593293
research-article2015
AOPXXX10.1177/1060028015593293Annals of PharmacotherapySucher et al
Review Article (Formulary Forum/ New Drug Approvals/ Drug Selection Perspectives)
Ceftolozane/Tazobactam: A New Cephalosporin and β-Lactamase Inhibitor Combination
Annals of Pharmacotherapy 1–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015593293 aop.sagepub.com
Allana J. Sucher, PharmD, BCPS1, Elias B. Chahine, PharmD, BCPS (AQ-ID)2, Peter Cogan, PhD1, and Matthew Fete, PhD1
Abstract Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of ceftolozane/tazobactam, a new antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. Data Sources: A literature search through clinicaltrials.gov and PubMed was conducted (January 2007-May 2015) using the search terms ceftolozane, ceftolozane/tazobactam, FR264205, CXA-101/ tazobactam, and CXA-201. References from retrieved articles and abstracts presented at recent meetings were reviewed to identify additional material. The prescribing information was also reviewed. Study Selection and Data Extraction: Preclinical data as well as phase 1, 2, and 3 studies published in English were evaluated. Data Synthesis: Ceftolozane/ tazobactam displays enhanced potency against Pseudomonas aeruginosa in vitro. Clinical trials have shown that ceftolozane/ tazobactam is noninferior to levofloxacin for the treatment of complicated urinary tract infections (76.9% vs 68.4%, 95% CI = 2.3-14.6) and when used in combination with metronidazole is noninferior to meropenem for the treatment of complicated intra-abdominal infections (83% vs 87.3%, 95% CI = −8.91 to 0.54). An alternate antibiotic should be considered in patients who have a severe β-lactam allergy or an estimated creatinine clearance between 30 and 50 mL/ min. Ceftolozane/tazobactam is well tolerated, with few drug interactions and no effects on the cytochrome P450 system. Conclusions: In an era of increasing resistance to antimicrobials, ceftolozane/tazobactam provides clinicians with an additional treatment option for infections caused by multidrug-resistant Gram-negative organisms, including extendedspectrum β-lactamase–producing bacteria and Pseudomonas aeruginosa. Keywords antibiotics, infectious disease, β-lactams, cephalosporins, antibiotic resistance
Introduction In response to increasing rates of drug-resistant infections, the Infectious Diseases Society of America (IDSA) launched the 10 × ’20 Initiative in 2010, a campaign that called for global commitment to develop 10 novel, safe, and effective antibiotics by the year 2020.1 This initiative focused on the development of antibiotics to target the increasingly resistant ESKAPE pathogens, which is an acronym that stands for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.1,2 In a 2013 update of this initiative, the IDSA stressed the need for new antimicrobial agents to treat Gram-negative organisms, including multidrug-resistant (MDR) pathogens.1,3,4 The Centers for Disease Control and Prevention (CDC) has recently classified extended-spectrum β-lactamases (ESBLs) and MDR Pseudomonas aeruginosa as serious threats, which are
defined as significant antibiotic-resistant threats that have the potential to worsen without ongoing public health monitoring and prevention activities.5 According to the CDC, there are approximately 140 000 health care–associated Enterobacteriaceae infections annually in the United States, and of these, almost 26 000 infections (19%) are caused by ESBL-producing microorganisms. In addition, there are approximately 51 000 health care–associated infections caused by Pseudomonas aeruginosa annually in the United States, and more than 6000 of these infections (13%) are 1
Regis University School of Pharmacy, Denver, CO, USA Palm Beach Atlantic University School of Pharmacy, West Palm Beach, FL, USA 2
Corresponding Author: Allana J. Sucher, Regis University School of Pharmacy, 3333 Regis Blvd, H-28, Denver, CO 80221-1099, USA. Email: [email protected]
Downloaded from aop.sagepub.com at MOUNT ALLISON UNIV on July 10, 2015
2
Annals of Pharmacotherapy O H N
HO O
NH2
O N N
NH
H
H N
S
H 2N S
N
N
N
O
N
O O
NH2
O-
Figure 1. Chemical structure of ceftolozane.a
caused by MDR strains.5 Because of their increasing prevalence in the United States and worldwide, it is important to have antimicrobial agents that are effective against infections caused by these pathogens.6,7 This article provides a comprehensive clinical review of ceftolozane/tazobactam (Zerbaxa, Cubist Pharmaceuticals, Inc), a new antipseudomonal cephalosporin combined with a well- established β-lactamase inhibitor that was developed to target resistant strains of Pseudomonas aeruginosa while maintaining low convulsion-inducing activity.8,9 Ceftolozane was previously known as FR264205 and CXA-101, and the combination of ceftolozane/tazobactam was formerly known as CXA-201.10,11 Ceftolozane/tazobactam was approved on December 19, 2014, for the treatment of adults with complicated urinary tract infections (cUTIs) and in combination with metronidazole for the treatment of adults with complicated intra-abdominal infections (cIAIs).12 Agents such as ceftolozane/tazobactam that have been designated as a Qualified Infectious Disease Product under the Generating Antibiotic Incentives Now (GAIN) Act are given priority and expedited review as well as an additional 5 years of marketing exclusivity.12
A search of PubMed (January 2007-May 2015) using the search terms ceftolozane, ceftolozane/tazobactam, FR264205, CXA-101/tazobactam, and CXA-201 was performed. All data available in English were reviewed. Supplementary sources included abstracts and poster presentations from Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and IDWeek as well as information available from the manufacturer.
