Focus on ceftazidime-avibactam for optimizing outcomes in complicated intra-abdominal and urinary tract infections.

Drug Evaluation

1.

Introduction

2.

Overview of the market

3.

Introduction to the

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compound Chemistry

5.

Pharmacodynamics

6.

PK and metabolism

7.

Efficacy and in vivo activity

8.

Safety and tolerability

9.

Regulatory affairs Conclusion

11.

Expert opinion

David P Nicolau Center for Anti-Infective Research and Development Hartford Hospital, Hartford, CT, USA

4.

10.

Focus on ceftazidime-avibactam for optimizing outcomes in complicated intra-abdominal and urinary tract infections Introduction: Complicated intra-abdominal infections and urinary tract infections are frequently associated with Gram-negative bacteria and treatment can be hampered by the involvement of resistant organisms. A common resistance mechanism is b-lactamase production which confers resistance to b-lactam antibiotics. Areas covered: This article summarizes b-lactamases found among Gram-negative bacteria as well as providing an overview of complicated intra-abdominal infections and urinary tract infections and the impact inappropriate antibiotic therapy and antibiotic resistance has in their treatment. The author reviews the activity of ceftazidime-avibactam, including animal model data and microbiological data from Phase II clinical trials. This article also highlights Phase III clinical trials of ceftazidime-avibactam that are ongoing or completed and briefly discusses other b-lactamase inhibitor combinations currently in development. Expert opinion: The increasing problem and complexity of b-lactamase resistance has been met by resurgence in the development of b-lactamase inhibitor combinations. These show promise in the treatment of resistant infections. One b-lactamase inhibitor in advanced development with a broad spectrum of activity is avibactam, covering class A, class C and some class D enzymes. Importantly, the activity of avibactam also includes carbapenemases such as the KPC and OXA-48. The combination of avibactam with the cephalosporin ceftazidime is attractive, given the spectrum of antimicrobial activity and the low toxicity of the cephalosporin class. Keywords: avibactam, b-lactamases, ceftazidime, intra-abdominal infections, urinary tract infections Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

Bacteria and antibiotic resistance Pathogenic Gram-negative bacteria of interest in many infection types include Pseudomonas aeruginosa and Acinetobacter baumannii as well as members of the Enterobacteriaceae such as Klebsiella pneumoniae, Escherichia coli and Enterobacter spp. A common antibiotic resistance mechanism in all these organisms is the production of b-lactamases, which confers resistance to b-lactam antibiotics. There are a large number of important b-lactamases which can be classified using their amino acid sequence (Ambler classification) as either class A, class C or class D (which utilize serine for the active site of b-lactamase hydrolysis) or class B, which are also termed “metallo-b-lactamases”, and require divalent zinc ions for hydrolysis [1,2]. A second classification system, referred to as the Bush, Jacoby, Medeiros classification, takes into account substrate and inhibitor profiles. This groups 1.1

10.1517/13543784.2015.1062873 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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D. P. Nicolau

Box 1. Drug summary. Drug name (generic) Phase (for indication under discussion) Indication (specific to discussion) Pharmacology description/ mechanism of action Route of administration Chemical structure

Ceftazidime-avibactam III Complicated intra-abdominal infections, complication urinary tract infections A 4:1 combination of ceftazidime (a b-lactam antibiotic) and avibactam (a b-lactamase inhibitor) Parenteral Ceftazidime: H2N

S


N

H

H

NH N O H3C

N 5

O

O

O

6

7 8

S 1

2 N+

4

3 O–

O

CH3 OH

(6R,7R,Z)-7-(2-(2-aminothiazol-4-yl)-2-(2-carboxypropan-2-yloxyimino) acetamido)-8-oxo-3-(pyridinium-1-ylmethyl)-5-thia-1-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylate (C22H22 N6O7S2) Avibactam: O

3 4

H

N 2

2

5

1N 7

N 6

O

O O

S O–

O

trans-7-oxo-6-(sulfoxy)-1,6-diazabicyclo[3.2.1]octan-2-carboxamide (C7H10 N3O6S) Pivotal trial(s)

[65,66]

b-lactamases together to correlate the enzyme with their phenotype, for example, group 1 enzymes are cephalosporinases and group 2 hydrolyze both cephalosporins and penicillins [2,3]. One group of b-lactamases, the extended-spectrum b-lactamases (ESBLs), are able to hydrolyze most penicillins and cephalosporins, including third-generation compounds, but they are inhibited by clavulanic acid [4,5]. There is no consensus on the precise definition of ESBLs as they are a diverse group. True ESBLs (Ambler class A) are typically mutants of CTX-M, TEM-1, TEM-2 and SHV-1; however, they may not always display an ESBL phenotype. Conversely, Ambler class D enzymes may display an ESBL phenotype but are not true ESBLs. In their 2005 review, Paterson and Bonomo defined ESBLs using the Bush, Jacoby, Medeiros classification as ‘group 2be and those of group 2d which share most of the fundamental properties of group 2be enzymes’ [4]. The activity of the cephalosporin class of antibiotics is also threatened by AmpC b-lactamases (class C or group 1 enzymes) which can be chromosomal or plasmid encoded and are not inhibited by clavulanic acid [6]. 2

The continued emergence and spread of b-lactamases producing organisms has resulted, in part, in the increased use of carbapenem antibiotics; this has in turn resulted in the emergence of carbapenemases such as the KPC serine carbapenemases and the NDM family of metallo-b-lactamases [7]. The carbapenemases are found in Ambler classes A, B and D. Carbapenemase-producing organisms have spread rapidly and can now be found across the globe [8,9]. In addition to the production of b-lactamases, A. baumannii and P. aeruginosa also exhibit resistance to antibiotics through low permeability of the outer membrane (loss of OprD proteins in P. aeruginosa and porin channels in A. baumannii), efflux pumps, synthesis of aminoglycosidemodifying enzymes and alterations in DNA gyrase and topoisomerase IV (quinolone resistance) [10,11]. These mechanisms of resistance also occur in members of the Enterobacteriaceae. Microbiology of complicated intra-abdominal infections

