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Zerbaxa was approved in 2014 for complicated urinary tract infections and intra-abdominal infections. It received an updated FDA indication in 2019 for hospital acquired and ventilator associated pneumonia
m Added description of the chemical structure, mechanism of action, pharmacokinetics and drug interactions and reactions of Zerbaxa
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Ceftolozane is combined with the [[beta-lactamase|β-lactamase]] inhibitor [[tazobactam]], which protects ceftolozane from degradation.<ref>{{cite journal |last1=Zhanel |first1=GG |last2=Chung |first2=P |last3=Adam |first3=H |last4=Zelenitsky |first4=S |last5=Denisuik |first5=A |last6=Schweizer |first6=F |last7=Lagacé-Wiens |first7=PR |last8=Rubinstein |first8=E |last9=Gin |first9=AS |last10=Walkty |first10=A |last11=Hoban |first11=DJ |last12=Lynch JP |first12=3rd |last13=Karlowsky |first13=JA |title=Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. |journal=Drugs |date=January 2014 |volume=74 |issue=1 |pages=31-51 |doi=10.1007/s40265-013-0168-2 |pmid=24352909}}</ref> It was approved for medical use in the United States in 2014.
Ceftolozane is combined with the [[beta-lactamase|β-lactamase]] inhibitor [[tazobactam]], which protects ceftolozane from degradation.<ref>{{cite journal |last1=Zhanel |first1=GG |last2=Chung |first2=P |last3=Adam |first3=H |last4=Zelenitsky |first4=S |last5=Denisuik |first5=A |last6=Schweizer |first6=F |last7=Lagacé-Wiens |first7=PR |last8=Rubinstein |first8=E |last9=Gin |first9=AS |last10=Walkty |first10=A |last11=Hoban |first11=DJ |last12=Lynch JP |first12=3rd |last13=Karlowsky |first13=JA |title=Ceftolozane/tazobactam: a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli. |journal=Drugs |date=January 2014 |volume=74 |issue=1 |pages=31-51 |doi=10.1007/s40265-013-0168-2 |pmid=24352909}}</ref> It was approved for medical use in the United States in 2014.

== 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 ''P. 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.<ref>{{Cite journal|last=Murano|first=Kenji|last2=Yamanaka|first2=Toshio|last3=Toda|first3=Ayako|last4=Ohki|first4=Hidenori|last5=Okuda|first5=Shinya|last6=Kawabata|first6=Kohji|last7=Hatano|first7=Kazuo|last8=Takeda|first8=Shinobu|last9=Akamatsu|first9=Hisashi|date=2008-03-01|title=Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure|url=http://www.sciencedirect.com/science/article/pii/S0968089607010425|journal=Bioorganic & Medicinal Chemistry|volume=16|issue=5|pages=2261–2275|doi=10.1016/j.bmc.2007.11.074|issn=0968-0896}}</ref>

Tazobactam is a penicillinate sul­fone β-lactamase inhibitor, which confers protection to the β-lactam ring.<ref>{{Cite journal|last=Bonomo|first=Robert A.|last2=Drawz|first2=Sarah M.|date=2010-01-01|title=Three Decades of β-Lactamase Inhibitors|url=https://cmr.asm.org/content/23/1/160|journal=Clinical Microbiology Reviews|language=en|volume=23|issue=1|pages=160–201|doi=10.1128/CMR.00037-09|issn=0893-8512|pmid=20065329}}</ref>

== 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 ''P. aeruginosa'' (e.g. PBP1b, PBP1c, and PBP3) and ''E. coli'' (e.g., PBP3).<ref name=":0">{{Cite journal|last=Shortridge|first=Dee|last2=Pfaller|first2=Michael A.|last3=Castanheira|first3=Mariana|last4=Flamm|first4=Robert K.|date=2018-6|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|url=http://www.liebertpub.com/doi/10.1089/mdr.2017.0266|journal=Microbial Drug Resistance|language=en|volume=24|issue=5|pages=563–577|doi=10.1089/mdr.2017.0266|issn=1076-6294}}</ref><ref>{{Cite journal|last=Snydman|first=David R.|last2=McDermott|first2=Laura A.|last3=Jacobus|first3=Nilda V.|date=2014-2|title=Activity of Ceftolozane-Tazobactam against a Broad Spectrum of Recent Clinical Anaerobic Isolates|url=http://aac.asm.org/lookup/doi/10.1128/AAC.02253-13|journal=Antimicrobial Agents and Chemotherapy|language=en|volume=58|issue=2|pages=1218–1223|doi=10.1128/AAC.02253-13|issn=0066-4804}}</ref>

