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Expert Opinion on Drug Metabolism & Toxicology

ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20

Pharmacokinetic drug evaluation of avibactam +ceftazidime for the treatment of hospital-acquiredpneumonia

Marco Falcone, Pierluigi Viale, Giusy Tiseo & Manjunath Pai

To cite this article: Marco Falcone, Pierluigi Viale, Giusy Tiseo & Manjunath Pai(2018): Pharmacokinetic drug evaluation of avibactam + ceftazidime for the treatment ofhospital-acquired pneumonia, Expert Opinion on Drug Metabolism & Toxicology, DOI:10.1080/17425255.2018.1434142

To link to this article: https://doi.org/10.1080/17425255.2018.1434142

Accepted author version posted online: 26Jan 2018.

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Publisher: Taylor & Francis

Journal: Expert Opinion on Drug Metabolism & Toxicology

DOI: 10.1080/17425255.2018.1434142

Pharmacokinetic drug evaluation of

avibactam + ceftazidime for the treatment of

hospital-acquired pneumonia

Falcone Marco1, Viale Pierluigi2, Tiseo Giusy3, Pai Manjunath 4

1 Department of Public Health and Infectious Diseases, “Sapienza” University of Rome, Italy; 2 Infectious Diseases

Unit, Department of Medical and Surgical Sciences, Hospital S. Orsola-Malpighi, University of Bologna, Italy;

3 Department of Internal Medicine and Medical Specialties, “Sapienza” University of Rome, Italy; 4 Albany College of

Pharmacy and Health Sciences, Albany, New York, USA

Corresponding author: Prof. Marco Falcone

Department of Public Health and Infectious Diseases, Policlinico Umberto I, Viale dell’Università 37,

00161 “Sapienza” University of Rome (Italy). Phone and fax number: +39 06491749. Email:

marco.falcone@uniroma1.it

Funding

This paper was not funded

Declaration of Interest

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Abbreviations

AUC area under curve

BAL bronchoalveolar lavage

CAZ-AVI Ceftazidime-avibactam

cIAI complicated intra-abdominal infections

CrCL creatinine clearance

CRE carbapenem-resistant Enterobacteriaceae

cUTI complicated urinary tract infections

CVVH continuous veno-venous hemofiltration

CYP cytochrome P450 enzymes

ELF epithelial lining fluid

ESBL extended spectrum β-lactamase-producing

FDA Food and Drug Administration

GNB Gram-negative bacilli

HAP hospital acquired pneumonia

ICU intensive care units

MDR multidrug-resistant

MIC minimum inhibitory concentration

mITT modified intent-to-treat

OAT organic anion transporter

PD pharmacodynamics

PK pharmacokinetic

TOC test-of-cure

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US United States

VAP ventilator-associated pneumonia

ABSTRACT

INTRODUCTION : Ceftazidime-avibactam (CAZ-AVI) is a combination of a third generation

cephalosporin and a non-β-lactam, β-lactamase inhibitor, recently approved for urinary tract

infections and complicated abdominal infections. Moreover, it represents a treatment option for

patients with hospital acquired pneumonia (HAP), especially when caused by multidrug-resistant

(MDR) bacteria.

AREAS COVERED: The review focuses on the pharmacokinetics (PK) of CAZ-AVI in HAP

and on preclinical and clinical studies evaluating PK/pharmacodynamics (PD) in this field.

EXPERT OPINION: In vitro and in vivo data about PK/PD of CAZ-AVI confirm that

penetration of CAZ-AVI in the epithelial lining fluid (ELF) represents approximately 30% of the

plasma concentrations. Clinical studies documented that CAZ-AVI 2000 mg/500 mg every 8 hours

is the optimal dose regimen to achieve the PK/PD target attainment in patients with HAP. Thus,

CAZ-AVI could represent an option both to treat HAP caused by Gram-negative bacilli (GNB)

displaying resistance to most of the antibiotics and to reduce the use of carbapenems, limiting the

onset of resistance profiles among GNB. Additional information about specific patients populations,

such as critically-ill subjects or pediatric patients, are needed for a more individualized use of CAZ-

AVI.

Keywords: ceftazidime-avibactam, hospital acquired pneumonia, new antibiotics, multidrug resistant organisms

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1. Introduction

Hospital acquired pneumonia (HAP) is one of the most frequent nosocomial infection worldwide

[1,2]. Ventilator-associated pneumonia (VAP) contributes to approximately half of all cases of HAP

and complicates the medical course of approximately 10% of mechanically-ventilated patients [3,

4]. Despite better supportive care, development of new diagnostic technologies and improvement of

infection control measures, HAP remains a cause of long hospital length of stay, high costs and high

mortality, largely due to the spread of multidrug-resistant (MDR) strains as causative organisms [5].

In particular, infections caused by MDR Gram-negative bacilli (GNB), including MDR P.

aeruginosa, extended spectrum β-lactamase-producing (ESBL) strains or carbapenem-resistant

Enterobacteriaceae (CRE), are increasingly reported worldwide [6]. Thus, the use of new molecules

could represent a valid strategy in this setting.

