Ceftolozane/tazobactam

Ceftolozane/tazobactam is indicated for the treatment of the following infections in adults caused by designated susceptible microorganisms:

• Complicated intra-abdominal infections;
• Acute pyelonephritis;
• Complicated urinary tract infections.
• Hospital-acquired bacterial pneumonia and Ventilator-associated bacterial pneumonia (HABP/VABP)

Ceftolozane contains a 7-aminothiadiazole, affording increased activity against gram-negative organisms, as well as an alkoximino group, providing stability against many β-lactamases. Ceftolozane has a dimethylacetic acid moiety that contributes to enhanced activity against Pseudomonas aeruginosa. The addition of a bulky side chain (a pyrazole ring) at the 3-position prevents hydrolysis of the β-lactam ring via steric hindrance.{{cite journal | vauthors = Murano K, Yamanaka T, Toda A, Ohki H, Okuda S, Kawabata K, Hatano K, Takeda S, Akamatsu H, Itoh K, Misumi K, Inoue S, Takagi T | display-authors = 6 | title = Structural requirements for the stability of novel cephalosporins to AmpC beta-lactamase based on 3D-structure | journal = Bioorganic & Medicinal Chemistry | volume = 16 | issue = 5 | pages = 2261–75 | date = March 2008 | pmid = 18082409 | doi = 10.1016/j.bmc.2007.11.074 }}

Tazobactam is a {{chem name|penicillinate}} sulfone β-lactamase inhibitor, which prevents hydrolysis of the amide bond of the β-lactam molecules by β-lactamase enzymes.{{cite journal | vauthors = Drawz SM, Bonomo RA | title = Three decades of beta-lactamase inhibitors | journal = Clinical Microbiology Reviews | volume = 23 | issue = 1 | pages = 160–201 | date = January 2010 | pmid = 20065329 | pmc = 2806661 | doi = 10.1128/CMR.00037-09 }}

Ceftolozane exerts bactericidal activities against susceptible gram-negative and gram-positive infections by inhibiting essential penicillin-binding proteins (PBPs), which are required for peptidoglycan cross-linking for bacterial cell wall synthesis, resulting in inhibition of cell wall synthesis and subsequent cell death. Ceftolozane is an inhibitor of PBPs of Pseudomonas aeruginosa (e.g. PBP1b, PBP1c, and PBP3) and E. coli (e.g., PBP3).{{cite journal | vauthors = Shortridge D, Pfaller MA, Castanheira M, Flamm RK | title = Antimicrobial Activity of Ceftolozane-Tazobactam Tested Against Enterobacteriaceae and Pseudomonas aeruginosa with Various Resistance Patterns Isolated in U.S. Hospitals (2013-2016) as Part of the Surveillance Program: Program to Assess Ceftolozane-Tazobactam Susceptibility | journal = Microbial Drug Resistance | volume = 24 | issue = 5 | pages = 563–577 | date = June 2018 | pmid = 29039729 | doi = 10.1089/mdr.2017.0266 | s2cid = 4873637 | doi-access = free }}{{cite journal | vauthors = Snydman DR, McDermott LA, Jacobus NV | title = Activity of ceftolozane-tazobactam against a broad spectrum of recent clinical anaerobic isolates | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 2 | pages = 1218–23 | date = February 2014 | pmid = 24277025 | doi = 10.1128/AAC.02253-13 | pmc = 3910869 }}

Tazobactam is a potent β-lactamase inhibitor of most common class A and C β-lactamases. Tazobactam has little clinically relevant in vitro activity against bacteria due to its reduced affinity to penicillin-binding proteins; however, it is an irreversible inhibitor of some β-lactamases (certain penicillinases and cephalosporinases) and can covalently bind to some chromosomal and plasmid-mediated bacterial beta-lactamases.

