Fifth Generation Cephalosporins

Microbiology:
Mode of Action:
Ceftaroline is a cephalosporin within vitroactivity against Gram-positive and -negative bacteria. The bactericidal action of ceftaroline is mediated through binding to essential penicillin-binding proteins (PBPs). Ceftaroline is bactericidal againstS. aureusdue to its affinity for PBP2a and againstStreptococcus pneumoniaedue 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 vitrostudies 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, bothin vitro and in clinical infections.

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 exhibitsin 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

INDICATIONS AND USAGE:
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,andEscherichia 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.

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:
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

Renal Dosing:
Dosage of Teflaro in Patients with Renal Impairment:

Estimated CrCla (mL/min)	Recommended Dosage Regimen for Teflaro
>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

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.

DOSAGE FORMS AND STRENGTHS:
600 mg or 400 mg of sterile Teflaro powder in single-use 20 mL vials.

SOURCE:
Package insert data:

Drug UPDATES:  ZERBAXA™ (ceftolozane and tazobactam) for injection, for intravenous use
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

Initial U.S. Approval:  2014

Mechanism of Action: Ceftolozane belongs to the cephalosporin class of antibacterial drugs. The bactericidal action of ceftolozane results from inhibition of cell wall biosynthesis, and is mediated through binding to penicillin-binding proteins (PBPs). Ceftolozane is an inhibitor of PBPs of P. aeruginosa (e.g., PBP1b, PBP1c, and PBP3) and E. coli (e.g., PBP3).

Tazobactam sodium has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins. It is an irreversible inhibitor of some beta-lactamases (e.g., certain penicillinases and cephalosporinases), and can bind covalently to some chromosomal and plasmid-mediated bacterial beta-lactamases.

INDICATIONS AND USAGE:
ZERBAXA™ (ceftolozane and tazobactam) for injection is indicated for the treatment of patients 18 years or older with the following infections caused by designated susceptible microorganisms.

1.1 Complicated Intra-abdominal Infections
ZERBAXA used in combination with metronidazole is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following Gram-negative and Gram-positive microorganisms: Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius.

1.2 Complicated Urinary Tract Infections, Including Pyelonephritis
ZERBAXA is indicated for the treatment of complicated urinary tract infections (cUTI), including pyelonephritis, caused by the following Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.

1.3 Usage
To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZERBAXA and other antibacterial drugs, ZERBAXA should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. 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.

HOW SUPPLIED: ZERBAXA 1.5 g (ceftolozane and tazobactam) for injection is supplied as a white to yellow sterile powder for reconstitution in single-dose vials; each vial contains ceftolozane 1 g (equivalent to 1.147 g of ceftolozane sulfate) and tazobactam 0.5 g (equivalent to 0.537 g of tazobactam sodium).