Ceftazidime-avibactam (CAZ-AVI) is a novel combination of a third generation cephalosporin and

a novel non-β-lactam, β-lactamase inhibitor (formerly NXL-104). This latter inhibits the activities

of Ambler class A and C β-lactamases and some Ambler class D enzymes [7-9]. A phase III study

comparing CAZ-AVI versus meropenem in hospitalized adults with HAP, including VAP, has been

recently completed (NCT01808092) [10]. Nevertheless, the knowledge of pharmacokinetic

(PK)/pharmacodynamics (PD) parameters of CAZ-AVI applied to this setting is crucial for the

forthcoming use of this new compound in the treatment of HAP.

In this review we discussed data from all studies evaluating PK and PD parameters of CAZ-AVI in

HAP. To this purpose we searched in the Pubmed database all potentially relevant studies. The

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search terms included (“Ceftazidime-avibactam” OR “NXL-104”) AND (“pharmacokinetics” OR

“pharmacodynamics”) AND (“hospital-acquired pneumonia” OR “pneumonia” OR “epithelial

lining fluid”). Moreover, we included in our discussion data of the ongoing not already published

clinical trial and data presented in abstract form during international congress. The search was

restricted to articles published in English language.

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2. Regulatory affairs

CAZ-AVI is approved by the Food and Drug Administration (FDA) for the treatment of patients 18

years or older with the following infections caused by designated susceptible microorganisms:

• cIAI, used in combination with metronidazole

• cUTI, including pyelonephritis [11].

CAZ-AVI use is limited at patients who have limited or no alternative treatment options. Moreover,

to reduce the development of drug-resistant bacteria and maintain the effectiveness of CAZ-AVI

and other antibacterial drugs, it should be used only to treat infections that are proven or strongly

suspected to be caused by susceptible bacteria [11].

The European Medicines Agency (EMA) approved the drug also for the treatment of infections due

to aerobic Gram-negative organisms in patients with limited treatment option and for HAP

(including VAP) [12].

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3. In vitro activity of ceftazidime-avibactam against clinical isolates

from HAP

The use of CAZ-AVI in patients with pneumonia is supported by in vitro data demonstrating the

activity of CAZ-AVI against GNB organisms isolated from patients with HAP [13-15]. In the

study of Sader and coworkers, a total of 18,864 GNB, including isolates from ICU patients and

non-ICU patients, were collected [13]; of these, 435 isolates were from patients with VAP and

the most common isolate was P. aeruginosa. CAZ-AVI exhibited in vitro activity against isolates of

P. aeruginosa and Enterobacteriaceae from VAP (MIC50/MIC90 0.12/0.5 mg/L; 99.1% susceptible)

[13]. Two subsequent epidemiological studies focused on CAZ-AVI activity against strains isolated

only from patients with HAP [14, 15]. Table 1 summarizes in vitro susceptibility rates of CAZ

alone and CAZ-AVI against different strains isolated from patients with HAP.

As expected, AVI restored the susceptibility of ceftazidime against strains of P. aeruginosa, E. coli

and K. pneumoniae but not against isolates of A. baumanni, due to the lack of activity against

metallo-β-lactamases such as NDM, VIM, IMP, VEB, PER [9]. Of importance, the 98.7% of

meropenem-non susceptible K. pneumoniae (n=150; MIC50/90, 0.5/2 μg/mL) isolates were

susceptible to CAZ-AVI [15]. In these in vitro studies, CAZ-AVI displayed MIC50 and MIC90

values of 0.5 and 2 µg/mL against isolates of carbapenem-resistant Enterobacteriaceae, but MIC

values >32 μg/mL against NDM-1 producing strains [14-15]. Strains of P. aeruginosa have MIC90

values of 8 μg/mL, that increased up to 16 μg/mL if only meropenem non-susceptible isolates were

considered [14]. Moreover, in clinical isolates from patients with VAP the MIC90 of all P.

aeruginosa and of meropenem non-susceptible P. aeruginosa strains were 16 and 32 μg/mL,

respectively [14]. These data indicate that a more difficult attainment of the PK/PD target could be

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reached not only in infections due to A. baumannii, but also in those involving MDR-P. aeruginosa

strains [14].

Although remote, the possibility of CAZ-AVI resistance exists. In the abovementioned study, the

0.1% of all Enterobacteriaceae were CAZ-AVI-non-susceptible [15]. Among these, 3 were NDM-1

producing strains exhibiting CAZ-AVI MIC values of >32 μg/mL and 5 included isolates (2 S.

marcescens, 1 E. aerogenes, 1 E. cloacae and 1 Providencia stuartii) with CAZ-AVI MIC values of

16 μg/mL [15]. Similarly, MIC50 and MIC90 of CAZ-AVI against isolates of A. baumannii were 16

and >32 μg/mL, respectively [15]. The resistance of species producing metallo-β-lactamases against

CAZ-AVI is expected and documented, since avibactam is not active against metallo-β-lactamases

(NDM, VIM, IMP, VEB, PER), due to the absence of the active-site serine residue [9]. More

However, resistance to CAZ-AVI has been reported also for clinical isolates of Pseudomonas

aeruginosa [16]. This could appear unexpected, since avibactam demonstrated to be able to

inactivate different AmpC-lactamase enzymes. However, the altered membrane permeability and

the enhancement of drug efflux seem to justify these findings [16].

Emergence of resistance to CAZ-AVI has been recently reported when CAZ-AVI was used as

monotherapy to treat K. pneumoniae-related infections [17]. An aspartate (D)-to-asparagine (N)

substitution at Ambler position 179 in the omega-loop of the KPC-2 was identified as the

mechanism and shown to enhance the affinity and retention of CAZ for a longer period of time than

AVI [18]. Importantly this change increases the size of the active site, which can no longer

hydrolyze aztreonam or imipenem [19]. As a consequence, carbapenems and aztreonam could be

used in theory to overcome this new mechanism of resistance.