1.2

Complicated intra-abdominal infections (cIAIs) are those that extend beyond the hollow viscus of origin and into the

Expert Opin. Investig. Drugs (2015) 24(9)


Ceftazidime-avibactam

peritoneal space and are associated with either abscess formation or peritonitis [12]. Members of the Enterobacteriaceae remain major pathogens in cIAIs with P. aeruginosa and A. baumannii increasing in prevalence in recent years [13]. Polymicrobial infections are also common. Rates of resistance among these pathogens vary by geography, location of care (e.g., intensive care unit [ICU]) and patient population. Resistance among IAI pathogens has been reported by the Study for Monitoring Antimicrobial Resistance Trends (SMART) for more than 10 years [14]. From SMART, Hoban et al. reported that the incidence of ESBL-producing E. coli and K. pneumoniae from IAIs in North America (2010 -- 2011) was 8.8 and 8.9%, respectively [15]. Additionally, the authors also reported that AmpC b-lactamase and KPC carbapenemase enzymes are increasingly detected among these organisms. Data from the SMART study also showed P. aeruginosa to be the third most common pathogen in IAIs and resistance to fluoroquinolones among P. aeruginosa to be increasing in North America, from ~ 22% in 2005 to 33% in 2010 [14]. Resistance among P. aeruginosa to piperacillin-tazobactam, cefepime and ceftazidime was between 23 and 26% over the same time period [16]. Although a North America study it should be noted that the majority of North American sites in SMART are located in the US. The CANWARD study of Canadian hospitals reported a statistically significant (p < 0.001) decrease in fluoroquinolone (ciprofloxacin) resistance among P. aeruginosa between 2007 and 2011, from 34.0 to 21.8% [17]. However, the isolates in the LagaceWiens et al. study were not solely from IAIs [17]. In their surveillance study of isolates collected from IAIs from US medical centers in 2012, Flamm et al. reported that 10.4% of E. coli and 16.3% of Klebsiella spp. demonstrated the extended-spectrum cephalosporin-resistant phenotype [18]. Agents with low MIC90s against these extended-spectrum cephalosporin-resistant E. coli were ceftazidime-avibactam (MIC90 0.25 mg/l) (Box 1), meropenem (0.12 mg/l) and tigecycline (0.25 mg/l). For the fluoroquinolones tested (levofloxacin, ciprofloxacin) and for piperacillin-tazobactam, the MIC90 was > 4 and > 64 mg/l, respectively [18]. Similar results were reported for extended-spectrum cephalosporin-resistant phenotype Klebsiella spp. with an MIC90 of 2 mg/l for ceftazidime-avibactam, 1 mg/l for tigecycline, > 4 mg/l for levofloxacin and > 64 mg/l for piperacillin-tazobactam. Inappropriate antibiotic therapy in IAIs Inappropriate therapy, when the causative pathogen is resistant to the antibiotic used for treatment, is an increasing problem as the occurrence and diversity of antibiotic resistance increases. A positive correlation has been shown to exist between inadequate antibiotic therapy and poor outcome in IAIs. Montravers et al., in their study of peritonitis after intra-abdominal surgery, established a significant relationship (p < 0.05) between mortality and adequate therapy, where 50% (27/54) of patients receiving inappropriate antibiotic therapy died compared with 26% (12/46) of patients 1.3

receiving appropriate therapy [19]. They concluded, using stepwise regression analysis, that four independent variables were significantly associated with mortality: shock, APACHE II score of ‡ 21, age of ‡ 62 years and inappropriate empiric antibiotic treatment [19]. Mosdell et al. demonstrated higher mortality among patients with secondary bacterial peritonitis who received inappropriate antibiotic therapy when compared with patients receiving appropriate therapy (12.2 and 5.6%) [20]. Furthermore, when comparing appropriate and inappropriate therapy, patients who received empirical treatment with an appropriate antibiotic agent at the time of surgery had fewer wound infections (14.4 and 26.5%, respectively), abscesses (10.5 and 34.7%, respectively), re-operations (13.9 and 36.7%, respectively) and total complications (18.9 and 51.0%, respectively). Microbiology of complicated urinary tract infections

1.4

Urinary tract infections (UTIs) are one of the most commonly occurring infections in humans. Complicated UTIs (cUTIs) usually develop in patients with urinary tracts that are structurally or functionally abnormal, and other contributory factors include renal insufficiency, transplantation, antibioticresistant pathogens, old age, male and recurrent UTI [21]. Uncomplicated UTIs typically occur in otherwise healthy premenopausal women. The distinction between cUTIs and uncomplicated UTIs is important for effective treatment. Catheter-associated UTIs are a particular problem in the healthcare setting, where urinary catheterization is widespread. In order to reduce the incidence of catheter-associated UTIs, the Infectious Diseases Society of America recommends restricting catheter use to patients who have clear indications and, if used, removing the catheter as soon as it is no longer needed [22]. Where a pathogen is isolated, E. coli is typically the most common cause of UTIs. In catheter-associated UTIs, the three most common pathogens have been reported to be E. coli (26.8%), P. aeruginosa (11.3%) and Klebsiella spp. (11.2%) [23]. As with other infections, antibiotic resistance among Gram-negative pathogens isolated from patients with UTIs varies geographically, by location of care and by patient population. Data from 2011 of Gram-negative bacteria isolated from bacteremic patients with UTIs reported the phenotypic ESBL rates among Klebsiella spp. as 16.1% in the US and 40.4% in the European Union [24]. Data from 2012 for isolates collected from US medical centers reported rates of extended-spectrum cephalosporin-resistant E. coli and Klebsiella spp. from UTIs to be 8.5 and 13.0%, respectively [18]. MIC90s against these extended-spectrum cephalosporin-resistant E. coli and Klebsiella spp. were reported to be 0.25 and 1 mg/l for ceftazidime-avibactam, 0.25 and 1 mg/l for tigecycline, > 4 mg/l for levofloxacin and 64 and ‡ 64 mg/l for piperacillin-tazobactam, respectively [18]. Sievert et al., reporting on catheter-associated organisms in the US, showed


