Ceftolozane/tazobactam

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Ceftolozane/tazobactam
Ceftolozane.svg
Tazobactam.svg
Combination of
Ceftolozane Cephalosporin antibiotic
Tazobactam Beta-lactamase inhibitor
Clinical data
Trade names Zerbaxa
AHFS/Drugs.com Monograph
MedlinePlus a615010
License data
Pregnancy
category
Routes of
administration 		Intravenous
ATC code
Legal status
Legal status
Identifiers
PubChem CID
ChemSpider
KEGG
CompTox Dashboard (EPA)
Chemical and physical data
Formula C23H30N12O8S2
Molar mass 666.69 g·mol−1
3D model (JSmol)
  • CC(C)(C(=O)O)O/N=C(/c1nc(sn1)N)\C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C[n+]4cc(c(n4C)N)NC(=O)NCCN)C(=O)[O-]
  • InChI=1S/C23H30N12O8S2/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)27-5-4-24/h7,12,18,25H,4-6,8,24H2,1-3H3,(H7,26,27,28,29,30,32,36,38,39,40,41,42)/b31-11-/t12-,18-/m1/s1
  • Key:JHFNIHVVXRKLEF-DCZLAGFPSA-N

Ceftolozane/tazobactam, sold under the brand name Zerbaxa, is a fixed-dose combination antibiotic medication used for the treatment of complicated urinary tract infections and complicated intra-abdominal infections in adults. [6] [5] [7] Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics. [8] It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

Contents

The most common side effects include nausea (feeling sick), headache, constipation, diarrhea and fever. [5] [7]

Ceftolozane is a type of antibiotic called a cephalosporin, which belongs to the wider group of antibiotics called beta-lactams. [5] It works by interfering with the production of molecules that bacteria need to build their protective cell walls. [5] This causes weakness in the bacterial cell walls which then become prone to collapse, ultimately leading to the death of the bacteria. [5]

Tazobactam blocks the action of bacterial enzymes called beta-lactamases. [5] These enzymes enable bacteria to break down beta-lactam antibiotics like ceftolozane, making the bacteria resistant to the antibiotic's action. [5] By blocking the action of these enzymes, tazobactam allows ceftolozane to act against bacteria that would otherwise be resistant to ceftolozane. [5]

Ceftolozane is combined with the β-lactamase inhibitor tazobactam, which protects ceftolozane from degradation. [9] It was approved for medical use in the United States in December 2014, [7] [10] and in the European Union in September 2015. [5] It is on the World Health Organization's List of Essential Medicines. [11]

Medical uses

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

Chemical structure

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. [12]

Tazobactam is a penicillinate sulfone β-lactamase inhibitor, which prevents hydrolysis of the amide bond of the β-lactam molecules by β-lactamase enzymes. [13]

Mechanism of action

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). [14] [15]

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. [14]

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. [16]

Pharmacokinetics

Absorption and distribution

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). [17] 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. [16]

Metabolism and elimination

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. [18] [19] Tazobactam is partially metabolized to an inactive metabolite, and both drug and metabolite are excreted in the urine (80% as unchanged drug). [20]

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. [21] [20]

Spectrum of activity

The in vitro activity of ceftolozane–tazobactam has been examined in five surveillance studies of isolates from Europe and North America. [22] 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.[ citation needed ]

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.[ citation needed ]

Adverse drug reactions

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%). [23]

Drug interactions

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 [23]

Chemical synthesis

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. [24]

History

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. [7] Participants were randomly assigned to receive ceftolozane/tazobactam plus metronidazole or meropenem. [7] Results showed ceftolozane/tazobactam plus metronidazole was effective for the treatment of cIAI. [7]

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. [7] Ceftolozane/tazobactam demonstrated it was effective in treating cUTI. [7]

Ceftolozane/tazobactam was shown to be at least as effective as other antibiotics in curing infections in three main studies. [5]

One study involved 1,083 participants who mostly had kidney infection or in some cases a complicated urinary-tract infection. [5] 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. [5]

The second study involved 993 participants with complicated intra-abdominal infections. [5] Ceftolozane/tazobactam was compared with another antibiotic, meropenem. [5] Both medicines cured 94% of participants (353 out of 375 given ceftolozane/tazobactam and 375 out of 399 given meropenem). [5]