Thus, CAZ-AVI demonstrated to decreased MIC value of ceftazidime alone when tested against

clinical isolates of bacteria causing HAP. However, there are some concerns about the efficacy of

CAZ-AVI against MDR-Pseudomonas aeruginosa and Acinetobacter baumannii.

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4. Pharmacokinetics (PK) and pharmacodynamics (PD) of CAZ-AVI

4.1 Basic principles of CAZ-AVI PK/PD

The knowledge of PK/PD parameters of an antibiotic is crucial to understand drug action, factors

affecting formation and disposition of drug metabolites, optimal dosage evaluated from animals to

humans, bioavailability of the drug and in vitro and in vivo correlations. The PK of ceftazidime

have been well characterized given it’s over three decades of clinical use.

Ceftazidime is a 'third generation' cephalosporin with a broad spectrum of in vitro activity against

Gram-positive and Gram-negative aerobic bacteria, particularly active against Pseudomonas

aeruginosa isolates. Ceftazidime exerts a time-dependent bactericidal effect. Thus, the PK property

that predicts better clinical efficacy in vitro is the time during which the tissue concentration of the

antibiotic is greater than the MIC of the organism [20]. Excretion is by glomerular filtration. It is

not metabolized. Ceftazidime penetrates into most body tissue and fluids, including cerebrospinal

fluid, and accumulates during renal failure, but is removed by hemodialysis and peritoneal dialysis

[21]. One of the most frequent clinical use of ceftazidime is pneumonia. However, some studies

indicated that the penetration of this compound in the lung tissue is about 20-30% of plasma

concentrations. Indeed some studies proposed its continuous administration in patients with VAP to

achieve better PK/PD objectives [20]. While the co-administration of a β-lactamase inhibitor can

restore antibacterial activity of the cephalosporin, previously approved β-lactamase inhibitors such

as tazobactam and clavulanic acid do not inhibit important classes of β-lactamases, including

Klebsiella pneumoniae carbapenemases (KPCs), New Delhi metallo-β-lactamase 1 (NDM-1), and

AmpC-type β-lactamases. The addiction of a new β-lactamase inhibitor to ceftazidime provided

partially a therapeutic option in these cases.

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Avibactam is a reversible β-lactamase inhibitor that has very limited plasma protein binding

(<10%) and is eliminated primarily unchanged in the urine [22]. The clearance of this compound

exceeds the glomerular filtration rate suggesting active secretion as a key transport mechanism.

Thus, the PK of avibactam is primarily affected by kidney function. Merdjan et al, evaluated the

single dose PK of a low dose (100 mg) of avibactam in patients with normal and varying degrees of

impaired renal function. This study shows that the half-life of avibactam increases by approximately

2-3 fold, 4 fold, and 12 fold with creatinine clearance (CrCL) values of 30-79 mL/min, <30 mL/min

(non-hemodialysis), and < 30 mL/min (hemodialysis) subjects, respectively [23]. The majority of

the interindiviudal variability in avibactam CL is predicted by CrCL. Although this relationship has

been modeled as a linear relationship, an Emax model may be better explain the upper tail of the

relationship. This is relevant to explore further given that patients with augment renal function

(>130 mL/min) may not have a substantially higher avibactam clearance compared to normal renal

function patients (>80 mL/min).

Das et al. have also demonstrated that the co-administration of ceftazidime does not alter the PK of

avibactam. Given the known propensity for OAT transporters, the only relevant interaction

(extension of half-life) as noted with several β-lactams includes that with co-administration of

probenecid. Avibactam also maintains a linear PK across a 40-fold dose range (50 mg to 2000 mg)

for single intravenous administration [9]. The recommended dosage and frequency of

administration in patients with normal renal function is 2.5 g every 8 hours [9]. This dosage is based

on a 4:1 ratio of ceftazidime:avibactam. Since the drug is excreted unchanged by the kidneys,

dosage adjustment is required in patients with moderately or severely impaired renal function, so

that the recommended dosage and frequency of administration of CAZ-AVI range from 2.5 g every

8 hour (CrCl > 50 ml/min) to 0.94 g every 48 hours (CrCl <5 ml/min) based on the patient’s

estimated CrCl [22]. The CrCl values for these dosage adjustments are calculated based on the

Cockcroft-Gault formula.

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The approved dosing regimens rely heavily on PK/PD modeling and simulation results. The PK/PD

target attainment analyses of CAZ-AVI have been extensively revised in animal models and in

humans. PK studies demonstrated that avibactam is generally well tolerated across all dosing

regimens, when given alone or with ceftazidime [22,24]. Peak plasma concentrations of avibactam

have been found to increase in direct proportion to increases in the dose [24]. In healthy adults,

avibactam has a volume of distribution of 20 to 24 L, a terminal half-life of 1.5 to 2.7 hours, and an

average clearance of 10.4 to 13.8 L/hour [24]. The protein binding of avibactam is reported to be

8% [24].