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D. P. Nicolau

non-ICU rates of resistance among E. coli of 13.2, 33.5 and 2.9% for cephalosporins, fluoroquinolones and carbapenems, respectively [23]. The rate of multidrug resistance (resistance to at least three antibiotics) was 2.3%. Carbapenem resistance was higher among Klebsiella spp. (12.6%) as was multidrug resistance (17.0%). For P. aeruginosa, rates of resistance in non-ICU settings were 9.9% for aminoglycosides, 28.3% for cephalosporins, 35.5% for fluoroquinolones, 22.3% for carbapenems and 17.1% for piperacillin-tazobactam. Multidrug resistance was reported among 15.6% of isolates. Fluoroquinolone resistance among A. baumannii has been reported at 52.6% globally [25]. Inappropriate antibiotic therapy in cUTI and catheter-associated UTIs

1.5

The association between inappropriate or inadequate therapy and prolonged hospitalization and/or poor clinical outcome has been shown in UTIs. Esparcia et al., in their study of elderly patients with severe UTIs, demonstrated that inadequate empiric antibiotic therapy was associated with previous hospitalization, presence of a urinary catheter and previous receipt of an antibiotic [26]. They also showed that inadequate empiric antibiotic therapy was an independent risk factor of mortality [26]. In a retrospective matched-cohort analysis, MacVane et al. showed that the cost of care and length of stay for patients with a UTI infection due to ESBL-producing E. coli or K. pneumoniae were 1.5 times greater than for those caused by non-ESBL- producing E. coli or K. pneumoniae [27]. When a patient is readmitted for a UTI, the same causative pathogen has been shown to be unlikely and there may also be a significant change in the microbial profile among readmitted patients. MacVane et al. found that only 16.3% of patients readmitted had the same causative pathogen [28]. They also demonstrated an increase in the incidence of Enterococcus faecalis (1.2 vs 9.3%, p = 0.046) and a decrease in the occurrence of Enterobacteriaceae (50.0 vs 25.6%, p = 0.006) among readmitted patients [28]. A higher proportion of readmission pathogens were also non-susceptible to commonly used antibiotics, for example, cefazolin nonsusceptibility increased from 24.4 to 63.6% (p = 0.004) and cefepime from 8.7 to 27.6% (p = 0.05). This higher rate of resistant pathogens among readmissions may be due to a number of factors; it is possible that these rates are higher because of previous therapy, irrespective of if that therapy was appropriate or not or that the previous therapy selected for resistance organisms. However, these results highlight the importance of selecting an appropriate antibiotic for the initial UTI episode based on patient demography as well as the impact of previous treatment on the selection of resistant pathogens. 2.

Overview of the market

The arsenal of resistance mechanisms present in bacteria has led to an increase in reports of infections caused by 4

multidrug-resistant pathogens, resulting in infections caused by organisms that are resistant to all available antibiotics [29]. There is clearly an unmet medical need for new antibiotics active against resistant Gram-negative organisms [30]. One approach in the development of antibiotics with activity against b-lactamase-producing bacteria is the combination of an antibiotic with a b-lactamase inhibitor. Agents in development that meet this description include ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-cilastatin-MK-7655 and the combination of a carbapenem with RPX7009. Avibactam is also currently under development in combination with aztreonam. The focus of this review is ceftazidimeavibactam; however, the other agents are briefly discussed below. Ceftolozane-tazobactam is a combination of a novel cephalosporin ceftolozane with the b-lactamase inhibitor tazobactam. This new compound has been recently approved in the US for the indication of cUTI including pyelonephritis as well as cIAIs when given with metronidazole. Ceftolozane is active against Pseudomonas spp. and the tazobactam protects ceftolozane from hydrolysis by b-lactamases and broadens its coverage to include most ESBL-producing Enterobacteriaceae [31]. As with ceftazidime-avibactam, both combinations contain a cephalosporin whose activity is impacted by b-lactamases. Tazobactam is an existing inhibitor, already marketed in combination with piperacillin, which has a structure based around the b-lactam ring. Avibactam has a broader spectrum of activity than tazobactam and is not a b-lactam. MK-7655 is a novel inhibitor of class A and class C b-lactamases which is under development in combination with imipenem-cilastatin. MK-7655 is similar in structure to avibactam and both are classified as members of the same non-b-lactam b-lactamase inhibitor group, the diazabicyclooctanes. MK-7655 is able to increase the activity of imipenem against KPC-producing Enterobacteriaceae; however, it is not effective against metallo-carbapenemases (i.e., IMP and VIM) [32]. The combination is in Phase II clinical trials for cUTIs (ClinicalTrials.gov Identifier: NCT01505634) and cIAIs (NCT01506271), with the cIAI trial completed in 2014. The boron-based inhibitor RPX7009 (b-lactamase inhibitor) is being developed in combination with a carbapenem, for use in the treatment of infections caused by bacteria with carbapenemases, in particular KPC. RPX7009 is an inhibitor of class A and class C b-lactamases, and, as with other b-lactamase inhibitors, it does not possess any direct antibiotic activity [33]. RPX7009 does not inhibit class B metallob-lactamases, and unlike avibactam, it does not inhibit class D carbapenemases such as OXA-48. Target indications include UTIs, IAIs, hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, as well as febrile neutropenia. The monobactam aztreonam is an existing antibiotic which is inactivated by some b-lactamases but is stable in the presence of metallo-b-lactamases. The combination of aztreonam



with avibactam creates a drug with an increased spectrum of activity [34]. A Phase I clinical trial (NCT01689207) to investigate the safety and tolerability in healthy volunteers of this combination has been completed, although results have not yet been published.


3.

