Clinical Infectious Diseases

INVITED ARTICLE
REVIEW OF ANTI-INFECTIVE AGENTS: Louis D. Saravolatz, Section Editor

Ceftazidime/Avibactam and Ceftolozane/Tazobactam:

Second-generation β-Lactam/β-Lactamase Inhibitor
Combinations
David van Duin1 and Robert A. Bonomo2,3,4,5
1
Division of Infectious Diseases, University of North Carolina, Chapel Hill; 2Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, 3Division of Infectious Diseases
and HIV Medicine, Department of Medicine, 4Department of Molecular Biology and Microbiology, and 5Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland,

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

Ohio

Ceftolozane/tazobactam and ceftazidime/avibactam are 2 novel β-lactam/β-lactamase combination antibiotics. The antimicrobial
spectrum of activity of these antibiotics includes multidrug-resistant (MDR) gram-negative bacteria (GNB), including Pseudomonas
aeruginosa. Ceftazidime/avibactam is also active against carbapenem-resistant Enterobacteriaceae that produce Klebsiella pneumoniae
carbapenemases. However, avibactam does not inactivate metallo-β-lactamases such as New Delhi metallo-β-lactamases. Both cefto-
lozane/tazobactam and ceftazidime/avibactam are only available as intravenous formulations and are dosed 3 times daily in patients
with normal renal function. Clinical trials showed noninferiority to comparators of both agents when used in the treatment of com-
plicated urinary tract infections and complicated intra-abdominal infections (when used with metronidazole). Results from pneumo-
nia studies have not yet been reported. In summary, ceftolozane/tazobactam and ceftazidime/avibactam are 2 new second-generation
cephalosporin/β-lactamase inhibitor combinations. After appropriate trials are conducted, they may prove useful in the treatment of
MDR GNB infections. Antimicrobial stewardship will be essential to preserve the activity of these agents.
Keywords. ceftolozane/tazobactam; ceftazidime/avibactam; multidrug resistance; Pseudomonas; Enterobacteriaceae.

A number of important initiatives have been introduced to ad- Ceftolozane/tazobactam and ceftazidime/avibactam are 2 an-
dress the issue of multidrug-resistant (MDR) bacteria. In addi- tibiotics with anti-GNB activity that were recently approved for
tion to the “bad bugs, no drugs” and the “10 × ’20” initiatives of the treatment of complicated intra-abdominal infections
the Infectious Disease Society of America, a comprehensive (cIAIs) and complicated urinary tract infections (cUTIs) by
plan to combat the rise of antibiotic-resistant bacteria called the US Food and Drug Administration (FDA). Their character-
Combating Antibiotic-Resistant Bacteria was recently released istics will be reviewed, with a focus on their respective antimi-
[1–3]. This plan describes the need to develop “at least 2 new crobial spectra and currently available clinical trial data.
antibiotic drug candidates, non-traditional therapeutics, and/
or vaccines from pre-clinical testing to clinical trials for treat- CHEMISTRY AND MODE OF ACTION
ment or prevention of human disease” by 2020.
Ceftolozane/tazobactam combines a novel cephalosporin with
The concerns regarding antibacterial resistance, especially in
an established β-lactam β-lactamase inhibitor, whereas ceftazi-
clinically important gram-negative bacteria (GNB), are contin-
dime/avibactam couples a well-known cephalosporin with a
uing to increase worldwide [4, 5]. A better understanding of the
novel non-β-lactam β-lactamase inhibitor. Both tazobactam
epidemiology of this multifaceted epidemic is needed. In the
and avibactam target the active site of serine β-lactamases
long term, prevention of spread of MDR GNB is most impor-
(Table 1). Tazobactam, a β-lactam sulfone, binds irreversibly
tant. Meanwhile, however, patients will continue to present with
to the active site of β-lactamases. The details of the process
difficult-to-treat infections caused by MDR GNB. Treatment
are quite complex as there is also a small amount of hydrolysis
choices for these infections have been limited, especially for in-
of tazobactam by certain class A β-lactamases such as SHV-1.
fections caused by bacteria that produce carbapenemases and/
In contrast, avibactam is a diazabicyclooctane non-β-lactam
or extended-spectrum β-lactamases (ESBLs) [6–8].
that binds covalently and reversibly to β-lactamases [9]. This
reversibility is a unique feature that allows avibactam to un-
dergo recyclization to inactivate another β-lactamase. The
Received 1 March 2016; accepted 6 April 2016; published online 20 April 2016.
Correspondence: R. A. Bonomo, Louis Stokes Cleveland Department of Veterans Affairs
crucial advantage of avibactam is its ability to inhibit ESBLs,
Medical Center, 10701 E Blvd, Cleveland, OH 44106 (robert.bonomo@va.gov). AmpC β-lactamases (as expressed in Pseudomonas aeruginosa
Clinical Infectious Diseases® 2016;63(2):234–41 and Enterobacteriaceae), and class A carbapenemases of the
© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society
of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.
Klebsiella pneumoniae carbapenemase (KPC and OXA-48)
DOI: 10.1093/cid/ciw243 family [10].

234 • CID 2016:63 (15 July) • REVIEW OF ANTI-INFECTIVE AGENTS

Table 1. Comparative In Vitro Inhibitory Activity of Tazobactam and Avibactam Against Selected β-Lactamases

Inhibited by

Enzymes Class Substrates Tazobactam Avibactam

TEM-1, TEM-2, SHV-1 A Penicillins, early cephalosporins Yes Yes

TEM-3, SHV-2 CTX-M-14 A Extended-spectrum cephalosporins, monobactams Yes Yes
KPC-2, KPC-3 A Broad spectrum including carbapenems No Yes
IMP-1, NDM-1, VIM-1 B Broad spectrum including carbapenems, but not monobactams No No
Escherichia coli AmpC C Cephalosporins High concentrations Yes
OXA-48 D Carbapenems No Yes

