Ceftolozane exerts its bactericidal activity by binding to and inactivating penicillin-binding proteins (PBPs), particularly PBP1b and PBP3, which are essential for bacterial cell wall synthesis. This binding inhibits the transpeptidase activity of PBPs, preventing the cross-linking of peptidoglycan chains, leading to weakening of the bacterial cell wall and ultimately bacterial cell lysis and death. Ceftolozane is designed to have enhanced activity against multidrug-resistant Pseudomonas aeruginosa and other difficult-to-treat Gram-negative pathogens.

Ceftolozane exhibits potent in vitro activity against a broad range of Gram-negative bacteria, including Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. It is particularly effective against multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa strains, including those resistant to other cephalosporins and carbapenems. Ceftolozane shows synergistic activity when combined with the β-lactamase inhibitor tazobactam, which protects ceftolozane from degradation by many β-lactamase enzymes.

Ceftolozane sulfate, in combination with tazobactam, is approved for the treatment of complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). The combination has demonstrated efficacy in clinical trials, showing non-inferiority or superiority to comparator antibiotics. The compound's enhanced activity against multidrug-resistant Pseudomonas aeruginosa makes it a valuable option for treating infections caused by this challenging pathogen. Its in vivo efficacy is well-established in clinical practice.

In vitro enzyme/receptor binding assays for ceftolozane typically involve assessing its binding affinity to penicillin-binding proteins (PBPs) from various bacterial species. These assays use radiolabeled penicillin or fluorescent probes to measure competitive binding. The compound's stability against β-lactamase enzymes can be evaluated using standard β-lactamase inhibition assays, where the hydrolysis of a chromogenic cephalosporin substrate is measured in the presence and absence of the compound.

Cellular assays for ceftolozane are conducted using standard microbiological techniques with bacterial cultures. The compound's antibacterial activity is evaluated by determining the minimum inhibitory concentration (MIC) against various bacterial strains, particularly Pseudomonas aeruginosa and other Gram-negative pathogens. Broth microdilution and agar dilution methods are commonly used. The synergistic activity with tazobactam is assessed by comparing MIC values with and without the β-lactamase inhibitor.

In vivo animal model experiments for ceftolozane/tazobactam have been conducted in murine models of infection, including models of complicated urinary tract infection and intra-abdominal infection. The compound combination is administered parenterally, and efficacy is assessed by measuring bacterial burden in target organs, survival rates, and clinical scores. Pharmacokinetic/pharmacodynamic (PK/PD) studies are also performed to determine optimal dosing regimens.

Absorption, Distribution and Excretion
The injection dose of Ceftolozane-tazobactam is 1 g/0.5 g every 8 hours for 1 day. After this, the area under the curve (AUC) is 172 mcg•h/mL. Both Cmax (peak concentration) and AUC are dose-dependent. At the above dose, the Cmax on the first day of administration of Ceftolozane-tazobactam was 69.1 mcg/mL. Ceftolozane is primarily excreted in the urine. Ceftolozane-tazobactam distributes rapidly through tissues and has good pulmonary penetration, making it an ideal drug for treating bacterial pneumonia. The renal clearance of Ceftolozane-tazobactam after a single dose is 3.41–6.69 L/h. Patients with impaired renal function (creatinine clearance ≤50 mL/min) require dose adjustment. Please refer to the official package insert for dosage adjustment guidelines.

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Metabolism/Metabolites
Almost no metabolism occurs within Ceftolozane. When administered in the form of Ceftolozane-tazobactam, the β-lactam ring of tazobactam is hydrolyzed to form an inactive metabolite.
Biological Half-Life
On day 1 of treatment, with a dose of 1 g/0.5 g every 8 hours, the biological half-life is 2.77 hours; on day 10 of treatment, with a dose of 1 g/0.5 g every 8 hours, the biological half-life is 3.12 hours.
Ceftolozane sulfate is administered intravenously in combination with tazobactam. The pharmacokinetic profile of ceftolozane is characterized by a half-life of approximately 2-3 hours, dose-proportional exposure, and renal excretion. Approximately 80-90% of the administered dose is excreted unchanged in the urine. Dose adjustment is required in patients with renal impairment. The compound's protein binding is approximately 20%.

Protein Binding
16% to 21% is bound to plasma proteins.
Ceftolozane/tazobactam is generally well-tolerated. Common adverse effects include gastrointestinal disturbances (nausea, diarrhea, constipation), headache, and hypersensitivity reactions. As with other cephalosporins, there is a risk of hypersensitivity in patients with penicillin allergy. Other potential adverse effects include elevations in liver enzymes and renal function tests. The combination is contraindicated in patients with known severe hypersensitivity to cephalosporins.

[1] Infections Caused by Resistant Gram-Negative Bacteria: Epidemiology and Management. Pharmacotherapy. 2015 Oct;35(10):949-62.