Introduction to the compound

Ceftazidime is an established parenteral extended-spectrum antipseudomonal cephalosporin with Gram-positive and Gram-negative activity. Ceftazidime has limited clinical utility against A. baumannii as in vitro susceptibility is generally < 50% [35]. Avibactam is a non-b-lactam b-lactamase inhibitor which inactivates susceptible b-lactamases by covalent acylation of the b-lactamases active site serine residue [36,37]. The spectrum of activity of avibactam covers Ambler class A and class C b-lactamases as well as some class D enzymes. Avibactam is able to inhibit carbapenemases such as KPC and OXA-48 but not (class B) metallo-b-lactamases [35]. Unlike clavulanic acid or tazobactam, avibactam deacylation occurs through regeneration of intact avibactam rather than hydrolysis, giving avibactam a unique, slowly reversible, mechanism of action [36]. Among Gram-negative pathogens, resistance to ceftazidime may be conferred through a variety of mechanisms. Although ESBLs and AmpC b-lactamases mediated mechanisms may be prominent, resistance may also be conferred through efflux and reduced permeability, as in the case of Pseudomonas and some Enterobacteriaceae. In addition, resistance to ceftazidime may also be related to non-ESBL, non-AmpC b-lactamases such as metallo-b-lactamases and carbapenemases. Avibactam is able to inhibit a range of b-lactamases resulting in increased antibiotic activity against both Enterobacteriaceae and P. aeruginosa [38,39]. Avibactam, at 4 mg/l, has been shown to reestablish the activity of ceftazidime in in vitro checkerboard assays against clinical strains of Enterobacteriaceae with known resistance mechanisms including ESBLs and carbapenemases [40]. The combination of ceftazidime with avibactam reduced the MIC90 from 64 mg/l (ceftazidime) to 0.25 mg/l (ceftazidime-avibactam) against ESBL-producing E. coli (Table 1) [38]. Similar reductions were seen for ESBL-producing K. pneumoniae and AmpC hyper-producing E. coli (Table 1). The combination of ceftazidime with avibactam has been shown to be active in vitro against Enterobacteriaceae with 99.8% of US isolates collected in 2012 inhibited by an MIC of £ 4 mg/l [41]. These isolates included ESBL-producing E. coli and K. pneumoniae, meropenem-non-susceptible K. pneumoniae and ceftazidime-non-susceptible Enterobacter cloacae. Similarly, KPC-Enterobacteriaceae collected in China in 2011 -- 2012 were inhibited by a ceftazidime-avibactam MIC of £ 2 mg/l [42]. The combination of ceftazidime with avibactam was not active against organisms with IMP or NDM metallo-b-lactamase enzymes [42]. Aktas et al.

demonstrated that ceftazidime-avibactam was active against OXA-48-producing K. pneumoniae [43]. Against P. aeruginosa, the MIC90 has been shown to decrease from 64 mg/l for ceftazidime alone to 8 mg/l for the combination of ceftazidime-avibactam [39]. As there were no breakpoints approved for avibactam combinations at the time the study was carried out, the breakpoints applied in the Levasseur et al. study were those approved by the Clinical Laboratory Standards Institute for ceftazidime alone and the percentage of isolates categorized as susceptible increased from 61.5% for ceftazidime alone to 93.7% for the combination [39]. This decrease in MIC for the combination of ceftazidime with avibactam was also shown by Flamm et al.: against European isolates of P. aeruginosa, the MIC90 values were > 32 mg/l for ceftazidime alone and 8 mg/l for ceftazidimeavibactam [44]. Among US isolates, ceftazidime-avibactam inhibited 96.9% of 1967 P. aeruginosa (at an MIC of £ 8 mg/l) collected in 2012, and for isolates collected in China between 2011 and 2012, the MIC90 for ceftazidimeavibactam was 8 mg/l [41,42]. The minimum bactericidal concentration:MIC ratios of ceftazidime-avibactam have been shown to be £ 4 against both P. aeruginosa and Enterobacteriaceae, including wildtype, ESBL, KPC and AmpC producers, which suggest bactericidal activity [45]. Time-kill kinetics showed time-dependent reduction in CFU/mL with a 3-log10 decrease in CFU/mL at 6 h for Enterobacteriaceae and a 2-log10 drop in CFU/mL at 6 h for some of the P. aeruginosa isolates tested. In addition, the same study also demonstrated that human serum (50%) and human serum albumin (4%) had a minimal effect on the MICs of ceftazidime-avibactam with MICs remaining within 1 -- 2 doubling dilutions [45]. 4.

Chemistry

Ceftazidime, as with other cephalosporins, contains a cephem nucleus fused with 7-aminothazolyl and a 3-dihydrothiazine ring. Avibactam, although not a b-lactam, has a structure that resembles b-lactams in some areas. Avibactam does not have clinically relevant antibiotic activity [38]. 5.

Pharmacodynamics

As with other cephalosporins the pharmacodynamic (PD) parameter of key importance for the activity of ceftazidime is free drug time above the MIC (fT>MIC) [46]. This has been demonstrated clinically using nosocomial pneumonia clinical trial data where ceftazidime was used as a comparator [47]. A two-compartment model was shown to be the best fit for the data and the authors concluded that exposures to ceftazidime predicted microbiological as well as clinical outcome, and the fT>MIC required to result in a likely favorable outcome was > 45% of the dosing interval. A second study, of ceftazidime and cefepime in the treatment of


5

D. P. Nicolau

Table 1. MICs (mg/l) of ceftazidime and ceftazidime-avibactam against b-lactamase-producing Escherichia coli and Klebsiella pneumoniae. ESBLproducing E. coli Antibiotic


Ceftazidime

Ceftazidimeavibactam

ESBL-producing K. pneumoniae

AmpC-hyperproducing E. coli

ESBL and AmpChyper-producing E. coli

n = 161

n = 29

n = 94

n=8

MIC50 (mg/l) MIC90 (mg/l) MIC range (mg/l) Susceptible (%) MIC50 (mg/l)

16 64 0.5 -- > 64 65.0 0.12

64 > 64 0.12 -- > 64 31.0 0.5

16 64 1 -- > 64 35.1 0.12

32 > 64 2 -- > 64 25.0 0.12

MIC90 (mg/l) MIC range (mg/l) Susceptible (%)