Abbreviation: KPC, Klebsiella pneumoniae carbapenemase

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

Ceftolozane and ceftazidime are structurally similar cephalo- is described in a minority of clinical isolates and results in low-
sporins (Figure 1). Ceftolozane is an oxyimino-aminothiazolyl level resistance to ceftazidime/avibactam (MIC = ∼8 mg/L).
cephalosporin with a pyrazole substituent at the 3-position side
chain instead of the lighter pyridium present in ceftazidime. ANTIMICROBIAL ACTIVITY

This heavier side-chain provides improved steric hindrance to Overall Spectrum of Activity
prevent hydrolysis mediated through AmpC β-lactamases Ceftolozane/tazobactam and ceftazidime/avibactam have simi-
[11]. Porin loss significantly increases in vitro minimum inhib- lar spectra of antimicrobial activity, but with some important
itory concentration (MIC) values of ceftazidime, but appears to differences. Their primary activity is against aerobic GNB. For
have no effect on the efficacy of ceftolozane [12]. This porin loss gram-positive bacteria, both cephalosporin combinations have

Figure 1. Chemical structures of ceftolozane, tazobactam, ceftazidime, and avibactam.

REVIEW OF ANTI-INFECTIVE AGENTS • CID 2016:63 (15 July) • 235

some antistreptococcal, very limited antistaphylococcal, and no Two of these 11 isolates expressed metallo-β-lactamases (MBLs),
antienterococcal activity. Both agents have in vitro activity which are known to be resistant to avibactam-mediated inhibition
against selected anaerobic bacteria, including Fusobacterium [36]. These data suggest that ceftazidime/avibactam will be a very
species and Propionibacterium species. However, activity useful addition to the quite limited number of antibiotics currently
against Bacteroides species is less predictable, and Clostridium available to treat KPC-producing carbapenem-resistant Enterobac-
species are resistant [13, 14]. Consequently, in clinical trials teriaceae (CRE). A concern to note is that avibactam-resistant var-
evaluating the use of ceftolozane/tazobactam and ceftazidime/ iants of SHV-1 and KPC-2 containing single point mutations are
avibactam in cIAI, metronidazole was added [15–17]. known. These avibactam-resistant variants have amino acid
Importantly, both ceftolozane/tazobactam and ceftazidime/ changes that are described in inhibitor-resistant SHVs and
avibactam are active against P. aeruginosa. In contrast, Acineto- TEMs. However, these KPC-2 variants also display decreased car-
bacter and Stenotrophomonas species are generally resistant bapenemase activity [37]. Fortunately, the combination of ceftazi-

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

[18–20]. Pending appropriate clinical trials, both combinations dime/avibactam still maintains activity as the inhibitor-resistant
have most promise for use in infections caused by MDR Pseu- β-lactamases are less able to hydrolyze the oxyimono-cephalosporin
domonas species and MDR Enterobacteriaceae. partner. Of greater concern are New Delhi metallo-β-lactamase
1–producing Enterobacteriaceae, which are increasingly common
Spectrum of Activity Against Selected MDR GNB in the Indian subcontinent and the Balkan countries [38].
Studies outlining the in vitro activity of ceftazidime/avibactam Noncarbapenemase β-lactamases that are inhibited by avibac-
and ceftolozane/tazobactam against Escherichia coli, K. pneu- tam include class A, class C, and some class D β-lactamases.
moniae, and P. aeruginosa are summarized in Tables 2 and 3. Ceftazidime/avibactam has excellent in vitro activity against
Clinically, the key microbiologic difference between ceftazi- ESBL-producing Enterobacteriaceae [36, 39]. In contrast, only
dime/avibactam and ceftolozane/tazobactam is that avibactam 58% of ESBL-producing K. pneumoniae isolates from patients with
inhibits carbapenemases of the KPC family [10]. pneumonia had a ceftolozane/tazobactam MIC ≤ 8 µg/mL [19].
In a large in vitro study, ceftazidime/avibactam was tested Around 78% of abdominal and urinary clinical ESBL-producing
against >20 000 clinical US Enterobacteriaceae isolates [36]. Only K. pneumoniae isolates demonstrated a ceftolozane/tazobactam
11 isolates displayed a ceftazidime/avibactam MIC > 8 µg/mL. MIC ≤ 8 µg/mL [18]. Ceftolozane/tazobactam has reliable

Table 2. In Vitro Susceptibility of Selected Subsets of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa to Ceftazidime/Avibactam

Ceftazidime/Avibactam

Isolates (No.) MIC50 MIC90 %S Reference

KPC-producing Enterobacteriaceae (129) 0.5 2 100 [21]

KPC-producing Enterobacteriaceae (120) 0.25 1 97.5 [22]
Escherichia coli (6486) 0.06 0.12 100 [22]
E. coli (375) 0.06 0.12 100 [23]
ESBL-producing E. coli (90) 0.12 0.25 100 [23]
Gentamicin-resistant E. coli (166) 0.12 0.25 100 [24]
Klebsiella pneumoniae (4421) 0.12 0.25 99.9 [22]
K. pneumoniae (254) 0.12 0.5 100 [23]
ESBL-producing K. pneumoniae (84) 0.25 1 100 [23]
Pseudomonas aeruginosa (5328) 2 4 96.8 [25]
Meropenem-nonsusceptiblea P. aeruginosa (396) 8 32 67.4 [25]
Non-ICU P. aeruginosa (2240) 2 4 97.5 [21]
ICU P. aeruginosa (842) 2 8 95.6 [21]
Meropenem-nonsusceptible P. aeruginosa (537) 4 16 87.0 [21]
Ceftazidime-nonsusceptible P. aeruginosa (482) 4 16 80.7 [21]
P. aeruginosa (3902) 2 4 97 [26]
MDR P. aeruginosa (580) 4 16 81 [26]
XDR P. aeruginosa (338) 8 32 74 [26]
P. aeruginosa (1743) 2 8 96.3 [27]
P. aeruginosa (881)b 2 8 95.8 [28]
Gentamicin-resistant P. aeruginosa (131) 4 16 88 [24]
β-lactam–resistant P. aeruginosa (55) 2 32 84 [29]

Abbreviations: ESBL, extended-spectrum β-lactamase; ICU, intensive care unit; KPC, Klebsiella pneumoniae carbapenemase; MDR, multidrug resistant; MIC50, minimal inhibitory concentration
that inhibits growth of 50% of the test population; MIC90, minimal inhibitory concentration that inhibits growth of 50% of the test population; S, susceptible; XDR, extensively drug resistant.
a
These isolates were also nonsusceptible to ceftazidime, cefepime, and piperacillin/tazobactam.

