Ceftazidim Avibactam Expert Rev Clin Pharmacol 2015

Expert Review of Clinical Pharmacology
ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20
Ceftazidimeavibactam for the treatment

of complicated urinary tract infections and
complicated intra-abdominal infections
Yogesh Mawal, Ian A Critchley, Todd A Riccobene & Angela K Talley
To cite this article: Yogesh Mawal, Ian A Critchley, Todd A Riccobene & Angela K Talley
(2015): Ceftazidimeavibactam for the treatment of complicated urinary tract infections
and complicated intra-abdominal infections, Expert Review of Clinical Pharmacology, DOI:
10.1586/17512433.2015.1090874
To link to this article: http://dx.doi.org/10.1586/17512433.2015.1090874
Published online: 30 Sep 2015.
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Drug Profile
Ceftazidimeavibactam for
the treatment of complicated
urinary tract infections and
complicated intra-abdominal
infections
Expert Rev. Clin. Pharmacol. Early online, 117 (2015)
Yogesh Mawal*1,
Ian A Critchley2,
Todd A Riccobene3
and Angela K Talley4
1
Forest Laboratories, Inc., a subsidiary
of Allergan plc (formerly Actavis plc),
New Jersey, USA
2
Allergan plc, California, USA
3
Allergan plc (formerly Actavis plc),
Jersey City, NJ, USA
4
Allergan plc (formerly Actavis plc),
California, USA
*Author for correspondence:
Tel.: +1 201 245 1874
yogeshmawal@hotmail.com
Treatment of complicated urinary tract infections and complicated intra-abdominal infections

is increasingly difficult due to the rising prevalence of multidrug-resistant Gram-negative
bacteria. Ceftazidimeavibactam is a combination of the established third-generation
cephalosporin ceftazidime with avibactam, a novel nonb-lactam b-lactamase inhibitor,
which restores the activity of ceftazidime against many b-lactamaseproducing Gramnegative bacteria, including extended-spectrum b-lactamases and Klebsiella pneumoniae
carbapenemases. Clinical and nonclinical studies supporting the safety and efficacy of
ceftazidimeavibactam include microbiological surveillance studies of clinically relevant
pathogens, in vivo animal models of infection, pharmacokinetic/pharmacodynamic target
attainment analyses, Phase I clinical pharmacology studies, and Phase II/III studies in the
treatment of complicated intra-abdominal infections and complicated urinary tract infections,
including patients with ceftazidime-nonsusceptible Gram-negative infections.
KEYWORDS: avibactam . ceftazidime . complicated intra-abdominal infections . complicated urinary tract infections
.
multidrug resistance
Both complicated intra-abdominal infections

(cIAIs) and complicated urinary tract infections (cUTIs) are common serious bacterial
infections in hospitalized patients and they
carry a considerable risk of morbidity and
mortality [1,2]. The definition of a cIAI is
usually an abscess formation or peritonitis
beyond the origin of the perforation into the
peritoneal cavity, requiring an invasive procedure for source control [2]. Infections are
often polymicrobial and may include Gramnegative and Gram-positive organisms, in
addition to various anaerobes. Among the
Gram-negative pathogens associated with
cIAIs, the most common are the Enterobacteriaceae, especially Escherichia coli and
Klebsiella spp. [2]. Urinary tract infections
(UTIs) associated with structural or functional
urinary tract abnormalities, or pyelonephritis,
are classified as cUTIs [1,3]. E. coli is
the predominant Gram-negative uropathogen,
www.tandfonline.com
10.1586/17512433.2015.1090874
although other Enterobacteriaceae including

Klebsiella spp. and Gram-negative bacteria
such as Pseudomonas aeruginosa are frequently
encountered [4].
Over the last 30 years, b-lactam antibiotics
including second- and third-generation cephalosporins, b-lactam/b-lactamase inhibitor combinations and carbapenems have been widely
used in clinical practice for the treatment of
cIAIs and cUTIs because of their broad coverage of clinically important Gram-negative
bacteria. For many of these organisms, resistance is mediated by the production of
b-lactamases such as CTX-M-like enzymes,
AmpC, and more recently, carbapenemases
such as OXA-48 and K. pneumoniae carbapenemases (KPCs) [4,5]. The US Center for
Disease Control has identified both extendedspectrum
b-lactamases
(ESBLs)
and
multidrug-resistant (MDR) P. aeruginosa as
serious public health threats in USA, and
2015 Actavis/Allergen
ISSN 1751-2433
Drug Profile
KPCs, class C (AmpC) enzymes and

some class D (OXA) enzymes, which is a
OH
broader spectrum of b-lactamase inhibiO
O
tory activity than other currently available
N
b-lactamase inhibitors, but is not active
H
N
N
H 2N
2
H
against class B (the metallo-b-lactamases).
N
S
S
N
As a single agent, avibactam has no
O
N+
N
N
meaningful antimicrobial activity at therOSO3Na
O
O
apeutic concentrations, but restores the
activity of a b-lactam such as ceftazidime
5H2O
O
O
against a broad range of b-lactamase
producing bacteria [5].
Figure 1. Chemical structures of ceftazidime and avibactam. (A) Ceftazidime pentahydrate, molecular weight, 636.6 g/mol. (B) Avibactam sodium, molecular weight,
New regulatory pathway options,
287.23 g/mol.
described recently by the US FDA [3],
Reproduced from the US Package [16].
were intended to address urgent unmet
medical needs for antibiotics in the treatcarbapenemase-resistant Enterobacteriaceae (CRE) as an urgent ment of MDR Gram-negative bacterial infections. These
threat [6].
allowed for a revised ceftazidimeavibactam development stratSince their emergence in 2001, CRE have proliferated as egy that permitted its approval prior to the availability of
problematic pathogens in hospitals in USA and worldwide [7]. Phase III data for the treatment of adult patients with cUTI,
Carbapenemase-mediated resistance among these pathogens, including pyelonephritis, or cIAI, when used in combination
including KPC-producing strains, leaves clinicians with few with metronidazole (AVYCAZ; Forest Pharmaceuticals, Inc.,
options for safe and effective treatment [811]. Last-resort ther- a subsidiary of Forest Laboratories, LLC, Cincinnati, OH,
apy such as colistin, either as monotherapy or in combination USA) [16]. The ceftazidimeavibactam prescribing information
with a carbapenem, is not supported by solid clinical evidence recommends reserving ceftazidimeavibactam for use in patients
and carries a risk of adverse events (AEs) that may harm the who have limited or no alternative treatment options, based on
individual patient [12].
the limited clinical safety and efficacy data that are available.
Infections caused by KPC-producing Enterobacteriaceae are
This review summarizes the in vitro and in vivo antibacterial
currently limited to inpatient facilities; however, their high pro- activity, pharmacodynamic (PD) and pharmacokinetic (PK)
pensity for transmission presents an urgent public health threat, properties of ceftazidimeavibactam, and its safety, tolerability
necessitating aggressive infection control measures [6]. An out- and efficacy observed in cIAI and cUTI clinical studies.
break of KPC infections at the US National Institutes of
Health in 2011 that was traced to a single patient resulted in Chemistry
18 patients being infected, of whom 11 died [13]. This outbreak Ceftazidime is a semi-synthetic, b-lactam antibacterial drug; it
and a more recent series of cases of CRE infections associated is a pentahydrate of (6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)with endoscopic retrograde cholangiopancreatography at the 2-(2-carboxypropan-2-yloxyimino)acetamido)-8-oxo-3-(pyridiniumUniversity of California, Los Angeles [14] outline the challenges 1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.
faced by healthcare centers in minimizing the risk of transmis- Its molecular weight is 636.6. The empirical formula is
sion and highlight the necessity for developing effective antibi- C22H32N6O12S2 [16].
otics to manage infections caused by MDR isolates.
The chemical structure of avibactam is sodium [(2S,5R)Combining a b-lactam antibiotic with a b-lactamase inhibi- 2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl] sulfate. Its
tor has been a well-proven and effective strategy for combating molecular weight is 287.23. The empirical formula is
resistance [5]. Ceftazidimeavibactam is the combination of cef- C7H10N3O6SNa [16].
tazidime, an established, third-generation broad-spectrum cephalosporin, with avibactam, a novel nonb-lactam b-lactamase Mode of action
inhibitor (formerly known as NXL104 and AV1330A). Ceftazi- Ceftazidime, like other b-lactams, inhibits bacterial cell wall
dime, which has a well-established safety profile, was approved synthesis by binding to the active sites of penicillin-binding
in USA in 1985 and is currently indicated for the treatment of proteins, ultimately resulting in cell death [15].
many types of bacterial infections including uncomplicated and
Avibactam is a potent member of a novel class of nonbcomplicated UTI and intra-abdominal infection (IAI) (FOR- lactam inhibitors called diazabicyclooctanes [17]. The avibactam
TAZ; GlaxoSmithKline, Research Triangle Park, NC, USA) carbonyl carbon residue at position 7 forms a covalent bond
[15]. However, the efficacy of ceftazidime is increasingly comwith the active site serine residue of b-lactamases, which is
promised by the spread of b-lactamaseproducing pathogens. responsible for binding to b-lactams and rendering them inacAvibactam exerts inhibitory activity against multiple serine- tive [18]. Subsequently, avibactam detaches and its fivebased b-lactamases including Ambler class A ESBLs, class A membered urea ring is recyclized, regenerating intact avibactam
A
Mawal, Critchley, Riccobene & Talley
Expert Rev. Clin. Pharmacol.
Ceftazidimeavibactam for cUTI & cIAI
Drug Profile
Table 1. Summary of b-lactamase spectrum of avibactam activity compared with clavulanic acid and
tazobactam.
Ambler
class
Functional
subgroup
b-Lactamase
Avibactam
Clavulanic
acid
Tazobactam
Sulbactam
Class A
(serine)
2be
CTX-M, PER, VEB