Regarding PD data, it has been demonstrated that the time that unbound plasma concentrations of

ceftazidime exceed the CAZ-AVI minimum inhibitory concentration (MIC) against the infecting

organism best correlates with efficacy in a neutropenic murine thigh infection model with

Enterobacteriaceae and Pseudomonas aeruginosa. The time above the threshold concentration best

predicts the efficacy of avibactam in in vitro and in vivo nonclinical models [25]. An interesting

study revealed that AUC and Cmax have an important role in the PD of avibactam [26].

Antibacterial effect of avibactam was assessed against a CTX-M-producing Escherichia coli,

AmpC-hyperproducing Enterobacter cloacae and KPC-producing Klebsiella pneumoniae. The

amount of avibactam required for maximum effect was greater for the KPC-producing K.

pneumoniae than the other two strains (CTX-M or AmpC hyper-producer). It has been

demonstrated that AUC or Cmax were best related to 24 h antibacterial effect for avibactam though

there was no consistent pattern favouring one over the other [26].

However, most of the knowledge about PK/PD data of CAZ-AVI derives from studies conducted in

heterogeneous animal models (septicemia, thigh infections, kidney infections, meningitis,

pneumonia), from healthy volunteers and from patients with cUTI and cIAI [7-8, 27-33]. Validation

of the predictive value of these PK/PD models and simulations to clinical effect continue to be

studied.

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In conclusion, the PK of avibactam does not appear to be altered by the co-administration of

ceftazidime and PD data suggest that CAZ-AVI is rapidly bactericidal versus β-lactamase-

producing Gram-negative bacilli that are not inhibited by ceftazidime alone. Since it is eliminated

by kidneys, dosage adjustment is required in patients with moderately or severely impaired renal

function.

4.2 PK/PD studies in animal models of pneumonia

Beyond the enhanced in vitro potency of CAZ-AVI compared with ceftazidime alone against a

variety of GNB isolates causing HAP, an important issue concerns the PK and PD parameters of

CAZ-AVI in pneumonia. An important first step is to understand the rate and extent of penetration

of the compound in the target organ, represented in this case by the lung. The following steps

include evaluation of the efficacy of CAZ-AVI in this type of infection model, to ascertain

exposure-response relationships that aid definition of the best human dosing regimens to test in

clinical trials.

Table 2 shows PK parameters in animal and human models of pneumonia. The clinical and animal

data derived from CAZ-AVI suggests that the epithelial lining fluid (ELF) exposure (based on area

under curve [AUC]) is approximately 30-35% of plasma concentration. Given the low molecular

weight of avibactam and marginal protein binding, this profile is lower than would be traditionally

predicted for this type of molecule. Moreover, as shown in the left column of the Table 2, in mice

models the ELF t½ and the plasma t½ of CAZ-AVI were similar, indicating similar patterns of

elimination but a similar lower than expected penetration of this agent. It should be noted that these

estimates are derived from median tendency profiles from highly variable measurements in ELF

compared to plasma in healthy volunteers. Higher variability in the PK profile of antimicrobials is

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often seen in critically ill patients and so the ELF profile of CAZ-AVI in patients with pulmonary

disease is important to investigate. Boselli et al., demonstrated the penetration of CAZ to be

20±8.9% in ELF with the continuous infusion of a 4 g dose of CAZ in 15 patients with severe HAP

on mechanical ventilation [34].

In mice affected by thigh infection (2 P. aeruginosa strains per animal, one inoculated in the left

thigh and the other in the right) and lung infection (1 strain per animal), both ceftazidime and

avibactam showed a linear, dose proportional PK and no differences in PK profiles in plasma and

ELF were observed for each drug, findings that could indicate the passive diffusion of the two drugs

from plasma to ELF. Thus, these data indicate that plasma concentrations could be used as a

surrogate for target attainment of CAZ-AVI in the lung. As a matter of fact, the concentrations of

ceftazidime and avibactam in the ELF were found to be around 4-fold lower than those in the

plasma, with a penetration ratio in the ELF of 0.24 and 0.20 for the total drug concentrations,

respectively [34]. These data have been further confirmed in humans (see below) [35].

Another preclinical study performed in mice (rendered neutropenic by administering intraperitoneal

injections of cyclophosphamide) affected by P. aeruginosa pneumonia and treated with CAZ-AVI

at the dosage of 2000 mg of ceftazidime+500 mg of avibactam as a 2 h infusion every 8 h, tried to

correlate efficacy of CAZ-AVI and PK/PD parameters of the drug in this pneumonia model. CAZ-

AVI showed a favorable ELF concentration-time profile and a good exposure in the lung [36]. As a

matter of fact, the CAZ-AVI fT>MIC, the PD index that correlates best with efficacy for β-lactam

antibiotics and representing the percentage of the dosing interval in which free drug concentrations

remain above the MIC, observed in the ELF was proportional to that calculated in the serum,

indicating a correspondence between serum concentrations and ELF penetration. As expected, the

efficacy of the drug reduced for increased CAZ-AVI MIC values [36]. The mean fT>MIC was 34%

in serum but corresponded with a mean of 0% (upper bound of 19%) in ELF for isolates with an

MIC of 32 µg/ml. Despite this observation, a reduction of >1 log10 CFU against 26 of 27 P.

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aeruginosa isolates with CAZ-AVI MICs ≤32 µg/L was shown, while no activity against a single

isolate against which the CAZ-AVI MIC was 64 µg /ml was observed. This suggests that PK/PD

thresholds defined in animal models based on serum data may be more reliable given the known

variability of ELF measurements that could potentially under predict the efficacy of CAZ-AVI [36].

