CLINICAL REVIEW  Ceftolozane–tazobactam

CLINICAL REVIEW

Ceftolozane–tazobactam:
A new-generation cephalosporin
David Cluck, Paul Lewis, Brooke Stayer, Justin Spivey, and Jonathan Moorman

T
he significant health threat of
antimicrobial resistance in gram-
negative pathogens, coupled
with the dearth of new antimicrobi-
als to combat these organisms, has
led to a gloomy perspective on how
gram-negative infections are best ap-
proached therapeutically. The Infec-
tious Diseases Society of America’s
“10 by ’20” initiative has been mod-
erately successful in stimulating the
development of new agents targeting
gram-positive organisms; however,
the newest agents targeting gram-
negative organisms were introduced
in 2005 and 2007, when tigecycline
and doripenem, respectively, came to
market.1,2 Both of those agents have
garnered recent negative attention
due to poor patient outcomes.3,4
Beta-lactam antimicrobial agents
have long been considered important
therapeutic options for use against
both gram-positive and gram-
negative infections. With the recent
introduction of newer antimicrobial
agents such as tedizolid, dalbavancin,
and oritavancin, the armamen-
Purpose. The chemistry, pharmacokinetic
and pharmacodynamic properties, efficacy,
and safety of the recently introduced com-
bination antimicrobial agent ceftolozane–
tazobactam are reviewed.
Summary. Ceftolozane –tazobactam
(Zerbaxa, Cubist Pharmaceuticals) is a
cephalosporin b-lactam and b-lactamase
inhibitor marketed as a fixed-dose combi-
nation agent for the treatment of compli-
cated urinary tract and intraabdominal in-
fections. Its dosing and chemistry provide
expansive antimicrobial coverage of gram-
negative organisms, including Pseudomo-
nas aeruginosa, and stable activity against
many b-lactamases, as well as coverage of
most extended-spectrum b-lactamase–
producing organisms and some anaerobes.
Ceftolozane–tazobactam is susceptible
to hydrolysis by carbapenemase enzymes
but is not affected by other resistance
mechanisms such as efflux pumps and
porin loss. Clinical trials demonstrated that
tarium for combating gram-positive
pathogens is expanding; however,
gram-negative pathogens continue
to impose a heavy burden on the
combination treatment with ceftolozane–
tazobactam plus metronidazole had ef-
ficacy comparable to that of levofloxacin
in patients with complicated urinary
tract infections, including pyelonephritis,
and comparable to that of meropenem
against complicated intraabdominal in-
fections. A Phase III trial of ceftolozane–
tazobactam versus meropenem for treat-
ment of bacterial pneumonia, including ven-
tilator-associated pneumonia, is underway.
Adverse effects reported with ceftolozane–
tazobactam use are comparable to those
seen with other b-lactams (e.g., hypersensi-
tivity, nausea, diarrhea, headache). Initially,
ceftolozane–tazobactam may be reserved
for targeted therapy against multidrug-
resistant pathogens.
Conclusion. Ceftolozane–tazobactam is a
new cephalosporin with enhanced activity
against multidrug-resistant P. aeruginosa
and other gram-negative pathogens.
Am J Health Syst Pharm. 2015; 72:2135-46
healthcare system. Pseudomonas ae-
ruginosa in particular continues to
be problematic in efforts to reduce
hospital-associated infections, as it

David Cluck, Pharm.D., is Clinical Assistant Professor, Depart-
ment of Pharmacy Practice, East Tennessee State University (ETSU)
Gatton College of Pharmacy, Johnson City. Paul Lewis, Pharm.D.,
is Clinical Pharmacist—Infectious Diseases, Department of Phar-
macy, Johnson City Medical Center, Johnson City. Brooke Stayer,
Pharm.D., is Clinical Pharmacist—Infectious Diseases, Department
of Pharmacy, Holston Valley Medical Center, Kingsport, TN. Justin
Spivey, Pharm.D., is Clinical Pharmacist—Infectious Diseases, De-
partment of Pharmacy, James H. Quillen Veterans Affairs (VA) Medi-
cal Center, Johnson City. Jonathan Moorman, M.D., is Professor of
Medicine and Chief, Division of Infectious Diseases, ETSU Quillen
College of Medicine, Johnson City.
Address correspondence to Dr. Cluck (cluckd@etsu.edu).
Dr. Moorman receives funding from the National Institutes of
Health (NIDDK grant ROIDK93526 and NIAID grant ROAI114748)
and VA Merit Award funding and has participated in clinical trials
sponsored by Gilead Sciences, GlaxoSmithKline, and Wyeth. This
article is the result of work supported with resources and the use of
facilities at James H. Quillen VA Medical Center.
The contents of this article do not represent the views of the
Department of Veterans Affairs or U.S. government.
DOI 10.2146/ajhp150049

Am J Health-Syst Pharm—Vol 72 Dec 15, 2015 2135

 CLINICAL REVIEW  Ceftolozane–tazobactam
is implicated in a multitude of infec-
tions in both immunocompetent and
immunocompromised hosts. This
organism often displays multiple
mechanisms of resistance to many
commonly used antimicrobials; thus,
alternative therapeutic options are
desperately needed. The complex in-
terplay among common mechanisms
of Pseudomonas resistance, such as
porin loss, efflux pumps, and con-
stitutive production of b-lactamases,
reinforces the need for an antimi-
crobial that is not affected by these
mechanisms. The most widely used
therapies for pseudomonal infections
(e.g., carbapenems) are often only
able to partially combat these mecha-
nisms and are now considered to be
drastically overused.5,6
Ceftolozane (Zerbaxa, Cubist
Pharmaceuticals; formerly known
as CXA-101 and FR264205) in a
fixed 2:1 combination with tazo-
bactam (ceftolozane–tazobactam;
formerly known as CXA-201) repre-
sents a valuable therapeutic option
for the aforementioned drug-resistant
phenotypes of P. aeruginosa. This
new semisynthetic cephalosporin
was approved for U.S. marketing in
December 2014. The labeling for
ceftolozane–tazobactam includes
indications for treatment of com-
plicated urinary tract infections
(cUTIs), including pyelonephritis,
and complicated intraabdominal
infections (cIAIs) in combination
with metronidazole. Ceftolozane–
tazobactam is also currently under
investigation in Phase III trials for the
treatment of hospital-acquired pneu-
monia, including ventilator-associated
pneumonia.
This article reviews the avail-
able data on the chemistry, spec-
trum of activity, pharmacokinetic
and pharmacodynamic properties,
clinical efficacy, comparative cost,
and potential place in therapy of
ceftolozane–tazobactam.
Chemistry and pharmacology
Ceftolozane is an oxyimino ceph-
2136 Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
alosporin that closely resembles
ceftazidime structurally; howev-
er, it also shares many similari-
ties with other extended-spectrum
cephalosporins, such as ceftriaxone
and cefepime. Ceftolozane contains
a 7-aminothiadiazole, affording
increased activity against gram-
negative organisms, as well as an
alkoximino group, providing sta-
bility against many b-lactamases.
Like ceftazidime, ceftolozane has a
dimethylacetic acid moiety that con-
tributes to enhanced activity against
P. 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.7
This side chain, in particular, contrib-
utes to the stability of ceftolozane in
the presence of AmpC b-lactamase, a
cephalosporinase frequently produced
by P. aeruginosa.8 The substituents on
the pyrazole ring were modified in an
effort to maximize antipseudomonal
activity while minimizing the risk of
epileptogenicity.9
Tazobactam is a penicillinate sul-
fone b-lactamase inhibitor, which
confers protection to the b-lactam
ring.10 The addition of tazobactam
to ceftolozane facilitates improved
activity against other Enterobacte-
riaceae, including most extended-
spectrum b-lactamase (ESBL) pro-
ducers and some anaerobes, as
discussed below.
Ceftolozane, like other b-lactams,
binds to penicillin-binding pro-
teins (PBPs), resulting in impaired
peptidoglycan cross-linking. The
inhibition of cross-linking leads to
disruption of cell wall synthesis and
eventual cell lysis. The PBP-binding
profile is important because it is a
key determinant of a b-lactam’s ac-
tivity profile. In comparison to
ceftazidime, ceftolozane was dem-
onstrated to have at least twofold
greater affinity for PBPs 1b, 1c, 2,
and 3.11 This binding profile partly
explains the demonstrated in vitro
potency of ceftolozane. Moreover,
ceftolozane was found to lack the ca-
pability to produce AmpC induction
via decreased affinity for PBP412; this
is noteworthy, as many other anti-
microbials with similar therapeutic
indications are capable of AmpC
induction, including imipenem and
cefoxitin.13
Spectrum of activity
Tables 1 and 2 provide a synopsis
of available in vitro data on the use
of ceftolozane–tazobactam against
a multitude of clinically relevant
gram-positive and gram-negative or-
ganisms, including resistant strains.
Ceftolozane has been demonstrated
to have reliable in vitro activity
against many gram-negative organ-
isms, with particular potency against
P. aeruginosa; this is in contrast to
the agent’s lack of activity against
many clinically important gram-
positive pathogens. Ceftolozane–
tazobactam has significant in vitro
activity against Streptococcus spe-
cies; however, like ceftazidime,
ceftolozane–tazobactam has dimin-
ished activity against Staphylococcus
aureus.14-17 As previously mentioned,
ceftolozane–tazobactam has been
extensively investigated for its en-
hanced activity against many gram-
negative organisms. Perhaps the
most important aspect of this agent’s
versatility is its improved activity
against strains of P. aeruginosa and
Enterobacteriaceae with resistant
phenotypes. Farrell et al.18 were able
to exemplify that versatility by testing
ceftolozane–tazobactam against
multidrug-resistant and extensively
drug-resistant isolates of P. aeruginosa
and Enterobacteriaceae. In multi-
drug-resistant strains of P. aeruginosa,
ceftolozane–tazobactam was found
to be second only to colistin in terms
of activity (a minimum inhibitory
concentration for 50% of isolates
[MIC50] of 2 mg/mL and an MIC
for 90% of isolates [MIC90] of 8 mg/
mL). In extensively drug-resistant
strains, ceftolozane–tazobactam
had appreciable activity (MIC50 and
MIC90, 4 and 16 mg/mL, respectively).
 CLINICAL REVIEW  Ceftolozane–tazobactam