TEM, SHV, ESBLs
GES
KPC
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
No
No
No
No
No
2f
Class B
(metallo)
3a
IMP, VIM, NDM
No
No
No
No
Class C
(serine)
1e
Chromosomal Enterobacteriaceae AmpC

Chromosomal Pseudomonas AmpC
Plasmidic ACC, DHA, FOX, LAT, MIX, MIR,
ACT
Yes
Yes
Yes
No
No
No
No
No
No
Yes
Yes
Yes
Penicillinase-type OXA-1, -10, -13

Penicillinase-type OXA-31
Carbapenemase-type OXA-23, -40, -48, -58
Variable
Variable
Variable
Variable
Variable
Variable
Variable
Variable
Variable
No
No
No
1
Class D
(serine)
2d
2de
2df
Variable activity is due to variable sequence homology among members of Class D family.
Data from [19,2127].
which is available to bind further b-lactamase molecules. The

half-life for deacylation and release of intact avibactam from
the b-lactamase TEM-1 enzyme is around 16 min [18].
Avibactams inhibition of b-lactamases by reversible acylation
differs from that of the b-lactam b-lactamase inhibitors clavulanic acid, sulbactam and tazobactam, which, after binding to
the active site, are hydrolyzed and rendered inactive.
A hydrolytic route has been proposed for the deacylation of
avibactam by the carbapenemase KPC-2, although the slow
kinetics of this reaction means that it is unlikely to curtail the
clinical effectiveness of ceftazidimeavibactam against Gramnegative bacteria harboring this enzyme [19].
Avibactam has a broader range of activity against clinically
important b-lactamases than clavulanic acid, tazobactam and
sulbactam (TABLE 1) [1927]. Clavulanic acid and tazobactam (but not
sulbactam) inhibit common class A b-lactamases, including SHV
and the ESBL CTX-M, but the activity of avibactam extends to
inhibition of KPCs [21,23], class C enzymes such as AmpC [18,2729]
and specific class D enzymes (e.g., OXA-48) [18,19]. The
higher potency of avibactams inhibition of b-lactamases compared with clavulanate, sulbactam and tazobactam has been
shown by lower IC50 (range 3170 nM) and reduced reactivation
rates for class A and C b-lactamases, including TEM-1,
KPC-2 and P99, and AmpC from P. aeruginosa [23,30].
Microbiology
Spectrum of activity against ceftazidime-resistant
pathogens
Many in vitro studies have shown that the addition of avibactam to ceftazidime restores activity against b-lactamase
producing strains of Gram-negative bacteria (TABLE 2). Avibactam
at a fixed concentration of 4 mg/l in combination with
ceftazidime has been shown to reduce the MIC90 value of ceftazidime by >128-fold to 8 mg/l against KPC-producing
www.tandfonline.com
Enterobacteriaceae [23,3032], which is the FDA susceptibility

breakpoint for ceftazidimeavibactam [16]. The activity of ceftazidimeavibactam against CTX-M producers among Enterobacteriaceae increased by 832-fold compared with ceftazidime
alone, and the MICs reduced to <1 mg/l [21,32]. Against TEM
or SHV b-lactamaseproducing E. coli and K. pneumoniae
strains, the addition of avibactam reduced the MIC by
256-fold compared with ceftazidime alone [32].
AmpC-mediated ceftazidime resistance in P. aeruginosa
strains was reversed with ceftazidimeavibactam, reducing the
MIC values for fully derepressed mutants and isolates to
8/4 mg/l [33], the FDA susceptibility breakpoint for ceftazidimeavibactam against P. aeruginosa [16].
Microbiology surveillance studies
Recent microbiological studies have revealed a concerning

increase in b-lactamaseproducing strains of Gram-negative
bacteria in USA. In 2005, 1.7% of E. coli and 3.2% of
K. pneumoniae isolates were ESBL producing and by 2011,
these rates had increased to 7.3 and 13.1%, respectively [34].
A study conducted in 24 centers in USA between 2009 and
2011 found that 6.8% of E. coli isolates and 10.3% of K. pneumoniae isolates from patients with UTI were ESBL producers [35]. Analysis of contemporary US surveillance data
collected in 2012 showed that ESBL prevalence rates for both
E. coli and K. pneumoniae were in excess of 10% in most of
the nine US Census Bureau regions [4]. The proportion of
CRE strains reported in USA rose from 1.2% in 2001 to 4.2%
in 2011, with CREs reported at three-times more centers in
the northeast than in the south, midwest and west. Rates of up
to 21% have been recorded in major metropolitan areas [811].
The in vitro activity of ceftazidimeavibactam against Gramnegative clinical isolates has been evaluated in two studies in
North/Latin America and two studies based solely in
3
Drug Profile
Table 2. Summary of in vitro studies of ceftazidimeavibactam activity against b-lactamaseproducing

strains of Gram-negative bacteria.
Author (year)
Enzymes and pathogens
Outcome
Levasseur et al.
(2015)
TEM or SHV among

Escherichia coli and Klebsiella
pneumoniae strains
256-fold reduction in MIC with ceftazidimeavibactam compared with

ceftazidime alone
CTX-M producers among

Enterobacteriaceae
832-fold reduction in MIC with ceftazidimeavibactam compared with

ceftazidime alone
KPC producers among

Enterobacteriaceae
>128-fold reduction in MIC with ceftazidimeavibactam compared with

ceftazidime alone
Aktas (2012)
OXA-48 or CTX-M-15 in
K. pneumoniae; CTX-M-15 in
E. coli
MIC90 against OXA-48 reduced to 0.5 mg/l with ceftazidimeavibactam

compared with 512 mg/l for ceftazidime alone;
MIC90 against CTX-M-15 reduced to 0.25 mg/l from 64 mg/l in
K. pneumoniae and to <0.008 mg/l from 32 mg/l in E. coli
[31]
Livermore et al.
(2011)
CTX-M, KPC, OXA-48 in

E. coli
MIC reduced to 0.251 mg/l with ceftazidimeavibactam from 64 mg/l with

ceftazidime alone
[22]
LagaceWiens et al.
(2011)
AmpC-hyperproducing E. coli
128-fold reduction in MIC90 to 1 mg/l with ceftazidimeavibactam from

>64 mg/l with ceftazidime alone
[39]
Mushtaq
(2010)
AmpC depressed strains in

Pseudomonas aeruginosa
MICs reduced to 8 mg/l with ceftazidimeavibactam at fixed dose of 4 mg/l

from 64128 mg/l with ceftazidime alone
[33]
Endimiani
(2009)
KPC isolates in
K. pneumoniae
MIC90 reduced to 8 mg/l with ceftazidimeavibactam from 512 mg/l with

ceftazidime
[87]
Stachyra et al.
(2009)
KPC-2-producing
Enterobacteriaceae
Avibactam at a fixed dose of 4 mg/l with ceftazidime reduced MIC 1000-fold

to 1 mg/l (E. coli, K. pneumoniae) and to 8 mg/l (Enterobacter cloacae) from
641024 mg/l with ceftazidime alone
[23]
Livermore et al.
(2008)
CTX-M-15-like-producing
Enterobacteriaceae
MIC reduced to 0.251 mg/l with ceftazidimeavibactam (avibactam at fixed

dose 4 mg/l) from 64 mg/l with ceftazidime alone
[21]
Other CTX-M types in

Enterobacteriaceae
MIC reduced to 0.121 mg/l with ceftazidimeavibactam from 28 mg/l with