[2] Ceftolozane/tazobactam for the treatment of complicated intra-abdominal infections. Expert Opin Pharmacother. 2015 Feb;16(2):271-80

Ceftolozane is a semi-synthetic broad-spectrum fifth-generation cephalosporin. It was approved by the U.S. Food and Drug Administration (FDA) in 2014 for use in combination with tazobactam to treat serious infections, such as intra-abdominal infections and complicated urinary tract infections. The drug is manufactured by Cubist Pharmaceuticals. More recently, in June 2019, the Ceftolozane-tazobactam combination was approved for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. Hospital-acquired pneumonia and ventilator-associated pneumonia are leading causes of morbidity and mortality in hospitalized patients, and Ceftolozane-tazobactam has effective antibacterial activity against a variety of pathogens that cause these infections, such as Pseudomonas aeruginosa. Ceftolozane is a semi-synthetic broad-spectrum fifth-generation cephalosporin antibiotic with bactericidal activity against certain Gram-negative and Gram-positive bacteria. After administration, Ceftolozane binds to and inactivates penicillin-binding proteins (PBPs) located on the inner membrane of bacterial cell walls. This interferes with the final transpeptidation step required for the formation of peptidoglycan chain crosslinks, a key component of the bacterial cell wall that gives it strength and rigidity. This inhibits bacterial cell wall synthesis and reduces cell wall stability, thereby weakening the bacterial cell wall and leading to bacterial cell lysis.
See also: Ceftolozane (note moved to).

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Drug Indications
Ceftolozane, in combination with [tazobactam], is used to treat infections in adults and children caused by specified susceptible microorganisms: - Complicated intra-abdominal infections (cIAI), in combination with [metronidazole] - Complicated urinary tract infections (cUTI), including pyelonephritis - Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP)

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Mechanism of Action
Ceftolozane belongs to the cephalosporin class of antimicrobial agents. Ceftolozane exerts its antimicrobial effect by inhibiting the formation of the bacterial cell wall, a barrier that protects bacteria from damage and confers resistance to certain antibiotics. Its antibacterial activity is also exerted through the binding of Ceftolozane to penicillin-binding proteins (PBPs), which are essential for peptidoglycan cross-linking in bacterial cell wall synthesis. By inhibiting cell wall synthesis, bacterial cells are killed, thus treating a variety of infections. Ceftolozane exhibits particularly high affinity for penicillin-binding proteins of Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and other enteric bacteria. Notably, Ceftolozane demonstrates higher in vitro affinity for penicillin-binding proteins 1b, 1c, 2, and 3 compared to other antibiotics such as ceftazidime and imipenem.
Ceftolozane sulfate (CAS# 936111-69-2) is the sulfate salt form of ceftolozane, a novel, semi-synthetic, broad-spectrum, fifth-generation cephalosporin antibiotic. It is administered in combination with tazobactam (Zerbaxa®) and is approved for the treatment of complicated urinary tract infections and complicated intra-abdominal infections. Ceftolozane exhibits potent activity against Gram-negative bacteria, including multidrug-resistant Pseudomonas aeruginosa. It exerts its bactericidal activity by binding to penicillin-binding proteins and inhibiting bacterial cell wall synthesis.

C23H32N12O12S3

764.7684

764.142

936111-69-2

689293-68-3;936111-69-2 (sulfate);

52918380

White to off-white solid

9

20

12

50

1360

2

CC(C)(C(=O)O)O/N=C(/C1=NSC(=N1)N)\C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C[N+]4=CC(=C(N4C)N)NC(=O)NCCN)C(=O)O.OS(=O)(=O)[O-]

UJDQGRLTPBVSFN-TVNHLQOTSA-M

InChI=1S/C23H30N12O8S2.H2O4S/c1-23(2,20(40)41)43-31-11(15-30-21(26)45-32-15)16(36)29-12-17(37)35-13(19(38)39)9(8-44-18(12)35)6-34-7-10(14(25)33(34)3)28-22(42)27-5-4-241-5(2,3)4/h7,12,18,25H,4-6,8,24H2,1-3H3,(H7,26,27,28,29,30,32,36,38,39,40,41,42)(H2,1,2,3,4)/p-1/b31-11-/t12-,18-/m1./s1

mono(5-amino-2-(((6R,7R)-7-((Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(((2-carboxypropan-2-yl)oxy)imino)acetamido)-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-4-(3-(2-aminoethyl)ureido)-1-methyl-1H-pyrazol-2-ium) monosulfate

FR-264205 CXA101FR-264205FR264205CXA-101 Zerbaxa FR264205 FR 264205 Ceftolozane sulfate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~50 mg/mL (~65.4 mM; ultrasonic and heat to 60°C)
H2O: ~10 mg/mL (~13.1 mM; with ultrasonication)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.27 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of 20% SBE-β-CD saline and mix well.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.27 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), Clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well.

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 (Please use freshly prepared in vivo formulations for optimal results.)