interferes with peptidoglycan cross-linking of the bacterial cell wall, causing eventual cell lysis.13 Tazobactam is an irreversible inhibitor of β-lactamase enzymes. Similar to other β-lactamase inhibitors, tazobactam has no antimicrobial activity when used as monotherapy. When given in combination with a β-lactam antibiotic, tazobactam is effective against Gram-negative organisms expressing class A β-lactamases, including narrow-spectrum β-lactamases and ESBLs that are predominantly produced by Enterobacteriaceae.14,15 Ceftolozane was discovered through an exercise in structure activity relationships focused on the development of cephalosporins with high affinity for PBPs, increased outermembrane permeability, improved stability toward AmpC β-lactamase-producing microorganisms, and good activity against Pseudomonas aeruginosa.8 Figure 1 highlights the structural features that correspond to these attributes. The oxime functionality is also common to most third- and fourth-generation cephalosporins and has been shown to improve β-lactamase stability.16 The dimethylacetic acid moiety is also present in ceftazidime and has been associated with high affinity for PBPs and enhanced activity against Pseudomonas aeruginosa.17 The thiadiazole present in ceftolozane’s structure, similar to the thiazole ring found in most extended-spectrum cephalosporins, is also present in ceftaroline and has been shown to increase activity against Gram-negative bacilli.18 The primary difference between ceftolozane and other late-generation cephalosporins is the incorporation of a substituted, 2-methylpyrazole ring at position 3 of the dihydrothiazine portion of the bicyclic ring system, which proved to have the optimal balance of activity against AmpC β-lactamase-producing Pseudomonas aeruginosa and the weakest convulsion-inducing effects.8
Chemistry and Pharmacology
Microbiology
Ceftolozane, like other cephalosporins, is a β-lactam antibiotic that binds penicillin-binding proteins (PBPs) and
Ceftolozane/tazobactam displays bactericidal activity both in vitro and in vivo activity against Enterobacter cloacae,
Data Sources
Downloaded from aop.sagepub.com at MOUNT ALLISON UNIV on July 10, 2015
3
Sucher et al Table 1. Interpretation of Minimum Inhibitory Concentrations for Ceftolozane/Tazobactam.a MICs (µg/mL) Pathogen b
Enterobacteriaceae Pseudomonas aeruginosa Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius Bacteroides fragilis
S
I
R
≤2/4 ≤4/4 ≤8/4 ≤8/4
4/4 8/4 16/4 16/4
≥8/4 ≥16/4 ≥32/4 ≥32/4
Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S, sensitive. a Source: Information from Zerbaxa.9 b This includes Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K pneumoniae, and Proteus mirabilis.
Escherichia coli, Klebsiella oxytoca, K pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Streptococcus anginosus, Streptococcus constellatus, Streptococcus salivarius, and Bacteroides fragilis, and it is approved by the Food and Drug Administration (FDA) for the treatment of cIAIs caused by these pathogens when used in combination with metronidazole.9 Ceftolozane/tazobactam is also approved by the FDA for the treatment of cUTIs, including pyelonephritis, caused by Escherichia coli, K pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.9 Table 1 includes the interpretation of the minimum inhibitory concentrations (MICs) of ceftolozane/tazobactam for these organisms. Standardized testing methods are recommended to determine the susceptibility of anaerobic bacteria such as B fragilis to ceftolozane/tazobactam.9 The MIC50 and MIC90 values for the bacteria for which ceftolozane/tazobactam is approved are included in Table 2.19,20 In clinical trials, ceftolozane/tazobactam was shown to be active against some strains of Escherichia coli and K pneumoniae that produced β-lactamases, including class A narrow-spectrum and ESBLs as well as class D oxa-type β-lactamase enzymes.9,15 Ceftolozane/tazobactam has in vitro activity against isolates of Pseudomonas aeruginosa that contain chromosomal class C ampC enzymes, which typically confer resistance to extended-spectrum cephalosporins and may lead to resistance to carbapenems if present in high levels and with another mechanism of resistance. In addition, ceftolozane/tazobactam has in vitro activity against isolates of Pseudomonas aeruginosa that have upregulation of efflux pumps or loss of outer-membrane porin, both of which confer antibiotic resistance.9,15 Ceftolozane/tazobactam is not active against Enterobacteriaceae that produce class A serine carbapenemases (eg, K pneumoniae carbapenemases) or organisms that produce class B metallo-β-lactamases.9,15
Resistance Reported mechanisms of resistance to β-lactams such as ceftolozane/tazobactam include β-lactamase production, PBP alteration, upregulation of efflux pumps, and outer membrane porin loss.13,14
Takeda et al21 investigated the effects of β-lactamase production, efflux pump expression, membrane protein deletion, and spontaneous mutations on antimicrobial activity of ceftolozane in comparison with ceftazidime, imipenem, and ciprofloxacin. They found that the MIC90 of ceftolozane was lower than that of the other agents and that it was less susceptible to AmpC β-lactamase than ceftazidime. Ceftolozane’s activity was not affected by efflux pump expression or deletion of the membrane protein OprD, which are known mechanisms of resistance for Pseudomonas aeruginosa. The frequency of selection for spontaneous mutants (6.1 × 10-9) for plates containing ceftolozane was lower than that of ceftazidime, imipenem, and ciprofloxacin at concentrations of drug that were 4 times the MIC. However, only imipenem displayed activity against strains of Pseudomonas aeruginosa that produced metallo-β-lactamase.21 A follow-up study by Takeda et al22 on the effects of AmpC β-lactamase production on antimicrobial activity found that ceftolozane had higher stability against AmpC β-lactamase than ceftazidime.