ceftazidime alone
USA [3640]. The addition of avibactam to ceftazidime resulted

in a 128-fold reduction in the MIC90 value against 1132 clinically relevant isolates of K. pneumoniae and Enterobacter spp.
collected from hospitalized patients in Latin America and
USA [38]. In a study of clinical isolates from patients admitted
to Canadian hospital wards (the CANWARD study), avibactam at a fixed concentration of 4 mg/l reduced the MIC90
value of ceftazidime by >64-fold against ESBL-producing
K. pneumoniae and by >512-fold against ESBL-producing and
AmpC-hyperproducing E. coli [39].
The US-based study by Castanheira et al. was conducted as
part of the International Network for Optimal Resistance Monitoring (INFORM) program. A total of 20,709 isolates were
collected from patients with bloodstream infection, pneumonia,
skin/soft tissue infections, UTIs and IAIs in 79 US hospitals
between 2010 and 2013 [37]. The other US-based study, by
Flamm et al., collected isolates from 501 patients with IAIs
and 2356 patients with UTIs from 73 centers during 2012 [36].
Both US-based studies confirmed the in vitro activity of
ceftazidimeavibactam against Enterobacteriaceae (TABLES 3 & 4)
and P. aeruginosa (TABLE 5) [36,37]. The ceftazidimeavibactam
4
Ref.
[32]
MIC90 values of 0.25 mg/l against Enterobacteriaceae are

lower than the FDA susceptibility breakpoint for ceftazidime
avibactam of 8/4 mg/l [16], and compared favorably with ceftazidime MIC90 values of 232 mg/l. MIC90 values of ceftazidimeavibactam were 0.5 mg/l against E. coli and Klebsiella
spp. in both studies, and ceftazidimeavibactam was also highly
active against contemporary clinical isolates of Enterobacter
spp., Citrobacter spp., Morganella morganii, Proteus mirabilis,
Proteus vulgaris and Serratia marcescens, with MIC90 values
ranging from 0.06 to 0.5 mg/l [36,37].
Potent activity against isolates that produced the commonly
detected b-lactamases in US hospitals was demonstrated by ceftazidimeavibactam in the INFORM program, with MIC90
values ranging from 0.252 mg/l against the isolates producing
KPCs, CTX-M-14- and -15like b-lactamases, SHV and plasmidic AmpCs [37]. Flamm et al. reported that avibactam
restored the activity of ceftazidime against extended-spectrum
cephalosporin-resistant strains (ceftazidime MIC90 32 mg/l)
with MIC90 values reduced to 0.25 mg/l (UTI) and 0.5 mg/l
(IAI) against E. coli, and to 1 mg/l (UTI) and 2 mg/l (IAI)
against K. pneumoniae [36].
Drug Profile
Table 3. In vitro activity of ceftazidimeavibactam and ceftazidime against Enterobacteriaceae clinical

isolates collected from patients in US hospitals.
UTI
Organism
n
MIC90 (mg/l)
CAZAVI
CAZ
IAI
BSI, pneumonia, SSSI, UTI, IAI
MIC90 (mg/l)
CAZAVI
CAZ
MIC90 (mg/l)
CAZAVI
CAZ
Enterobacteriaceae
2188
0.25
410
0.25
32
20,709
0.25
Escherichia coli
913
0.12
0.5
164
0.12
6468
0.12
Klebsiella spp.
501
0.25
104
0.5
32
Klebsiella pneumoniae
4421
0.25
32
Data from [36].
Data from [37].

BSI: Bloodstream infection; CAZ: Ceftazidime; CAZAVI: Ceftazidimeavibactam; IAI: Intra-abdominal infection; MIC90: Minimum inhibitory concentration that inhibits
90% of isolates; SSSI: Skin/soft tissue infection; UTI: Urinary tract infection.
The susceptibility of clinical isolates was assessed in both US were associated with protein sequence changes that affected the
surveillance studies (TABLES 4 & 5). Rates of susceptibility to cefta- omega loop of the enzyme.
zidimeavibactam reported in the INFORM program were
The spontaneous mutation frequency of ceftazidimeavibac>99.8% for all Enterobacteriaceae isolates [37]. Avibactam tam among derepressed chromosomal AmpC in P. aeruginosa
restored the activity of ceftazidime against producers of KPC has been reported as 10 9 at eight-times the MIC of 4 mg/l
(from 2.5 to 97.5% susceptible), CTX-M-15like producers [42], and the development of plasmid-encoded AmpC resistance
(from 12.6 to 100% susceptible) and CTX-M-14like pro- to ceftazidimeavibactam in the clinical setting is considered to
ducers (83 to 100% susceptible).
be low [43]. The overall risk of mutations reducing the clinical
Of the 3902 P. aeruginosa isolates collected in the success of ceftazidimeavibactam combination is difficult to
INFORM program, 96.9% were susceptible to ceftazidime ascertain; however, no development of resistance on therapy
avibactam at 8/4 mg/l [40], which is the FDA susceptibility has been detected in animal infection models or in Phase II
breakpoint [16], and 80.9% of 634 ceftazidime-nonsusceptible clinical studies [44,45].
(ceftazidime-NS) isolates were susceptible. Regarding the
MDR strains of P. aeruginosa, ceftazidimeavibactam was Animal models of infection studies
active against 81.0% of isolates, compared with 22.4% sus- Studies of ceftazidimeavibactam in murine models of peritoceptibility to ceftazidime alone. In the US-based study by neal sepsis and kidney infection are summarized in TABLE 6
Flamm et al., 96% of P. aeruginosa isolates from IAIs and [4648].
99% from UTIs were inhibited by ceftazidimeavibactam at concentrations of
Table 4. In vitro susceptibility of Enterobacteriaceae isolates collected
8 mg/l (TABLE 5) [36]. Ceftazidimeavifrom patients in US hospitals to ceftazidimeavibactam and ceftazidime.
bactam was active (MIC 8 mg/l)
Organism
n
CAZAVI %
CAZ %
against ceftazidime-NS P. aeruginosa
susceptibility
susceptibility
(75% of IAI isolates and 93.8% of UTI
isolates) and meropenem-nonsusceptible
Enterobacteriaceae
20,709
99.9
89.4
P. aeruginosa (77% of isolates from IAI
Escherichia coli
6486
100.0
91.8
and 97% of isolates from UTI).
Development of resistance
Limited studies are available on the selection of resistance to avibactam, although

the propensity for resistance development
to ceftazidimeavibactam in vitro is considered to be low. In an in vitro study
against two strains each of Enterobacter
cloacae and K. pneumoniae that were harboring the KPC-3 enzyme, single-step
mutations were selected at a frequency of
10 9 at up to 16-times the MIC of ceftazidimeavibactam [41]. Most mutations
www.tandfonline.com
4421
99.9
85.4
Klebsiella oxytoca
1159
100.0
97.4
Proteus mirabilis
1626
99.9
99.1
Enterobacter cloacae
2261
99.9
79.1
Serratia marcescens
1260
99.8
97.1
KPC producers
120
97.5
2.5
CTX-M-15-like producers
284
100.0
12.6
CTX-M-14-like producers
107
100.0
83.0
Susceptible breakpoint of 8 mg/l used for ceftazidimeavibactam.

CAZ: Ceftazidime; CAZAVI: Ceftazidimeavibactam.
Data from [37].
Drug Profile
Table 5. In vitro activity of ceftazidimeavibactam and ceftazidime against Pseudomonas aeruginosa clinical
isolates collected from patients in US hospitals.
Organism
UTI
Ceftazidimeavibactam
MIC90
155
Ceftazidime-NS
P. aeruginosa (MIC 16 mg/l)
Meropenem-NS
P. aeruginosa (MIC 4 mg/l)
Ceftazidime
%S
MIC90
%S
98.7
16
16
NA
33
NA
n
IAI
Ceftazidime
MIC90
%S
MIC90
%S
89.7
82
96.3
32
85.4
>32
12
16
NA
>32
>32
75.8
13
16
NA
>32
53.8
MIC values were measured in mg/L.