It should be noted that ceftolozane
alone or in combination with tazo-
bactam has excellent activity against
P. aeruginosa.19,20 To provide some
practical perspective, the prescrib-
ing information for ceftolozane–
tazobactam lists the breakpoints
for susceptibility and resistance to
P. aeruginosa as ≤4 and ≥16 mg/mL,
respectively. The breakpoints for
Enterobacteriaceae are one dilution
lower (susceptible at ≤2 mg/mL and
resistant at ≥8 mg/mL).21
There is significant variabili-
ty in the activity of ceftolozane–
tazobactam against anaerobic organ-
isms. Ceftolozane–tazobactam has
adequate in vitro activity against
Bacteroides fragilis and other species
such as Prevotella and Fusobacterium
species; however, it has diminished or
no activity against other Bacteroides
species and anaerobic gram-positive
cocci.22

Table 1.
Susceptibility of Gram-positive and Gram-negative Organisms to Ceftolozane–Tazobactam14-27,a

Organism MIC50 (mg/mL) MIC90 (mg/mL) MIC Range (mg/mL)b

Acinetobacter baumannii 0.50 2.00 ≤0.12–16.00
Bacteroides fragilis 1.00 4.00 ≤0.125 to ≥256.00
Citrobacter spp. 0.25 8.00 ≤0.12–256.00
Clostridium difficile ≥256.00 ≥256.00 0.25 to ≥256.00
Clostridium perfringens 0.25 32.00 ≤0.125–32.00
Enterobacter cloacae 0.25 8.00 ≤0.12 to ≥32.00
Escherichia coli 0.12 0.50 ≤0.12 to >32.00
Klebsiella oxytoca ≤0.12 0.50 ≤0.12–2.00
Klebsiella pneumoniae 0.25 8.00 ≤0.12 to ≥32.00
Proteus mirabilis 0.50 0.50 ≤0.12–16.00
Pseudomonas aeruginosa 0.50 1.00–8.00b ≤0.12 to >128.00
Serratia marcescens 0.50 1.00 ≤0.12 to ≥32.00
Staphylococcus aureus 32 64 4–128
Stenotrophomonas maltophilia 16.0 >64.0 0.5 to >64.0
Streptococcus pneumoniae ≤0.12 8.00 ≤0.12–16.00
Streptococcus pyogenes ≤0.12 ≤0.12 ≤0.12–2.00
MIC50 = minimum inhibitory concentration for 50% of isolates, MIC90 = minimum inhibitory concentration for 90% of isolates.
a

Range of values variously reported in multiple in vitro studies.

b

Table 2.
Susceptibility of Gram-negative Organisms to Ceftolozane–Tazobactam and Other
Antimicrobials14-20,23-30,a

MIC90 (mg/mL)
Ceftolozane–
Organism Tazobactam Ceftazidime Cefepime Meropenem
Enterobacter cloacae 8.00 >32.00 2.00–8.00 b
≤0.06
Ceftazidime-resistant strains >16.00 >64.00 >16.00 0.25
Escherichia coli 0.50 8.00 4.00 to >16.00b ≤0.06
ESBL phenotype 4.00 >32.00 >16.00 ≤0.12 to >8.00b
Klebsiella pneumoniae 8.00 to >32.00b ≥32.00 >16.00 ≤0.06 to 2.00b
ESBL phenotype >16.00 to >32.00b >32.00 to >64.00b >16.00 ≤0.12 to >8.00b
KPC >16 >64 >16 >8
Proteus mirabilis 0.50 32.00 ≤0.50 ≤0.06
ESBL phenotype 8.00 >64.00 >16.00 ≤0.12
Pseudomonas aeruginosa 1 to >32b 32 16 8
Ceftazidime-resistant strains 4–16b 256 64 32
Meropenem-resistant strains 4–8b >32 >16 32
MIC90 = minimum inhibitory concentration for 90% of isolates, ESBL = extended-spectrum b-lactamase, KPC = K. pneumoniae carbapenemase.
a

Range of values variously reported in multiple in vitro studies.