Pharmacokinetics Pooled data from 10 pharmacokinetic (PK) studies of ceftolozane administered as monotherapy or as a 2:1 combination with tazobactam point to a 2-compartment PK model characterized by first-order elimination.23 Plasma PK data collected from 2 published phase 1 trials in healthy adults following single and multiple doses of ceftolozane/ tazobactam, including ceftolozane 1000 mg administered as a 1-hour intravenous infusion every 8 hours for 10 days with or without 500 mg tazobactam, are summarized in Table 3.11,24 All examined PK parameters for ceftolozane doses up to 2000 mg as a single dose or 3000 mg daily were found to be dose proportional and linear in studied populations. Additionally, ceftolozane area under the plasma concentration curve (AUC) values showed no significant change over a 10-day treatment course, indicating no appreciable drug accumulation.11,24 Plasma protein binding of ceftolozane is approximately 20%.24 The steady-state volume of distribution roughly approximates the extracellular
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4
Annals of Pharmacotherapy
Table 2. In Vitro Activity of Ceftolozane/Tazobactam Against Approved Microorganisms.19,20 Organism Gram-negative aerobes Enterobacter cloacae Escherichia coli Klebsiella oxytoca K pneumoniae Proteus mirabilis Pseudomonas aeruginosa Gram-positive aerobes Streptococcus salivarius Streptococcus anginosus Streptococcus constellatus Gram-negative anaerobes Bacteroides fragilis
n
MIC50 (µg/mL)
MIC90 (µg/mL)
Range (µg/mL)
2166 9429 899 4410 1600 6316
0.25 0.25 0.25 0.25 0.5 0.5
8 0.5 1 16 0.5 4
0.03 to >64 0.03 to >64 0.03 to >32 0.03 to >64 0.03 to 32 0.03 to >64
1 1 0.5
2 2 2
44 35 14 244
0.12 to 4 ≤0.03 to 4 ≤0.03 to 4 ≤0.125 to ≥256
1
Abbreviations: n, number of isolates; MIC50, minimum inhibitory concentration that inhibits the growth of 50% of organisms; MIC90, minimum inhibitory concentration that inhibits the growth of 90% of organisms.
Table 3. Ceftolozane Plasma Pharmacokinetic Parameters in Healthy Adult Participants After 1000-mg Dose Administered as a 1-Hour IV Infusion Every 8 Hours for 10 Days.11,24 Agent Day 1 C C C+T Day 10 C C C+T
n
Cmax (µg/mL)a
AUC (µg h/mL)a
Clearance (L/h)a
Vss (L)a
t1/2 (hours)a
6b 5d 10d
52.8 ± 12.5 68.8 ± 11.7 69.1 ± 7.8
148.6 ± 27c 168 ± 28.6e 172 ± 23.7e
6.73 ± 1.22 6.01 ± 0.84 5.86 ± 0.80
17.8 ± 3.8 14.1 ± 2.6 14.6 ± 2.3
2.38 ± 0.36 2.30 ± 0.39 2.77 ± 0.83
6b 5d 10d
58.0 ± 6.0 73.4 ± 11.2 74.4 ± 10.1
143.3 ± 22.1c 195 ± 30e 197 ± 33e
6.98 ± 1.07 5.54 ± 0.74 5.58 ± 0.70
17.1 ± 2.3 13.4 ± 2.4 14.2 ± 2.4
2.69 ± 0.65 2.73 ± 0.66 3.12 ± 0.68
Abbreviations: AUC, area under the plasma concentration-time curve; C, ceftolozane; C + T, ceftolozane with 500 mg tazobactam; n, number of participants; Cmax, maximum plasma concentration; IV, intravenous; t1/2, elimination half-life; Vss, volume of distribution at steady state. a Data reported as mean ± SD after first dose (day 1) and after multiple doses (day 10). b Ge et al.24 c AUC0-∞. d Miller et al.11 e AUC0-last.