0.25 £ 0.004 -- 2 100

1 0.06 -- 2 100

0.5 0.004 -- 2 100

0.12 0.015 -- 0.12 100

Susceptibility (%S) was determined according to CLSI M100-S20 guidelines [69]. Breakpoints used for both ceftazidime and ceftazidime-avibactam were: susceptible £ 4 mg/l; intermediate 8 mg/l; resistant ‡ 16 mg/l. Data from Lagac e-Wiens et al. (Table 2) [38].

ventilator-associated pneumonia, found that achieving a > 53% fT>MIC was a predictor of success [48]. The PD of combinations of ceftazidime and avibactam have been studied in several in vitro models and clinical studies. Using a hollow-fiber PD model, ceftazidime-avibactam resulted in rapid killing of eight b-lactamase-producing isolates of Enterobacteriaceae which were resistant to ceftazidime [49]. Regrowth appeared at an avibactam concentration of ~ < 0.3 mg/l. When a 1 g dose of ceftazidime was simulated, avibactam at a concentration of between > 0.25 and < 0.5 mg/l was required to suppress growth for 25 h. The critical threshold avibactam concentration (CT), below which bacterial regrowth could occur because of the inability of avibactam to suppress b-lactamase activity, was investigated by Nichols et al. using data from three hollow-fiber experiments [50]. In these models, the concentration of ceftazidime was maintained at 10 mg/l and avibactam was added to achieve Cmax values of 9, 31 or 37 mg/l. Bacteria studied were E. cloacae (AmpC producer, ceftazidime MIC of > 128 mg/l, ceftazidime-avibactam MIC of 4 mg/l) and two K. pneumoniae, one a SHV-5 producer (ceftazidime MIC of 64 mg/l, ceftazidime-avibactam MIC of 2 mg/l) and the second a CTX-M-15, TEM-1 and OXA-1 producer (ceftazidime MIC of > 128 mg/l, ceftazidime-avibactam MIC of 1 mg/l). The authors concluded that the minimum concentration of avibactam required for b-lactamase suppression was < 0.3 mg/l. In a PD model of pulmonary infection, neutropenic mice were infected with P. aeruginosa and treated with ceftazidime every 2 h either alone or in combination with avibactam given every 2 or 8 h [51]. The percentage time of the dosing interval that exceeded the MIC threshold (%>fT CT) of 0.25, 1 and 5 mg/l for avibactam was calculated. Results indicated that the effect of avibactam decreased with decreased dosing frequency and, for a static effect against most strains of P. aeruginosa the %>fT CT 1 mg/l was between 20 and 25%. In a similar study, neutropenic mice were 6

infected in the thigh with P. aeruginosa and treated with ceftazidime every 2 h either alone or in combination with avibactam [52]. Results indicated that the avibactam effect was dependent on %>fT CT 1 mg/l. The mean value was 37.7%. Pharmacokinetic (PK) data from five Phase I studies in healthy volunteers and a Phase II study in patients with cIAI were adequately described by a two-compartment model with creatinine clearance as the primary covariant impacting ceftazidime and avibactam clearance. Interestingly, the data also indicated decreased AUC and Cmax of 20 and 38% for ceftazidime and 34 and 59% for avibactam among cIAI patients [53]. 6.

PK and metabolism

In healthy patients, the PK of ceftazidime and avibactam have been shown to be unaffected when the two drugs are co-administered compared with administration alone, either after a single dose or repeat dosing [54]. Both ceftazidime and avibactam are primarily cleared by the kidneys and clearance is reduced in renally impaired patients, resulting in a requirement for dosage adjustment in renally impaired patients [55,56]. The Cmax and AUC of ceftazidime increases directly with dose [57]. Avibactam had approximately linear PK across the dose range of 0.5 -- 2 g for single intravenous (i.v.) administration [58]. The terminal elimination half-life (t½) of ceftazidime and avibactam are similar (~ 2 h for ceftazidime, 1.5 -- 2.7 h for avibactam) following i.v. infusion [57,58]. 7.

Efficacy and in vivo activity

Animal and in vitro models of infection The combination of ceftazidime with avibactam has been tested in a number of animal models. In murine septicemia and thigh infection models due to KPC-producing K. 7.1




pneumoniae avibactam in combination with ceftazidime was shown to be effective, with avibactam restoring the efficacy of ceftazidime against these difficult-to-treat infections [59]. In the septicemia model, ceftazidime alone exhibited ED50 values of 1578 and 709 mg/kg against the two KPCproducing K. pneumoniae isolates, VA-361 and VA-406 (these isolates also carried TEM-1 and SHV-11, and in the case of VA-406, the SHV-12 b-lactamase). These elevated ED50s were reduced when ceftazidime was combined with avibactam. At a ceftazidime:avibactam ratio of 4:1, the ED50s for VA-361 and VA-406 were reduced to 15.1 and 3.8 mg/kg, respectively. The MICs for ceftazidime-avibactam were 0.25 mg/l against VA-361 and £ 0.06 mg/l for VA-406. In the neutropenic murine thigh infection model, using a constant ratio of 4:1 ceftazidime:avibactam, a > 2 log reduction in CFU was measured at a dose of ‡ 128:32 mg/kg [59]. In another study using a murine model of septicemia, the combination of ceftazidime with avibactam had greater efficacy than ceftazidime alone against ceftazidime-resistant b-lactamase-producing isolates [60]. The ED50 decreased from > 90 mg/kg for ceftazidime alone to < 5 -- 65 mg/kg for the combination. Further, in a comparison of ceftazidimeavibactam, piperacillin-tazobactam and cefotaxime-avibactam at a ratio of 4:1 against eight isolates of Enterobacteriaceae (two AmpC producers and six CTX-M producers) ceftazidime-avibactam was the most effective. ED50 values were 2 -- 27 mg/kg for ceftazidime-avibactam, > 90 mg/kg for piperacillin-tazobactam and 14 -- > 90 mg/kg for cefotaxime-avibactam [60]. Crandon et al. compared the efficacies of ceftazidime and ceftazidime-avibactam using a hollow fiber system and neutropenic and immunocompetent murine thigh infection models [61]. In total, 27 P. aeruginosa isolates (ceftazidime MICs of 8 -- 128 mg/l; ceftazidime-avibactam MICs of 4 -- 32 mg/l) were used in the neutropenic mouse studies and 15 isolates were also evaluated in immunocompetent mice. The murine model used a human simulated dose of 2.0 g ceftazidime and 0.5 g avibactam given as a 2-h infusion q8h. Against all 27 isolates tested, bacterial densities decreased by ‡ 0.5 log for 10 isolates in the case of ceftazidime and for 22 isolates in the case of ceftazidime-avibactam. In immunocompetent animals, ‡ 0.3 log reductions were seen for 10 in the case of ceftazidime and against all 15 isolates for ceftazidime-avibactam. The hollow fiber model used the same simulated dose as the murine model and the ceftazidime-avibactam MICs were 4 mg/l against three P. aeruginosa isolates and 8 mg/l against four isolates (ceftazidime MICs ‡ 32 mg/l). Use of ceftazidime resulted in regrowth of all isolates whereas ceftazidime-avibactam resulted in a static response or better against 4 of 7 isolates. The addition of avibactam to ceftazidime has also been shown to reestablish the activity of ceftazidime against ceftazidime-resistant Enterobacteriaceae in vivo. A total of 18 clinically isolated strains of Enterobacteriaceae, including K. pneumoniae and Enterobacter spp., with MICs for