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-lactamase (certain penicillinases and cephalosporinases) and can covalently bind to some chromosomal and plasmid-mediated bacterial beta-lactamases.<ref name=":0" />

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 <ref>{{Cite web|url=https://www.dovepress.com/ceftolozanetazobactam-a-novel-antipseudomonal-cephalosporin-and-beta-l-peer-reviewed-article-IDR|title=Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and &beta;-lactamase-inhibitor combination|last=Bounthavong|first=Mark|last2=Hsu|first2=Donald I.|date=2013-11-29|website=Infection and Drug Resistance|language=English|doi=10.2147/idr.s36140|access-date=2019-06-23|last3=Hong|first3=Mai-Chi}}</ref>
<br />

== 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)<ref>{{Cite journal|last=Moorman|first=Jonathan|last2=Spivey|first2=Justin|last3=Stayer|first3=Brooke|last4=Lewis|first4=Paul|last5=Cluck|first5=David|date=2015-12-15|title=Ceftolozane–tazobactam: A new-generation cephalosporin|url=https://academic.oup.com/ajhp/article/72/24/2135/5111554|journal=American Journal of Health-System Pharmacy|language=en|volume=72|issue=24|pages=2135–2146|doi=10.2146/ajhp150049|issn=1079-2082}}</ref>. 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 (''t''max) 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.<ref>{{Cite web|url=https://www.dovepress.com/ceftolozanetazobactam-a-novel-antipseudomonal-cephalosporin-and-beta-l-peer-reviewed-article-IDR|title=Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and &beta;-lactamase-inhibitor combination|last=Bounthavong|first=Mark|last2=Hsu|first2=Donald I.|date=2013-11-29|website=Infection and Drug Resistance|language=English|doi=10.2147/idr.s36140|access-date=2019-06-23|last3=Hong|first3=Mai-Chi}}</ref>

=== Metabolism and elimination ===
The metabolism and excretion of ceftolo­zane are similar to those of most b-lactam antimicrobial agents. Certolozane is not metabolized to any significant extent and thus predominantly eliminated unchanged in the urine. <ref>{{Cite journal|last=Chandorkar|first=Gurudatt|last2=Xiao|first2=Alan|last3=Mouksassi|first3=Mohamad-Samer|last4=Hershberger|first4=Ellie|last5=Krishna|first5=Gopal|date=2015-2|title=Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections|url=http://doi.wiley.com/10.1002/jcph.395|journal=The Journal of Clinical Pharmacology|language=en|volume=55|issue=2|pages=230–239|doi=10.1002/jcph.395}}</ref><ref>{{Cite journal|last=Chandorkar|first=Gurudatt|last2=Hershberger|first2=Ellie|last3=Krishna|first3=Gopal|last4=Miller|first4=Benjamin|last5=Wooley|first5=Myra|date=2014-04-01|title=Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam|url=https://aac.asm.org/content/58/4/2249|journal=Antimicrobial Agents and Chemotherapy|language=en|volume=58|issue=4|pages=2249–2255|doi=10.1128/AAC.02151-13|issn=0066-4804|pmid=24492369}}</ref> Tazobac­tam is partially metabolized to an in­active metabolite, and both drug and metabolite are excreted in the urine (80% as unchanged drug).<ref name=":1">{{Cite web|url=https://www.dovepress.com/ceftolozanetazobactam-and-ceftazidimeavibactam-for-the-treatment-of-co-peer-reviewed-article-TCRM|title=Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections|last=Nailor|first=Michael D.|last2=Nicolau|first2=David P.|date=2016-12-01|website=Therapeutics and Clinical Risk Management|language=English|doi=10.2147/tcrm.s120811|access-date=2019-06-23|last3=Goodlet|first3=Kellie J.}}</ref>

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.<ref>{{Cite journal|last=Friedland|first=Ian|last2=Trinh|first2=MyMy|last3=Benziger|first3=David|last4=Hershberger|first4=Ellie|last5=Miller|first5=Benjamin|date=2012-06-01|title=Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses|url=https://aac.asm.org/content/56/6/3086|journal=Antimicrobial Agents and Chemotherapy|language=en|volume=56|issue=6|pages=3086–3091|doi=10.1128/AAC.06349-11|issn=0066-4804|pmid=22450972}}</ref><ref name=":1" />


==Spectrum of activity==
==Spectrum of activity==
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In these same studies, ceftolozane–tazobactam exhibited MIC<sub>90</sub> values of <1&nbsp;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 MIC<sub>90</sub> for [[extended spectrum beta-lactamase]] (ESBL) expressing ''[[Klebsiella pneumonia]]'' being >32&nbsp;μg/mL.
In these same studies, ceftolozane–tazobactam exhibited MIC<sub>90</sub> values of <1&nbsp;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 MIC<sub>90</sub> for [[extended spectrum beta-lactamase]] (ESBL) expressing ''[[Klebsiella pneumonia]]'' being >32&nbsp;μg/mL.