volume and suggests that ceftolozane can reasonably be expected to distribute to extravascular sites of infection. Increased body weight and active infection both increase the apparent volume of distribution but do not cause any significant changes in steady-state PK parameters such as AUC.23 The total clearance of 1000 mg ceftolozane when administered in combination with 500 mg tazobactam over a 10-day treatment course was found to be 5.86 ± 0.08 L/h on day 1 and 5.58 ± 0.70 L/h on day 10. Renal clearance closely approximated these values (day 1: 5.58 ± 1.34; day 10: 6.80 ± 3.34), indicating that renal excretion was the exclusive route of elimination.11 Additionally, 100% of the administered ceftolozane dose was recovered from urine, primarily unchanged, within 24 hours, proving that ceftolozane is
renally eliminated and does not undergo significant metabolism.11,23 Likewise, clearance of tazobactam occurs primarily through renal excretion, though a single inactive metabolite (M1) results from nonenzymatic hydrolysis of the β-lactam ring.25,26 Compromised renal function has been shown to significantly decrease the clearance of both ceftolozane and tazobactam.26 Compared with individuals with normal renal function, the median AUC for ceftolozane was increased 1.4-fold, 2.5-fold, and 4.4-fold in those with mild, moderate, and severe renal impairment, respectively, and the median AUC for tazobactam was increased 1.2-fold, 2.2fold, and 3.8-fold.26 In those with end-stage renal disease receiving hemodialysis, the AUC of ceftolozane decreased by 66% after dialysis, and the AUC of tazobactam decreased
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5
Sucher et al by 56%.26 Although mild renal impairment does not necessitate a dosage adjustment, patients with a creatinine clearance of 50 mL or less, including those receiving hemodialysis, require a decreased dose.9,26 The dose of ceftolozane/tazobactam should be given at the earliest possible time after completion of dialysis on hemodialysis days.9 No clinically relevant trend on PK parameters of ceftolozane/ tazobactam was observed with regard to age in a population PK analysis, and no dosage adjustment is recommended based on patient age.9,23
Pharmacodynamics As with other β-lactam antibiotics, the percentage of time that ceftolozane plasma concentrations exceed the MIC of a pathogen (%T>MIC) is the best PK correlate to efficacy.27-29 Lepak et al27 exposed 6 strains of Streptococcus pneumoniae and 14 strains of Pseudomonas aeruginosa with varying degrees of β-lactam resistance to ceftolozane monotherapy and found that the mean %T>MIC to achieve stasis and 1log10 killing in Pseudomonas aeruginosa were 31.2 ± 6.99 and 39.4 ± 7.53, respectively.27 As a comparison, the %T>MIC to achieve stasis for ceftazidime against Pseudomonas aeruginosa is 40% to 45%, which may indicate that ceftolozane had more rapid killing kinetics.27,28 Likewise, Craig and Andes28 explored the relationship between %T>MIC and the bactericidal activity of ceftolozane dosed in neutropenic mice every 6 hours against 4 strains of Pseudomonas aeruginosa, 3 strains of Escherichia coli, 5 strains of K pneumoniae, and 1 strain of Enterobacter cloacae, including 5 strains that produced at least 1 ESBL.28 The mean %T>MICs required to achieve stasis and 1log10 killing of non-ESBL strains were 25.2 ± 2.8 and 31.5 ± 2.8, respectively, and were 31.1 ± 4.4 and 34.8 ± 4.9 for ESBLproducing strains. These values were lower than that for other cephalosporins, which have been shown to have mean %T>MIC values of 35% to 43% for stasis, again indicating that ceftolozane may have more rapid killing kinetics.27,28 Another study found greater efficacy of ceftolozane with or without tazobactam compared with piperacillin/ tazobactam, as measured by significantly greater reductions in colony-forming units of non-ESBL expressing organisms in a neutropenic mouse thigh infection model.29 These latter studies also found that the addition of tazobactam at a 2:1 ratio improved the bactericidal activity of ceftolozane against several ESBL-expressing strains.28,29
Clinical Efficacy Table 4 includes the results from 2 phase 3 clinical trials: ASPECT-cIAI and ASPECT-cUTI.30-32 The study comparing ceftolozane/tazobactam with piperacillin/ tazobactam in ventilator-associated pneumonia has been terminated.33
ASPECT-cIAI30 compared ceftolozane/tazobactam plus metronidazole with meropenem in patients with cIAIs. Eligible patients were 18 years of age or older with clinical evidence of cIAI as demonstrated by a performed or planned operative or percutaneous drainage of an infectious focus. Exclusion criteria were cIAI managed by staged abdominal repair in which the fascia was not closed, low likelihood of adequate source control at surgery, creatinine clearance
research-article2015
AOPXXX10.1177/1060028015593293Annals of PharmacotherapySucher et al
Review Article (Formulary Forum/ New Drug Approvals/ Drug Selection Perspectives)
Ceftolozane/Tazobactam: A New Cephalosporin and β-Lactamase Inhibitor Combination
Annals of Pharmacotherapy 1–11 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028015593293 aop.sagepub.com
Allana J. Sucher, PharmD, BCPS1, Elias B. Chahine, PharmD, BCPS (AQ-ID)2, Peter Cogan, PhD1, and Matthew Fete, PhD1