b

Am J Health-Syst Pharm—Vol 72 Dec 15, 2015 2137

 CLINICAL REVIEW  Ceftolozane–tazobactam
Mechanisms of resistance
The versatility of ceftolozane–
tazobactam is secondary to its lack
of susceptibility to common mecha-
nisms of resistance commonly seen
in gram-negative organisms, includ-
ing production of b-lactamases, po-
rin loss, and efflux pumps.18 Altera-
tion of PBPs and membrane changes
also do not appear to adversely affect
ceftolozane’s activity. 11 Narrow-
spectrum b-lactamases have mini-
mal effects on ceftolozane, whereas
ESBLs adversely affect ceftolozane
and thus necessitate its use in com-
bination with tazobactam. In vitro
data corroborated this finding, with
ceftolozane–tazobactam shown to be
active against the most commonly
encountered ESBLs, CTX-M-14 and
CTX-M-15. 29-32 Moreover, com-
bined data from the clinical trials
summarized below revealed that
patients harboring ESBL-producing
organisms who were treated with
ceftolozane–tazobactam experienced
positive outcomes, with a clinical
cure rate of 97.4%, as compared with
an 84.7% cure rate among patients
who received comparator drugs.33 It
should be noted that activity may be
attenuated against some SHV-type
ESBLs, and ceftolozane–tazobactam
remains vulnerable to organisms
producing Klebsiella pneumoni-
ae carbapenemase or metallo-b-
lactamase.19,31,34 Data presented in Ta-
ble 3 illustrate the multifaceted nature
of resistance often seen in Pseudomo-
nas species, as well as the stability of
ceftolozane–tazobactam with regard
to most resistance mechanisms.
Pharmacokinetics and
pharmacodynamics
Absorption and distribution. As
ceftolozane–tazobactam has not been
studied in pediatric populations, the
data presented below are applicable
only to populations of patients 18
years of age or older. Ge et al.45 and
Miller et al.46 administered single and
multiple doses of ceftolozane with
or without tazobactam to 64 and 58
2138 Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
study participants, respectively, to
determine the agent’s pharmacoki-
netic profile and safety. Intravenous
ceftolozane doses of up to 3 g, ad-
ministered alone or in combination
with tazobactam, were found to
display linear pharmacokinetics.
Ceftolozane–tazobactam is available
as a 2:1 fixed combination (Hence-
forth, all doses are characterized as
such; for example, a 1.5-g dose of
ceftolozane–tazobactam is composed
of 1 g of ceftolozane and 500 mg of
tazobactam). 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.
Miller et al.46 found that ceftolozane
does not significantly accumulate,
with a maximum drug concentration
(Cmax) of 69.1 mg/mL on day 1 and
74.4 mg/mL on day 10 at the standard
recommended dosage of 1.5 g every
eight hours; that peak value is slightly
higher than that produced by a 1-g
dose of meropenem, the b-lactam
comparator used in clinical trials,
which has a mean Cmax of 49 mg/mL
(range, 39–58 mg/mL) after a 30-
minute infusion.47 These characteris-
tics are comparable to those of other
cephalosporin congeners, ceftazi-
dime and cefepime, which have
reported Cmax values of 69 and 81.7
mg/mL, respectively.48,49 Ceftolozane
and tazobactam are approximately
18% and 30% protein bound, re-
spectively.21 The mean steady-state
volume of distribution of ceftolozane
is 13.5 L, corresponding to the extra-
cellular fluid volume.21 These data
signify a pharmacokinetic profile
closely resembling those of ceftazi-
dime and cefepime, indicating that
tazobactam has no significant effect
on the pharmacokinetics of ceftolo-
zane. Importantly, ceftolozane has
excellent distribution to the lungs.
A Phase I trial conducted by Miller
and colleagues50 revealed that with a
3-g dose of ceftolozane–tazobactam,
an adequate time of drug concen-
tration above the MIC (t>MIC) in
plasma and epithelial lining fluid
(ELF) was achieved in greater than
90% of a simulated population of
patients with ventilator-associated
pneumonia. Moreover, Chandorkar
et al.51 demonstrated intrapulmo-
nary penetration of ceftolozane–
tazobactam comparable to that of
piperacillin–tazobactam, with an
ELF:plasma ratio of 0.48; it should
be noted that this study used 1.5
g of ceftolozane–tazobactam, as
compared with the 3-g dose used
in the previously described Phase
I trial. Cerebrospinal fluid (CSF)
penetration by tazobactam is low but
improved with inflamed meninges;
ceftolozane’s CSF penetration is
unknown.52
Metabolism and excretion. The
metabolism and excretion of ceftolo-
zane are similar to those of most b-
lactam antimicrobial agents. Ceftolo-
zane is predominantly eliminated
unchanged in the urine.53,54 Tazobac-
tam is partially metabolized to an in-
active metabolite, and both drug and
metabolite are excreted in the urine
(80% as unchanged drug). The half-
life of ceftolozane is 2.5–3.0 hours,
and the half-life of tazobactam is ap-
proximately 1.0 hour; the clearance
of both drugs is directly proportional
to renal function.45,46 Ceftolozane is
eliminated entirely by glomerular
filtration; thus, dosage adjustment is
required in patients with renal im-
pairment.53 Tazobactam undergoes
active tubular secretion, so its clear-
ance is inhibited by piperacillin but
not by ceftolozane. Two thirds of a
dose of ceftolozane–tazobactam is
removed by hemodialysis.21,54
Pharmacodynamics. The amount
of time the plasma concentration
of ceftolozane exceeds the MIC
for the susceptible organism is the
best predictor of efficacy.55,56 For all
cephalosporins, the optimal value
for the percentage of dosing interval
above the MIC has been shown to be
at least 50%, which should be attain-
able with ceftolozane–tazobactam at