Based on a proposed susceptibility breakpoint of 8 mg/L (FDA susceptibility interpretative criteria for ceftazidime-avibactam is 8/4 mg/L) [16].
The susceptibility rate for ceftazidime was determined by the Clinical Laboratory Standards Institute (CSLI) breakpoints [71].
NA: Not available.
A murine model of pyelonephritis caused by injection of

approximately 104 CFU of AmpC- or ESBL-producing Enterobacteriaceae into the kidney of immunocompromised mice
assessed ceftazidime alone and combined with avibactam and
administered at 4, 8, 24 and 32 h post-infection [46]. The bacterial burden at 48 h was reduced by 2.6 log104.5 log10 CFU
with ceftazidimeavibactam, compared with the group given
ceftazidime alone (p < 0.05).
In a murine septicemia model, ceftazidimeavibactam demonstrated potent in vitro activity and efficacy against
ceftazidime-resistant Enterobacteriaceae producing class A and
C b-lactamases [47]. Ceftazidimeavibactam in a 4:1 ratio
against two KPC-producing strains of K. pneumoniae, both
with ceftazidime MIC values of 256 mg/l, reduced the
median effective doses for 50% (ED50) of mice to 15.1 mg/kg
(K. pneumoniae VA-361) and 3.8 mg/kg (K. pneumoniae
VA-406), compared with 1578 and 709 mg/kg, respectively,
with ceftazidime alone [47]. In a second murine septicemia
study of ESBL- and AmpC-producing Enterobacteriaceae isolates (ceftazidime MIC 64 mg/l), ceftazidimeavibactam in a
4:1 ratio reduced the unit dose ED50 to <558 mg/kg from
>84 mg/kg with ceftazidime alone [48]. Unit dose ED50 values
against two AmpC and six CTX-M producers ranged from 2
27 mg/kg for ceftazidimeavibactam, compared with >90 mg/
kg for ceftazidime alone.
Ceftazidime in combination with avibactam has also demonstrated significant bacterial killing and efficacy in a number of
other animal models of infection, including the neutropenic
mouse thigh infection model [47,49,50] and lung infection
model [5153], and a rabbit model of meningitis in animals
inoculated with ceftazidime-NS Enterobacteriaceae strains [54].
The organisms evaluated in these studies included bacteria that
produce the clinically important class A and C b-lactamases
including the ESBL, KPC and AmpC enzymes.
Pharmacodynamics
The percent of time that unbound concentration of the drugs

remains above the MIC over a dosing interval (%f T > MIC)
is well-established as the PK/PD index that best defines the
efficacy for b-lactam antibiotics such as ceftazidime [5558],
whereas the percent of time that free drug concentrations are
above a threshold concentration (CT) over a dose interval (%
f T > CT) was determined to be the PK/PD index associated
with the efficacy of avibactam [52,5961].
Target for ceftazidime
A PK/PD target of 50% f T > MIC was associated with the

efficacy of cephalosporins against both ESBL-producing Enterobacteriaceae and non-ESBL producers [62,63]. Neutropenic
mouse models have shown that bacteriostasis is achieved at
Table 6. Summary of ceftazidimeavibactam in vivo efficacy against extended-spectrum b-lactamaseproducing Enterobacteriaceae in animal models of infection.
Author (year)
Enzyme and bacterial spp.
Findings
Ref.
Borgonovi
(2007)
Class A ESBL and/or AmpC in

Enterobacteriaceae spp.
Ceftazidimeavibactam reduced bacterial kidney burden in

immunodepressed male CD1 mice by 2.6 log10 to 4.5, compared with
ceftazidime alone (p < 0.05)
[46]
Endimiani et al.
(2011)
KPC-producing Klebsiella
pneumoniae
Ceftazidimeavibactam reduced bacterial load in murine infection models

by >2-log CFU, compared with no decrease for ceftazidime alone
[47]
Levasseur et al.
(2014)
SHV-, TEM- or AmpC-producing

Enterobacteriaceae spp.
Ceftazidimeavibactam reduced unit dose ED50 in murine septicemia model

to <565 mg/kg from >90 mg/kg with ceftazidime alone
[48]
ESBL: Extended-spectrum b-lactamase.
about 30% f T > MIC with ceftazidime for Enterobacteriaceae

and at 40% f T > MIC for P. aeruginosa [56,64]. In patients
with nosocomial pneumonia, a %f T > MIC 45% was associated with favorable clinical and microbiological outcomes [58]
and a ceftazidime f T > MIC >53% was associated with favorable microbiological outcomes in patients with ventilatorassociated bacterial pneumonia [65]. Taken together, these data
suggested that 4050% f T > MIC was an appropriate target
for ceftazidime in analyses of probability of PK/PD target
attainment (PTA).
Avibactam target in combination with ceftazidime for

Enterobacteriaceae
The PK/PD target for avibactam was defined in a series of

experiments using the hollow fiber infection model with eight
ceftazidime-resistant Enterobacteriaceae strains producing
different b-lactamases (AmpC, CTX-M-15, SHV-5, SHV-1,
TEM-1, TEM-10, KPC-3) with high ceftazidime MICs
(64 mg/l) and a range of ceftazidimeavibactam MICs
(0.1254 mg/l) [60]. Continuous infusion of ceftazidime (8 or
16 mg/l) in combination with avibactam concentrations that
were varied to simulate single-dose human PK profiles caused
rapid killing of ceftazidime-resistant Enterobacteriaceae followed by regrowth between 12 and 24 h [60]. The concentration of avibactam at 12 h ranged from 0.15 to 0.28 mg/l, and
was therefore considered the CT to suppress bacterial growth.
Further experiments showed that continuous infusion of avibactam at 0.250.5 mg/l over 4.5 h in the presence of ceftazidime
2000 mg every 8 h suppressed regrowth for 1224 h.
These data suggested that an avibactam concentration of
between 0.25 and 0.5 mg/l at the mid-point of an 8 h dosing
interval would be required for growth suppression. Hence,
a CT of 0.5 mg/l would be appropriate for estimating the
PK/PD target attainment for avibactam when combined with
ceftazidime against Enterobacteriaceae.
A single simulated clinical dose of ceftazidimeavibactam
(2000 mg ceftazidime and 500 mg avibactam) tested in the
hollow fiber system was rapidly cidal against all eight
ceftazidime-resistant Enterobacteriaceae strains, and growth of
all organisms was held below the limit of detection (<102
CFU/ml) for the entire 8 h period of the experiment [60].
Drug Profile
the PK/PD target for avibactam is time dependent [52]. The

mean %f T > CT value for a CT of 1 mg/l associated with stasis was 20%, for 1-log kill was 24% and for 2-log kill was
30.3%. In the thigh infection model, the mean %f T > CT for
a CT of 1 mg/l avibactam was 40.2% for bacterial stasis and
50.3% for 1-log kill.
These data supported an appropriate target of 4050%
f T > CT for a CT of 1 mg/l for estimating avibactam PK/PD
target attainment against P. aeruginosa. The similar magnitude
of the target %f T > MIC for ceftazidime and %f T > CT for
avibactam suggested that concentrations of the inhibitor would
exceed the CT for about the same period of time that concentrations of the b-lactam are above the MIC.
Animal models using human-simulated PK
A series of studies have evaluated free drug concentrationtime

profiles in animals which approximated those in humans given
2000 mg ceftazidime every 8 h (2-h infusion), with or without
avibactam at 500 mg every 8 h (2-h infusion) [49,50].
A murine thigh infection model evaluating ceftazidime
avibactam against 27 isolates of P. aeruginosa (ceftazidime
MICs 8128 mg/l and ceftazidimeavibactam MICs 432
mg/l) compared ceftazidimeavibactam with ceftazidime alone
administered 2 h post-infection [49]. The change in bacterial
burden in the thigh was determined after 24 h and compared
with 0 h controls. Bacterial killing (0.7>3-log reductions in
bacterial counts) occurred against 16/17 isolates with ceftazidimeavibactam MICs of 8 mg/l and 5/8 isolates with ceftazidimeavibactam MICs of 16 mg/l. After the 24-h treatment
period, no bacterial colonies were observed from thigh homogenates plated on drug-containing plates, suggesting no resistance
development to ceftazidimeavibactam.
In a second study by the same investigators, simulated
human exposures of ceftazidimeavibactam resulted in decreases
in CFU against 13/14 Enterobacteriaceae isolates with ceftazidimeavibactam MICs >8 mg/l [50]. The remaining isolate, an
En. cloacae strain with a ceftazidime MIC >128 mg/l and ceftazidimeavibactam MIC of 8 mg/l, showed a static response to
ceftazidimeavibactam. Variable activity was noted at ceftazidimeavibactam MICs of 32 mg/l, and efficacy (which was
unexpected given 0% f T > MIC) was observed against isolates
with ceftazidimeavibactam MIC values 128 mg/l.
Avibactam target in combination with ceftazidime for

P. aeruginosa
PK & metabolism
The ceftazidimeavibactam PK/PD target against P. aeruginosa

was established in neutropenic mouse thigh infection and lung
infection models using seven well-characterized P. aeruginosa
strains from clinical sources that were ceftazidime resistant
(MIC 32128 mg/l) and exhibited ceftazidimeavibactam
MICs ranging from 2 to 16 mg/l [52,59].
Dose fractionation studies with both the thigh and lung
infection models demonstrated that the PK/PD index best associated with efficacy was %f T > CT for a CT of 1 mg/l. In the
lung infection model, the effect of avibactam was decreased
with a reduction in dose frequency, further substantiating that
The Cmax and area under the curve of ceftazidime increase

directly with dose [15], and avibactam demonstrated approximately linear PK across the dose range studied (502000 mg)
for single intravenous (iv.) administration [66]. The PK parameters of ceftazidime and avibactam given in combination as a
single 2-h infusion and as multiple 2-h infusions every 8 h for
11 days are shown in TABLE 7 [16,66]. There was no appreciable
accumulation of ceftazidime (2000 mg) or avibactam (500 mg)
following multiple iv. infusions every 8 h for up to 11 days in
healthy adults with normal renal function [66,67]. The distribution of both ceftazidime (mean volume of distribution at steady
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Drug Profile
Table 7. Pharmacokinetic parameters of ceftazidimeavibactam in healthy adult males.