The addition of tazobactam strengthens the therapeutic response to ceftolozane, giving it the ability to treat a broader range of bacterial infections and resistant organisms.{{cite journal | vauthors = Hong MC, Hsu DI, Bounthavong M | title = Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination | language = en | journal = Infection and Drug Resistance | volume = 6 | pages = 215–23 | date = November 2013 | pmid = 24348053 | doi = 10.2147/idr.s36140 | url= | pmc = 3848746 | doi-access = free }}

Ceftolozane–tazobactam is available as a 2:1 fixed combination (such that a 1.5 g dose of ceftolozane–tazobactam is composed of 1 g of ceftolozane and 500 mg of tazobactam).{{cite journal | vauthors = Cluck D, Lewis P, Stayer B, Spivey J, Moorman J | title = Ceftolozane-tazobactam: A new-generation cephalosporin | journal = American Journal of Health-System Pharmacy | volume = 72 | issue = 24 | pages = 2135–46 | date = December 2015 | pmid = 26637512 | doi = 10.2146/ajhp150049 }} Ceftolozane-tazobactam is administered intravenously. For both ceftolozane and tazobactam, the peak plasma concentration occurs immediately after a 60 minute infusion, with a time to maximum concentration of approximately one hour.

The binding of ceftolozane to human plasma proteins is approximately 16% to 21%, while the binding of tazobactam is approximately 30%. The mean steady-state volume of distribution in healthy adult males after a single 1.5 g IV dose is 13.5 L for ceftolozane and 18.2 L for tazobactam, which is similar to extracellular fluid volume. Tissue distribution of ceftalozone-tazobactam is rapid and shows good penetration into the lung, rendering it an ideal treatment for bacterial pneumonia.

The metabolism and excretion of ceftolozane are similar to those of most β-lactam antimicrobial agents. Ceftolozane is not metabolized to any significant extent and thus predominantly eliminated unchanged in the urine.{{cite journal | vauthors = Chandorkar G, Xiao A, Mouksassi MS, Hershberger E, Krishna G | title = Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections | journal = Journal of Clinical Pharmacology | volume = 55 | issue = 2 | pages = 230–9 | date = February 2015 | pmid = 25196976 | doi = 10.1002/jcph.395 | pmc = 4303958 }}{{cite journal | vauthors = Wooley M, Miller B, Krishna G, Hershberger E, Chandorkar G | title = Impact of renal function on the pharmacokinetics and safety of ceftolozane-tazobactam | journal = Antimicrobial Agents and Chemotherapy | volume = 58 | issue = 4 | pages = 2249–55 | date = 2014-04-01 | pmid = 24492369 | doi = 10.1128/AAC.02151-13 | pmc = 4023800 | doi-access = free }} Tazobactam is partially metabolized to an inactive metabolite, and both drug and metabolite are excreted in the urine (80% as unchanged drug).{{cite journal | vauthors = Goodlet KJ, Nicolau DP, Nailor MD | title = Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections | language = en | journal = Therapeutics and Clinical Risk Management | volume = 12 | pages = 1811–1826 | date = 2016-12-01 | pmid = 27942218 | doi = 10.2147/tcrm.s120811 | pmc = 5140030 | doi-access = free }}

The half-life of ceftolozane is 2.5–3.0 hours, and the half-life of tazobactam is approximately 1.0 hour; the clearance of both drugs is directly proportional to renal function. Tazobactam primarily undergoes renal excretion via active tubular secretion. Coadministration of ceftolozane with tazobactam does not result in an interaction, since ceftolozane is primarily eliminated by glomerular filtration.{{cite journal | vauthors = Miller B, Hershberger E, Benziger D, Trinh M, Friedland I | title = Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses | journal = Antimicrobial Agents and Chemotherapy | volume = 56 | issue = 6 | pages = 3086–91 | date = June 2012 | pmid = 22450972 | doi = 10.1128/AAC.06349-11 | pmc = 3370713 | doi-access = free }}

The in vitro activity of ceftolozane–tazobactam has been examined in five surveillance studies of isolates from Europe and North America.{{cite web |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2014/206829Orig1s000MedR.pdf |title=Medical review |website=fda.gov }} In these studies, ceftolozane–tazobactam was notable for its activity against Pseudomonas aeruginosa, a common cause of hospital-acquired infections that is commonly multi-drug resistant. Ninety percent of Pseudomonas aeruginosa isolates were inhibited by a ceftolozane–tazobactam at a concentration of 4 μg/mL (MIC₉₀), making it the most potent anti-pseudomonal antibiotic in clinical use.{{cn|date=March 2023}}