== Adverse drug reactions ==
The adverse-event (AE) 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%).<ref name=":2">{{Cite journal|last=Sorbera|first=Maria|last2=Chung|first2=Elizabeth|last3=Ho|first3=Christopher W.|last4=Marzella|first4=Nino|date=2014|title=Ceftolozane/Tazobactam: A New Option in the Treatment of Complicated Gram-Negative Infections|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264669/|journal=Pharmacy and Therapeutics|volume=39 (12)|pages=825,828-832|pmc=PMC4264669|pmid=25516692|via=NCBI-NIH}}</ref>

== 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 (BLIs) 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.

<ref name=":2" />


==References==
==References==

Revision as of 16:43, 23 June 2019

Ceftolozane/tazobactam
Clinical data
Trade namesZerbaxa
License data
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
  • US: Approved January 2015
Identifiers
  • (6R,7R)-3-([3-Amino-4-(2-aminoethylcarbamoylamino)-2-methylpyrazol-1-ium-1-yl]methyl)-7-([(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
CAS Number
PubChem CID
ChemSpider
KEGG
Chemical and physical data
FormulaC23H30N12O8S2
Molar mass666.689 g/mol 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 (TOL-TAZ), sold under the brand name Zerbaxa, is a combination antibiotic. It is used for the treatment of complicated urinary tract infections and complicated intra abdominal infections.[1] Ceftolozane is a cephalosporin antibiotic, developed for the treatment of infections with gram-negative bacteria that have become resistant to conventional antibiotics.[2] It was studied for urinary tract infections, intra-abdominal infections and ventilator-associated bacterial pneumonia.

Ceftolozane is combined with the β-lactamase inhibitor tazobactam, which protects ceftolozane from degradation.[3] It was approved for medical use in the United States in 2014.

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 P. 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.[4]

Tazobactam is a penicillinate sul­fone β-lactamase inhibitor, which confers protection to the β-lactam ring.[5]

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 P. aeruginosa (e.g. PBP1b, PBP1c, and PBP3) and E. coli (e.g., PBP3).[6][7]

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-lactamase (certain penicillinases and cephalosporinases) and can covalently bind to some chromosomal and plasmid-mediated bacterial beta-lactamases.[6]

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 [8]

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)[9]. 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 (tmax) 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.[10]

Metabolism and elimination

The metabolism and excretion of ceftolo­zane are similar to those of most b-lactam antimicrobial agents. Certolozane is not metabolized to any significant extent and thus predominantly eliminated unchanged in the urine. [11][12] Tazobac­tam is partially metabolized to an in­active metabolite, and both drug and metabolite are excreted in the urine (80% as unchanged drug).[13]

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.[14][13]

Spectrum of activity

The in vitro activity of ceftolozane–tazobactam has been examined in five surveillance studies of isolates from Europe and North America.[15] In these studies, ceftolozane–tazobactam was notable for its activity against Pseudomonas aeruginosa, a moderately common cause of hospital-acquired infections that is commonly multi-drug resistant. Ninety percent of P. 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.

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 (ESBL) expressing Klebsiella pneumonia being >32 μg/mL.

Adverse drug reactions

The adverse-event (AE) 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%).[16]

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 (BLIs) 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.

[16]

