demonstrate that it does not induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP3A4/5. Therefore there is minimal potential for drug-drug interactions with CYP450 substrates, inhibitors, or inducers.
In pharmacokinetic studies (n = 6) using a 1 hour infusion, the Cmax of ceftaroline ranged from 19 mcg/mL (SD 0.71) after a single IV 600 mg dose and 21.3 mcg/mL (SD 4.1) after multiple IV 600 mg doses given twice daily for 14 days. The Tmax ranged from 1 hour (0.92 to 1.25) after a single IV dose and 0.92 hour (0.92 to 1.08) after multiple IV doses. The AUC was 56.8 mcg x hour/mL (SD 9.31) after a single IV dose and 56.3 mcg x hour/mL (SD 8.9) after multiple IV doses. The Cmax and systemic exposure (AUC) increase approximately in proportion to the dose within the single dose range of 50 to 1,000 mg with no appreciable accumulation observed after multiple 600 mg IV infusions given every 12 hours for up to 14 days in healthy adults with normal renal function. The AUC, half-life, and clearance of ceftaroline were similar after administration of 600 mg IV every 8 hours for 5 days as either a 5-minute or 60-minute infusion. The Tmax occurred approximately 5 minutes after the end of either infusion duration. The mean Cmax was 32.5 mcg/mL for the 5-minute infusion (n = 11) and 17.4 mcg/mL for the 60-minute infusion (n = 12).