236 • CID 2016:63 (15 July) • REVIEW OF ANTI-INFECTIVE AGENTS

Table 3. In Vitro Susceptibility of Selected Subsets of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa to Ceftolozane/Tazobactam

Ceftolozane/Tazobactam

Isolates (No.) MIC50 MIC90 %S Reference

Escherichia coli (3843) 0.25 0.5 99.2 [30]

ESBL-producing E. coli (715) 0.5 4 95.7 [30]
E. coli (2691) 0.25 0.5 99.3 [31]
ESBL-producing E. coli (327) 0.5 4 94.5 [31]
E. coli (1306) NR 0.5 98 [32]
E. coli (368) 0.25 1 98.6 [19]
ESBL-producing E. coli (76) 0.5 4 93.4 [19]
E. coli (341) 0.25 0.5 98.5 [18]

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

CTX-M-15–producing E. coli (219) <0.25 0.5 100 [33]
E. coli (250) 0.25 0.5 100 [34]
Klebsiella pneumoniae (1408) 0.5 >32 82.7 [30]
ESBL-producing K. pneumoniae (493) 2 >32 78.7 [30]
Meropenem-nonsusceptible K. pneumoniae (140) >32 >32 1.4 [30]
K. pneumoniae (1298) 0.25 16 89.1 [31]
ESBL-producing K. pneumoniae (244) 32 >32 41.8 [31]
Meropenem-nonsusceptible K. pneumoniae (100) >32 >32 4 [31]
K. pneumoniae (1205) NR 4 89 [32]
K. pneumoniae (370) 0.25 >32 84.9 [19]
ESBL-producing K. pneumoniae (132) 4 >32 57.6 [19]
K. pneumoniae (126) 0.25 16 88.9 [18]
Pseudomonas aeruginosa (2435) 0.5 1 99 [35]
Ceftazidime-nonsusceptible P. aeruginosa (398) 1 4 94.5 [35]
Meropenem-nonsusceptible P. aeruginosa (401) 1 4 96.5 [35]
P. aeruginosa (2191) 1 >32 86.3 [30]
MDR P. aeruginosa (698) 4 >32 57.4 [30]
XDR P. aeruginosa (538) 32 >32 46.3 [30]
P. aeruginosa (1971) 0.5 2 98.5 [31]
Ceftazidime-nonsusceptible P. aeruginosa (338) 4 8 91.1 [31]
Meropenem-nonsusceptible P. aeruginosa (388) 1 8 92.8 [31]
P. aeruginosa (1257) NR 2 97 [32]
P. aeruginosa (1019) 0.5 4 94.1 [19]
Ceftazidime-nonsusceptible P. aeruginosa (269) 4 >32 77.7 [19]
Meropenem-nonsusceptible P. aeruginosa (268) 2 >32 78 [19]
P. aeruginosa (500) 0.5 4 94.4 [34]
Ceftazidime-nonsusceptible P. aeruginosa (120) 2 >64 80.8 [34]
Meropenem-nonsusceptible P. aeruginosa (177) 2 32 85.3 [34]
P. aeruginosa (212) 0.5 4 93.4 [18]

Abbreviations: ESBL, extended-spectrum β-lactamase; MDR, multidrug resistant; MIC50, minimal inhibitory concentration that inhibits growth of 50% of the test population; MIC90, minimal
inhibitory concentration that inhibits growth of 90% of the test population; NR, not reported; S, susceptible; XDR, extensively drug resistant.

activity against Enterobacteriaceae that produce the globally im- ceftazidime-resistant and meropenem-resistant pseudomonal
portant ESBLs CTX-M-14 and CTX-M-15 [33]. isolates displayed MICs to ceftolozane/tazobactam of ≤8 µg/
However, when considering these in vitro susceptibilities, mL [18, 19, 30].
previous reports of treatment failures of piperacillin/tazobactam Similarly, ceftazidime/avibactam has potent in vitro antipseu-
in serious infections caused by ESBL-producing organisms sug- domonal activity; 84%–97% of clinical isolates had a ceftazidime/
gest that caution should be used when considering treatment of avibactam MIC ≤ 8 µg/mL in several large studies [20, 41, 42]. Of
such infections with ceftolozane/tazobactam until clinical data note, in a study on archived Pseudomonas isolates—collected >10
become available [40]. years before the release of avibactam—a resistance rate of 18%
Ceftolozane/tazobactam shows potent in vitro activity against was found [29]. Resistance was found to be mediated by de-
Pseudomonas species, although baseline resistance is already de- creased cell wall permeability and increased efflux, rather than
tectable. Between 86% and 95% of clinical P. aeruginosa isolates changes in penicillin-binding protein or novel β-lactamases.
show a ceftolozane/tazobactam MIC ≤ 8 µg/mL [18, 19, 30]. This further emphasizes the ongoing struggle of treating infec-
When evaluating specifically more resistant strains, 60%–80% tions caused by MDR Pseudomonas species. The mechanism of

REVIEW OF ANTI-INFECTIVE AGENTS • CID 2016:63 (15 July) • 237

efflux and decreased cell wall permeability can pose a significant that of piperacillin (0.48 vs 0.26, respectively). The ELF concen-
threat to all future drug development. trations of ceftolozane exceeded 8 mg/L for >60% of the dosing
interval, suggesting that the growth of susceptible Pseudomonas
PHARMACOKINETICS
species should be inhibited in the lungs. Of note, the tazobac-
Dosing tam concentration was 2-fold higher in ELF when given with
Both ceftolozane/tazobactam and ceftazidime/avibactam are piperacillin as compared to ceftolozane. This is unlikely to be
available for intravenous use only. The currently approved dos- of much importance in lower respiratory tract infections caused
ages for adult patients with an estimated creatinine clearance by Pseudomonas species—as tazobactam adds little to the anti-
>50 mL/minute are ceftolozane 1 g with tazobactam 500 mg pseudomonal effect of ceftolozane—but it may be important
every 8 hours and ceftazidime 2 g with avibactam 500 mg every when treating β-lactamase–producing Enterobacteriaceae in
8 hours. Both drugs are primarily cleared through the kidneys, the lungs.