ceftazidime of between 8 and 32 mg/l were tested in a neutropenic thigh infection model [62]. The model used concentrations simulating a humanized dose of 2.0 g ceftazidime and 0.5 g avibactam given as a 2-h infusion in humans q8h. A total of 94% (17 of 18) of Enterobacteriaceae were resistant to ceftazidime and therapy with ceftazidime failed against 10 of 13 isolates tested. The combination of ceftazidime with avibactam resulted in a reduction in bacterial density of 0.48 to 3.33 log10 CFU against the majority of isolates (13/14, 92.9%). The efficacy of ceftazidime-avibactam has been investigated against P. aeruginosa in a murine lung infection model using a ceftazidime-avibactam dose of 2.0 g ceftazidime and 0.5 g avibactam (given as a 2-h infusion q8h) [63]. The model used P. aeruginosa with ceftazidime-avibactam MICs of £ 64 mg/l and achieved a reduction of > 1 log10 CFU against the majority of isolates with ceftazidime-avibactam MICs of £ 32 mg/l. Ceftazidime-avibactam has been shown to be uninhibited by lung surfactant [64]. Also, using checkerboard studies and species commonly associated with nosocomial pneumonia such as members of the Enterobacteriaceae, P. aeruginosa and S. aureus, ceftazidime-avibactam demonstrated a lack of antagonism with other antibiotics commonly used in the treatment of pneumonia such as tobramycin, levofloxacin, linezolid and vancomycin [64]. Clinical efficacy Phase II clinical trials in cIAIs and cUTIs have been completed and the data have been published by Lucasti et al. and Vasquez et al. [65,66]. The Lucasti et al. study of cIAIs was a prospective, randomized, double-blind, active-controlled trial (ClinicalTrials.gov identifier: NCT00752219) that aimed to evaluate the safety and efficacy of ceftazidime-avibactam plus metronidazole compared with meropenem in hospitalized patients with cIAIs [65]. Patients received either i.v. ceftazidime (2 g) plus avibactam (0.5 g) in combination with metronidazole (0.5 g) or the comparator meropenem (1 g). Each was administered q8h for 5 -- 14 days. A total of 203 patients were randomized (101 in ceftazidime-avibactam arm, 102 in comparator arm). In total, 87 and 90 patients in the ceftazidime-avibactam and meropenem arms were clinically evaluable, respectively, and 68 and 76 patients were microbiologically evaluable, respectively. In this study, both ceftazidime-avibactam and meropenem displayed 100% in vitro susceptibility to the most prominent pathogen, E. coli (n = 105). Susceptibly of the next most common pathogens K. pneumoniae (n = 17) and P. aeruginosa (n = 10) were 82 and 100% and 80 and 90% for ceftazidime-avibactam and meropenem, respectively [65]. There were a total of six pathogens with a ceftazidime-avibactam MIC of >8 mg/l (three K. pneumoniae, two P. aeruginosa, one A. baumannii) and two of these isolates were also resistant to meropenem (one P. aeruginosa and one A. baumannii). Three of these resistant isolates were isolated from patients in 7.2


7

D. P. Nicolau


Table 2. Favorable microbiological response according to pathogens isolated from urinary tract infection patients at the test-of-cure visit (microbiologically evaluable population) in a Phase II clinical trial.

Primary diagnosis Acute pyelonephritis Other cUTI Baseline pathogen E. coli P. aeruginosa C. koseri E. cloacae P. mirabilis Ceftazidime-resistant pathogens E. coli E. cloacae

Ceftazidime-avibactam (n = 27)

Imipenem-cilastatin (n = 35)

Observed difference (95% CI)

N

%

N

%

13/18 6/9

72.2 66.7

14/19 11/16

73.7 68.8

-1.5 (-35.5, 32.6) -2.1 (-49.0, 44.9)

19/25 0/2 1/1 0/0 0/0

76.0 0.0 100 -

23/33 0/0 0/0 1/1 1/1

69.7 100 100

6.3 (-20.1, 32.8)

6/7 0/0

85.7 -

8/10 1/1

80.0 100

Reproduced from Vazquez et al. (Table 4) [66]. 2012, Informa Healthcare. Reproduced with permission of Informa Healthcare. cUTI: Complicated urinary tract infection; n: Number of patients.