Parameter
Cmax (mg/l)
AUC (mg.h/l)
Ceftazidime geometric mean (%CV)
Avibactam geometric mean (%CV)
single dose
multiple dose
single dose
multiple dose
(n = 16)
(n = 16)
(n = 16)
(n = 16)
88.1 (14)
90.4 (16)
15.2 (14)
289 (15)
291 (15)
14.6 (17)
38.2 (19)
42.1 (16)
T (h)
3.27 (33)
2.76 (7)
2.22 (31)
2.71 (25)
CL (l/h)
6.93 (15)
6.86 (15)
11.9 (16)#
13.1 (19)
Vss (l)
18.1 (20)
17 (16)
23.2 (23)#
22.2 (18)
2000 mg ceftazidime + 500 mg avibactam administered as a 2-h infusion.
Every 8 h for 11 days.
AUC0inf reported for single dose infusion, AUC0tau reported for multiple dose infusions.
n = 15.
#
n = 13.
AUC0inf: Area under concentrationtime curve from time 0 to infinity; AUC0-tau: Area under concentrationtime curve over dosing interval; CL: Plasma clearance;
Cmax: Maximum observed concentration; %CV: %Coefficient of variance; T: Terminal elimination half-life; Vss: Volume of distribution at a steady state.
Data from [16].
state [Vss] ranged from 17.0 to 28.2 l in the ceftazidimeavibactam Phase I studies) [61] and avibactam (range of mean Vss:
15.224.4 l) [66] in healthy subjects approximated the extracellular fluid volume. The PK properties of ceftazidime and avibactam were not affected when the two drugs were coadministered compared with when they were administered
alone, either after single or repeat dosing [66]. Binding of avibactam (5.78.2%) and ceftazidime (523%) to human plasma
proteins was low and independent of the concentration [61]. No
clinically significant differences were seen in the PK of avibactam based on age or sex; therefore, no dosage adjustment based
on age or sex is necessary [68].
Avibactam and ceftazidime are both primarily cleared by the
kidneys and their clearance is reduced in renally impaired
patients [66,69,70]. Hence, dosage adjustment of ceftazidime
avibactam is required in patients with creatinine clearance
<50 ml/min [16].
No drugdrug interactions were observed in healthy subjects
given metronidazole as a 1-h infusion every 8 h, followed 1 h
later by a 2-h infusion of ceftazidimeavibactam every 8 h,
demonstrating that ceftazidimeavibactam may be administered
with metronidazole to provide coverage for anaerobic pathogens
in cIAI [71].
levels of renal function [61,73]. The renal function groups

ranged from normal (CrCL >80 ml/min) to end-stage renal
disease (CrCL 5 ml/min), and the dose regimens simulated were based on the dose adjustments by renal function
for ceftazidime, with the avibactam dose adjusted to maintain the ceftazidimeavibactam ratio at 4:1 [61]. A cIAI
population was used to simulate exposures and calculate
the PTA, as cIAI patients showed lower ceftazidimeavibactam exposures than cUTI patients or healthy individuals.
PTA was calculated as the percentage of simulated subjects
who met the PK/PD dose targets for both ceftazidime and
avibactam (joint PTA). The most stringent joint target was
defined as 50% f T > MIC for ceftazidime (using the ceftazidimeavibactam MIC) and 50% f T >1.0 mg/l for avibactam. The percent free fraction used to calculate free
drug concentrations was 85% for ceftazidime and 92% for
avibactam [61].
The PK/PD target attainment results supported a breakpoint
of 8/4 mg/l for the dose regimen of 2000 mg ceftazidime combined with 500 mg avibactam given as a 2-h iv. infusion every
8 h for subjects with normal renal function or mild renal
impairment.
Population PK & PK/PD target attainment simulations
Phase II studies
PK data from Phase I and II studies were used to develop

population PK models for avibactam and ceftazidime [72]. The
PK of both drugs were well-described by a two-compartment
model with first-order elimination from the central compartment. The primary predictors of variability in ceftazidime and
avibactam PK were identified to be creatinine clearance
(CrCL), subject status (cIAI or cUTI patients vs healthy subjects) and body weight.
The population PK models for ceftazidime and avibactam were used to conduct simulations across six different
Two Phase II, randomized, comparative clinical studies have

been conducted with ceftazidimeavibactam, one in patients
with cUTI and the other one in cIAI [44,45]. Both studies were
initial assessments of the efficacy and safety of ceftazidime
avibactam compared with a carbapenem and were not designed
to demonstrate statistical noninferiority.
The cUTI study was a multicenter, randomized, investigatorblinded study that enrolled 137 patients with serious cUTIs
including acute pyelonephritis. Patients were randomized 1:1 to
receive either ceftazidimeavibactam or imipenemcilastatin [44].
Clinical studies
Drug Profile
The primary efficacy endpoint was Table 8. Favorable microbiological outcome (eradication) at test of
microbiological outcome at the test-ofcure in patients with complicated urinary tract infection.
cure (TOC) visit, 59 days after the end
Treatment
Imipenem
Ceftazidime
of study therapy, in the microbiologically
difference (CI)
cilastatin,
avibactam,
evaluable (ME) population [44]. The
n/N (%)
n/N (%)
microbiological response at TOC was
Overall
also assessed in the microbiological modiME population
19/27 (70.4)
25/35 (71.4)
1.1 (95%
fied intent-to-treat population (mMITT).
CI: 27.2, 25.0)
Dose selections of ceftazidimeavibac4.1 (95%
mMITT population
31/46 (67.4)
31/49 (63.3)
tam and imipenemcilastatin were based
CI: 17.1, 25.4)
on the US labeled doses of these antibiot,
By baseline pathogen (mMITT population)
ics for the treatment of UTI at the time
Enterobacteriaceae
31/43 (72.1)
31/47 (66.0)
the study was conducted [15,74]. Ceftazidimeavibactam 625 mg (500 mg ceftaziEscherichia coli
31/43 (72.1)
26/42 (61.9)
dime/125
mg
avibactam)
was
0/3 (0.0)
0/2 (0.0)
administered as a 30-min iv. infusion
,#
every 8 h [44]. This was increased in the Ceftazidime-NS pathogens
9/14 (64.3)
10/18 (55.6)
8.7 (90% CI:
20.2, 35.7)
subsequent Phase III cUTI clinical trial
to 2500 mg (2000 mg ceftazidime/

Ceftazidimeavibactam imipenemcilastatin, nonstratified MiettinenNurminen method.
Data from [44].

500 mg avibactam) every 8 h, adminis
Data from [61].
tered iv. as a 2-h infusion, based on PK/