the standard recommended dosing
regimen.46,56
Soon et al.57 sought to characterize
the pharmacodynamics of ceftolo-
zane alone or in combination with
tazobactam in a series of experiments.
Four isogenic strains of Escherichia
coli differing only in their production
of b-lactamase were tested. Various
concentrations of ceftolozane (0–256
mg/L) with and without tazobactam
(0–64 mg/L) were tested against E.
coli (1 million–100 million colony-
forming units [CFU] per milliliter).
Ceftolozane was not demonstrated
to have enhanced activity at higher
concentrations and was ineffective
without tazobactam against strains
that produced an ESBL. The com-
bination of ceftolozane and tazo-
bactam produced nearly complete
bacterial killing at eight hours after
inoculation. The investigators con-
cluded that ceftolozane and tazobac-
tam had rapid bactericidal activity at
concentrations of ≥4 and ≥16 mg/L,
respectively, against b-lactamase–
producing strains of E. coli.
Craig and Andes 58 conducted
a pharmacodynamic study using
a neutropenic mouse model to
test ceftolozane alone or in com-
bination with tazobactam against
various strains of P. aeruginosa and
Enterobacteriacae, including ESBL-
producing strains. The purposes
of the study were to characterize
the pharmacokinetic and pharma-
codynamic profiles of ceftolozane,
to compare the killing kinetics of
ceftolozane and ceftazidime, and to
examine the effect of tazobactam
plus ceftolozane in various ratios
on ESBL-producing organisms.
Neutropenia was induced with in-
traperitoneal cyclophosphamide 150
mg/kg for four days and 100 mg/kg
one day prior to induction of infec-
tion. Thigh infection was induced
by injection of pathogens (100,000–
1 million CFU). The pharmacokinet-
ic profile was determined after infect-
ed neutropenic mice were exposed to
25, 100, or 400 mg/kg of ceftolozane.
CLINICAL REVIEW  Ceftolozane–tazobactam
Plasma samples were then serially
collected. To examine the rate of in
vivo killing of two strains of P. aerugi-
nosa, mice were treated with 200 mg/
kg of ceftolozane or ceftazidime. For
strains producing an ESBL, subjects
were exposed to ceftolozane 400 or
800 mg/kg alone or in combination
with tazobactam at a ratio of 2:1, 4:1,
or 8:1. This study had several signifi-
cant findings, including the favorable
effect of tazobactam on MIC values
for ESBL-producing strains. The ad-
dition of tazobactam to ceftolozane
was associated with 8- to 16-fold
reductions in MIC values for organ-
isms producing an ESBL. The study
also concluded that the optimal
ceftolozane-to-tazobactam ratio is
2:1, with t>MIC being closely cor-
related with efficacy (r 2 = 61%).
Perhaps most notably, the results
suggested that relative to other ceph-
alosporins, ceftolozane–tazobactam
was associated with lower t>MIC
values due to more rapid bacterial
killing.
Clinical efficacy
Phase II trials. Two Phase II clini-
cal trials have examined the use of
ceftolozane–tazobactam in patients
with a complicated urinary tract
infection (cUTI) or a complicated in-
traabdominal infection (cIAI). Umeh
and Friedland59 conducted a pro-
spective, randomized, multicenter,
double-blind Phase II trial compar-
ing the safety and efficacy of ceftolo-
zane versus ceftazidime in patients
with cUTIs, including pyelonephritis.
Patients were randomly assigned
2:1 to receive ceftolozane (n =
86) or ceftazidime (n = 43) 1 g i.v.
every eight hours for 7–10 days. The
dosing of ceftolozane was based on
the dose-ranging studies discussed
above. The primary efficacy end-
point was microbiological response
in the coprimary populations (the
microbiological modified intention-
to-treat [mMITT] and microbiologi-
cally evaluable [ME] populations), as
assessed at a test of cure (TOC) visit
Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
6–9 days after completion of therapy;
secondary endpoints included clini-
cal response, safety, and ceftolozane
pharmacokinetics. Treatment effi-
cacy at the visit was also evaluated via
investigator assessment of clinical re-
sponse. Of the 129 patients enrolled,
103 qualified for the microbiological
intention-to-treat (mMITT) patients
and 82 qualified for the ME group.
The baseline characteristics were
similar in the two treatment groups,
with approximately one third of pa-
tients having pyelonephritis. Micro-
biological cure rates in the mMITT
population at the TOC visit were
83.1% and 76.3% in ceftolozane- and
ceftazidime-treated patients, respec-
tively; the corresponding cure rates in
the ME population were 85.5% and
92.6%, respectively. Both treatment
groups had high rates of microbio-
logical eradication at the TOC visit,
with rates of 92% and 95% in the
ceftolozane and ceftazidime groups,
respectively. Clinical response rates,
as well as rates of sustained clinical
cure in the mMITT and ME groups
at the TOC visit, exceeded 90%.
Lucasti and colleagues 60 con-
ducted a Phase II trial assessing the
safety and efficacy of i.v. ceftolozane–
tazobactam plus metronidazole ver-
sus meropenem in adult patients
with cIAI requiring surgical inter-
vention. Patients were stratified by
site of infection and randomly as-
signed (2:1) to receive ceftolozane–
tazobactam 1.5 g every eight hours
with or without metronidazole 500
mg i.v. every eight hours (n = 82) or
meropenem 1 g i.v. every eight hours
plus a sodium chloride injection pla-
cebo (n = 39) for 4–7 days. Metroni-
dazole could be added to ceftolozane–
tazobactam at the discretion of the
physician and was used in more than
90% of patients in the study. The
primary study outcome was clinical
efficacy, as assessed at the TOC visit
and late follow-up assessments con-
ducted 7–14 and 21–28 days after the
end of therapy, respectively. Efficacy
was monitored in mMITT and ME
2139
 CLINICAL REVIEW  Ceftolozane–tazobactam
Table 3.
Mechanisms of Pseudomonas aeruginosa Resistance to Ceftolozane–Tazobactam and Other
Antimicrobials23,35-44,a
Mechanism
Beta-lactamases
AmpC
ESBL
MBL or KPC
Efflux pumps
MexAB-OprM
MexCD-OprJ
MexEF-OprN
MexXY-OprM
Other
Loss of OprD (porins)
Membrane changes
Topoisomerase changes (gyrA and
parC)
Reduced aminoglycoside permeability
Aminoglycoside-modifying enzymes
(AAC, ANT, APH)
a
ESBL = extended-spectrum b-lactamase, MBL = metallo-b-lactamase, KPC = Klebsiella pneumoniae carbapenemase, pR = partially resistant, R = resistant.
b
Not applicable.
populations. Secondary outcomes
included safety and tolerability in
the MITT population, clinical re-
sponse in the clinically evaluable
(CE) population, clinical response
in different subpopulations with
risk factors for poor response (e.g.,
disease severity score, impaired renal
function), and overall microbio-
logical success by pathogen. A total of
122 patients were enrolled, of whom
121 received study drug. Notably,
most patients in this study had an ap-
pendiceal origin of infection. In the
mMITT population, clinical cure was
seen in 83.6% of the patients treated
with ceftolozane–tazobactam (95%
confidence interval [CI], 71.9–
91.8%) and 96.0% of the patients
who received meropenem (95% CI,
79.6–99.9%) (absolute difference,
–12.4%; 95% CI, –34.9% to 11.1%).
In the ME population, clinical cure
was seen in 88.7% and 95.8% of the
patients (absolute difference, 7.1%;
95% CI, –30.7% to 16.9%) who re-
ceived ceftolozane–tazobactam and
meropenem, respectively. Patients
2140 Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
Ceftolozane–
Tazobactam Cefepime
. . .b
...
R R
...
...
...
...
...
...
...
...
...
in both treatment groups with a risk
factor for poor response responded
well to ceftolozane–tazobactam.
Patients in the ME population also
experienced greater than 90% mi-
crobiological success at the TOC
visit. Notably, both regimens were
found to have 100% efficacy against
P. aeruginosa isolates. The study con-
cluded that ceftolozane–tazobactam
appears efficacious in the treatment
of cIAIs and worthy of further in-
vestigation in a larger study.
Phase III trials. The efficacy and
safety of i.v. ceftolozane–tazobactam
for the treatment of cUTIs, includ-
ing pyelonephritis, were evalu-
ated based on pooled data from two
identical Phase III, randomized,
multicenter double-blind studies.61
Adult hospitalized patients (n =
1083) who exhibited clinical signs
and symptoms consistent with
pyelonephritis or another type of
cUTI and required i.v. therapy were
randomly assigned 1:1 to receive
either ceftolozane–tazobactam 1.5
g every eight hours (n = 543) or
Piperacillin–
Tazobactam Imipenem
pR R ...
R pR ...
R R
R R ...
R R ...
R R R
R R ...
... ... R
... ... ...
... ... ...
... ... ...
... ... ...
levofloxacin 750 mg daily (n =
540) for seven days. Notably, 82%
of the patients were diagnosed as
having pyelonephritis. The pri-
mary objective was to demonstrate
the noninferiority of ceftolozane–
tazobactam to levofloxacin in terms
of a composite outcome (micro-
biological eradication and clinical
cure) at the TOC visit five to nine
days after the end of therapy. The
primary outcome was reported
based on findings in the mMITT
and ME populations. Clinical re-
sponse, microbiological eradication,
and per-pathogen microbiological
eradication rates in the ME popula-
tion were also evaluated in the study.
Safety was evaluated in all patients
who received study drug.
Ceftolozane–tazobactam yielded
significantly higher cure rates than
levofloxacin in both the mMITT and
ME populations (Table 4). Overall
microbiological eradication rates for
ceftolozane–tazobactam and levo-
floxacin were 84.7% and 75.1%, re-
spectively (absolute difference, 9.6%;
 CLINICAL REVIEW  Ceftolozane–tazobactam

Meropenem Aztreonam Aminoglycosides Fluoroquinolones Polymixins

... R ... ... ...

pR R ... ... ...
R R ... ... ...

R R ... R ...
R ... ... R ...
R R ... R ...
R R R R ...

pR ... ... ... ...

... ... ... ... R

... ... ... R ...

... ... R ... ...

... ... R ... ...

95% CI, 1.8–17.4%) in the ME popu-
lation. Ceftolozane–tazobactam use
was also associated with significantly
higher microbiological eradication
rates than levofloxacin use in patients
infected with Enterobacteriaceae or
P. aeruginosa. These findings indicate
that ceftolozane–tazobactam is an
efficacious and well-tolerated treat-
ment for patients with cUTIs, includ-
ing pyelonephritis, and those harbor-
ing levofloxacin-resistant isolates at
baseline (Table 5).62
The efficacy and safety of i.v.
ceftolozane–tazobactam in the treat-
ment of cIAI were also evaluated in
two large Phase III multicenter, mul-
tinational, randomized, double-blind
noninferiority trials.63 Hospitalized
adult patients with cIAI who required
surgical intervention were randomly
assigned to receive ceftolozane–
tazobactam 1.5 g (n = 487) every
eight hours plus metronidazole
500 mg every eight hours or me-
ropenem 1 g every eight hours plus
placebo (n = 506) for 4–14 days;
most patients who received study
drug had an appendiceal origin of
infection. The primary objective
was to demonstrate the noninfe-
riority of ceftolozane–tazobactam
to meropenem based on the clini-
cal cure rate at the TOC visit 26–30
days after initiation of therapy. It
should be noted that two noninferior-
ity margins were used: the European
Medicines Agency–defined margin of
12.5% at a one-sided alpha of 0.005
was used in the CE and intention-
to-treat (ITT) populations, and the
Food and Drug Administration–
specified margin of 10% at a one-
sided alpha of 0.025 was used in the
MITT and ME populations. Per-
pathogen responses and safety were
also evaluated. The results are shown
in Table 6. The investigators con-
cluded that ceftolozane–tazobactam
plus metronidazole was noninferior
to meropenem in terms of the overall
clinical cure rate.
It is worth noting that a subset of
patients with cIAI (n = 72) from the
previously described Phase III tri-
als who had P. aeruginosa infection
at baseline were also evaluated. The
study demonstrated clinical cure rates
in the ME population similar to those
seen in the trial overall (100% for
ceftolozane–tazobactam and 96.4%
for meropenem).64
A Phase III, multicenter, ran-
domized trial currently underway is
comparing ceftolozane–tazobactam
3 g i.v. every eight hours with me-
ropenem 1 g i.v. every eight hours
in the treatment of adult patients
with either ventilator-associated or
hospital-acquired bacterial pneu-
monia. The primary outcome is
all-cause mortality; secondary end-
points include clinical response rates
in various subgroups, including CE,
mITT, and ITT populations, at a
TOC visit 7–14 days after completion
of therapy. Efficacy against baseline
P. aeruginosa isolates is also being ex-
amined as a secondary endpoint. The
study is projected to be completed in
February 2018.65
Safety and tolerability
The dose-ranging studies con-