Abstract Objective: To review the chemistry, pharmacology, microbiology, pharmacokinetics, pharmacodynamics, clinical efficacy, tolerability, dosage, and administration of ceftolozane/tazobactam, a new antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. Data Sources: A literature search through clinicaltrials.gov and PubMed was conducted (January 2007-May 2015) using the search terms ceftolozane, ceftolozane/tazobactam, FR264205, CXA-101/ tazobactam, and CXA-201. References from retrieved articles and abstracts presented at recent meetings were reviewed to identify additional material. The prescribing information was also reviewed. Study Selection and Data Extraction: Preclinical data as well as phase 1, 2, and 3 studies published in English were evaluated. Data Synthesis: Ceftolozane/ tazobactam displays enhanced potency against Pseudomonas aeruginosa in vitro. Clinical trials have shown that ceftolozane/ tazobactam is noninferior to levofloxacin for the treatment of complicated urinary tract infections (76.9% vs 68.4%, 95% CI = 2.3-14.6) and when used in combination with metronidazole is noninferior to meropenem for the treatment of complicated intra-abdominal infections (83% vs 87.3%, 95% CI = −8.91 to 0.54). An alternate antibiotic should be considered in patients who have a severe β-lactam allergy or an estimated creatinine clearance between 30 and 50 mL/ min. Ceftolozane/tazobactam is well tolerated, with few drug interactions and no effects on the cytochrome P450 system. Conclusions: In an era of increasing resistance to antimicrobials, ceftolozane/tazobactam provides clinicians with an additional treatment option for infections caused by multidrug-resistant Gram-negative organisms, including extendedspectrum β-lactamase–producing bacteria and Pseudomonas aeruginosa. Keywords antibiotics, infectious disease, β-lactams, cephalosporins, antibiotic resistance
Introduction In response to increasing rates of drug-resistant infections, the Infectious Diseases Society of America (IDSA) launched the 10 × ’20 Initiative in 2010, a campaign that called for global commitment to develop 10 novel, safe, and effective antibiotics by the year 2020.1 This initiative focused on the development of antibiotics to target the increasingly resistant ESKAPE pathogens, which is an acronym that stands for Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species.1,2 In a 2013 update of this initiative, the IDSA stressed the need for new antimicrobial agents to treat Gram-negative organisms, including multidrug-resistant (MDR) pathogens.1,3,4 The Centers for Disease Control and Prevention (CDC) has recently classified extended-spectrum β-lactamases (ESBLs) and MDR Pseudomonas aeruginosa as serious threats, which are
defined as significant antibiotic-resistant threats that have the potential to worsen without ongoing public health monitoring and prevention activities.5 According to the CDC, there are approximately 140 000 health care–associated Enterobacteriaceae infections annually in the United States, and of these, almost 26 000 infections (19%) are caused by ESBL-producing microorganisms. In addition, there are approximately 51 000 health care–associated infections caused by Pseudomonas aeruginosa annually in the United States, and more than 6000 of these infections (13%) are 1
Regis University School of Pharmacy, Denver, CO, USA Palm Beach Atlantic University School of Pharmacy, West Palm Beach, FL, USA 2
Corresponding Author: Allana J. Sucher, Regis University School of Pharmacy, 3333 Regis Blvd, H-28, Denver, CO 80221-1099, USA. Email: [email protected]
Downloaded from aop.sagepub.com at MOUNT ALLISON UNIV on July 10, 2015
2
Annals of Pharmacotherapy O H N
HO O
NH2
O N N
NH
H
H N
S
H 2N S
N
N
N
O
N
O O
NH2
O-
Figure 1. Chemical structure of ceftolozane.a
caused by MDR strains.5 Because of their increasing prevalence in the United States and worldwide, it is important to have antimicrobial agents that are effective against infections caused by these pathogens.6,7 This article provides a comprehensive clinical review of ceftolozane/tazobactam (Zerbaxa, Cubist Pharmaceuticals, Inc), a new antipseudomonal cephalosporin combined with a well- established β-lactamase inhibitor that was developed to target resistant strains of Pseudomonas aeruginosa while maintaining low convulsion-inducing activity.8,9 Ceftolozane was previously known as FR264205 and CXA-101, and the combination of ceftolozane/tazobactam was formerly known as CXA-201.10,11 Ceftolozane/tazobactam was approved on December 19, 2014, for the treatment of adults with complicated urinary tract infections (cUTIs) and in combination with metronidazole for the treatment of adults with complicated intra-abdominal infections (cIAIs).12 Agents such as ceftolozane/tazobactam that have been designated as a Qualified Infectious Disease Product under the Generating Antibiotic Incentives Now (GAIN) Act are given priority and expedited review as well as an additional 5 years of marketing exclusivity.12
A search of PubMed (January 2007-May 2015) using the search terms ceftolozane, ceftolozane/tazobactam, FR264205, CXA-101/tazobactam, and CXA-201 was performed. All data available in English were reviewed. Supplementary sources included abstracts and poster presentations from Interscience Conference of Antimicrobial Agents and Chemotherapy (ICAAC) and IDWeek as well as information available from the manufacturer.
