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Ceftolozane/tazobactam

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.[5][4][6] Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that are resistant to conventional antibiotics.[7] It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

Ceftolozane/tazobactam
Combination of
CeftolozaneCephalosporin antibiotic
TazobactamBeta-lactamase inhibitor
Clinical data
Trade namesZerbaxa
AHFS/Drugs.comMonograph
MedlinePlusa615010
License data
  • US DailyMedCeftolozane and tazobactam
Pregnancy
category
Routes of
administration
Intravenous
ATC code
Legal status
Legal status
Identifiers
PubChem CID
  • 53234134
ChemSpider
  • 25999973
KEGG
  • D10577
Chemical and physical data
FormulaC23H30N12O8S2
Molar mass666.69 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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

The most common side effects include nausea (feeling sick), headache, constipation, diarrhea and fever.[4][6]

Ceftolozane is a type of antibiotic called a cephalosporin, which belongs to the wider group of antibiotics called beta-lactams.[4] It works by interfering with the production of molecules that bacteria need to build their protective cell walls.[4] This causes weakness in the bacterial cell walls which then become prone to collapse, ultimately leading to the death of the bacteria.[4]

Tazobactam blocks the action of bacterial enzymes called beta-lactamases.[4] These enzymes enable bacteria to break down beta-lactam antibiotics like ceftolozane, making the bacteria resistant to the antibiotic's action.[4] By blocking the action of these enzymes, tazobactam allows ceftolozane to act against bacteria that would otherwise be resistant to ceftolozane.[4]

Ceftolozane is combined with the β-lactamase inhibitor tazobactam, which protects ceftolozane from degradation.[8] It was approved for medical use in the United States in December 2014,[6][9] and in the European Union in September 2015.[4] It is on the World Health Organization's List of Essential Medicines.[10]

Medical uses edit

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

Chemical structure edit

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.[11]

Tazobactam is a penicillinate sulfone β-lactamase inhibitor, which prevents hydrolysis of the amide bond of the β-lactam molecules by β-lactamase enzymes.[12]

Mechanism of action edit

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).[13][14]

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.[13]

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.[15]

Pharmacokinetics edit

Absorption and distribution edit

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).[16] 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.[15]

Metabolism and elimination edit

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.[17][18] Tazobactam is partially metabolized to an inactive metabolite, and both drug and metabolite are excreted in the urine (80% as unchanged drug).[19]

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.[20][19]

Spectrum of activity edit

The in vitro activity of ceftolozane–tazobactam has been examined in five surveillance studies of isolates from Europe and North America.[21] 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 edit

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%).[22]

Drug interactions edit

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[22]

Chemical synthesis edit

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.[23]

History edit

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.[6] Participants were randomly assigned to receive ceftolozane/tazobactam plus metronidazole or meropenem.[6] Results showed ceftolozane/tazobactam plus metronidazole was effective for the treatment of cIAI.[6]

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.[6] Ceftolozane/tazobactam demonstrated it was effective in treating cUTI.[6]

Ceftolozane/tazobactam was shown to be at least as effective as other antibiotics in curing infections in three main studies.[4]

One study involved 1,083 participants who mostly had kidney infection or in some cases a complicated urinary-tract infection.[4] 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.[4]

The second study involved 993 participants with complicated intra-abdominal infections.[4] Ceftolozane/tazobactam was compared with another antibiotic, meropenem.[4] Both medicines cured 94% of participants (353 out of 375 given ceftolozane/tazobactam and 375 out of 399 given meropenem).[4]

The third study involved 726 participants who were using a ventilator and who had either hospital-acquired pneumonia or ventilator-associated pneumonia.[4] 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.[4]