Am J Health-Syst Pharm—Vol 72 Dec 15, 2015 2141

 CLINICAL REVIEW  Ceftolozane–tazobactam

ducted by Ge et al.45 and Miller et al.46
examined the safety of ceftolozane
administered alone and in combi-
nation with tazobactam. Among 18
study participants who received sin-
gle doses of ceftolozane, 94% of the
adverse events reported were mild
in severity, with 1 subject reporting
body aches of moderate intensity.46
The most common adverse event was
constipation (33%). In subjects re-
ceiving multiple doses of ceftolozane
with and without tazobactam (up to
3 and 1.5 g per day, respectively), 48
adverse events in 40 patients were
thought to be related to the study
drug. Of these adverse events, 69%
were mild infusion-related reac-
tions; paresthesia, nausea, vomiting,
hypoesthesia, and flushing were de-
scribed. A single case of menstrual
cramps was the only moderately
severe adverse effect encountered.46
No adverse effect was felt to be
dose related.63 In a Phase I study of
ceftolozane–tazobactam involving
patients with varying degrees of renal
impairment, 7 of 36 patients experi-
enced a total of 12 adverse effects. All
events reported were of mild sever-
ity, with the exception of a moderate
headache and a serious adverse event
(thrombosis of an arteriovenous fis-
tula) in a patient receiving intermit-
tent hemodialysis (IHD) seven days
after the last dose of study drug. No
patient discontinued study drug due
to adverse events.54
Adverse-event data from two
Phase II clinical trials indicated that
ceftolozane–tazobactam was well
tolerated.59,60 In a study of adults
with cUTIs who were treated with
ceftolozane or ceftazidime, adverse
events were reported by 40 of 85

Table 4.
Outcomes of Ceftolozane–Tazobactam Use in Complicated Urinary Tract Infections61,a

Fraction (%) Patients

Ceftolozane– Absolute % Difference
Outcome Tazobactam Levofloxacin (95% CI)
Composite cure (microbiological eradication
+ clinical cure)
mMITT population 306/398 (76.9) 275/402 (68.4) 8.5 (2.3–14.6)
ME population 284/341 (83.3) 266/353 (75.4) 8.0 (2.0–14.0)
Microbiological eradication in ME population
Enterobacteriaceae spp. 278/313 (88.8) 253/325 (77.8) 11.0 (5.2–16.7)
Escherichia coli 237/262 (90.5) 226/284 (79.6) 10.9 (4.9–16.8)
Klebsiella pneumoniae 21/25 (84.0) 14/23 (60.9) 23.1 (–2.0 to 45.4)
Pseudomonas aeruginosa 6/7 (85.7) 7/12 (58.3) 27.4 (–15.9 to 56.3)
CI = confidence interval, mMITT = microbiological modified intention-to-treat, ME = microbiologically evaluable.
a

Table 5.
Outcomes of Ceftolozane–Tazobactam Use in Complicated Urinary Tract Infections Involving
Levofloxacin-Resistant Isolates62,a

Fraction (%) Patients

Ceftolozane– Absolute % Difference
Outcome Tazobactam Levofloxacin (95% CI)
Composite cure (microbiological eradication
+ clinical cure)
mMITT population 60/100 (60.0) 44/112 (39.3) 20.7 (7.23–33.17)
ME population 57/89 (64.0) 43/99 (43.4) 20.6 (6.33–33.72)
Microbiological eradication in ME population
Enterobacteriaceae spp. 55/77 (71.4) 38/84 (45.2) 26.2 (10.96–39.72)
Escherichia coli 43/59 (72.9) 30/68 (44.1) 28.8 (11.59–43.55)
Klebsiella pneumoniae 9/11 (81.8) 3/10 (30.0) 51.8 (9.5–75.05)
Pseudomonas aeruginosa 3/3 (100) 3/8 (37.5) 62.5 (–2.09 to 86.32)
CI = confidence interval, mMITT = microbiological modified intention-to-treat, ME = microbiologically evaluable.
a