Since penetration of some antibiotics in the lung could be different in uninfected and infected

models, another important point of evaluation is the impact of infection status upon the PK of CAZ-

AVI. In the abovementioned study, the ELF fT>MICs were similar between infected and uninfected

mice, highlighting that the host’s infection status has not an impact on the pulmonary

pharmacokinetic profile of CAZ-AVI [36].

PD profile of CAZ-AVI has been also studied by Berkhout et al using a different PD index [31]. In

this study, PD responses were explored in murine neutropenic thigh and lung infection models.

Differently from the previous study of Housman and coworkers, investigators used as PD index the

%fT>CT, that is analogous to %fT>MIC, but considers CT instead of MIC values [31]. CT represents

the threshold concentration of avibactam during a declining concentration-time curve, below which

β-lactamase is no longer effectively inhibited in vivo. For this reason, while the ceftazidime PK/PD

target is well established as 50% %fT>MIC, the avibactam PK/PD target is best defined by

%fT>CT. The effect of AVI was primarily dependent on the time during which plasma levels were

above the threshold %fT>CT 1 mg/L, with a mean value of 37.7% of the dosing interval required for

a static effect [32]. Thus, the effect of avibactam was not dependent on the peak concentration

Cmax and its efficacy is related primarily to a time above a certain threshold rather than the total

daily dose. A more efficacious therapy was obtained with the more frequent dosing regimen for any

given AUC [31].

Thus, the penetration of CAZ-AVI in the ELF is about 30% of the plasma concentration, but should

be better evaluated in critically-ill patients. The avibactam PK/PD target is best defined by %fT>CT

and its efficacy is related to the time above the threshold concentrations.

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4.3. PK/PD data from patients with pneumonia

A phase I study assessed lung exposure to CAZ-AVI by measuring and comparing the

concentrations of ceftazidime and avibactam in the ELF and plasma following two different dosing

regimens (2000 mg of ceftazidime+500 mg of avibactam or 3000 mg of ceftazidime+1000 mg of

avibactam) in 43 healthy volunteers [35]. All subjects were males, aged 18–50 years and have a

BMI of 19–30 kg/m2. In each subject cohorts, a bronchoscopy with bronchoalveolar lavage (BAL)

and plasma samples collection for PK evaluation were performed [35]. It has been demonstrated

that both ceftazidime and avibactam penetrate into human ELF, with elimination patterns similar

between ELF and plasma [35]. Table 2 described the PK data for the 2 different dosages of CAZ-

AVI used in this study. As shown, plasma and ELF concentrations of ceftazidime and avibactam

were dose-proportional. In particular, a 1.5 and 2 fold increases in AUCt were observed for

ceftazidime (2000–3000 mg) and avibactam (500–1000 mg), respectively [35]. Similarly to what

observed in mice, both ceftazidime and avibactam reach proportionally concentrations 25-30%

lower in the ELF compared to plasma (ELF/plasma ratio 0.313/0.349 for CAZ/AVI 2000+500 mg

and 0.324/0.320 for CAZ/AVI 3000 + 1000 mg) [35]. Finally, CAZ-AVI demonstrated to be well

tolerated in both dosages cohort of subjects because the overall incidence of adverse events was

similar in the two cohorts. The findings derived from the phase I study were in line with the

previous data from animal studies, proving a higher concentrations achieved in ELF for CAZ-AVI

than those associated with efficacy in the mouse model.

Recently, Das et al tried to determine the usefulness of plasma levels as a surrogate measure for

lung penetration in patients with HAP [37]. They pooled PK/PD information from preclinical

pneumonia mice models and data from Phase I and Phase II studies in patients with cIAI. They

concluded that the similar ELF and plasma concentration profiles of CAZ-AVI and the

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demonstrated PK/PD in infected mouse models allow the use of plasma concentration as a surrogate

for lung exposure in patients with HAP, including VAP [38]. Moreover, using a Monte Carlo

simulation, it has been determined that CAZ-AVI 2000 mg/500 mg 2-hour infusion every 8 hours

was the optimal dose regimen to achieve the PK/PD target attainment in patients with HAP [37].

In conclusion, PK/PD studies in humans confirmed preclinical data in animals. CAZ-AVI

penetrates in the ELF of healthy subjects so that plasma levels could be used as a surrogate measure

for lung penetration.

4.4 Comparison with PK/PD of other anti-Gram negative antimicrobial agents

To better understand the ability of CAZ-AVI in penetrating in the ELF, a comparison with other

already known or novel anti-Gram negatives antimicrobial agents is needed. Overall, an ELF

penetration lower than 50% has been observed for almost all β-lactam, except for the cephalosporin

cefepime.