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

and the dosages have to be renally adjusted (Table 4). Both are dia-
lyzable and the dose that is scheduled near hemodialysis should be Ceftazidime/Avibactam
given after hemodialysis in patients with end-stage renal disease. The pharmacokinetics of ceftazidime/avibactam are similar to
those of ceftolozane/tazobactam. The primary route of elimina-
Ceftolozane/Tazobactam tion is renal excretion for both ceftazidime and avibactam, re-
The maximum plasma concentration of ceftolozane occurs at sulting in high levels of the parent compounds in the urine. The
around an hour after the start of infusion. The mean plasma pharmacokinetics of ceftazidime are known for most patient
half-life of ceftolozane is 2.7 hours in healthy, uninfected adults, populations [48]. In brief, the steady-state volume of distribu-
and significant accumulation does not occur after multiple doses tion is around 15 L, and only 10%–17% of drug is protein-
[43]. This relatively short half-life accounts for the need to ad- bound. The half-life is around 1.5 hours, and peak plasma
minister a dose every 8 hours. Ceftolozane is excreted through concentrations occur 30 minutes after intravenous infusion of
the kidneys with minimal metabolism and appears as parent ceftazidime [48, 49].
compound in the urine. The clearance of tazobactam, which Similarly, avibactam plasma concentrations also peak shortly
has been extensively previously reviewed, does not appear to be after infusion with a maximum noted at 30–60 minutes after
influenced when coadministering ceftolozane [44]. This is in start of infusion, followed by a biphasic decrease [50]. In the
contrast to coadministration with piperacillin, which leads to a same study of 32 healthy volunteers, elderly (defined as age
decrease in clearance of tazobactam with a corresponding in- ≥65 years) men but not elderly women were found to have a
crease in the area under the curve (AUC) [43, 45]. The steady- lower maximum concentration (Cmax) of avibactam compared
state volume of distribution of ceftolozane is 12.9 L, which is with young adults (defined as age 18–45 years); elderly men had
close to the average extracellular volume, suggesting potential a mean Cmax of 26 µg/mL compared with 34–38 µg/mL in the
therapeutic levels at extracellular sites of infection. The volume young and elderly female cohorts [50]. As this was a small study
of distribution was found to be increased in patients with obesity, in healthy volunteers, the clinical relevance of this finding re-
and further increased in patients with infection [46]. mains to be determined. The half-life of avibactam ranged
Ceftolozane/tazobactam is currently being studied for use in from 1.7 to 3.2 hours; this tended to be somewhat longer in
pneumonia. In this context, the pharmacokinetics in the lung the elderly adults. The volume of distribution of avibactam
were evaluated in healthy volunteers and compared to those ranged from 15 L to 24 L [50].
of piperacillin/tazobactam [47]. The ratio of epithelial lining Even in supratherapeutic doses, ceftazidime/avibactam did
fluid (ELF) to plasma AUC of ceftolozane was comparable to not increase QT duration in healthy male volunteers [51]. Ad-
verse events were observed in 30% of volunteers who received
Table 4. Recommended Dosing for Ceftolozane/Tazobactam and the supratherapeutic dose of ceftazidime 3000 mg with avibac-
Ceftazidime/Avibactam tam 2000 mg. Most were mild and included nausea, vomiting,
and headache [51].
Estimated Estimated
Creatinine Creatinine Ceftazidime/
Clearance, Ceftolozane/ Clearance, Avibactam, CLINICAL EXPERIENCE
mL/min Tazobactam, mg mL/min mg
Ceftolozane/Tazobactam
>50 1000/500 q8h >50 2000/500 q8h
In a phase II cUTI study, 86 patients received ceftolozane dosed
30–50 500/250 q8h 31–50 1000/250 q8h
at 1 g every 8 hours and 43 patients were treated with ceftazi-
15–29 250/125 q8h 16–30 750/190 q12h
ESRD on 500/250 × 1 loading dose, 6–15 750/190 q24h dime. Microbiological cure rates in the ceftolozane (83%) and
hemodialysisa followed by 100/50 q8h <6a 750/190 q48h ceftazidime (76%) arms were comparable. Adverse events in
Abbreviation: ESRD, end-stage renal disease.
the ceftolozane vs ceftazidime arms included constipation (9%
a
Give after completion of hemodialysis on hemodialysis days. vs 5%), sleep disorder (7% vs 5%), and diarrhea (4 vs 7%) [52].

238 • CID 2016:63 (15 July) • REVIEW OF ANTI-INFECTIVE AGENTS

 In phase III cUTI trials, ceftolozane/tazobactam (n = 398) was every 8 hours. More than 90% of patients were infected with
compared to levofloxacin (n = 402) [53]. Of note, in vitro fluoro- E. coli. In the clinically evaluable population (n = 64), a favorable
quinolone resistance at baseline was seen in more than a quarter clinical response was observed in 24 of 28 (86%) of patients in the
of uropathogens, whereas baseline resistance to ceftolozane/ ceftazidime/avibactam arm vs 29 of 36 (81%) in the imipenem/
tazobactam was only found in 2.7% of isolates. Clinical cure cilastatin arm. Microbiological responses were evaluated in the
and microbiological eradication were required for the composite microbiologically evaluable population (n = 62); 19 of 27 (70%) pa-
cure outcome. Superiority of ceftolozane/tazobactam compared tients had a favorable microbiological response in the ceftazidime/
with levofloxacin was found in both the modified intention-to- avibactam arm vs 25 of 35 (71%) in the imipenem/cilastatin arm.
treat (mITT) analysis (77% vs 68%), as well as in the per-protocol Drug-related serious adverse events were uncommon: 1 of the 68
(83% vs 75%) analysis. In contrast, outcomes were similar when (1.5%) patients treated with ceftazidime/avibactam developed
only patients with baseline levofloxacin-susceptible pathogens acute renal failure and another patient developed diarrhea.