Data presented for pathogens with 2 isolates in either treatment group.
#
Includes ceftazidime-resistant or ceftazidime-intermediate baseline pathogens. Susceptibility designations
PD target attainment analysis, and is the determined
according to CLSI, 2013 [75].
dose approved by the FDA [16]. Imipe- ME: Microbiologically evaluable (patients with a clinical and microbiological assessment at test of cure receiving 7 days of study treatment or classified as failures after completing at least 48 h of study treatment, with
nemcilastatin was given at a dose of
no major protocol violations); mMITT: Microbiological modified intent-to-treat population (patients with
500 mg iv. over 30 min every 6 h. After 1 baseline uropathogen, receiving 1 one dose of the study drug); NS: Nonsusceptible.
4 days of iv. treatment, patients who
showed clinical improvement could be switched to oral therapy MIC 8 mg/l and P. aeruginosa ceftazidime MIC 16 mg/l)
(ciprofloxacin 500 mg twice daily) to receive a total treatment [61,75]. Favorable microbiological response rates for this subgroup were 64% with ceftazidimeavibactam and 56% with
course (iv. plus oral therapy) of 714 days [44].
One hundred and thirty-five patients received at least one imipenemcilastatin.
The cIAI study was a multinational, randomized, doubledose study therapy with either ceftazidimeavibactam (n = 68)
or imipenemcilastatin (n = 67). Patient demographics and blind study comparing ceftazidimeavibactam 2500 mg iv.
baseline characteristics were generally balanced across the treat- every 8 h as a 30-min infusion (plus metronidazole 500 mg iv.
ment groups for all analysis populations [44,61]. A favorable every 8 h for coverage against anaerobic pathogens) with meromicrobiological response at TOC was achieved by a similar penem 1000 mg iv. every 8 h in adult patients with qualifying
proportion of patients in the ceftazidimeavibactam and imipe- disease characteristics of cIAI. Treatment was administered for
nemcilastatin treatment groups in both the ME [44] and a minimum of 5 days and a maximum of 14 days [45]. The primMITT populations (TABLE 8) [61]. In a subgroup analysis of the mary efficacy endpoint was clinical response at the TOC visit,
mMITT population by baseline uropathogen, favorable micro- 2 weeks after the end of study therapy, in the ME population.
biological response rates in patients infected with the most The clinical response at TOC was also assessed for the mMITT
common pathogen, E. coli, were 72% for ceftazidimeavibac- population.
A total of 203 patients received at least one dose of study
tam and 62% for imipenemcilastatin (TABLE 8) [61]. No patients
with a cUTI caused by P. aeruginosa showed a favorable micro- therapy with either ceftazidimeavibactam plus metronidazole
biological response; however, it is notable the dosage regimens (n = 101) or meropenem (n = 102). Demographic data and
in both treatment groups (ceftazidimeavibactam 625 mg iv. baseline disease characteristics were generally similar across both
every 8 h; imipenem 500 mg iv. every 6 h) were lower than treatment groups for all study populations [45]. Favorable clinithe labeled dose for ceftazidimeavibactam (2500 mg every cal response at TOC was similar between the ceftazidime
8 h) [16] and for imipenemcilastatin for moderate to severe avibactam group and the meropenem group in both the ME
infections due to P. aeruginosa (1000 mg every 6 h or 8 h) [74]. population [45] and the mMITT population (TABLE 9) [61].
The most predominant pathogen was E. coli, and 82% of
Over a third of patients in the mMITT population had infections due to ceftazidime-NS Gram-negative pathogens, defined patients given ceftazidimeavibactam showed a clinical cure
for all Phase II and Phase III clinical studies as isolates compared with 89% of patients given meropenem [61]. The
whose susceptibility results are classified as intermediate or clinical cure rate of infections caused by P. aeruginosa was
resistant to ceftazidime using Clinical and Laboratory Stand- 100% in both groups. Of note, 30% of patients in the
ards Institute methodology (Enterobacteriaceae ceftazidime mMITT population had cIAI due to a ceftazidime-NS
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Drug Profile
Table 9. Favorable clinical response at test of cure in patients with complicated intra-abdominal infections
caused by Gram-negative aerobes.
Overall
ME population
mMITT population
Ceftazidimeavibactam plus
metronidazole, n/N (%)
Meropenem,
n/N (%)
62/68 (91.2)
70/85 (82.4)
71/76 (93.4)
79/89 (88.8)
Treatment difference (CI)
2.2% (95% CI: 20.4%, 12.2%)

6.4 (95% CI: 17.3, 4.2)
By baseline pathogen (mMITT population),#

Enterobacteriaceae
57/70 (81.4)
64/74 (86.5)
Escherichia coli
49/60 (81.7)
55/62 (88.7)
6/8 (75.0)
11/13 (84.6)
Enterobacter cloacae
1/1 (100)
4/5 (80.0)
6/6 (100)
5/5 (100)
27/30 (90.0)
19/23 (82.6)
,
Ceftazidime-NS pathogens
7.4 (90% CI:
8.5, 25.3)
Ceftazidimeavibactam meropenem, nonstratified MiettinenNurminen method.
Data from [45].
Data from [61].

#
All pathogens with >2 isolates in either treatment group.
Includes ceftazidime-resistant or ceftazidime-intermediate baseline pathogens. Susceptibility designations determined according to CLSI, 2013 [75].
ME: Microbiologically evaluable (patients with qualifying complicated intra-abdominal infection, 1 susceptible baseline pathogen who received an adequate course of
therapy and were evaluable at test of cure); mMITT: Microbiological modified intent-to-treat population (patients with qualifying complicated intra-abdominal infection
receiving 1 one dose of the study drug and 1 baseline pathogen regardless of susceptibility); NS: Nonsusceptible.
pathogen (defined above). In this important subgroup, a clinical cure rate of 90% was obtained with ceftazidimeavibactam
and 83% was obtained with meropenem [61].
In the Phase II cUTI and cIAI studies, ceftazidimeavibactam appeared effective in the treatment of cUTI and cIAI, with
microbiological and clinical response rates comparable with the
carbapenem comparators. Importantly, ceftazidimeavibactam
appeared to be effective in the treatment of infections caused
by ceftazidime-NS Gram-negative bacteria in both studies.
Phase III studies
Two ceftazidimeavibactam Phase III studies have been completed and results made available. One, the RECLAIM study,
was initiated as two separate studies evaluating ceftazidimeavibactam plus metronidazole compared with meropenem in
patients with cIAI (RECLAIM-1 and -2) and were combined
to form a single global Phase III study database following
agreement with both US and European regulatory agencies [76].
The clinical efficacy of ceftazidimeavibactam compared with
best available therapy (BAT) was also assessed in the Phase III
REPRISE resistant pathogen study, which enrolled patients
with cIAI or cUTI caused by ceftazidime-resistant pathogens [77]. Both Phase III studies evaluated the labeled dose regimen for ceftazidimeavibactam (2500 mg iv. every 8 h over a
2-h infusion, with the addition of metronidazole in patients
with cIAI).
The primary endpoint of the RECLAIM study was clinical
cure rate at the TOC visit, 2835 days after randomization.
Noninferiority between treatments was defined as the difference in the clinical cure rates between treatment groups
10
having a 95% CI lower limit of greater than 10% for

the mMITT population [76]. Recently reported data from the
RECLAIM study showed overall clinical cure rates in the
mMITT population of 82% (337/413) for ceftazidime
avibactam and 85% (349/410) for meropenem (treatment
difference 3.5%; 95% CI: 8.6 to 1.6%), demonstrating
noninferiority between treatments. Among the patients
included in the mMITT population with cIAIs caused by
ceftazidime-NS pathogens, there were similar clinical cure
rates in the ceftazidimeavibactam group (83% [39/47]) and
the meropenem group (86% [55/64]) (treatment difference
3.0%; 95% CI: 17.9, 10.6) [76].
In a subgroup of patients with moderate renal impairment
at baseline (CrCL 3050 ml/min), clinical cure rates were
lower compared with patients with normal renal function or
mild renal impairment (CrCL >50 ml/min) [61]. The reduction in clinical cure rates in this subgroup was more marked
in patients treated with ceftazidimeavibactam (clinical cure
rate at TOC was 45% [14/31]) compared with meropenemtreated patients (74% [26/35]). This difference may have
been due to a rapid improvement in CrCL after enrollment
into the study, without a corresponding rapid correction in
dosing. Within this subgroup, patients treated with ceftazidimeavibactam received a daily dose that was 33% lower
than is currently recommended in the approved prescribing
information for patients with CrCL of 3050 ml/min [16,61].
This underlines the importance of daily monitoring of CrCL
in patients with changing renal function who are receiving
ceftazidimeavibactam, and adjusting the dose where
necessary [16].
The REPRISE Phase III study was a prospective, open-label