In these same studies, ceftolozane–tazobactam exhibited MIC₉₀ values of <1 μg/mL for Escherichia coli, Citrobacter koseri, Morganella morganii, Proteus mirabilis, Salmonella species, and Serratia marcescens. Somewhat poorer activity is observed for the Klebsiella and Enterobacter species, with the MIC₉₀ for extended spectrum beta-lactamase expressing Klebsiella pneumoniae being >32 μg/mL.{{cn|date=March 2023}}

The adverse-event profile of ceftolozane/tazobactam from two phase 2 trials (comparing either ceftolozane alone or in combination with tazobactam to ceftazidime or meropenem) suggests that ceftolozane/tazobactam is well tolerated. The most common AEs reported with ceftolozane/tazobactam were headache (5.8%), constipation (3.9%), hypertension (3%), nausea (2.8%), and diarrhea (1.9%).{{cite journal | vauthors = Sorbera M, Chung E, Ho CW, Marzella N | title = Ceftolozane/Tazobactam: a new option in the treatment of complicated gram-negative infections | journal = Pharmacy & Therapeutics | volume = 39 | issue = 12 | pages = 825–32 | date = December 2014 | pmid = 25516692 | pmc = 4264669 }}

Based on previous trial data and ongoing clinical trials, no significant drug–drug or food–drug interactions have been associated with ceftolozane/tazobactam administration. However, drug–drug interactions similar to those observed with the cephalosporin class of antimicrobials and β-lactamase inhibitors should be considered as potential interactions until further drug–drug interactions have been completely elucidated. Moreover, as a result of drug accumulation in renal impairment, caution should be taken when coadministering ceftolozane/tazobactam with other renally eliminated medications due to possible nephrotoxicity

Researchers at Cubist Pharmaceuticals (prior to the acquisition of Cubist by Merck) discovered and developed a synthesis of ceftolozane sulfate based on a palladium-mediated coupling in the presence of the cephalosporin nucleus, marking a significant advancement in the chemistry of cephalosporin antibiotics. This chemistry was determined to be general to the family of cephalosporin antibiotics. Key elements of the coupling reaction were the use of a designed, electron-deficient phosphite ligand in tandem with the addition of an exogenous chloride scavenging reagent, which functioned through the in situ precipitation of potassium chloride. This work is described only in the patent literature.U. S. Patent Application No. WO2016025839 (A1) 2016

The efficacy of ceftolozane/tazobactam to treat complicated intra-abdominal infections (cIAI) in combination with metronidazole was established in a clinical trial with a total of 979 adults. Participants were randomly assigned to receive ceftolozane/tazobactam plus metronidazole or meropenem. Results showed ceftolozane/tazobactam plus metronidazole was effective for the treatment of cIAI.

The efficacy of ceftolozane/tazobactam to treat complicated urinary tract infections (cUTI) was established in a clinical trial where 1,068 adults were randomly assigned to receive ceftolozane/tazobactam or levofloxacin. Ceftolozane/tazobactam demonstrated it was effective in treating cUTI.

Ceftolozane/tazobactam was shown to be at least as effective as other antibiotics in curing infections in three main studies.

One study involved 1,083 participants who mostly had kidney infection or in some cases a complicated urinary-tract infection. Ceftolozane/tazobactam successfully treated the infection in about 85% of the cases where it was given (288 of 340), compared with 75% (266 of 353) of those given another antibiotic called levofloxacin.

The second study involved 993 participants with complicated intra-abdominal infections. Ceftolozane/tazobactam was compared with another antibiotic, meropenem. Both medicines cured 94% of participants (353 out of 375 given ceftolozane/tazobactam and 375 out of 399 given meropenem).

The third study involved 726 participants who were using a ventilator and who had either hospital-acquired pneumonia or ventilator-associated pneumonia. It found ceftolozane/tazobactam to be at least as effective as meropenem: the infection had resolved in 54% of participants (197 out of 362) after 7 to 14 days of treatment with ceftolozane/tazobactam compared with 53% of participants (194 out of 362) on meropenem.

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