interferes with peptidoglycan cross-linking of the bacterial cell wall, causing eventual cell lysis.13 Tazobactam is an irreversible inhibitor of β-lactamase enzymes. Similar to other β-lactamase inhibitors, tazobactam has no antimicrobial activity when used as monotherapy. When given in combination with a β-lactam antibiotic, tazobactam is effective against Gram-negative organisms expressing class A β-lactamases, including narrow-spectrum β-lactamases and ESBLs that are predominantly produced by Enterobacteriaceae.14,15 Ceftolozane was discovered through an exercise in structure activity relationships focused on the development of cephalosporins with high affinity for PBPs, increased outermembrane permeability, improved stability toward AmpC β-lactamase-producing microorganisms, and good activity against Pseudomonas aeruginosa.8 Figure 1 highlights the structural features that correspond to these attributes. The oxime functionality is also common to most third- and fourth-generation cephalosporins and has been shown to improve β-lactamase stability.16 The dimethylacetic acid moiety is also present in ceftazidime and has been associated with high affinity for PBPs and enhanced activity against Pseudomonas aeruginosa.17 The thiadiazole present in ceftolozane’s structure, similar to the thiazole ring found in most extended-spectrum cephalosporins, is also present in ceftaroline and has been shown to increase activity against Gram-negative bacilli.18 The primary difference between ceftolozane and other late-generation cephalosporins is the incorporation of a substituted, 2-methylpyrazole ring at position 3 of the dihydrothiazine portion of the bicyclic ring system, which proved to have the optimal balance of activity against AmpC β-lactamase-producing Pseudomonas aeruginosa and the weakest convulsion-inducing effects.8
Chemistry and Pharmacology
Microbiology
Ceftolozane, like other cephalosporins, is a β-lactam antibiotic that binds penicillin-binding proteins (PBPs) and
Ceftolozane/tazobactam displays bactericidal activity both in vitro and in vivo activity against Enterobacter cloacae,
Data Sources
Downloaded from aop.sagepub.com at MOUNT ALLISON UNIV on July 10, 2015
3
Sucher et al Table 1. Interpretation of Minimum Inhibitory Concentrations for Ceftolozane/Tazobactam.a MICs (µg/mL) Pathogen b
Enterobacteriaceae Pseudomonas aeruginosa Streptococcus anginosus, Streptococcus constellatus, and Streptococcus salivarius Bacteroides fragilis
S
I
R
≤2/4 ≤4/4 ≤8/4 ≤8/4
4/4 8/4 16/4 16/4
≥8/4 ≥16/4 ≥32/4 ≥32/4
Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S, sensitive. a Source: Information from Zerbaxa.9 b This includes Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, K pneumoniae, and Proteus mirabilis.
Escherichia coli, Klebsiella oxytoca, K pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Streptococcus anginosus, Streptococcus constellatus, Streptococcus salivarius, and Bacteroides fragilis, and it is approved by the Food and Drug Administration (FDA) for the treatment of cIAIs caused by these pathogens when used in combination with metronidazole.9 Ceftolozane/tazobactam is also approved by the FDA for the treatment of cUTIs, including pyelonephritis, caused by Escherichia coli, K pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa.9 Table 1 includes the interpretation of the minimum inhibitory concentrations (MICs) of ceftolozane/tazobactam for these organisms. Standardized testing methods are recommended to determine the susceptibility of anaerobic bacteria such as B fragilis to ceftolozane/tazobactam.9 The MIC50 and MIC90 values for the bacteria for which ceftolozane/tazobactam is approved are included in Table 2.19,20 In clinical trials, ceftolozane/tazobactam was shown to be active against some strains of Escherichia coli and K pneumoniae that produced β-lactamases, including class A narrow-spectrum and ESBLs as well as class D oxa-type β-lactamase enzymes.9,15 Ceftolozane/tazobactam has in vitro activity against isolates of Pseudomonas aeruginosa that contain chromosomal class C ampC enzymes, which typically confer resistance to extended-spectrum cephalosporins and may lead to resistance to carbapenems if present in high levels and with another mechanism of resistance. In addition, ceftolozane/tazobactam has in vitro activity against isolates of Pseudomonas aeruginosa that have upregulation of efflux pumps or loss of outer-membrane porin, both of which confer antibiotic resistance.9,15 Ceftolozane/tazobactam is not active against Enterobacteriaceae that produce class A serine carbapenemases (eg, K pneumoniae carbapenemases) or organisms that produce class B metallo-β-lactamases.9,15
Resistance Reported mechanisms of resistance to β-lactams such as ceftolozane/tazobactam include β-lactamase production, PBP alteration, upregulation of efflux pumps, and outer membrane porin loss.13,14
Takeda et al21 investigated the effects of β-lactamase production, efflux pump expression, membrane protein deletion, and spontaneous mutations on antimicrobial activity of ceftolozane in comparison with ceftazidime, imipenem, and ciprofloxacin. They found that the MIC90 of ceftolozane was lower than that of the other agents and that it was less susceptible to AmpC β-lactamase than ceftazidime. Ceftolozane’s activity was not affected by efflux pump expression or deletion of the membrane protein OprD, which are known mechanisms of resistance for Pseudomonas aeruginosa. The frequency of selection for spontaneous mutants (6.1 × 10-9) for plates containing ceftolozane was lower than that of ceftazidime, imipenem, and ciprofloxacin at concentrations of drug that were 4 times the MIC. However, only imipenem displayed activity against strains of Pseudomonas aeruginosa that produced metallo-β-lactamase.21 A follow-up study by Takeda et al22 on the effects of AmpC β-lactamase production on antimicrobial activity found that ceftolozane had higher stability against AmpC β-lactamase than ceftazidime.