study in patients with cIAI or cUTI caused by ceftazidimeresistant Gram-negative pathogens, defined similarly as for
ceftazidime-NS above [77]. Interim data from 126 patients
have been reported, of whom 64 received ceftazidimeavibactam (cUTI, n = 58; cIAI, n = 6) and 62 received a
carbapenem-based regimen (BAT) (cUTI, n = 56; cIAI,
n = 6). The primary endpoint was clinical cure at TOC in
the mMITT population, which was similar with ceftazidime
avibactam (93% [55/59]) and BAT (90% [47/52]). In
patients with cUTI, per-patient microbiological response rates
were higher with ceftazidimeavibactam (78% [43/55]) than
with BAT (50% [24/48]).
The majority of available clinical Phase III data is from
patients with cIAI, and confirms ceftazidimeavibactam to be
an effective treatment in infections caused by Enterobacteriaceae or P. aeruginosa, including those with ceftazidimeresistant phenotypes, which is consistent with the Phase II
cIAI study. Results are awaited from a recently completed
Phase III cIAI study in Asia (RECLAIM 3, clinicaltrials.gov
identifier NCT01726023), a Phase III cUTI study (RECAPTURE
1,
NCT01595438
and
RECAPTURE
2,
NCT01599806 combined into a single study database) and a
Phase III study in hospital-acquired bacterial pneumonia
(including
ventilator-associated
bacterial
pneumonia)
(REPROVE, NCT01808092).
Safety & tolerability
As a chemical class, the cephalosporins, including ceftazidime,
have a well-established safety profile and are generally considered to be well-tolerated during many years of use, with a low
incidence of reported AEs [15]. The safety of avibactam alone
and in combination with ceftazidime has been evaluated in
healthy volunteers in Phase I studies, including one study
which showed that supratherapeutic doses of ceftazidimeavibactam were not associated with QT/QTc prolongation [78].
Ceftazidimeavibactam was generally well-tolerated in the
Phase II cUTI and cIAI studies [44,45]. The most common
adverse reactions to ceftazidimeavibactam in Phase II studies
(incidence of 10% in either indication) were vomiting,
nausea, constipation and anxiety [16].
In the Phase II cUTI study, 68% (46/68) patients in the
ceftazidimeavibactam group and 76% (51/67) patients in the
comparator group experienced AEs [44]. The most common
events in both treatment groups were headache and injection/
infusion site reactions. Gastrointestinal events were also common in both treatment groups; constipation and abdominal
pain were more common in the ceftazidimeavibactam group
(10 and 15%, respectively) than in the comparator group
(3 and 6%, respectively). During antibiotic treatment, drugrelated treatment-emergent AEs were reported in 35% (24/68)
and 51% (34/67) of patients who received ceftazidime
avibactam or imipenemcilastatin, respectively. Three serious
treatment-emergent AEs that were drug related were reported
in the ceftazidimeavibactam group (renal failure, diarrhea and
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Drug Profile
an accidental overdose of ceftazidimeavibactam due to misadministration of study drug this serious treatment-emergent
AE was not associated with any other AE), and one patient in
the imipenemcilastatin group experienced a serious AE (SAE)
of an increase in serum creatinine, which was considered to be
probably drug related.
In the cIAI Phase II study, AEs were observed in 64%
(65/101) patients treated with ceftazidimeavibactam plus
metronidazole and 58% (59/102) patients treated with meropenem [45]. Overall, the types of events reported were comparable between the two treatment groups, although nausea
(10%), vomiting (14%) and abdominal pain (8%) were more
common in the ceftazidimeavibactam plus metronidazole
group than in the meropenem group (6, 5 and 3%, respectively). Elevated liver enzymes were more common among the
patients who received meropenem (increased alanine aminotransferase, 13%; increased aspartate aminotransferase, 15%)
than among those who received ceftazidimeavibactam (alanine aminotransferase, 8%; aspartate aminotransferase, 9%).
In the ceftazidimeavibactam group, SAEs were reported in
9% (9/101) of patients (one of these, elevated liver enzymes,
was considered to be study drug related), compared with
11% (11/102) of patients in the meropenem group, none of
which were related to the study drug. There were five deaths
in the study (three in the ceftazidimeavibactam group and
two in the meropenem group), and these were not considered
to be related to study treatment.
Overall AE rates observed in the Phase III RECLAIM study
were 46% in the ceftazidimeavibactam plus metronidazole
group (n = 532) and 43% in the meropenem group (n = 534)
[76]. Rates of SAEs were 8% in both groups, and the most
frequently reported AEs with ceftazidimeavibactam plus metronidazole were diarrhea, nausea, vomiting and fever. Death
occurred in 2.5% (13/529) of patients who received ceftazidimeavibactam and 1.5% (8/529) of patients who received
meropenem [16]. These data were made available for regulatory
review during the ceftazidimeavibactam approval process, in
advance of publication of Phase III safety data [61].
In a subgroup of patients with moderate renal impairment at
baseline (CrCL 3050 ml/min), death occurred in 26% (8/31)
of patients in the ceftazidimeavibactam and 9% (3/35) of
patients in the meropenem group [16]. None of these deaths
were considered to be study drug related. The majority of these
patients were in the mMITT population, and their outcomes
were classified as clinical failure or indeterminate at the TOC
visit (6/8 in the ceftazidimeavibactam group and 2/3 in the
meropenem group) [61]. Death was attributed to various causes
including progression of underlying infection, delayed surgical
intervention and lack of efficacy of the study drug against baseline pathogens [61]. Among patients with normal renal function
or mild impairment, there was no difference between treatments in the number of deaths (1% [n = 5] patients in each
group).
Interim data from the Phase III REPRISE study have shown
that 28% (18/64) of patients in the ceftazidimeavibactam
11
Drug Profile
group and 50% (31/62) of patients in the BAT group experienced an AE, and the SAE rates were 4.7 and 6.5%, respectively [77]. The most frequently reported AEs in both groups
were gastrointestinal disorders. Safety data for patients with
moderate renal impairment at baseline enrolled in this study
are expected to be reported elsewhere.
The AEs observed in the completed and reported ceftazidimeavibactam Phase III studies were consistent with the AE
profile seen with ceftazidimeavibactam in Phase II studies.
Together, these data show that ceftazidimeavibactam possesses
an AE profile that is comparable with ceftazidime alone and/or
metronidazole (cIAI) and, likewise, is consistent with the AE
profile of the cephalosporin class.
Expert commentary
Third-generation cephalosporins have had an important role in

the treatment of cUTI and cIAI; however, the rising prevalence
of b-lactamaseproducing strains is limiting their effectiveness.
Carbapenems are increasingly favored as the first-line therapy
for these serious infections, but the emergence of
carbapenemase-producing bacteria also threatens their utility.
Therefore, new treatment options for cUTI and cIAI are
urgently needed. Ceftazidimeavibactam, a combination of an
established third-generation cephalosporin and a novel
b-lactamase inhibitor, has the potential to meet this need by
providing a new effective treatment option for certain MDR
Gram-negative bacteria causing these infections.
Data generated by PK/PD studies, animal infection models,
Phase I/II clinical studies for ceftazidimeavibactam, and previous findings on the efficacy and safety of ceftazidime alone
supported FDA approval of ceftazidimeavibactam for the
treatment of cIAI and cUTI in advance of completion of
Phase III studies. As the clinical data supporting approval were
primarily from Phase II studies and interim Phase III data, the
use of ceftazidimeavibactam is currently reserved for patients
with limited or no other treatment options [16].
Ceftazidime and avibactam have complementary PK profiles
and no drugdrug interactions, making their co-administration
practicable. Both agents have predictable PK and are primarily
excreted unchanged by the renal route; therefore, dosage adjustment is necessary in patients with moderately or more severely
impaired renal function [16]. Avibactam has a broad spectrum
of inhibitory activity against b-lactamases, covering Ambler
class A enzymes, including KPCs and CTX-M ESBLs, class C
b-lactamases including AmpC and some class D enzymes (e.g.,
OXA-48), which represents a significant advance on currently
available b-lactamase inhibitors. In combination with ceftazidime, avibactam restored the in vitro activity of ceftazidime
against b-lactamaseproducing Enterobacteriaceae and P. aeruginosa, common causative pathogens in cUTI and cIAI infections. A PK/PD target attainment analysis based on data from
Phase I and Phase II studies in humans, in vitro studies and
in vivo animal models of infection supported an in vitro susceptibility breakpoint MIC value of 8/4 mg/l for ceftazidime
avibactam against Enterobacteriaceae and P. aeruginosa. The
12
PK/PD analysis supports a dosage regimen of ceftazidimeavibactam 2000 mg500 mg by 2-h iv. infusion every 8 h for use
in cUTI and cIAI [16].
In the Phase II studies in cUTI and cIAI, ceftazidime
avibactam demonstrated overall clinical and microbiological
response rates that were similar to the carbapenem comparators. It is notable that the dose of ceftazidimeavibactam in
the cUTI study was one-quarter of the approved dose [16,44]
and, similarly, the dose of imipenem was also lower than the
labeled dose for moderate to severe infections due to P. aeruginosa or pathogens with decreased susceptibility. It is likely
that this accounts for the lack of clinical response observed
for both treatment groups in the limited number of infections
due to P. aeruginosa in the Phase II cUTI study. Based on
PK/PD target attainment analyses, the dose of ceftazidime
avibactam was increased in the Phase III cUTI study to the
currently labeled dose of 2000 mg500 mg (2-h infusion)
every 8 h [16]. The clinical cure rate against P. aeruginosa in
the Phase II cIAI study, which used the currently approved
dose of ceftazidimeavibactam (2000 mg500 mg every 8 h)
[16], was 100% [45,61]. Importantly, ceftazidimeavibactam also
demonstrated high microbiological success rates against
ceftazidime-NS pathogens in both Phase II clinical studies.
The approved dose of ceftazidimeavibactam was given to
patients enrolled in the Phase III studies, and its clinical effectiveness has been confirmed by the Phase III studies for
which the results are available, which included infections
caused by ceftazidime-NS pathogens.
Ceftazidimeavibactam was well-tolerated in Phase I, II and
III studies, with a safety profile reflective of the cephalosporin
class. Ceftazidimeavibactam provides clinicians with a much
needed new treatment option for patients with cUTI or cIAI,
with limited or no treatment options, particularly in those
infections due to ESBL- and KPC-producing bacteria or
ceftazidime-NS P. aeruginosa.
Five-year view
Treatment guidelines are increasingly taking into account the