References edit

  1. ^ "Ceftolozane / tazobactam (Zerbaxa) Use During Pregnancy". Drugs.com. 14 June 2019. Retrieved 14 May 2020.
  2. ^ . Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  3. ^ "Health Canada New Drug Authorizations: 2015 Highlights". Health Canada. 4 May 2016. Retrieved 7 April 2024.
  4. ^ a b c d e f g h i j k l m n o p q r s t u "Zerbaxa EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 14 May 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  5. ^ a b c d e "Zerbaxa- ceftolozane and tazobactam injection, powder, lyophilized, for solution". DailyMed. 3 June 2019. Retrieved 14 May 2020.
  6. ^ a b c d e f g h . U.S. Food and Drug Administration (FDA) (Press release). Archived from the original on 2015-05-09. Retrieved 2015-06-02.   This article incorporates text from this source, which is in the public domain.
  7. ^ Long TE, Williams JT (October 2014). "Cephalosporins currently in early clinical trials for the treatment of bacterial infections". Expert Opinion on Investigational Drugs. 23 (10): 1375–87. doi:10.1517/13543784.2014.930127. PMID 24956017. S2CID 5234167.
  8. ^ Zhanel GG, Chung P, Adam H, Zelenitsky S, Denisuik A, Schweizer F, et al. (January 2014). "Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli". Drugs. 74 (1): 31–51. doi:10.1007/s40265-013-0168-2. PMID 24352909. S2CID 44694926.
  9. ^ "Drug Approval Package: Zerbaxa (ceftolozane/tazobactam) Injection NDA #206829". U.S. Food and Drug Administration (FDA). 24 December 1999. Retrieved 14 May 2020.
  10. ^ 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.
  11. ^ Murano K, Yamanaka T, Toda A, Ohki H, Okuda S, Kawabata K, et al. (March 2008). "Structural requirements for the stability of novel cephalosporins to AmpC beta-lactamase based on 3D-structure". Bioorganic & Medicinal Chemistry. 16 (5): 2261–75. doi:10.1016/j.bmc.2007.11.074. PMID 18082409.
  12. ^ Drawz SM, Bonomo RA (January 2010). "Three decades of beta-lactamase inhibitors". Clinical Microbiology Reviews. 23 (1): 160–201. doi:10.1128/CMR.00037-09. PMC 2806661. PMID 20065329.
  13. ^ a b Shortridge D, Pfaller MA, Castanheira M, Flamm RK (June 2018). "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". Microbial Drug Resistance. 24 (5): 563–577. doi:10.1089/mdr.2017.0266. PMID 29039729. S2CID 4873637.
  14. ^ Snydman DR, McDermott LA, Jacobus NV (February 2014). "Activity of ceftolozane-tazobactam against a broad spectrum of recent clinical anaerobic isolates". Antimicrobial Agents and Chemotherapy. 58 (2): 1218–23. doi:10.1128/AAC.02253-13. PMC 3910869. PMID 24277025.
  15. ^ a b Hong MC, Hsu DI, Bounthavong M (November 2013). "Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination". Infection and Drug Resistance. 6: 215–23. doi:10.2147/idr.s36140. PMC 3848746. PMID 24348053.
  16. ^ Cluck D, Lewis P, Stayer B, Spivey J, Moorman J (December 2015). "Ceftolozane-tazobactam: A new-generation cephalosporin". American Journal of Health-System Pharmacy. 72 (24): 2135–46. doi:10.2146/ajhp150049. PMID 26637512.
  17. ^ Chandorkar G, Xiao A, Mouksassi MS, Hershberger E, Krishna G (February 2015). "Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections". Journal of Clinical Pharmacology. 55 (2): 230–9. doi:10.1002/jcph.395. PMC 4303958. PMID 25196976.
  18. ^ Wooley M, Miller B, Krishna G, Hershberger E, Chandorkar G (2014-04-01). "Impact of renal function on the pharmacokinetics and safety of ceftolozane-tazobactam". Antimicrobial Agents and Chemotherapy. 58 (4): 2249–55. doi:10.1128/AAC.02151-13. PMC 4023800. PMID 24492369.
  19. ^ a b 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.
  20. ^ Miller B, Hershberger E, Benziger D, Trinh M, Friedland I (June 2012). "Pharmacokinetics and safety of intravenous ceftolozane-tazobactam in healthy adult subjects following single and multiple ascending doses". Antimicrobial Agents and Chemotherapy. 56 (6): 3086–91. doi:10.1128/AAC.06349-11. PMC 3370713. PMID 22450972.
  21. ^ "Medical review" (PDF). fda.gov.
  22. ^ a b Sorbera M, Chung E, Ho CW, Marzella N (December 2014). "Ceftolozane/Tazobactam: a new option in the treatment of complicated gram-negative infections". Pharmacy & Therapeutics. 39 (12): 825–32. PMC 4264669. PMID 25516692.
  23. ^ U. S. Patent Application No. WO2016025839 (A1) 2016