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

were analyzed. Rates of adverse events were similar; headache oc- A cIAI phase 2 trial compared ceftazidime/avibactam plus
curred in 6% vs 5%, constipation in 4% vs 3% [53]. metronidazole (n = 101) vs meropenem (n = 102) [17]. Note
In a phase II cIAI study, 83 patients were randomized to cef- that the dosing for this trial was 4 times higher than the dos-
tolozane/tazobactam plus metronidazole vs 39 patients to mer- ing in the UTI study; 2 g of ceftazidime was given with 500 mg
openem [15]. While not statistically significant, the clinical cure of avibactam every 8 hours. This is also the dose that is rec-
rate in the microbiologically mITT (m-mITT) population— ommended in the package insert for patients with normal
those patients who received at least 1 dose of study medication renal function. Clinical response rates were comparable in the
and had a bacterial pathogen isolated from cultures—was numer- m-mITT population: 82% (70/85 patients) in the ceftazidime/
ically lower in the patients treated with ceftolozane/tazobactam avibactam plus metronidazole arm vs 88% (79/89 patients) in
plus metronidazole; clinical cure was observed in 51 of 61 the meropenem arm (difference, −6.4%; 95% CI, −23.8% to
(84%) patients vs 24 of 25 (96%) patients in the meropenem 6.0%). In this trial the predominant pathogen was also E. coli,
arm (difference, −12%; 95% confidence interval [CI], −35% which represented 69% of GNB. Gastrointestinal side effects
to 11%). Adverse event rates were similar [15]. such as nausea (10% vs 6%), vomiting (14% vs 5%), and abdom-
In 2 large multicenter phase 3 cIAI randomized controlled inal pain (8% vs 3%) were more common in the ceftazidime/
trials, patients were randomized to ceftolozane/tazobactam avibactam plus metronidazole group compared with the mero-
plus metronidazole (n = 389) vs meropenem (n = 417) [16]. A penem group [17]. This was likely due to the metronidazole
numerically lower cure rate was again observed in the m-mITT component of the therapy. The pooled results of 2 phase 3 trials
analysis: 83% vs 87% (weighted difference, −4.2%; 95% CI, comparing ceftazidime/avibactam plus metronidazole vs mero-
−9% to 0.5%) in patients treated with ceftolozane/tazobactam penem in adult hospitalized patients with cIAI were recently
plus metronidazole vs meropenem, respectively. However, this presented [55]. Again, noninferiority to meropenem was es-
difference was not statistically significant and the 95% CI did tablished. In the mITT analysis, 83% of 520 patients in the
not include the a priori noninferiority boundary of a 10% dif- ceftazidime/avibactam plus metronidazole arm had a clinical
ference. Of note, in patients with moderate renal failure (creat- cure, compared to 85% of 523 patients receiving meropenem.
inine clearance, 30–50 mL/minute), a numerically lower cure In the clinically evaluable population, clinical cure rates were
rate was noted in the phase 3 intra-abdominal infection trial: higher: 92% vs 93% in the ceftazidime/avibactam plus metroni-
11 of 23 (48%) in the ceftolozane/tazobactam plus metronidazole dazole vs meropenem arms, respectively [55]. Notably, sub-
arm vs 9 of 13 (69.2) in the meropenem arm. The decreased cure group analysis indicated that patients with moderate renal
rate in the patients aged ≥65 years (69% vs 82%) was also impairment (estimated creatinine clearance between 30 and
thought to be secondary to changes in renal clearance. These 50 mL/minute) had lower cure rates in the ceftazidime/avibac-
findings prompted the FDA to include a warning in the package tam plus metronidazole arm (45%) vs the meropenem arm
insert of ceftolozane/tazobactam to monitor renal function at (74%). This may have been secondary to an observed delay in
least daily in patients with changing renal function and to change dose readjustment back to full dosing in patients with recovery
ceftolozane/tazobactam dosing as needed. of renal function [56]. Importantly, the dosing strategy used in
Reported adverse events included hypokalemia (2.9%), head- these phase 3 cIAI trials for moderate renal failure was 1000/
ache (2.5%), and increased alanine aminotransferase (2.5%) and 250 mg ceftazidime/avibactam every 12 hours. The current pack-
aspartate aminotransferase (1.6%) levels [16]. age insert recommendations are to give 1000/250 mg ceftazidime/
avibactam every 8 hours to patients with moderate renal failure.
Ceftazidime/Avibactam
FORMULARY CONSIDERATIONS
In a phase 2 trial on cUTIs, 68 patients received ceftazidime/
avibactam and 67 were randomized to imipenem/cilastatin [54]. Both ceftolozane/tazobactam and ceftazidime/avibactam will be
The dosing was 500 mg of ceftazidime and 125 mg of avibactam most useful in the treatment of infections caused by MDR GNB.