issues surrounding emerging antibiotic resistance [2,7,79], with
recommendations to reduce the risk of new antibiotic-resistant
strains through measures such as appropriate prescribing. This
aims to address the association between antibiotic usage,
including carbapenems, and the increasing frequency of CREs
found in Enterobacteriaceae [80]. Antimicrobial stewardship and
regional intervention strategies can slow the rate of spread of
CREs; however, the marked rise of ESBL- or carbapenemaseexpressing Enterobacteriaceae and MDR P. aeruginosa over the
last 510 years is expected to continue [81]. Novel antimicrobials are required to provide additional treatment options not
just in the short term, but also over the medium and long
term, as only a continued focus on developing innovative treatment strategies is likely to meet the challenge of controlling
MDR pathogens.
Combining a b-lactam with a b-lactamase inhibitor is a
proven strategy for responding to the threat posed by the
emergence of resistant strains, and combining ceftazidime with

avibactam in a 4:1 ratio restores the activity of ceftazidime
against ESBL-producing Gram-negative pathogens [15,16].
The novel cephalosporin ceftolozane (CXA-201) in combination with an established b-lactamase inhibitor, tazobactam, has
recently been approved by the FDA for patients with cIAIs
(with metronidazole) and cUTIs that are proven or strongly
suspected to be caused by susceptible bacteria (ZERBAXA;
Cubist Pharmaceuticals U.S., Lexington, MA, USA) [82]. Ceftolozanetazobactam has a spectrum of activity against Gramnegative pathogens such as E. coli and K. pneumoniae, including
ESBL producers, and P. aeruginosa, including certain MDR
and carbapenemase-producing strains. Exceptions to its spectrum of activity include bacteria that produce serine carbapenemases (e.g., KPCs) and metallo-b-lactamases [82].
Another b-lactamase inhibitor, MK-7655, of the same diazabicyclooctane class as avibactam, is currently in Phase II
clinical development. MK-7655 displays good in vitro activity
against class A and class C carbapenemases, especially in combination with imipenemcilastatin [83]. The serine b-lactamase
inhibitor RPX7009 combined with meropenem has shown
good activity against Enterobacteriaceae, including KPCs, and
is currently in Phase III trials in patients with cUTIs [84].
Plazomicin is a novel aminoglycoside that is currently in
Drug Profile
Phase III clinical development for patients with cUTI [85]. It

has shown good in vitro activity against Enterobacteriaceae [86],
which extends to ESBL and KPC producers. It remains to be
seen whether the clinical success of these agents will be sufficient to support approval for the treatment of cUTI and
cIAI; however, they would be welcome additions to ceftolozanetazobactam and ceftazidimeavibactam in the armamentarium against serious infections associated with MDR Gramnegative pathogens.
Financial & competing interests disclosure
Clinical studies were funded by AstraZeneca; Cerexa, Inc., a wholly-owned

subsidiary of Forest Laboratories, LLC and Forest Laboratories, Inc. All
authors were employees of Forest Laboratories LLC. Actavis acquired Forest
Laboratories in July 2014. As a result of the acquisition, all authors are
shareholders of Allergan plc (formerly Actavis plc). AK Talley is a consultant for Allergan plc (formerly Actavis plc). IA Critchley is currently
employed by Allergan plc and TA Riccobene is currently employed by
Allergan plc (formerly Actavis plc). The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Editorial assistance for this manuscript was provided by Micron
research and was funded by Forest Laboratories LLC.
Key issues
.
Infections due to drug-resistant Gram-negative pathogens are associated with significant morbidity and mortality, and extendedspectrum b-lactamase- and carbapenemase-producing Enterobacteriaceae and multidrug-resistant Pseudomonas aeruginosa have been
designated as serious or urgent threats to public health by the US Center for Disease Control.
Ceftazidimeavibactam is a combination of the established third-generation cephalosporin ceftazidime and the novel nonb-lactam
b-lactamase inhibitor avibactam, and was recently approved by the US FDA for the treatment of complicated intra-abdominal infections
(cIAIs) and complicated urinary tract infections (cUTIs) caused by designated susceptible microorganisms. Approval of ceftazidimeavibactam in advance of pivotal Phase III data was based in part on existing data for ceftazidime, along with nonclinical microbiology, pharmacokinetic/pharmacodynamic analyses, and clinical data supporting the safety and efficacy of ceftazidimeavibactam in patients with cIAI
and cUTI from Phase II studies. As only limited clinical data are available pending final Phase III trial results, ceftazidimeavibactam is
reserved for use in patients with limited or no other treatment options.
Avibactam has a broader spectrum of inhibitory action than current b-lactamase inhibitors, which includes certain enzymes for which
there are a limited number of, or an absence of, other effective agents (e.g., CTX-M, KPC, AmpC, OXA-48); hence, ceftazidime
avibactam addresses a critical unmet need for effective therapy against pathogens producing these enzymes.
The administration of avibactam with ceftazidime does not significantly alter the pharmacokinetics of ceftazidime. Ceftazidime
avibactam is cleared primarily via the kidneys and dose adjustment is required in patients with renal impairment (creatinine clearance
<50 ml/min).
In clinical studies, the safety profile of ceftazidimeavibactam appears to be comparable with ceftazidime alone and is consistent with
the adverse event profile of the cephalosporin class.
Ceftazidimeavibactam appears efficacious and well-tolerated in clinical studies of adult patients with cUTI and cIAI, including infections
caused by ceftazidime-nonsusceptible pathogens.
www.tandfonline.com
13
Drug Profile
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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Ceftazidimeavibactam for the treatment

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Date: 23 October 2015, At: 02:50

Downloaded by [University of California, San Diego] at 02:50 23 October 2015

Treatment of complicated urinary tract infections and complicated intra-abdominal infections

Both complicated intra-abdominal infections

although other Enterobacteriaceae including

KPCs, class C (AmpC) enzymes and

Downloaded by [University of California, San Diego] at 02:50 23 October 2015

Mawal, Critchley, Riccobene & Talley

Expert Rev. Clin. Pharmacol.

Ceftazidimeavibactam for cUTI & cIAI

CTX-M, PER, VEB

Downloaded by [University of California, San Diego] at 02:50 23 October 2015

IMP, VIM, NDM

Chromosomal Enterobacteriaceae AmpC

Penicillinase-type OXA-1, -10, -13

which is available to bind further b-lactamase molecules. The

Enterobacteriaceae [23,3032], which is the FDA susceptibility

Recent microbiological studies have revealed a concerning

Mawal, Critchley, Riccobene & Talley

Downloaded by [University of California, San Diego] at 02:50 23 October 2015

Table 2. Summary of in vitro studies of ceftazidimeavibactam activity against b-lactamaseproducing

Enzymes and pathogens

TEM or SHV among

256-fold reduction in MIC with ceftazidimeavibactam compared with

CTX-M producers among

832-fold reduction in MIC with ceftazidimeavibactam compared with

KPC producers among

>128-fold reduction in MIC with ceftazidimeavibactam compared with

MIC90 against OXA-48 reduced to 0.5 mg/l with ceftazidimeavibactam

CTX-M, KPC, OXA-48 in

MIC reduced to 0.251 mg/l with ceftazidimeavibactam from 64 mg/l with

128-fold reduction in MIC90 to 1 mg/l with ceftazidimeavibactam from

AmpC depressed strains in

MICs reduced to 8 mg/l with ceftazidimeavibactam at fixed dose of 4 mg/l

MIC90 reduced to 8 mg/l with ceftazidimeavibactam from 512 mg/l with

Avibactam at a fixed dose of 4 mg/l with ceftazidime reduced MIC 1000-fold

MIC reduced to 0.251 mg/l with ceftazidimeavibactam (avibactam at fixed

Other CTX-M types in

MIC reduced to 0.121 mg/l with ceftazidimeavibactam from 28 mg/l with

USA [3640]. The addition of avibactam to ceftazidime resulted

MIC90 values of 0.25 mg/l against Enterobacteriaceae are

Ceftazidimeavibactam for cUTI & cIAI

Table 3. In vitro activity of ceftazidimeavibactam and ceftazidime against Enterobacteriaceae clinical

BSI, pneumonia, SSSI, UTI, IAI

Downloaded by [University of California, San Diego] at 02:50 23 October 2015

Data from [36].

Data from [37].

Limited studies are available on the selection of resistance to avibactam, although

Susceptible breakpoint of 8 mg/l used for ceftazidimeavibactam.

Mawal, Critchley, Riccobene & Talley

Downloaded by [University of California, San Diego] at 02:50 23 October 2015

MIC values were measured in mg/L.

A murine model of pyelonephritis caused by injection of

The percent of time that unbound concentration of the drugs

A PK/PD target of 50% f T > MIC was associated with the

Enzyme and bacterial spp.