The third study involved 726 participants who were using a ventilator and who had either hospital-acquired pneumonia or ventilator-associated pneumonia. [5] 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. [5]

Related Research Articles

<span class="mw-page-title-main">Beta-lactamase</span> Class of enzymes

Beta-lactamases (β-lactamases) are enzymes produced by bacteria that provide multi-resistance to beta-lactam antibiotics such as penicillins, cephalosporins, cephamycins, monobactams and carbapenems (ertapenem), although carbapenems are relatively resistant to beta-lactamase. Beta-lactamase provides antibiotic resistance by breaking the antibiotics' structure. These antibiotics all have a common element in their molecular structure: a four-atom ring known as a beta-lactam (β-lactam) ring. Through hydrolysis, the enzyme lactamase breaks the β-lactam ring open, deactivating the molecule's antibacterial properties.

<span class="mw-page-title-main">Cephalosporin</span> Class of pharmaceutical drugs

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.

<span class="mw-page-title-main">Aztreonam</span> Chemical compound

Aztreonam, sold under the brand name Azactam among others, is an antibiotic used primarily to treat infections caused by gram-negative bacteria such as Pseudomonas aeruginosa. This may include bone infections, endometritis, intra abdominal infections, pneumonia, urinary tract infections, and sepsis. It is given by intravenous or intramuscular injection or by inhalation.

<span class="mw-page-title-main">Amoxicillin/clavulanic acid</span> Combination antibiotic medication

Amoxicillin/clavulanic acid, also known as co-amoxiclav or amox-clav, sold under the brand name Augmentin, among others, is an antibiotic medication used for the treatment of a number of bacterial infections. It is a combination consisting of amoxicillin, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor. It is specifically used for otitis media, streptococcal pharyngitis, pneumonia, cellulitis, urinary tract infections, and animal bites. It is taken by mouth or by injection into a vein.

<span class="mw-page-title-main">Meropenem</span> Broad-spectrum antibiotic

Meropenem, sold under the brand name Merrem among others, is an intravenous carbapenem antibiotic used to treat a variety of bacterial infections. Some of these include meningitis, intra-abdominal infection, pneumonia, sepsis, and anthrax.

<span class="mw-page-title-main">Tazobactam</span> Chemical compound

Tazobactam is a pharmaceutical drug that inhibits the action of bacterial β-lactamases, especially those belonging to the SHV-1 and TEM groups. It is commonly used as its sodium salt, tazobactam sodium.

<span class="mw-page-title-main">Ceftazidime</span> Antibiotic medication

Ceftazidime, sold under the brand name Fortaz among others, is a third-generation cephalosporin antibiotic useful for the treatment of a number of bacterial infections. Specifically it is used for joint infections, meningitis, pneumonia, sepsis, urinary tract infections, malignant otitis externa, Pseudomonas aeruginosa infection, and vibrio infection. It is given by injection into a vein, muscle, or eye.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Piperacillin/tazobactam</span> Combination antibiotic medication

Piperacillin/tazobactam, sold under the brand name Tazocin among others, is a combination medication containing the antibiotic piperacillin and the β-lactamase inhibitor tazobactam. The combination has activity against many Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. It is used to treat pelvic inflammatory disease, intra-abdominal infection, pneumonia, cellulitis, and sepsis. It is given by injection into a vein.

<span class="mw-page-title-main">Carbapenem</span> Class of highly effective antibiotic agents

Carbapenems are a class of very effective antibiotic agents most commonly used for treatment of severe bacterial infections. This class of antibiotics is usually reserved for known or suspected multidrug-resistant (MDR) bacterial infections. Similar to penicillins and cephalosporins, carbapenems are members of the beta-lactam antibiotics drug class, which kill bacteria by binding to penicillin-binding proteins, thus inhibiting bacterial cell wall synthesis. However, these agents individually exhibit a broader spectrum of activity compared to most cephalosporins and penicillins. Furthermore, carbapenems are typically unaffected by emerging antibiotic resistance, even to other beta-lactams.