REVIEW OF ANTI-INFECTIVE AGENTS • CID 2016:63 (15 July) • 239

The need for these agents is limited in patients with cUTI and Disclosure of Potential Conflicts of Interest. Conflicts that the editors con-
sider relevant to the content of the manuscript have been disclosed.
cIAI caused by bacteria with a more favorable susceptibility pat-
tern. However, the incidence of MDR GNB is increasing at an References
alarming pace, and these 2 agents represent important additions 1. White House Office of the Press Secretary. Fact sheet: Obama administration re-
to currently available antibiotics. leases national action plan to combat antibiotic-resistant bacteria. The White
House, 2015. Available at: https://www.whitehouse.gov/the-press-office/2015/03/
For both drugs there is an issue of preexisting in vitro resis- 27/fact-sheet-obama-administration-releases-national-action-plan-combat-ant.
tance. The percentages of Enterobacteriaceae and Pseudomonas Accessed 5 November 2015.
2. Boucher HW, Talbot GH, Benjamin DK Jr, et al. 10×′20 Progress—development
species that are resistant to these antibiotics is likely to dramat-
of new drugs active against gram-negative bacilli: an update from the Infectious
ically increase following their widespread clinical use, as it has Diseases Society of America. Clin Infect Dis 2013; 56:1685–94.
for virtually any other antibiotic. We are in need of reliable clin- 3. Boucher HW, Talbot GH, Bradley JS, et al. Bad bugs, no drugs: no ESKAPE! An up-
date from the Infectious Diseases Society of America. Clin Infect Dis 2009; 48:1–12.
ical data to evaluate the role of ceftazidime/avibactam in the 4. Munoz-Price LS, Poirel L, Bonomo RA, et al. Clinical epidemiology of the global

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

treatment of CRE. However, extrapolating from its in vitro expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;
13:785–96.
activity, its safety profile, and the known clinical efficacy of 5. Sader HS, Farrell DJ, Flamm RK, Jones RN. Antimicrobial susceptibility of gram-
β-lactam antibiotics, there is great promise that the outcomes negative organisms isolated from patients hospitalised with pneumonia in US and
European hospitals: results from the SENTRY Antimicrobial Surveillance Pro-
of patients infected with KPC-producing CRE will improve. It gram, 2009–2012. Int J Antimicrob Agents 2014; 43:328–34.
would be terrible if we were to lose the opportunity to treat fu- 6. van Duin D, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobac-
teriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis 2013;
ture critically ill patients because of overuse in patients with in-
75:115–20.
fections caused by more susceptible organisms. Therefore, the 7. Han JH, Bilker WB, Nachamkin I, et al. The effect of a hospital-wide urine culture
introduction into hospital formularies should be considered screening intervention on the incidence of extended-spectrum beta-lactamase-
producing Escherichia coli and Klebsiella species. Infect Control Hosp Epidemiol
with great care and the appropriate restrictions should be put 2013; 34:1160–6.
in place. 8. Andes D, Craig WA. Treatment of infections with ESBL-producing organisms:
pharmacokinetic and pharmacodynamic considerations. Clin Microbiol Infect
The need for either ceftolozane/tazobactam or ceftazidime/ 2005; 11(suppl 6):10–7.
avibactam will vary greatly from hospital to hospital, depending 9. Ehmann DE, Jahic H, Ross PL, et al. Avibactam is a covalent, reversible, non-beta-
lactam beta-lactamase inhibitor. Proc Natl Acad Sci U S A 2012; 109:11663–8.
on the population that they serve and specifically on their local 10. Stachyra T, Levasseur P, Pechereau MC, et al. In vitro activity of the {beta}-lactamase
antibiogram. Hospitals that have low rates of multidrug resis- inhibitor NXL104 against KPC-2 carbapenemase and Enterobacteriaceae expressing
KPC carbapenemases. J Antimicrob Chemother 2009; 64:326–9.
tance in their isolates of P. aeruginosa and Enterobacteriaceae
11. Murano K, Yamanaka T, Toda A, et al. Structural requirements for the stability of
will have a limited need for these drugs. novel cephalosporins to AmpC beta-lactamase based on 3D-structure. Bioorg Med
In summary, ceftolozane/tazobactam and ceftazidime/avi- Chem 2008; 16:2261–75.
12. Castanheira M, Mills JC, Farrell DJ, Jones RN. Mutation-driven beta-lactam resis-
bactam are second-generation cephalosporin/β-lactamase in- tance mechanisms among contemporary ceftazidime-nonsusceptible Pseudomo-
hibitor combinations with potential to improve outcomes of nas aeruginosa isolates from U.S. hospitals. Antimicrob Agents Chemother
2014; 58:6844–50.
patients infected with MDR GNB. Pathogen-specific random- 13. Snydman DR, McDermott LA, Jacobus NV. Activity of ceftolozane-tazobactam
ized trials are needed to determine the efficacy in those settings. against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents
Chemother 2014; 58:1218–23.
If overused, widespread resistance is likely to evolve rapidly by 14. Dubreuil LJ, Mahieux S, Neut C, Miossec C, Pace J. Anti-anaerobic activity of a
the selection of resistant strains. new beta-lactamase inhibitor NXL104 in combination with beta-lactams and met-
ronidazole. Int J Antimicrob Agents 2012; 39:500–4.
15. Lucasti C, Hershberger E, Miller B, et al. Multicenter, double-blind, randomized,
Notes
phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus met-
Disclaimer. Funding organizations were not involved in the design and ronidazole compared with meropenem in adult patients with complicated intra-
conduct of the study; the collection, management, analysis, and interpreta- abdominal infections. Antimicrob Agents Chemother 2014; 58:5350–7.
tion of the data; or the preparation, review, or approval of the manuscript. 16. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metroni-
The content is solely the responsibility of the authors and does not neces- dazole for complicated intra-abdominal infections in an era of multidrug resis-
sarily represent the official views of the National Institutes of Health (NIH) tance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI).
or the Department of Veterans Affairs. Clin Infect Dis 2015; 60:1462–71.
17. Lucasti C, Popescu I, Ramesh MK, Lipka J, Sable C. Comparative study of the ef-
Financial support. D. v. D. was supported by the National Institute of
ficacy and safety of ceftazidime/avibactam plus metronidazole versus meropenem
Allergy and Infectious Diseases (NIAID) of the NIH (award numbers in the treatment of complicated intra-abdominal infections in hospitalized adults:
UM1AI104681 and 1R21AI114508). Funds and facilities provided by the results of a randomized, double-blind, phase II trial. J Antimicrob Chemother
Cleveland Department of Veterans Affairs, the Veterans Affairs Merit Re- 2013; 68:1183–92.
view ( program award number 1I01BX001974), and the Geriatric Research 18. Sader HS, Farrell DJ, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested
Education and Clinical Center VISN to R. A. B. supported this work. This against aerobic gram-negative organisms isolated from intra-abdominal and uri-
work was also supported by funds from the NIAID of the NIH (award num- nary tract infections in European and United States hospitals (2012). J Infect 2014;
bers R01AI063517 and R01AI100560 to R. A. B.), and through the Antibiotic 69:266–77.
Resistance Leadership Group under NIH award number UM1AI104681, and 19. Farrell DJ, Sader HS, Flamm RK, Jones RN. Ceftolozane/tazobactam activity tested
against gram-negative bacterial isolates from hospitalised patients with pneumonia
NIH award number R01AI072219.
in US and European medical centres (2012). Int J Antimicrob Agents 2014; 43:533–9.
Potential conflict of interest. R. A. B. has been a grant investigator for and
20. Sader HS, Castanheira M, Flamm RK, Farrell DJ, Jones RN. Antimicrobial activity
received grants from AstraZeneca, Merck, Melinta, Steris, NIH, and Veterans of ceftazidime-avibactam against gram-negative organisms collected from U.S.
Affairs Merit Review. D. v. D. has served as a consultant for Sanofi-Pasteur, medical centers in 2012. Antimicrob Agents Chemother 2014; 58:1684–92.
Tetraphase, Actavis, and Astellas, and has received research funding from 21. Sader HS, Castanheira M, Flamm RK, Mendes RE, Farrell DJ, Jones RN. Ceftazi-
Scynexis and Steris. Both authors have submitted the ICMJE Form for dime/avibactam tested against gram-negative bacteria from intensive care unit