2142 Am J Health-Syst Pharm—Vol 72 Dec 15, 2015


(47.1%) and 16 of 42 (38.1%) of
patients, respectively. 59 Constipa-
tion, diarrhea, nausea, headache,
infusion-site reactions, insomnia,
pyrexia, and sleep disorders were
experienced by at least 3% of pa-
tients in the ceftolozane group. Three
patients reported serious or severe
adverse events (single occurrences of
recurrent pyelonephritis, abdominal
pain, and worsening anemia); these
events were not felt to be treatment
related. One subject in the ceftolo-
zane group discontinued therapy
due to decreasing renal function
(creatinine clearance [CLcr] of <50
mL/min). The researchers noted that
the frequency and types of adverse
events described were similar in the
two treatment groups.59 In an addi-
tional Phase II study of patients with
cIAIs, the rates of adverse events were
similar for ceftolozane–tazobactam
and meropenem (50% and 48.8%,
respectively).60
At the time of writing, data from
only one of the Phase III clinical tri-
als of ceftolozane–tazobactam had
been published; however, adverse
events are described in the package
insert as well as study abstracts.21,61,63
The previously described Phase III
clinical trials included a total of 1015
Table 6.
Outcomes of Ceftolozane–Tazobactam Use in Complicated Intraabdominal Infections63,a
Ceftolozane–Tazobactam
Outcome
Clinical cure
CE population
ITT population
MITT population
ME population
Microbiological eradication in ME
population
Gram-negative aerobes
Escherichia coli
Klebsiella pneumoniae
Pseudomonas aeruginosa
Gram-negative anaerobes
CI = confidence interval, CE = clinically evaluable, ITT = intention-to-treat, MITT = microbiological intention-to-treat, ME =microbiologically evaluable.
a
CLINICAL REVIEW  Ceftolozane–tazobactam
patients treated with ceftolozane–
tazobactam and 1032 patients treated
with comparator regimens (mer-
openem 1 g every eight hours or
levofloxacin 750 mg daily). The most
common adverse reactions (occur-
ring in at least 5% of patients) were
nausea, diarrhea, headache, and
pyrexia. Treatment discontinuation
due to adverse effects occurred in 20
of 1015 (2%) and 20 of 1032 (1.9%)
patients receiving ceftolozane–
tazobactam and comparator agents,
respectively. The only serious adverse
event reported was development
of Clostridium difficile infection,
which was reported in both Phase
III trials.61,63 There were more deaths
in the Phase II and III trials of
ceftolozane–tazobactam for cIAI;
however, the deaths were not thought
to be attributable to study drug.60,63
Overall, the safety and tolerability
profiles of ceftolozane–tazobactam
appear to mirror those of other ceph-
alosporins. Completed and ongoing
Phase III clinical trials will provide
much-needed additional data re-
garding the safety and tolerability of
this agent.
Dosing and administration
The manufacturer recommends
Fraction (%) Patients
Plus Metronidazole
353/375 (94.1)
359/476 (83.8)
323/389 (83.0)
259/275 (94.2)
234/243 (96.3)
193/201 (96.0)
28/28 (100)
25/25 (100)
107/109 (98.2)
Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
that ceftolozane–tazobactam be
administered as a 1.5-g dose every
eight hours by i.v. infusion over one
hour in adults (≥18 years of age) with
normal renal function or mild renal
dysfunction (CLcr of ≥50 mL/min).21
The duration of administration of
ceftolozane–tazobactam was 4–14
days in patients with cIAI and up to 7
days in patients with cUTI.
The dosing of this agent has been
investigated in multiple Phase I or
II pharmacokinetic studies.45,46 The
dosing schedules in these studies var-
ied and, in some cases, included the
administration of ceftolozane with
and without tazobactam. As previ-
ously discussed, no adverse effect
described to date has been correlated
with the amount of ceftolozane–
tazobactam administered.
Dosage adjustment is recom-
mended in patients with CLcr values
of ≤50 mL/min. 21 Recommenda-
tions are to administer 750 mg of
ceftolozane–tazobactam i.v. every
eight hours in patients with an esti-
mated CLcr of 30–50 mL/min, with
further dose reduction (to 375 mg)
recommended in patients with an
estimated CLcr of 15–29 mL/min. In
patients with end-stage renal disease
receiving IHD, a single loading dose
Absolute % Difference
Meropenem (95% CI)
375/399 (94.0) 0 (–4.2 to 4.3)
424/494 (85.8) –2.2 (–8.0 to 3.4)
364/417 (87.3) –4.2 (–8.9 to 0.5)
304/321 (94.7) –1.0 (–4.5 to 2.6)
269/282 (95.4) 0.9 (–2.8 to 4.5)
214/225 (95.1) 0.9 (–3.3 to 5.1)
22/25 (88.0) 12 (–2.4 to 30.0)
28/28 (100) 0 (–13.3 to 12.1)
134/137 (97.8) 0.4 (–4.5 to 4.6)
2143
 CLINICAL REVIEW  Ceftolozane–tazobactam
of 750 mg of ceftolozane–tazobactam
followed by a 150-mg maintenance
dose administered every eight hours
for the remainder of the treatment
period is recommended. It is sug-
gested that a ceftolozane–tazobactam
dose be administered at the earliest
possible time after completion of an
IHD session.21
Pharmacoeconomic and
formulary considerations
The wholesale acquisition cost
(WAC) for seven days of treatment
with ceftolozane–tazobactam is ap-
proximately $1700.66,67 At $83 per
1.5-g vial, the cost of therapy per
day is approximately $250.66 Rela-
tive to the comparator agents used
in the aforementioned clinical tri-
als (meropenem and levofloxacin),
ceftolozane–tazobactam is signifi-
cantly more costly. 67 Moreover,
doripenem, which shares the
same indications as ceftolozane–
tazobactam, costs approximately
$800 for seven days of therapy
based on available WAC data. 67
While actual acquisition costs vary
by institution, the cost of thera-
py with ceftolozane–tazobactam
will likely play a significant role in
how this drug is used. Adding this
agent to a formulary would pro-
vide another option for multidrug-
resistant Pseudomonas infections
and could potentially decrease car-
bapenem usage; however, the utility of
ceftolozane–tazobactam may be
limited by both its small number of
approved indications and its cost.
From an antimicrobial steward-
ship perspective, prescribing of this
product should likely be restricted
to infectious diseases clinicians in
order to help ensure its appropriate
use.
Place in therapy
Like ceftaroline, ceftolozane ap-
pears destined for niche utility and
will be mostly reserved for treatment-
resistant gram-negative organisms,
most notably P. aeruginosa. Ceftolo-
2144 Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
zane alone appears to have increased
stability in the presence of AmpC
b-lactamases but perhaps to a lesser
extent than cefepime.19 The combina-
tion with tazobactam affords activity
against ESBL-producing organisms.
Ceftolozane–tazobactam is suscep-
tible to hydrolysis by carbapenemases
such as metallo-b-lactamase and
K. pneumoniae carbapenemase but
maintains susceptibility to other
forms of resistance such as efflux
pumps and loss of porin channels.
P. aeruginosa, an organism whose
antimicrobial resistance mostly in-
volves AmpC, efflux pumps, and
porin channel reduction, remains
highly susceptible to ceftolozane–
tazobactam; thus, the combination
agent may serve as an appealing alter-
native to colistin for salvage therapy.
While ceftolozane–tazobactam
has activity against gram-positive
pathogens, it should not be relied on
for gram-positive pathogen coverage
in patients with mixed infections.
Tazobactam enhances the activ-
ity of ceftolozane against anaerobic
pathogens, particularly B. fragilis.
However the combination has been
shown to provide reduced or limited
coverage of other species of Bacteroi-
des and variable coverage of gram-
positive anaerobes. In the clinical
trials of ceftolozane–tazobactam for
cIAI, concomitant use of metroni-
dazole was required for anaerobe
coverage—a further indication of
the agent’s potentially limited utility
in clinical practice. Other concerns
regarding ceftolozane–tazobactam
include a slight increase in mortal-
ity compared with meropenem in
intraabdominal infections (2.5%
versus 1.5%) and reduced efficacy in
patients with baseline CLcr values of
<50 mL/min.21
Conclusion
Ceftolozane–tazobactam is a new
cephalosporin with enhanced ac-
tivity against multidrug-resistant
P. aeruginosa as well as other gram-
negative pathogens.
References
1. Infectious Diseases Society of America.
The 10 by ’20 initiative: pursuing global
commitment to develop 10 new anti-
microbial drugs by 2020. Clin Infect Dis.
2010; 50:1081-3.
2. Boucher HW, Talbot GH, Benjamin DK
et al. 10 by ’20 progress—development
of new drugs active against gram nega-
tive bacilli: an update from the Infectious
Diseases Society of America. Clin Infect
Dis. 2013; 56:1685-94.
3. Food and Drug Administration. FDA
drug safety communication: FDA ap-
proves label changes for antibacte-
rial Doribax (doripenem) describing
increased risk of death for ventilator
patients with pneumonia (March 6,
2014). www.fda.gov/Drugs/DrugSafety/
ucm387971.htm (accessed 2014 Dec 12).
4. Food and Drug Administration. FDA drug
safety communication: FDA warns of
increased risk of death with iv antibacte-
rial Tygacil (tigecycline) and approves
new boxed warning (September 27,
2013). www.fda.gov/drugs/drugsafety/
ucm369580.htm (accessed 2014 Dec 12).
5. Livermore DM. Of Pseudomonas, porins,
pumps and carbapenems. J Antimicrob
Chemother. 2001; 47:247-50.
6. Lister PD, Wolter DJ, Hanson ND.
Antibacterial-resistant Pseudomonas
aeruginosa: clinical impact and complex
regulation of chromosomally encoded
resistance mechanisms. Clin Microbiol
Rev. 2009; 22:582-610.
7. Murano K, Yamanaka T, Toda A et al.
Structural requirements for the stability
of novel cephalosporins to AmpC beta
lactamase based on 3D-structure. Bioorg
Med Chem. 2008; 16:2261-75.
8. Toda A, Ohki H, Yamanaka T et al. Syn-
thesis and SAR of novel parenteral anti-
pseudomonal cephalosporins: discovery
of FR264205. Bioorg Med Chem Lett.
2008; 18:4849-52.
9. Takeda S, Ishii Y, Hatano K et al. Stabil-
ity of FR264205 against AmpC beta–
lactamase of Pseudomonas aeruginosa. Int
J Antimicrob Agents. 2007; 30:443-5.
10. Drawz SM, Bonomo RA. Three decades
of beta lactamase inhibitors. Clin Micro-
biol Rev. 2010; 23:160–201.
11. Moyá B, Zamorano L, Juan C et al. Affin-
ity of the new cephalosporin CXA-101
to penicillin-binding proteins of Pseu-
domonas aeruginosa. Antimicrob Agents
Chemother. 2010; 54:3933-7.
12. Moya B, Dotsch A, Juan C et al. Beta
lactam resistance response triggered by
inactivation of a nonessential penicillin-
binding protein. PLoS Pathog. 2009;
5: e1000353.
13. Livermore DM. b-lactamases in labora-
tory and clinical resistance. Clin Microbiol
Rev. 1995; 8:557-84.
14. Brown NP, Pillar CM, Sahm DF et al. Ac-
tivity profile of CXA-101 and CXA-101/
tazobactam against target gram-positive
and gram-negative pathogens. Abstract
and poster presented at 49th Annual In-
terscience Conference on Antimicrobial