References

  1. ^ [1][dead link]
  2. ^ Long, T. E.; Williams, J. T. (2014). "Cephalosporins currently in early clinical trials for the treatment of bacterial infections". Expert Opinion on Investigational Drugs. 23 (10): 1375. doi:10.1517/13543784.2014.930127.
  3. ^ Zhanel, GG; Chung, P; Adam, H; Zelenitsky, S; Denisuik, A; Schweizer, F; Lagacé-Wiens, PR; Rubinstein, E; Gin, AS; Walkty, A; Hoban, DJ; Lynch JP, 3rd; Karlowsky, JA (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.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  4. ^ Murano, Kenji; Yamanaka, Toshio; Toda, Ayako; Ohki, Hidenori; Okuda, Shinya; Kawabata, Kohji; Hatano, Kazuo; Takeda, Shinobu; Akamatsu, Hisashi (2008-03-01). "Structural requirements for the stability of novel cephalosporins to AmpC β-lactamase based on 3D-structure". Bioorganic & Medicinal Chemistry. 16 (5): 2261–2275. doi:10.1016/j.bmc.2007.11.074. ISSN 0968-0896.
  5. ^ Bonomo, Robert A.; Drawz, Sarah M. (2010-01-01). "Three Decades of β-Lactamase Inhibitors". Clinical Microbiology Reviews. 23 (1): 160–201. doi:10.1128/CMR.00037-09. ISSN 0893-8512. PMID 20065329.
  6. ^ a b Shortridge, Dee; Pfaller, Michael A.; Castanheira, Mariana; Flamm, Robert K. (2018-6). "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. ISSN 1076-6294. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Snydman, David R.; McDermott, Laura A.; Jacobus, Nilda V. (2014-2). "Activity of Ceftolozane-Tazobactam against a Broad Spectrum of Recent Clinical Anaerobic Isolates". Antimicrobial Agents and Chemotherapy. 58 (2): 1218–1223. doi:10.1128/AAC.02253-13. ISSN 0066-4804. {{cite journal}}: Check date values in: |date= (help)
  8. ^ Bounthavong, Mark; Hsu, Donald I.; Hong, Mai-Chi (2013-11-29). "Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination". Infection and Drug Resistance. doi:10.2147/idr.s36140. Retrieved 2019-06-23.{{cite web}}: CS1 maint: unflagged free DOI (link)
  9. ^ Moorman, Jonathan; Spivey, Justin; Stayer, Brooke; Lewis, Paul; Cluck, David (2015-12-15). "Ceftolozane–tazobactam: A new-generation cephalosporin". American Journal of Health-System Pharmacy. 72 (24): 2135–2146. doi:10.2146/ajhp150049. ISSN 1079-2082.
  10. ^ Bounthavong, Mark; Hsu, Donald I.; Hong, Mai-Chi (2013-11-29). "Ceftolozane/tazobactam: a novel antipseudomonal cephalosporin and β-lactamase-inhibitor combination". Infection and Drug Resistance. doi:10.2147/idr.s36140. Retrieved 2019-06-23.{{cite web}}: CS1 maint: unflagged free DOI (link)
  11. ^ Chandorkar, Gurudatt; Xiao, Alan; Mouksassi, Mohamad-Samer; Hershberger, Ellie; Krishna, Gopal (2015-2). "Population pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with varying degrees of renal function and patients with bacterial infections". The Journal of Clinical Pharmacology. 55 (2): 230–239. doi:10.1002/jcph.395. {{cite journal}}: Check date values in: |date= (help)
  12. ^ Chandorkar, Gurudatt; Hershberger, Ellie; Krishna, Gopal; Miller, Benjamin; Wooley, Myra (2014-04-01). "Impact of Renal Function on the Pharmacokinetics and Safety of Ceftolozane-Tazobactam". Antimicrobial Agents and Chemotherapy. 58 (4): 2249–2255. doi:10.1128/AAC.02151-13. ISSN 0066-4804. PMID 24492369.
  13. ^ a b Nailor, Michael D.; Nicolau, David P.; Goodlet, Kellie J. (2016-12-01). "Ceftolozane/tazobactam and ceftazidime/avibactam for the treatment of complicated intra-abdominal infections". Therapeutics and Clinical Risk Management. doi:10.2147/tcrm.s120811. Retrieved 2019-06-23.{{cite web}}: CS1 maint: unflagged free DOI (link)
  14. ^ Friedland, Ian; Trinh, MyMy; Benziger, David; Hershberger, Ellie; Miller, Benjamin (2012-06-01). "Pharmacokinetics and Safety of Intravenous Ceftolozane-Tazobactam in Healthy Adult Subjects following Single and Multiple Ascending Doses". Antimicrobial Agents and Chemotherapy. 56 (6): 3086–3091. doi:10.1128/AAC.06349-11. ISSN 0066-4804. PMID 22450972.
  15. ^ "Medical review" (PDF).
  16. ^ a b Sorbera, Maria; Chung, Elizabeth; Ho, Christopher W.; Marzella, Nino (2014). "Ceftolozane/Tazobactam: A New Option in the Treatment of Complicated Gram-Negative Infections". Pharmacy and Therapeutics. 39 (12): 825, 828–832. PMC 4264669. PMID 25516692 – via NCBI-NIH.{{cite journal}}: CS1 maint: PMC format (link)
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