240 • CID 2016:63 (15 July) • REVIEW OF ANTI-INFECTIVE AGENTS

 (ICU) and non-ICU patients, including those with ventilator-associated pneumo- 38. Berrazeg M, Diene S, Medjahed L, et al. New Delhi metallo-beta-lactamase around
nia. Int J Antimicrob Agents 2015; 46:53–9. the world: an eReview using Google Maps. Euro Surveill 2014; 19.
22. Castanheira M, Mills JC, Costello SE, Jones RN, Sader HS. Ceftazidime-avibactam 39. Li H, Estabrook M, Jacoby GA, Nichols WW, Testa RT, Bush K. In vitro suscept-
activity tested against Enterobacteriaceae isolates from U.S. hospitals (2011 to ibility of characterized beta-lactamase-producing strains tested with avibactam
2013) and characterization of beta-lactamase-producing strains. Antimicrob combinations. Antimicrob Agents Chemother 2015; 59:1789–93.
Agents Chemother 2015; 59:3509–17. 40. Paterson DL, Ko WC, Von Gottberg A, et al. Antibiotic therapy for Klebsiella
23. Flamm RK, Sader HS, Farrell DJ, Jones RN. Ceftazidime-avibactam and compar- pneumoniae bacteremia: implications of production of extended-spectrum beta-
ator agents tested against urinary tract isolates from a global surveillance program lactamases. Clin Infect Dis 2004; 39:31–7.
(2011). Diagn Microbiol Infect Dis 2014; 80:233–8. 41. Walkty A, DeCorby M, Lagace-Wiens PR, Karlowsky JA, Hoban DJ, Zhanel GG.
24. Denisuik AJ, Karlowsky JA, Denisuik T, et al. In vitro activity of ceftazidime- In vitro activity of ceftazidime combined with NXL104 versus Pseudomonas aer-
avibactam against 338 molecularly characterized gentamicin-nonsusceptible uginosa isolates obtained from patients in Canadian hospitals (CANWARD 2009
gram-negative clinical isolates obtained from patients in Canadian hospitals. Anti- study). Antimicrob Agents Chemother 2011; 55:2992–4.
microb Agents Chemother 2015; 59:3623–6. 42. Levasseur P, Girard AM, Claudon M, et al. In vitro antibacterial activity of the cef-
25. Sader HS, Castanheira M, Farrell DJ, Flamm RK, Jones RN. Ceftazidime- tazidime-avibactam (NXL104) combination against Pseudomonas aeruginosa clin-
avibactam activity when tested against ceftazidime-nonsusceptible Citrobacter ical isolates. Antimicrob Agents Chemother 2012; 56:1606–8.
spp., Enterobacter spp., Serratia marcescens, and Pseudomonas aeruginosa from 43. Miller B, Hershberger E, Benziger D, Trinh M, Friedland I. Pharmacokinetics and

Downloaded from https://academic.oup.com/cid/article/63/2/234/1745233 by King Saud University user on 13 April 2023