the ceftazidime-avibactam treatment arm and three were in the meropenem treatment arm. Favorable microbiological response for ceftazidime-avibactam plus metronidazole or meropenem was 90.4% (47 of 52) and 92.5% (49 of 53), respectively for E. coli and 100% for K. pneumoniae and P. aeruginosa for both treatment groups. Moreover, for those E. coli displaying non-susceptibility to ceftazidime, a favorable microbiologic outcome was observed in 95% (19/20) receiving ceftazidime-avibactam plus metronidazole and 93% (13/14) given meropenem [65]. The cUTI trial was a Phase II, prospective, multicenter, investigator and patient-blinded, randomized comparative study (Clinicaltrials.gov identifier: NCT00690378) that aimed to compare the efficacy and safety of ceftazidimeavibactam and imipenem-cilastatin in hospitalized patients with cUTI due to Gram-negative pathogens [66]. Patients in the study were randomized to receive either i.v. ceftazidime (0.5 g) plus avibactam (0.125 g) q8h or i.v. imipenemcilastatin (0.5 g) q6h. Each was administered for a minimum of 4 days and step-down therapy to oral ciprofloxacin was permitted. A total of 69 patients were randomized to ceftazidime-avibactam and 68 to imipenem-cilastatin. The clinically evaluable population was defined as patients who had clinical evidence of a cUTI and received either at least 7 days of study drug or were classed as an evaluable clinical failure after completing at least 48 h of i.v. study therapy. Patients in the clinically evaluable population also had to have a clinical outcome assessment at the test of cure visit. This group was made up of 28 patients in the ceftazidimeavibactam arm and 36 patients in the imipenem-cilastatin arm. The microbiologically evaluable population was made up of 27 patients in the ceftazidime-avibactam arm and 35 patients in the imipenem-cilastatin arm. The microbiologically evaluable population was defined as patients who had 8

no major protocol violations, had a positive urine culture on enrolment (‡ 105 CFU/mL [>104 CFU/mL if bacteremic]) of at least one pathogen presumed or known to be susceptible to the study antibiotics. Patients in this population also had to have a clinical and microbiological assessment at the test of cure visit (including a quantitative urine culture), and had either received at least 7 days of study therapy (i.v. or i.v. plus oral) or were classified as failures after completing at least 48 h of i.v. therapy. The primary efficacy end-point was a favorable microbiological response at the test-of-cure visit, 5 -- 9 days after the last dose of the study therapy, in the microbiologically evaluable population. Favorable microbiological response was defined as eradication of all uropathogens (reduction of the urine pathogen count from ‡ 105 to < 104 CFU/mL, with no pathogen present in the blood). All microorganisms, including E. coli and P. aeruginosa, collected from patients were susceptible to imipenem. MIC data for ceftazidimeavibactam was not included in the publication; however, 67.2% of E. coli isolates were susceptible to ceftazidime alone. Rates of favorable microbiological response were similar in the two treatment arms, with response rates of 70.4% for patients in the ceftazidime-avibactam arm and 71.4% in the imipenem-cilastatin arm. For UTIs due to E. coli, the response rates were 76.0% for ceftazidime-avibactam and 69.7% for imipenem-cilastatin. Rates of favorable microbiological response were maintained when the infection was due to ceftazidime-resistant pathogens (Table 2). 8.

Safety and tolerability

Ceftazidime is a marketed antibiotic with a long and wellestablished safety profile. Studies have shown that the safety profile of the combination of ceftazidime with avibactam




appears to be consistent with that of ceftazidime alone. In the Phase II clinical trial of cIAIs, rates of adverse events were similar between ceftazidime-avibactam plus metronidazole and the comparator (meropenem) (64.4 and 57.8%, respectively) [65]. The most common adverse events in the ceftazidimeavibactam plus metronidazole group were nausea and vomiting; in the meropenem group, the most common events were elevations in liver enzymes. Serious adverse events were reported in 9 (8.9%) patients in the ceftazidime-avibactam plus metronidazole group (one event, elevated liver enzymes, was considered to be study drug-related) and 11 (10.8%) patients in the meropenem group. There were a total of five deaths in the study (three in the ceftazidime-avibactam plus metronidazole group and two in the meropenem group), none were considered to be related to study drug [65]. In the cUTI trial, rates of adverse events were 67.6% in the ceftazidime-avibactam group and 76.1% in the comparator group (imipenem-cilastatin); the most common adverse events in both treatment arms included constipation, diarrhea, abdominal pain, headache and anxiety as well as injection-/infusion-site reactions [66]. Serious treatment-emergent adverse events were reported for 8.8% (6 of 68) patients in the ceftazidime-avibactam group and 3.0% (2 of 67) patients in the imipenem-cilastatin group. Among these serious treatment-emergent adverse events, a total of four events were considered drug-related: three in the ceftazidimeavibactam group (renal failure, diarrhea, accidental overdose) and one in the imipenem-cilastatin group (increase in serum creatinine level) [66]. 9.

Regulatory affairs

Phase I and Phase II trials of ceftazidime-avibactam have been completed. Two Phase III studies in cUTIs have been completed recently, although results have not yet been published (ClinicalTrials.gov Identifier: NCT01595438, NCT01599806). Three Phase III clinical trials in IAIs have been completed and results of two of these have been reported [67], whereas results are awaited on the third trial (NCT01726023). In addition, the results from a Phase III study of cIAIs and cUTIs caused by ceftazidime-resistant pathogens (NCT01644643) were reported in 2015 [68]. Ceftazidime-avibactam is also being assessed in a Phase III study of hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia (NCT01808092). Ceftazidime-avibactam has US FDA Fast Track designation as it is being developed to treat serious life-threatening infections. Prior to the completion of Phase III studies and availability of Phase III results, the US FDA, based on the data from the Phase II program, gave approval on 25 February 2015 for the use of ceftazidime-avibactam in the treatment of cIAIs (in combination with metronidazole) and cUTIs, including kidney infections (pyelonephritis), in adults who have limited or no alternative treatment options.

10.

Conclusion

The range of b-lactamases and other resistance mechanisms among Gram-negative organisms is complex and, because of these resistance mechanisms, there is an unmet medical need in the treatment of Gram-negative infections including cIAIs and cUTIs. In recent years there has been renewed interest in antibiotic-b-lactamase inhibitor combinations to meet that need. The addition of avibactam to ceftazidime improves its in vitro activity against resistant Enterobacteriaceae and P. aeruginosa. In vitro and animal infection model data along with microbiology data from Phase II clinical trials of cIAIs and cUTIs demonstrate that ceftazidime-avibactam is active against common ceftazidime-susceptible and -resistant Gram-negative organisms including Enterobacteriaceae and P. aeruginosa and may make a valuable treatment option for infections caused by many multidrug-resistant Gram-negative pathogens. The full publication of recently completed ceftazidime-avibactam Phase III clinical trials in cIAIs and cUTIs is eagerly awaited. 11.