Pharmacokinetics Pooled data from 10 pharmacokinetic (PK) studies of ceftolozane administered as monotherapy or as a 2:1 combination with tazobactam point to a 2-compartment PK model characterized by first-order elimination.23 Plasma PK data collected from 2 published phase 1 trials in healthy adults following single and multiple doses of ceftolozane/ tazobactam, including ceftolozane 1000 mg administered as a 1-hour intravenous infusion every 8 hours for 10 days with or without 500 mg tazobactam, are summarized in Table 3.11,24 All examined PK parameters for ceftolozane doses up to 2000 mg as a single dose or 3000 mg daily were found to be dose proportional and linear in studied populations. Additionally, ceftolozane area under the plasma concentration curve (AUC) values showed no significant change over a 10-day treatment course, indicating no appreciable drug accumulation.11,24 Plasma protein binding of ceftolozane is approximately 20%.24 The steady-state volume of distribution roughly approximates the extracellular
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Annals of Pharmacotherapy
Table 2. In Vitro Activity of Ceftolozane/Tazobactam Against Approved Microorganisms.19,20 Organism Gram-negative aerobes Enterobacter cloacae Escherichia coli Klebsiella oxytoca K pneumoniae Proteus mirabilis Pseudomonas aeruginosa Gram-positive aerobes Streptococcus salivarius Streptococcus anginosus Streptococcus constellatus Gram-negative anaerobes Bacteroides fragilis
n
MIC50 (µg/mL)
MIC90 (µg/mL)
Range (µg/mL)
2166 9429 899 4410 1600 6316
0.25 0.25 0.25 0.25 0.5 0.5
8 0.5 1 16 0.5 4
0.03 to >64 0.03 to >64 0.03 to >32 0.03 to >64 0.03 to 32 0.03 to >64
1 1 0.5
2 2 2
44 35 14 244
0.12 to 4 ≤0.03 to 4 ≤0.03 to 4 ≤0.125 to ≥256
1
Abbreviations: n, number of isolates; MIC50, minimum inhibitory concentration that inhibits the growth of 50% of organisms; MIC90, minimum inhibitory concentration that inhibits the growth of 90% of organisms.
Table 3. Ceftolozane Plasma Pharmacokinetic Parameters in Healthy Adult Participants After 1000-mg Dose Administered as a 1-Hour IV Infusion Every 8 Hours for 10 Days.11,24 Agent Day 1 C C C+T Day 10 C C C+T
n
Cmax (µg/mL)a
AUC (µg h/mL)a
Clearance (L/h)a
Vss (L)a
t1/2 (hours)a
6b 5d 10d
52.8 ± 12.5 68.8 ± 11.7 69.1 ± 7.8
148.6 ± 27c 168 ± 28.6e 172 ± 23.7e
6.73 ± 1.22 6.01 ± 0.84 5.86 ± 0.80
17.8 ± 3.8 14.1 ± 2.6 14.6 ± 2.3
2.38 ± 0.36 2.30 ± 0.39 2.77 ± 0.83
6b 5d 10d
58.0 ± 6.0 73.4 ± 11.2 74.4 ± 10.1
143.3 ± 22.1c 195 ± 30e 197 ± 33e
6.98 ± 1.07 5.54 ± 0.74 5.58 ± 0.70
17.1 ± 2.3 13.4 ± 2.4 14.2 ± 2.4
2.69 ± 0.65 2.73 ± 0.66 3.12 ± 0.68
Abbreviations: AUC, area under the plasma concentration-time curve; C, ceftolozane; C + T, ceftolozane with 500 mg tazobactam; n, number of participants; Cmax, maximum plasma concentration; IV, intravenous; t1/2, elimination half-life; Vss, volume of distribution at steady state. a Data reported as mean ± SD after first dose (day 1) and after multiple doses (day 10). b Ge et al.24 c AUC0-∞. d Miller et al.11 e AUC0-last.