<span class="mw-page-title-main">Cefotaxime</span> Chemical compound

Cefotaxime is an antibiotic used to treat a number of bacterial infections in human, other animals and plant tissue culture. Specifically in humans it is used to treat joint infections, pelvic inflammatory disease, meningitis, pneumonia, urinary tract infections, sepsis, gonorrhea, and cellulitis. It is given either by injection into a vein or muscle.

Ampicillin/sulbactam is a fixed-dose combination medication of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the brand name Unasyn, generic only outside the United States, is an intravenous antibiotic. The second, an oral form called sultamicillin, is marketed under the brand name Ampictam outside the United States, and generic only in the United States. Ampicillin/sulbactam is used to treat infections caused by bacteria resistant to beta-lactam antibiotics. Sulbactam blocks the enzyme which breaks down ampicillin and thereby allows ampicillin to attack and kill the bacteria.

<span class="mw-page-title-main">Cefditoren</span> Chemical to treat skin infections

Cefditoren, also known as cefditoren pivoxil is an antibiotic used to treat infections caused by Gram-positive and Gram-negative bacteria that are resistant to other antibiotics. It is mainly used for treatment of community acquired pneumonia. It is taken by mouth and is in the cephalosporin family of antibiotics, which is part of the broader beta-lactam group of antibiotics.

β-Lactamase inhibitor Drugs that inhibit β-Lactamase enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Avibactam</span> Chemical compound

Avibactam is a non-β-lactam β-lactamase inhibitor developed by Actavis jointly with AstraZeneca. A new drug application for avibactam in combination with ceftazidime was approved by the FDA on February 25, 2015, for treating complicated urinary tract (cUTI) and complicated intra-abdominal infections (cIAI) caused by antibiotic resistant-pathogens, including those caused by multi-drug resistant Gram-negative bacterial pathogens.

<span class="mw-page-title-main">Ceftazidime/avibactam</span> Combination antibiotic medication

Ceftazidime/avibactam, sold under the brand name Avycaz among others, is a fixed-dose combination medication composed of ceftazidime, a cephalosporin antibiotic, and avibactam, a β-lactamase inhibitor. It is used to treat complicated intra-abdominal infections, urinary tract infections, and pneumonia. It is only recommended when other options are not appropriate. It is given by infusion into a vein.

Meropenem/vaborbactam, sold under the brand name Vabomere among others, is a combination medication used to treat complicated urinary tract infections, complicated abdominal infections, and hospital-acquired pneumonia. It contains meropenem, a beta-lactam antibiotic, and vaborbactam, a beta-lactamase inhibitor. It is given by injection into a vein.

<span class="mw-page-title-main">Cefiderocol</span> Antibiotic

Cefiderocol, sold under the brand name Fetroja among others, is an antibiotic used to treat complicated urinary tract infections when no other options are available. It is indicated for the treatment of multi-drug-resistant Gram-negative bacteria including Pseudomonas aeruginosa. It is given by injection into a vein.

Imipenem/cilastatin/relebactam, sold under the brand name Recarbrio, is a fixed-dose combination medication used as an antibiotic. In 2019, it was approved for use in the United States for the treatment of complicated urinary tract and complicated intra-abdominal infections. It is administered via intravenous injection.

References

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  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  3. ↑ https://www.tga.gov.au/resources/prescription-medicines-registrations/zerbaxa-merck-sharp-dohme-australia-pty-ltd-0
  4. ↑ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada . 4 May 2016. Retrieved 7 April 2024.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 "Zerbaxa EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 14 May 2020. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  6. 1 2 3 4 5 "Zerbaxa- ceftolozane and tazobactam injection, powder, lyophilized, for solution". DailyMed. 3 June 2019. Retrieved 14 May 2020.
  7. 1 2 3 4 5 6 7 8 "FDA approves new antibacterial drug Zerbaxa". U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 2015-05-09. Retrieved 2015-06-02.PD-icon.svg This article incorporates text from this source, which is in the public domain .
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  11. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
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  20. 1 2 Goodlet KJ, Nicolau DP, Nailor MD (2016-12-01). "Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections". Therapeutics and Clinical Risk Management. 12: 1811–1826. doi: 10.2147/tcrm.s120811 . PMC   5140030 . PMID   27942218.
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  22. ↑ "Medical review" (PDF). fda.gov.
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  24. ↑ U. S. Patent Application No. WO2016025839 (A1) 2016
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