United States medical centers (2011–2014). Diagn Microbiol Infect Dis 2015; safety of intravenous ceftolozane-tazobactam in healthy adult subjects following
83:389–94. single and multiple ascending doses. Antimicrob Agents Chemother 2012;
26. Sader HS, Castanheira M, Mendes RE, Flamm RK, Farrell DJ, Jones RN. Ceftazidime- 56:3086–91.
avibactam activity against multidrug-resistant Pseudomonas aeruginosa isolated in 44. Sorgel F, Kinzig M. The chemistry, pharmacokinetics and tissue distribution of pi-
U.S. medical centers in 2012 and 2013. Antimicrob Agents Chemother 2015; 59: peracillin/tazobactam. J Antimicrob Chemother 1993; 31 suppl A:39–60.
3656–9. 45. Wise R, Logan M, Cooper M, Andrews JM. Pharmacokinetics and tissue penetra-
27. Huband MD, Castanheira M, Flamm RK, Farrell DJ, Jones RN, Sader HS. In vitro tion of tazobactam administered alone and with piperacillin. Antimicrob Agents
activity of ceftazidime-avibactam against contemporary Pseudomonas aeruginosa Chemother 1991; 35:1081–4.
isolates from United States medical centers by census region (2014). Antimicrob 46. Chandorkar G, Xiao A, Mouksassi MS, Hershberger E, Krishna G. Population
Agents Chemother 2016; 60:2537–41. pharmacokinetics of ceftolozane/tazobactam in healthy volunteers, subjects with
28. Flamm RK, Farrell DJ, Sader HS, Jones RN. Ceftazidime/avibactam activity tested varying degrees of renal function and patients with bacterial infections. J Clin
against gram-negative bacteria isolated from bloodstream, pneumonia, intra- Pharmacol 2015; 55:230–9.
abdominal and urinary tract infections in US medical centres (2012). J Antimicrob 47. Chandorkar G, Huntington JA, Gotfried MH, Rodvold KA, Umeh O. Intrapulmo-
Chemother 2014; 69:1589–98. nary penetration of ceftolozane/tazobactam and piperacillin/tazobactam in
29. Winkler ML, Papp-Wallace KM, Hujer AM, et al. Unexpected challenges in treat- healthy adult subjects. J Antimicrob Chemother 2012; 67:2463–9.
ing multidrug-resistant gram-negative bacteria: resistance to ceftazidime-avibactam 48. Rains CP, Bryson HM, Peters DH. Ceftazidime. An update of its antibacterial ac-
in archived isolates of Pseudomonas aeruginosa. Antimicrob Agents Chemother tivity, pharmacokinetic properties and therapeutic efficacy. Drugs 1995; 49:
2015; 59:1020–9. 577–617.
30. Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN. Antimicrobial activity 49. Leroy A, Leguy F, Borsa F, Spencer GR, Fillastre JP, Humbert G. Pharmacokinetics
of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobac- of ceftazidime in normal and uremic subjects. Antimicrob Agents Chemother
teriaceae with various resistance patterns isolated in European hospitals (2011– 1984; 25:638–42.
12). J Antimicrob Chemother 2014; 69:2713–22. 50. Tarral A, Merdjan H. Effect of age and sex on the pharmacokinetics and safety of
31. Farrell DJ, Flamm RK, Sader HS, Jones RN. Antimicrobial activity of ceftolozane- avibactam in healthy volunteers. Clinical Ther 2015; 37:877–86.
tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with 51. Das S, Armstrong J, Mathews D, Li J, Edeki T. Randomized, placebo-controlled
various resistance patterns isolated in U.S. hospitals (2011–2012). Antimicrob study to assess the impact on QT/QTc interval of supratherapeutic doses of
Agents Chemother 2013; 57:6305–10. ceftazidime-avibactam or ceftaroline fosamil-avibactam. J Clin Pharmacol 2014;
32. Sutherland CA, Nicolau DP. Susceptibility profile of ceftolozane/tazobactam and 54:331–40.
other parenteral antimicrobials against Escherichia coli, Klebsiella pneumoniae, 52. Umeh O, Cebrik D, Friedland I. A double-blind, randomized, phase 2 study to
and Pseudomonas aeruginosa from US hospitals. Clin Ther 2015; 37:1564–71. compare the safety and efficacy of intravenous CXA-101 (CXA) and intravenous
33. Estabrook M, Bussell B, Clugston SL, Bush K. In vitro activity of ceftolozane- ceftazidime (CTZ) in complicated urinary tract infections (cUTI). In: 50th Annual
tazobactam as determined by broth dilution and agar diffusion assays against Interscience Conference on Antimicrobial Agents and Chemotherapy, Boston,
recent U.S. Escherichia coli isolates from 2010 to 2011 carrying CTX-M-type ex- MA, 2010.
tended-spectrum beta-lactamases. J Clin Microbiol 2014; 52:4049–52. 53. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-
34. Tato M, Garcia-Castillo M, Bofarull AM, Canton R, Group CS. In vitro activity of tazobactam compared with levofloxacin in the treatment of complicated urinary-
ceftolozane/tazobactam against clinical isolates of Pseudomonas aeruginosa and tract infections, including pyelonephritis: a randomised, double-blind, phase 3
Enterobacteriaceae recovered in Spanish medical centres: results of the CENIT trial (ASPECT-cUTI). Lancet 2015; 385:1949–56.
study. Int J Antimicrob Agents 2015; 46:502–10. 54. Vazquez JA, Gonzalez Patzan LD, Stricklin D, et al. Efficacy and safety of ceftazi-
35. Walkty A, Karlowsky JA, Adam H, et al. In vitro activity of ceftolozane-tazobactam dime-avibactam versus imipenem-cilastatin in the treatment of complicated uri-
against Pseudomonas aeruginosa isolates obtained from patients in Canadian hos- nary tract infections, including acute pyelonephritis, in hospitalized adults:
pitals in the CANWARD study, 2007 to 2012. Antimicrob Agents Chemother results of a prospective, investigator-blinded, randomized study. Curr Med Res
2013; 57:5707–9. Opin 2012; 28:1921–31.
36. Castanheira M, Mills JC, Costello SE, Jones RN, Sader HS. Ceftazidime-avibactam 55. Mazuski JE, Gasnik L, Broadhurst H, et al. Efficacy and safety of ceftazidime-
activity tested against Enterobacteriaceae from United States hospitals (2011– avibactam plus metronidazole versus meropenem in the treatment of complicated
2013) and characterization of beta-lactamase producing strains. Antimicrob intra-abdominal infection—results from a phase III programme. In: 25th Europe-
Agents Chemother 2015; 59:3509–17. an Congress on Clinical Microbiology and Infectious Diseases, Copenhagen,
37. Papp-Wallace KM, Winkler ML, Taracila MA, Bonomo RA. Variants of the KPC- Denmark, 2015.
2 beta-lactamase which are resistant to inhibition by avibactam. Antimicrob 56. Food and Drug Administration. Briefing package NDA 206494 ceftazidime-
Agents Chemother 2015; 59:3710–7. avibactam. Silver Spring, Maryland: FDA, 2014:1–55.

REVIEW OF ANTI-INFECTIVE AGENTS • CID 2016:63 (15 July) • 241