ceftolozane, tazobactam, sold, under, brand, name, zerbaxa, fixed, dose, combination, antibiotic, medication, used, treatment, complicated, urinary, tract, infections, complicated, intra, abdominal, infections, adults, ceftolozane, cephalosporin, antibiotic, d. 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 5 4 6 Ceftolozane is a cephalosporin antibiotic developed for the treatment of infections with gram negative bacteria that are resistant to conventional antibiotics 7 It was studied for urinary tract infections intra abdominal infections and ventilator associated bacterial pneumonia Ceftolozane tazobactamCombination ofCeftolozaneCephalosporin antibioticTazobactamBeta lactamase inhibitorClinical dataTrade namesZerbaxaAHFS Drugs comMonographMedlinePlusa615010License dataUS DailyMed Ceftolozane and tazobactamPregnancycategoryAU B1 1 Routes ofadministrationIntravenousATC codeJ01DI54 WHO Legal statusLegal statusAU S4 Prescription only 2 CA only 3 US only EU Rx only 4 In general Prescription only IdentifiersPubChem CID53234134ChemSpider25999973KEGGD10577Chemical and physical dataFormulaC 23H 30N 12O 8S 2Molar mass666 69 g mol 13D model JSmol Interactive imageSMILES 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 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 s1Key JHFNIHVVXRKLEF DCZLAGFPSA NThe most common side effects include nausea feeling sick headache constipation diarrhea and fever 4 6 Ceftolozane is a type of antibiotic called a cephalosporin which belongs to the wider group of antibiotics called beta lactams 4 It works by interfering with the production of molecules that bacteria need to build their protective cell walls 4 This causes weakness in the bacterial cell walls which then become prone to collapse ultimately leading to the death of the bacteria 4 Tazobactam blocks the action of bacterial enzymes called beta lactamases 4 These enzymes enable bacteria to break down beta lactam antibiotics like ceftolozane making the bacteria resistant to the antibiotic s action 4 By blocking the action of these enzymes tazobactam allows ceftolozane to act against bacteria that would otherwise be resistant to ceftolozane 4 Ceftolozane is combined with the b lactamase inhibitor tazobactam which protects ceftolozane from degradation 8 It was approved for medical use in the United States in December 2014 6 9 and in the European Union in September 2015 4 It is on the World Health Organization s List of Essential Medicines 10 Contents 1 Medical uses 2 Chemical structure 3 Mechanism of action 4 Pharmacokinetics 4 1 Absorption and distribution 4 2 Metabolism and elimination 5 Spectrum of activity 6 Adverse drug reactions 7 Drug interactions 8 Chemical synthesis 9 History 10 ReferencesMedical uses editCeftolozane tazobactam is indicated for the treatment of the following infections in adults caused by designated susceptible microorganisms Complicated intra abdominal infections 4 5 Acute pyelonephritis 4 5 Complicated urinary tract infections 4 5 Hospital acquired bacterial pneumonia and Ventilator associated bacterial pneumonia HABP VABP 5 Chemical structure editCeftolozane contains a 7 aminothiadiazole affording increased activity against gram negative organisms as well as an alkoximino group providing stability against many b 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 b lactam ring via steric hindrance 11 Tazobactam is a penicillinate sulfone b lactamase inhibitor which prevents hydrolysis of the amide bond of the b lactam molecules by b lactamase enzymes 12 Mechanism of action editCeftolozane 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 13 14 Tazobactam is a potent b lactamase inhibitor of most common class A and C b 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 b lactamases certain penicillinases and cephalosporinases and can covalently bind to some chromosomal and plasmid mediated bacterial beta lactamases 13 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 15 Pharmacokinetics editAbsorption and distribution edit 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 16 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 15 Metabolism and elimination edit The metabolism and excretion of ceftolozane are similar to those of most b lactam antimicrobial agents Ceftolozane is not metabolized to any significant extent and thus predominantly eliminated unchanged in the urine 17 18 Tazobactam is partially metabolized to an inactive metabolite and both drug and metabolite are excreted in the urine 80 as unchanged drug 19 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 20 19 Spectrum of activity editThe in vitro activity of ceftolozane tazobactam has been examined in five surveillance studies of isolates from Europe and North America 21 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 mg 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 lt 1 mg 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 gt 32 mg mL citation needed Adverse drug reactions editThe 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 22 Drug interactions editBased 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 b 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 22 Chemical synthesis editResearchers 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 23 History editThe 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 6 Participants were randomly assigned to