A great variability in the ELF concentrations has been demonstrated for piperacillin-tazobactam. In

patients with VAP, the alveolar percentage penetration of piperacillin was 40-50% while that of

tazobactam range from 65 to 85% [38]. A more recently study conducted in critically ill patients,

showed a median piperacillin and tazobactam pulmonary penetration ratio of 49.3% and 121.2%,

respectively [39]. The penetration of meropenem in the ELF of lung infected mice was

approximately 40%, with a variability of the penetration, with the 10th percentile being 12%

penetration while the 90th percentile was 131% [40]. This high variability has been confirmed also

in humans [40]. In 39 patients with VAP, the mean (±standard deviation [SD]) AUCELF and

AUCplasma values of meropenem (administered at the dosage of 2 g or 500 mg meropenem

intravenously as a 3-h infusion every 8 h or 1 g intravenously as a half-hour infusion every 8 h)

were 82.3 (±140.1) mg • h/liter and 150.8 (87.4) mg • h/liter, respectively [41]. The median (25th

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and 75th percentile values) AUCELF and AUCplasma values were 130.9 (90.1 to 189.3) mg• h/liter and

35.0 (12.5 to 92.1) mg •h/liter, respectively with a median AUCELF/AUCplasma penetration ratio was

25.4% [41]. These findings have been confirmed also for other carbapenems. An ELF/plasma ratio

of 0.44 (or 0.55 based on unbound concentration assuming a protein binding of 20%) was identified

for imipenem [42]. Differently from the above-mentioned β-lactams, cefepime showed a mean

penetration rate into the ELF of 20 adults with severe nosocomial pneumonia of 100% [43].

Of interest, other new available antimicrobial agents showed better ELF penetration ratio compared

to CAZ-AVI. Melchers MJ and collaborators in a murine model described that the mean ELF

penetration ratio of ceftolozane was 0.33 and that of tazobactam was 0.77 [44]. The ELF

penetration of the new combination meropenem/RPX700 has been recently reported in adult healthy

volunteers. It appears to be 63% for meropenem and 53% for RPX7009. When unbound plasma

concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009,

respectively [45].

Taken together, these findings indicated that CAZ-AVI showed an ELF penetration similar to old β-

lactam agents, but fails to guarantee better lung penetration, similar to that other new available anti-

Gram negatives agents promise.

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5. Drug-drug interactions

In vitro, AVI is a substrate of OAT1 and OAT3 transporters, two OAT3 transporters expressed on

the basolateral membrane of the renal proximal tubule and considered the rate limiting step in the

renal clearance of organic anion drugs, metabolites, and toxins in vivo. They may contribute to the

active uptake from the blood compartment and to excretion of AVI. As a potent OAT inhibitor,

probenecid inhibits OAT uptake of avibactam by 56%–70% and can decrease the elimination of

avibactam when co-administrated [46]. Thus, the co-administration of the two drugs is not

recommended. However, avibactam did not interact with various other membrane transport proteins

or cytochrome P450 enzymes in vitro, suggesting it has limited propensity for drug–drug

interactions involving cytochrome P450 enzymes [46].

In the study of Dallow et al, microbiological interactions between CAZ-AVI and other drugs

frequently used in HAP have been evaluated. The mean fractional inhibitory concentration index of

CAZ-AVI in presence of tobramycin, levofloxacin, vancomycin, linezolid,tigecycline and colistin

showed no interactions irrespective of the tested bacterial species (Enterobacter cloacae,

Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and

Enterococcus faecalis) [47].

It is possible to conclude that CAZ-AVI has limited drug-drug interactions.

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6. Clinical data: results from phase 3 study (REPROVE)

A prospective, multicenter, randomized, non-inferiority trial (REPROVE), to assess the efficacy,

safety and tolerability of CAZ-AVI administered intravenously as a two-hour infusion (2000mg/500

mg every 8 hours) versus meropenem administered intravenously as a 30-minute infusion (1000mg

every 8 hours) among adult patients with clinically diagnosed HAP or VAP has been recently

completed (NCT01808092) [12]. Overall, 879 patients from 18 to 90 years with HAP, including

VAP, were included in the study. Out of these, 62 patients with moderate or severe renal

impairment at baseline were excluded. Primary outcome measure was the number of patients with

clinical cure at test-of-cure (TOC) visit in the clinically modified intent-to-treat (mITT) analysis set

(day 21 to 25). A total of 356 patients for CAZ-AVI cohort and 370 patients in the meropenem

group were finally included in the mITT population. Among these, clinical cure was achieved in

245 (68.8%) patients in the CAZ-AVI cohort and in 270 (72.9%) in meropenem group (p value for

non-inferiority 0.007) [12]. All-cause mortality rate at day 28 from randomization was also similar

in the two groups. Safety and tolerability observations for CAZ-AVI were consistent with the

comparator and the known profile for ceftazidime alone [12]. Thus, the REPROVE results, recently

published, validated the use of CAZ-AVI for the treatment of HAP caused by GNB, showing the

non-inferiority of CAZ-AVI compared to meropenem.

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7. Conclusions

Despite CAZ-AVI demonstrates in vitro efficacy against GNB isolates from patients with HAP,

there are some concerns about its efficacy against MDR-Pseudomonas aeruginosa and

Acinetobacter baumannii. Preclinical data in mice showed that penetration of the drug in the lung is

about 30% of the plasma concentration. Both mice models and preclinical human studies (phase I)

demonstrated that CAZ-AVI penetrates in the lung with PK patterns profile similar between ELF

and plasma. ELF/plasma ratio of CAZ-AVI concentrations range from 0.22 to 0.27 and from 0.31 to

0.35, in mice and humans respectively. Thus, plasma concentrations could be used as a surrogate

for target attainment of CAZ-AVI in the lung. The avibactam PK/PD target is best defined by

%fT>CT and its efficacy is related to the time above the threshold concentrations. A CAZ-AVI

dosage of 2000 mg/500 mg 2-hour infusion every 8 hours appears as an optimal regimen to achieve

the PK/PD target attainment in patients with HAP.