Agents and Chemotherapy. San Francis-
co, CA; 2009 Sep 12–15.
15. Zhanel GG, Adam HJ, Baxter M et al. In
vitro activity of ceftolozane/tazobactam
against 5,715 gram-negative and gram-
positive pathogens isolated from patients
in Canadian hospitals in 2011 and 2012:
CANWARD surveillance study. Abstract
presented at 52nd Annual Interscience
Conference on Antimicrobial Agents and
Chemotherapy. San Francisco, CA; 2012
Sep 9–12.
16. Pillar CM, Sahm D, Brown N et al. Ac-
tivity profile of CXA-101 against gram-
positive and gram-negative pathogens
by broth and agar dilution. Abstract and
poster presented at 48th Annual Inter-
science Conference on Antimicrobial
Agents and Chemotherapy. Washington,
DC; 2008 Oct 25–28.
17. Brown NP, Pillar CM, Sahm DF et al.
Disk diffusion testing of CXA-101 and
CXA-101 in combination with tazobac-
tam against target pathogens. Abstract
and poster presented at 49th Annual
Interscience Conference on Antimicro-
bial Agents and Chemotherapy. San Fran-
cisco, CA; 2009 Sep 12–15.
18. Farrell DJ, Flamm RK, Sader HS et al.
Antimicrobial activity of ceftolozane/
tazobactam tested against Enterobacte-
riaceae and Pseudomonas aeruginosa with
various resistance patterns isolated in US
hospitals (2011–2012). Antimicrob Agents
Chemother. 2013; 57:6305-10.
19. Sader HS, Rhomberg PR, Farrell DJ et
al. Antimicrobial activity of CXA-101, a
novel cephalosporin tested in combina-
tion with tazobactam against Enterobac-
teriaceae, Pseudomonas aeruginosa, and
Bacteroides fragilis strains having various
resistance phenotypes. Antimicrob Agents
Chemother. 2011; 55:2390-4.
20. Bulik CC, Christensen H, Nicolau DP. In
vitro potency of CXA-101, a novel cepha-
losporin, against Pseudomonas aeruginosa
displaying various resistance phenotypes,
including multidrug resistance. Antimi-
crob Agents Chemother. 2010; 54:557-9.
21. Zerbaxa (ceftolozane and tazobactam)
package insert. Lexington, MA: Cubist
Pharmaceuticals; 2014.
22. Snydman DR, McDermott LA, Jacobus
NV. Activity of ceftolozane/tazobactam
against a broad spectrum of recent clini-
cal anaerobic isolates. Antimicrob Agents
Chemother. 2013; 58:1218-23.
23. Takeda S, Nakai T, Wakai Y et al. In vitro
and in vivo activities of a new cephalo-
sporin, FR264205, against Pseudomonas
aeruginosa. Antimicrob Agents Chemother.
2007; 51:826-30.
24. Walkty A, Karlowsky JA, Adam H et al. In
vitro activity of ceftolozane-tazobactam
against Pseudomonas aeruginosa isolates
obtained from patients in Canadian
hospitals in the CANWARD study, 2007–
2012. Antimicrob Agents Chemother. 2013;
57:5707-9.
25. Juan C, Zamorano L, Perez JL et al. Activ-
ity of a new antipseudomonal cephalo-
sporin, CXA-101 (FR264205), against
CLINICAL REVIEW  Ceftolozane–tazobactam
carbapenem-resistant and multidrug-
resistant Pseudomonas aeruginosa clinical
strains. Antimicrob Agents Chemother.
2010; 54:846-51.
26. Sader HS, Farrell DJ, Castanheira M et
al. Antimicrobial activity of ceftolozane/
tazobactam tested against Pseudomonas
aeruginosa and Enterobacteriaceae with
various resistance patterns isolated
in European hospitals (2011–2012). J
Antimicrob Chemother. 2014; 69:2713-22.
27. Livermore DM, Mushtaq S, Ge Y. Che-
querboard titration of cephalosporin
CXA-101 (FR264205) and tazobactam
versus beta-lactamase–producing En-
terobacteriaceae. J Antimicrob Chemother.
2010; 65:1972-4.
28. Zamorano L, Juan C, Fernández-Olmos
A et al. Activity of the new cephalosporin
CXA-101 (FR264205) against Pseudomo-
nas aeruginosa isolates from chronically
infected cystic fibrosis patients. Clin
Microbiol Infect. 2010; 16:1482-7.
29. Estabrook M, Bussell B, Clugston SL,
Bush K. In vitro activity of ceftolozane-
tazobactam as determined by broth
dilution and agar diffusion assays against
recent U.S. Escherichia coli isolates from
2010 to 2011 carrying CTX-M-type
extended-spectrum b-lactamases. J Clin
Microbiol. 2014; 52:4049-52.
30. Titelman E, Karlsson IM, Ge Y et al. In
vitro activity of CXA-101 plus tazobac-
tam (CXA-201) against CTX-M-14- and
CTX-M-15-producing Escherichia coli
and Klebsiella pneumoniae. Diagn Micro-
biol Infect Dis. 2011; 70:137-41.
31. Melchers MJ, van Mil CH, Mouton JW.
In vitro activity of ceftolozane alone and
in combination with tazobactam against
extended spectrum beta-lactamase har-
bouring “Enterobacteriaceae”. Abstract
presented at 52nd Annual Interscience
Conference on Antimicrobial Agents and
Chemotherapy. San Francisco, CA; 2012
Sep 9–12.
32. Giske CG, Ge J, Nordmann P. Activity of
cephalosporin CXA-101(FR264205) and
comparators against extended-spectrum-
beta-lactamase-producing Pseudomonas
aeruginosa. J Antimicrob Chemother.
2009; 64:430-1.
33. Popejoy MW, Cloutier D, Huntington
JA et al. Ceftolozane/tazobactam for the
treatment of cUTI and cIAI caused by
ESBL-producing Enterobacteriaceae. Ab-
stract presented at IDWeek. Philadelphia,
PA; 2014 Oct 8–12.
34. Papp-Wallace KM, Bethel CR, Distler AM
et al. Inhibitor resistance in the KPC-2
beta–lactamase, a preeminent property
of this class A beta–lactamase. Antimicrob
Agents Chemother. 2010; 54:890-7.
35. Livermore DM. Multiple mechanisms of
antimicrobial resistance in Pseudomonas
aeruginosa: our worst nightmare? Clin
Infect Dis. 2002; 34:634-40.
36. Rodrigez-Baño J, Dolores Navarro M,
Retamar P et al. b-lactam/b-lactam in-
hibitor combinations for the treatment
of bacteremia due to extended-spectrum
b-lactamase-producing Escherichia coli: a
Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
post hoc analysis of prospective cohorts.
Clin Infect Dis. 2012; 54:167-74.
37. Tamma PD, Girdwood S, Gopaul R et al.
The use of cefepime for treating AmpC b-
lactamase–producing Enterobacteriaceae.
Clin Infect Dis. 2013; 57:781-8.
38. Siedner MJ, Galar A, Guzmán-Suarez
BB et al. Cefepime vs other antibacterial
agents for the treatment of Enterobacter
species bacteremia. Clin Infect Dis. 2014;
58:1554-63.
39. Cabot G, Mulet X, Moya B et al. Dy-
namics and mechanisms of resistance
development to ceftazidime, meropenem
and ceftolozane/tazobactam in wild-type
and mutator P. aeruginosa strains. In:
Abstracts: 52nd Interscience Conference
on Antimicrobial Agents and Chemo-
therapy. Washington, DC; American
Society for Microbiology; 2012.