Expert opinion

The increasing problem of resistance in common Gramnegative pathogens such as the Enterobacteriaceae and P. aeruginosa has severely reduced the effective armamentarium. In Enterobacteriaceae, the complexity of b-lactamase-based resistance is being met head-on by resurgence in the development of b-lactamase inhibitor combinations. These novel compounds show promising activity against these increasingly multidrug-resistant pathogens and large Phase III clinical trial data are eagerly awaited to define both their efficacy and safety profiles. In the case of ceftazidime-avibactam, the evidence base includes three Phase III clinical trials that have been completed and reported in conference proceedings [67,68] and is set to widen with a further three Phase III trials that have been completed but not yet reported (NCT01595438, NCT 01599806 and NCT01726023). One Phase III trial is also ongoing (NCT 01808092). Avibactam has a spectrum of activity covering class A, class C and some class D enzymes. Importantly the activity of avibactam also includes carbapenemases such as the KPC and OXA-48. The combination of avibactam with the cephalosporin ceftazidime is attractive, given the antimicrobial spectrum of activity and the low toxicity of the cephalosporin class. Ceftazidime-avibactam has demonstrated potent activity in in vitro and in vivo murine models of infection against KPCbased resistance. However, the lack of a suitable comparator means it is unlikely that any clinical trials of this compound, in the treatment of infection due to KPC-producing organisms, will be undertaken in the near future. As such, experience with this compound will likely be acquired in those patients who have been defined as a failure on conventional


9


D. P. Nicolau

therapies (i.e., salvage therapy). Unfortunately this reserved approach will limit the potential clinical utility of this agent to bolster outcomes as an early effective empiric therapy in the very patients who are at increased risk of infection-related morbidity and mortality. Although new therapies for enzyme-mediated resistance are becoming available for clinical use, a major concern for the treatment of the infected patient is the lack of development of agents with activity against class B metallo-b-lactamases. Organisms containing these enzymes, such as NDM, have the capacity to spread rapidly and agents active against them are urgently needed. P. aeruginosa continues to be a pathogen that is identified as possessing resistance to multiple classes of antimicrobials. In addition to providing an effective treatment option against enzyme-mediated resistance in Enterobacteriaceae, agents such as ceftolozane-tazobactam and ceftazidime-avibactam appear to have enhanced antipseudomonal activity and thus may be useful alternative therapies. However, to fully understand the clinical value of these agents for P. aeruginosa-based infections, additional clinical trials must be undertaken in the intensive care setting where this pathogen is a prominent epidemiologic entity in infections such as nosocomial pneumonia. Although some of these new b-lactam/b-lactamase inhibitors may provide additional treatment options for P. aeruginosa-based infections, another major deficit in antimicrobial drug development is the lack of agents with potent activity against Acinetobacter species, Stenotrophomonas maltophilia Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Acknowledgments Editorial assistance was provided by Micron Research Ltd, Ely, UK. As part of the review process, the article was sent to AstraZeneca to review the data accuracy.

Declaration of interests The author has acted as investigator and speaker for AstraZeneca and Forest Laboratories, LLC. The author has no other 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 apart from those disclosed. Editorial assistance was utilized in the production of this manuscript and funding was provided by Forest Laboratories, LLC.

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of a randomized, double-blind, Phase II trial. J Antimicrob Chemother 2013;68:1183--92 Presents Phase II clinical trial data on the use of ceftazidime-avibactam in complicated intra-abdominal infections. Vazquez JA, Gonza´lez Patza´n LD, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenemcilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigatorblinded, randomized study. Curr Med Res Opin 2012;28:1921--31 Presents Phase II clinical trial data on the use of ceftazidime-avibactam in complication urinary tract infections.

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Clinical Microbiology and Infectious Diseases; 25-28 April, 2015; Copenhagen, Denmark 69.

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Affiliation David P Nicolau PharmD FCCP FIDSA Center for Anti-Infective Research and Development Hartford Hospital, 80 Seymour Street, Hartford, CT 06102-5037, USA Tel: +1 860 972 3941; Fax: +1 860 545 3992; E-mail: [email protected]

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A new ASPECT for complicated urinary tract infections.

Cefodizime given once daily for the treatment of upper urinary tract infections and complicated lower urinary tract infections.

A comparative study on aztreonam, ceftazidime and amikacin in the treatment of complicated urinary tract infections.

Drugs for urinary tract infections.

tazobactam for the treatment of complicated urinary tract and intra-abdominal infections.

Ceftazidime-Avibactam (Avycaz): For the Treatment of Complicated Intra-Abdominal and Urinary Tract Infections.

Critical evaluation of ceftolozane-tazobactam for complicated urinary tract and intra-abdominal infections.

Oral temafloxacin compared to norfloxacin for the treatment of complicated urinary tract infections.

Cefoxitin sodium in complicated urinary tract infection.

Comparison of netilmicin and amikacin in treatment of complicated urinary tract infections.

[Urinary tract infections].

Pharmacokinetics and bioavailability of intravenous-to-oral enoxacin in elderly patients with complicated urinary tract infections.

Urinary tract infections.

[urinary tract infections].

Comparison of tobramycin and gentamicin in the treatment of complicated urinary tract infections.

Open, randomized comparison of pefloxacin and cefotaxime in the treatment of complicated urinary tract infections.

Comparison of i.v. ofloxacin and piperacillin in the treatment of complicated urinary tract infections.

Hyperammonemia in Urinary Tract Infections.

Urinary tract infections in pregnancy.

Urinary tract infections in adults.

Non-Antibiotic Prophylaxis for Urinary Tract Infections.

Suggestions for treating recurrent urinary tract infections.

Antimicrobial treatment for urinary tract infections.

Cross-sectional imaging of complicated urinary infections affecting the lower tract and male genital organs.