receive ceftolozane tazobactam plus metronidazole or meropenem 6 Results showed ceftolozane tazobactam plus metronidazole was effective for the treatment of cIAI 6 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 6 Ceftolozane tazobactam demonstrated it was effective in treating cUTI 6 Ceftolozane tazobactam was shown to be at least as effective as other antibiotics in curing infections in three main studies 4 One study involved 1 083 participants who mostly had kidney infection or in some cases a complicated urinary tract infection 4 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 4 The second study involved 993 participants with complicated intra abdominal infections 4 Ceftolozane tazobactam was compared with another antibiotic meropenem 4 Both medicines cured 94 of participants 353 out of 375 given ceftolozane tazobactam and 375 out of 399 given meropenem 4 The third study involved 726 participants who were using a ventilator and who had either hospital acquired pneumonia or ventilator associated pneumonia 4 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 4 References edit Ceftolozane tazobactam Zerbaxa Use During Pregnancy Drugs com 14 June 2019 Retrieved 14 May 2020 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 Health Canada New Drug Authorizations 2015 Highlights Health Canada 4 May 2016 Retrieved 7 April 2024 a b c d e f g h i j k l m n o p q r s t u Zerbaxa EPAR European Medicines Agency EMA 17 September 2018 Retrieved 14 May 2020 Text was copied from this source which is c European Medicines Agency Reproduction is authorized provided the source is acknowledged a b c d e Zerbaxa ceftolozane and tazobactam injection powder lyophilized for solution DailyMed 3 June 2019 Retrieved 14 May 2020 a b c d e f g h 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 nbsp This article incorporates text from this source which is in the public domain Long TE Williams JT October 2014 Cephalosporins currently in early clinical trials for the treatment of bacterial infections Expert Opinion on Investigational Drugs 23 10 1375 87 doi 10 1517 13543784 2014 930127 PMID 24956017 S2CID 5234167 Zhanel GG Chung P Adam H Zelenitsky S Denisuik A Schweizer F et al January 2014 Ceftolozane tazobactam a novel cephalosporin b lactamase inhibitor combination with activity against multidrug resistant gram negative bacilli Drugs 74 1 31 51 doi 10 1007 s40265 013 0168 2 PMID 24352909 S2CID 44694926 Drug Approval Package Zerbaxa ceftolozane tazobactam Injection NDA 206829 U S Food and Drug Administration FDA 24 December 1999 Retrieved 14 May 2020 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 Murano K Yamanaka T Toda A Ohki H Okuda S Kawabata K et al March 2008 Structural requirements for the stability of novel cephalosporins to AmpC beta lactamase based on 3D structure Bioorganic amp Medicinal Chemistry 16 5 2261 75 doi 10 1016 j bmc 2007 11 074 PMID 18082409 Drawz SM Bonomo RA January 2010 Three decades of beta lactamase inhibitors Clinical Microbiology Reviews 23 1 160 201 doi 10 1128 CMR 00037 09 PMC 2806661 PMID 20065329 a b Shortridge D Pfaller MA Castanheira M Flamm RK June 2018 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 Microbial Drug Resistance 24 5 563 577 doi 10 1089 mdr 2017 0266 PMID 29039729 S2CID 4873637 Snydman DR McDermott LA Jacobus NV February 2014 Activity of ceftolozane tazobactam against a broad spectrum of recent clinical anaerobic isolates Antimicrobial Agents and Chemotherapy 58 2 1218 23 doi 10 1128 AAC 02253 13 PMC 3910869 PMID 24277025 a b Hong MC Hsu DI Bounthavong M November 2013 Ceftolozane tazobactam a novel antipseudomonal cephalosporin and b lactamase inhibitor combination Infection and Drug Resistance 6 215 23 doi 10 2147 idr s36140 PMC 3848746 PMID 24348053 Cluck D Lewis P Stayer B Spivey J Moorman J December 2015 Ceftolozane tazobactam A new generation cephalosporin American Journal of Health System Pharmacy 72 24 2135 46 doi 10 2146 ajhp150049 PMID 26637512 Chandorkar G Xiao A Mouksassi MS Hershberger E Krishna G February 2015 Population pharmacokinetics of ceftolozane tazobactam in healthy volunteers subjects with varying degrees of renal function and patients with bacterial infections Journal of Clinical Pharmacology 55 2 230 9 doi 10 1002 jcph 395 PMC 4303958 PMID 25196976 Wooley M Miller B Krishna G Hershberger E Chandorkar G 2014 04 01 Impact of renal function on the pharmacokinetics and safety of ceftolozane tazobactam Antimicrobial Agents and Chemotherapy 58 4 2249 55 doi 10 1128 AAC 02151 13 PMC 4023800 PMID 24492369 a b 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 Miller B Hershberger E Benziger D Trinh M Friedland I June 2012 Pharmacokinetics and safety of intravenous ceftolozane tazobactam in healthy adult subjects following single and multiple ascending doses Antimicrobial Agents and Chemotherapy 56 6 3086 91 doi 10 1128 AAC 06349 11 PMC 3370713 PMID 22450972 Medical review PDF fda gov a b Sorbera M Chung E Ho CW Marzella N December 2014 Ceftolozane Tazobactam a new option in the treatment of complicated gram negative infections Pharmacy amp Therapeutics 39 12 825 32 PMC 4264669 PMID 25516692 U S Patent Application No WO2016025839 A1 2016 Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Ceftolozane tazobactam amp oldid 1218178709, wikipedia, wiki, book, books, library,

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