40. Moulds N, Lister P. Impact of character-
ized resistance mechanisms on the sus-
ceptibility of Pseudomonas aeruginosa to
CXA-101. Abstract and poster presented
at 50th Annual Interscience Conference
on Antimicrobial Agents and Chemo-
therapy. Boston, MA; 2010 Sep 12–15.
41. Moore RA, Chan L, Hancock RE. Evi-
dence for two distinct mechanisms of re-
sistance to polymyxin B in Pseudomonas
aeruginosa. Antimicrob Agents Chemother.
1984; 26:539-45.
42. Gunn JS, Lim KB, Krueger J et al. PmrA-
PmrB–regulated genes necessary for
4-aminoarabinose lipid A modification
and polymyxin resistance. Mol Microbiol.
1998; 27:1171-82.
43. Poole K. Aminoglycoside resistance in
Pseudomonas aeruginosa. Antimicrob
Agents Chemother. 2005; 49:2479-87.
44. Jalal S, Wretlind B. Mechanisms of quin-
olone resistance in clinical strains of
Pseudomonas aeruginosa. Microb Drug
Resist. 1998; 4:257-61.
45. Ge Y, Whitehouse MJ, Friedland I,
Talbot GH. Pharmacokinetics and safety
of CXA-101, a new antipseudomonal
cephalosporin, in healthy adult male
and female subjects receiving single- and
multiple-dose intravenous infusions.
Antimicrob Agents Chemother. 2010;
54:3427-31.
46. Miller B, Hershberger E, Benziger D et al.
Pharmacokinetics and safety of intrave-
nous ceftolozane-tazobactam in healthy
adult subjects following single and mul-
tiple ascending doses. Antimicrob Agents
Chemother. 2012; 56:3086-91.
47. Merrem (meropenem) package insert.
Wilmington, DE: AstraZeneca Pharma-
ceuticals; 2013.
48. Ceftazidime package insert. Research Tri-
angle Park, NC: GlaxoSmithKline; 2007.
49. Cefepime package insert. Lake Forest, IL:
Hospira Inc.; 2012.
50. Miller B, Chandorkar G, Umeh O et
al. Safety and PK of iv ceftolozane/
tazobactam 3 g q8h and cumulative frac-
tion of response in plasma and epithelial
lining fluid in a simulated VAP popula-
tion. In: Abstracts: 52nd Interscience
Conference on Antimicrobial Agents
2145
 CLINICAL REVIEW  Ceftolozane–tazobactam
and Chemotherapy. Washington, DC:
American Society for Microbiology;
2012.
51. Chandorkar G, Huntington JA, Gotfried
MH et al. Intrapulmonary penetration of
ceftolozane/tazobactam and piperacillin/
tazobactam in healthy adult subjects. J
Antimicrob Chemother. 2012; 67:2463-9.
52. Nau R, Kinzig-Schippers M, Sörgel F et al.
Kinetics of piperacillin and tazobactam
in ventricular cerebrospinal fluid of hy-
drocephalic patients. Antimicrob Agents
Chemother. 1997; 41:987-91.
53. Chandorkar G, Xiao A, Mouksassi MS
et al. Population pharmacokinetics of
ceftolozane/tazobactam in healthy vol-
unteers, subjects with varying degrees of
renal function and patients with bacte-
rial infections. J Clin Pharmacol. 2015;
55:230-9.
54. Wooley M, Miller B, Krishna G et al.
Impact of renal function on the phar-
macokinetics and safety of ceftolozane-
tazobactam. Antimicrob Agents Chemother.
2014; 58:2249-55.
55. Vogelman B, Gudmundsson S, Legett J
et al. Correlation of antimicrobial phar-
macokinetic parameters with therapeutic
efficacy in an animal model. J Infect Dis.
1988; 158:831-47.
56. Craig WA. Interrelationship between
pharmacokinetics and pharmacodynam-
ics in determining dosage regimens for
broad-spectrum cephalosporins. Diagn
Microbiol Infect Dis. 1995; 22:89-96.
57. Soon RL, Forrest A, Holden PN et al. In
vitro pharmacodynamics of ceftolozane/
tazobactam against b-lactamase pro-
2146 Am J Health-Syst Pharm—Vol 72 Dec 15, 2015
ducing Escherichia coli. In: Abstracts:
52nd Interscience Conference on An-
timicrobial Agents and Chemotherapy.
Washington, DC: American Society for
Microbiology; 2012.
58. Craig WA, Andes DR. In vivo activities
of ceftolozane, a new cephalosporin,
with and without tazobactam against
Pseudomonas aeruginosa and Enterobacte-
riaceae, including strains with extended-
spectrum beta-lactamases, in the thighs
of neutropenic mice. Antimicrob Agents
Chemother. 2013; 54:1577-82.
59. Umeh O, Friedland I. A double blind,
randomized, phase 2 study to compare
the safety and efficacy of intravenous
CXA-101 (CXA) and intravenous ceftazi-
dime (CTZ) in complicated urinary tract
infections (cUTI). Poster and presenta-
tion at 50th Annual Interscience Confer-
ence on Antimicrobial Agents and Che-
motherapy. Boston, MA; 2010 Sep 12–15.
60. Lucasti C, Hershberger E, Miller B,
Yankelev S. Multicenter, double-blind,
randomized, phase II trial to assess safety
and efficacy of ceftolozane-tazobactam
plus metronidazole compared to mero-
penem in adult patients with complicated
intra-abdominal infections. Antimicrob
Agents Chemother. 2014; 58:5350-7.
61. Wagenlehner F, Umeh O, Huntington J
et al. Efficacy and safety of ceftolozane/
tazobactam versus levofloxacin in the
treatment of complicated urinary tract
infections (cUTI) in hospitalized adults:
results from the phase 3 ASPECT-cUTI
trial. Presentation at 24th European
Congress of Clinical Microbiology and
Infectious Diseases. Barcelona, Spain;
2014 May 10–13.
62. Sakoulas G, Umeh O, Huntington J et al.
Efficacy of ceftolozane/tazobactam versus
levofloxacin in the treatment of com-
plicated urinary tract infections (cUTI)
caused by levofloxacin-resistant patho-
gens: results from the cUTI trial. Abstract
presented at IDWeek. Philadelphia, PA;
2014 Oct 8–12.
63. Solomkin J, Hershberger E, Miller B et al.
Ceftolozane/tazobactam plus metronida-
zole for complicated intra-abdominal in-
fections in an era of multidrug resistance:
results from a randomized, double-blind,
phase 3 trial (ASPECT-cIAI). Clin Infect
Dis. 2015; 60:1462-71.
64. Miller B, Popejoy MW, Hershberger E
et al. Characteristics and outcomes of
complicated intra-abdominal infections
involving Pseudomonas aeruginosa
from a phase 3 ceftolozane/tazobactam
study. Abstract presented at IDWeek.
Philadelphia, PA; 2014 Oct 8–12.
65. ClinicalTrials.gov. Safety and efficacy
study of ceftolozane/tazobactam to treat
ventilated nosocomial pneumonia
(ASPECT-NP). www.clinicaltrials.gov/
ct2/show/NCT02070757?term=ceftoloza
ne&rank=1 (accessed 2014 Dec 17).
66. Merck & Co., Inc. Zerbaxa (ceftolozane
and tazobactam) product guide for phar-
macy. www.zerbaxa.com/pdf/ZERBAXA-
Ordering-Dosing.pdf (accessed 2015
Mar 23).
67. Ceftolozane/tazobactam (Zerbaxa)—a
new intravenous antibiotic. Med Lett
Drugs Ther. 2015; 57:31-3.