volume and suggests that ceftolozane can reasonably be expected to distribute to extravascular sites of infection. Increased body weight and active infection both increase the apparent volume of distribution but do not cause any significant changes in steady-state PK parameters such as AUC.23 The total clearance of 1000 mg ceftolozane when administered in combination with 500 mg tazobactam over a 10-day treatment course was found to be 5.86 ± 0.08 L/h on day 1 and 5.58 ± 0.70 L/h on day 10. Renal clearance closely approximated these values (day 1: 5.58 ± 1.34; day 10: 6.80 ± 3.34), indicating that renal excretion was the exclusive route of elimination.11 Additionally, 100% of the administered ceftolozane dose was recovered from urine, primarily unchanged, within 24 hours, proving that ceftolozane is
renally eliminated and does not undergo significant metabolism.11,23 Likewise, clearance of tazobactam occurs primarily through renal excretion, though a single inactive metabolite (M1) results from nonenzymatic hydrolysis of the β-lactam ring.25,26 Compromised renal function has been shown to significantly decrease the clearance of both ceftolozane and tazobactam.26 Compared with individuals with normal renal function, the median AUC for ceftolozane was increased 1.4-fold, 2.5-fold, and 4.4-fold in those with mild, moderate, and severe renal impairment, respectively, and the median AUC for tazobactam was increased 1.2-fold, 2.2fold, and 3.8-fold.26 In those with end-stage renal disease receiving hemodialysis, the AUC of ceftolozane decreased by 66% after dialysis, and the AUC of tazobactam decreased
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Sucher et al by 56%.26 Although mild renal impairment does not necessitate a dosage adjustment, patients with a creatinine clearance of 50 mL or less, including those receiving hemodialysis, require a decreased dose.9,26 The dose of ceftolozane/tazobactam should be given at the earliest possible time after completion of dialysis on hemodialysis days.9 No clinically relevant trend on PK parameters of ceftolozane/ tazobactam was observed with regard to age in a population PK analysis, and no dosage adjustment is recommended based on patient age.9,23
Pharmacodynamics As with other β-lactam antibiotics, the percentage of time that ceftolozane plasma concentrations exceed the MIC of a pathogen (%T>MIC) is the best PK correlate to efficacy.27-29 Lepak et al27 exposed 6 strains of Streptococcus pneumoniae and 14 strains of Pseudomonas aeruginosa with varying degrees of β-lactam resistance to ceftolozane monotherapy and found that the mean %T>MIC to achieve stasis and 1log10 killing in Pseudomonas aeruginosa were 31.2 ± 6.99 and 39.4 ± 7.53, respectively.27 As a comparison, the %T>MIC to achieve stasis for ceftazidime against Pseudomonas aeruginosa is 40% to 45%, which may indicate that ceftolozane had more rapid killing kinetics.27,28 Likewise, Craig and Andes28 explored the relationship between %T>MIC and the bactericidal activity of ceftolozane dosed in neutropenic mice every 6 hours against 4 strains of Pseudomonas aeruginosa, 3 strains of Escherichia coli, 5 strains of K pneumoniae, and 1 strain of Enterobacter cloacae, including 5 strains that produced at least 1 ESBL.28 The mean %T>MICs required to achieve stasis and 1log10 killing of non-ESBL strains were 25.2 ± 2.8 and 31.5 ± 2.8, respectively, and were 31.1 ± 4.4 and 34.8 ± 4.9 for ESBLproducing strains. These values were lower than that for other cephalosporins, which have been shown to have mean %T>MIC values of 35% to 43% for stasis, again indicating that ceftolozane may have more rapid killing kinetics.27,28 Another study found greater efficacy of ceftolozane with or without tazobactam compared with piperacillin/ tazobactam, as measured by significantly greater reductions in colony-forming units of non-ESBL expressing organisms in a neutropenic mouse thigh infection model.29 These latter studies also found that the addition of tazobactam at a 2:1 ratio improved the bactericidal activity of ceftolozane against several ESBL-expressing strains.28,29
Clinical Efficacy Table 4 includes the results from 2 phase 3 clinical trials: ASPECT-cIAI and ASPECT-cUTI.30-32 The study comparing ceftolozane/tazobactam with piperacillin/ tazobactam in ventilator-associated pneumonia has been terminated.33
ASPECT-cIAI30 compared ceftolozane/tazobactam plus metronidazole with meropenem in patients with cIAIs. Eligible patients were 18 years of age or older with clinical evidence of cIAI as demonstrated by a performed or planned operative or percutaneous drainage of an infectious focus. Exclusion criteria were cIAI managed by staged abdominal repair in which the fascia was not closed, low likelihood of adequate source control at surgery, creatinine clearance