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8. Expert opinion

CAZ-AVI represents a valid treatment option for patients with HAP, especially when caused by

MDR difficult-to-treat bacteria. Data about PK/PD of CAZ-AVI confirm similar penetration of

CAZ-AVI in the ELF compared to historic data with CAZ alone. CAZ-AVI could represent a

treatment option both to treat HAP caused by GNB displaying resistance to most of the antibiotics

and to reduce the use of carbapenems, limiting the onset of resistance profiles among GNB.

However, some key questions remain unanswered. First of all, the phase III trial (REPROVE) of

CAZ-AVI in HAP showed a clinical cure rate of 68.8%, lower than that is expected based on

preclinical PK/PD data. Despite CAZ-AVI has demonstrated to be non-inferior to meropenem, the

rate of clinical success remains relatively low. This data is in line with previous observations. As a

matter of fact, it is known that even in patients with HAP, generally considered to be less severe

than VAP, serious complications, including respiratory failure, pleural effusions, septic shock, renal

failure, and empyema, occur in approximately 50% of patients, [48]. Moreover, a recent double-

blind, randomized, multicenter study of 781 patients with HAP comparing efficacy of ceftobiprole

versus ceftazidime plus linezolid showed a cure rate of 59.6% and 58.8% respectively [49].

Another important limitation to be highlighted is the penetration of CAZ-AVI in the ELF is lower

than that demonstrated for other agents (see Table 3). This aspect could partially explained the poor

clinical response rates observed in the REPROVE study. Moreover, emerging data about resistance

to CAZ-AVI have been reported. Thus, a larger clinical experience of this drug is needed and

should be correlated with more robust PK data in patients with HAP.

A better knowledge of CAZ-AVI in patients with VAP is also required. As a matter of fact, patients

with HAP-not VAP can be more different from those affected by VAP. These subjects are usually

more compromised, critically-ill and hospitalized in ICU settings. Since some factors such as

underlying host immune status, baseline disease severity, multiple organ dysfunction, change in

metabolism, volume distribution and protein binding could be altered in critically-ill patients, PK

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and PD parameters could modify in these subjects. Thus, specific information in these populations

could be useful for a better optimization of PK/PD target attainment.

PK/PD data of CAZ-AVI lung penetration derived from healthy volunteer are based on examination

of male patients only, aged 18–50 years and with a normal BMI. In a phase I open-label study,

small differences in PK parameters between the young and elderly cohorts are described [50].

Consequently, more information in female and elderly patients is required. Moreover, it is not

known if obesity could influenced the PK/PD of CAZ-AVI in patients with pneumonia.

A final consideration about the use of CAZ-AVI in patients with HAP refers to special populations.

A phase I trial evaluated the PK profile, safety, and tolerability of CAZ-AVI in hospitalized

pediatric patients, providing successful characterization of the single-dose PK profile of ceftazidime

and avibactam in a pediatric population aged from 3 months to 18 years [50]. The PK profiles of

single-dose ceftazidime and avibactam in this hospitalized pediatric population were similar to

those previously observed in adult population and no new safety concerns were identified [50]. The

knowledge of PK/PD of CAZ-AVI in this population is important to support its potential use in

subjects with cystic fibrosis, a patient population at high risk of repeated respiratory-tract infections.

Recently, PK/PD parameters of CAZ-AVI have been studied in 12 adults with cystic fibrosis. An

improved PD of CAZ-AVI (2.5 g every 8 h infused over 2 h) in comparison with that of CAZ has

been observed in this patients’ group [51]. However, data is still limited and a large clinical

experience in this setting is needed.

In conclusion, CAZ-AVI could represent a valid option for the treatment of HAP. Additional

information about specific patients populations, such as critically-ill subjects or pediatric patients, is

required for a more individualized use of CAZ-AVI in certain clinical conditions.

Drug name Ceftazidime-avibactam

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17.

Table 1.Summary of ceftazidime-avibactam susceptibility rates against different Gram-negative isolates from HAP, including VAP.

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Flamm1 Flamm1 Sader2

Europe USA USA

PHP

(not VAP)

VAP

PHP

(not VAP)

VAP

PHP

(all cases)

VAP

P. aeruginosa CAZ 73% 65.7% 79.7% 70.4% 82.4% 85.8%

CAZ-AVI* 94.8% 85.5% 96.0% 95.4% 96.6% 97.8% Meropenem non susceptible P. aeruginosa

CAZ 44.4% 48.5% 54.1% 45.5% 54.2% 64.8% CAZ-AVI* 85.2% 71.2% 87.3% 84.8% 86.3% 92%

E. coli CAZ 89.9% 73.8% 86.7% 96.9% 86.1% 88.1% CAZ-AVI* 100% 100% 100% 100% 99.9% 100%

ESBL E. coli CAZ 42% 24.1% 35.1% 0 28.1% 28.6% CAZ-AVI* 100% 100% 100% 100% 99.6% 100%

Klebsiella spp

CAZ 74.6% 75.9% 87% 89.6% 85.2% 88.8% CAZ-AVI* 100% 100% 100% 100% 99.9% 99%

ESBL Klebsiella spp

CAZ 4.5% 28.6% 7.1% 11.1% 22.9% 24.1% CAZ-AVI* 100% 100% 100% 100% 99.5% 93.1%

Meropenem non susceptible klebsiella spp

CAZ 0 8.3% 0 11.1% 2.7% 0 CAZ-AVI* 100% 100% 100% 100% 98.7% 75%

Acinetobacter baumannii CAZ 20.8% 7.3% 25.5% 30% 37.5% 51.3% CAZ-AVI* 0 0 0 0 35% 38.5%

PHP: Patients Hospitalized with Pneumonia VAP: Ventilator-Associated Pneumonia CAZ: ceftazidime, CAZ-AVI: ceftazidime-avibactam

1 Flamm RK, Nichols WW, Sader HS et al. In vitro activity of ceftazidime/avibactam against Gram-negative pathogens isolated from pneumonia in hospitalised patients, including ventilated patients. Int J Antimicrob Agents. 2016;47:235-42 2 Sader HS, Castanheira M, Flamm RK. Antimicrobial activity of ceftazidime-avibactam when tested against gram-negative bacteria isolated from patients hospitalized with pneumonia in U.S. Medical Centers, 2011 to 2015. Antimicrob Agents Chemother. 2017;6. pii: e02083-16

* Criteria as published by the Clinical and Laboratory Standards Institute (CLSI). Clinical and Laboratory Standards Institute. Performance standards forantimicrobial susceptibility testing; twenty-third informational supplement.Document M100-S23. Wayne, PA: CLSI; 2013

* US Food and Drug Administration (FDA) interpretive criteria were applied to ceftazidime/avibactam

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European Committee on Antimicrobial Susceptibility Testing. Breakpoint tablesfor interpretation of MICs and zone diameters, Version 3.0. EUCAST; 2013,January. http://www.eucast.org/clinical breakpoints/

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Table 2. PK parameters in plasma and ELF of ceftazidime and avibactam in animal models and humans.

Mice models*

Humans (healthy volunteers)**

Dosage 2000 mg of ceftazidime + 500 mg of avibactam q8h

Humans (healthy volunteers)**

Dosage 3000 mg of ceftazidime + 1000 mg of avibactam q8h

Ceftazidime

Avibactam

Ceftazidime

Avibactam

Ceftazidime

Avibactam

ELF/plasma ratio Total Free ELF t½ (h), mean ± SD

Plasma t½ (h) mean ± SD

0.24 0.27

0.39 ± 0.12

0.28 ± 0.02

0.22 0.24

0.34 ± 0.07

0.24 ± 0.04

ELF/plasma ratio

ELF t½ (h), composite profile

ELF Tmax (h), composite profile

ELF AUCτ (mg•h/L), composite profile

ELF Cmax (mg/L), composite profile

Plasma t½ (h), mean ± SD

Plasma Tmax (h), median (range)

Plasma AUCτ (mg•h/L), mean (%)

Plasma Cmax (mg/L), mean (%)

0.313

3.77

2.0

92.3

23.2

2.86 ± 0.294

2.00 (1.97–2.02)

295 (13.0)

90.1 (13.3)

0.349

1.94

2.0

13.7

5.1

3.29 ± 0.82

2.00 (1.97–2.02)

39.2 (9.7)

14.5 (9.7)

0.324

ND

2.0

147

32.7

2.94 ± 0.318

2.00 (1.97–2.03)

454 (9.4)

140 (9.6)

0.320

1.94

2.0

24.8

7.9

3.61 ± 0.47

2.00 (1.97–2.03)

77.6 (9.9)

28.5 (10.2)

ELF: epithelial lining fluid, SD: standard deviation, AUCτ: AUC during the dosing interval

Pharmacokinetic parameters in ELF were derived from the composite concentration–time profile consisting of the median concentration at each scheduled timepoint.

*Berkhout J, Antimicrob Agents Chemother. 2015;59:2299-304 **Nicolau D P, Antimicrob Chemother 2015; 70: 2862–2869

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Table 3. ELF penetration of ceftazidime-avibactam and other old and new anti-Gram negative agents.

Anti-Gram negative antimicrobial agents

ELF/plasma ratio

Mice models Humans

OLD DRUGS

Piperacillin-tazobactam

40-50% for piperacillin; 65-85% for tazobactam 1

49.3% for piperacillin 121.2% for tazobactam.2

Cefepime

100%3

Meropenem

40%4 25.4%5

NEW DRUGS

Ceftazidime-avibactam

24% for ceftazidime 27% for avibactam6

31% for ceftazidime 35% for avibactam7

Ceftolozane-tazobactam

33% for ceftolozane 77% for tazobactam8

48% for ceftolozane9

Meropenem- RPX7009

63% for meropenem 53% for RPX7009 65% for meropenem 79% for RPX7009 (of unbound plasma concentrations)10

1 Boselli E et al. Crit Care Med. 2008;36:1500-6 2 Felton TW et al. Clin Pharmacol Ther. 2014;96:438-48 3 Boselli E et al. Crit Care Med. 2003;31:2102-6. 4 Drusano GL et al. Antimicrob Agents Chemother. 2011;55:3406-12 5 Lodise TP et al. Antimicrob Agents Chemother. 2011;55:1606-10. 6 Berkhout J et al. Antimicrob Agents Chemother. 2015;59:2299-304 7 Nicolau D P et al. Antimicrob Chemother 2015; 70: 2862–2869 8 Melchers MJ et al. Antimicrob Agents Chemother. 2015;59:3373-6 9 Chandorkar G et al. J Antimicrob Chemother. 2012;67:2463-9 10 Wenzler E et al. Antimicrob Agents Chemother. 2015;59:7232-9

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