Antibacterials in the pipeline and perspectives for the near future

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ScienceDirect Antibacterials in the pipeline and perspectives for the near future Ian M Gould1,2, Chathuri Gunasekera1,3 and Ali Khan1 Antimicrobial resistance is a global threat to the management of infections in our patients. Sound stewardship of antibacterial agents at our disposal must be accompanied by a concerted effort to develop new agents to bolster our armamentarium. This review will cover the latest antibiotics that have come through the pipeline and the role they can play in the management of infections that are increasingly difficult to treat due to resistance mechanisms. Addresses 1 Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB25 2ZN, United Kingdom 2 University of Aberdeen, Aberdeen, United Kingdom 3 University of Colombo, Colombo, Sri Lanka Corresponding author: Gunasekera, Chathuri ([email protected])

Current Opinion in Pharmacology 2019, 48:69–75 This review comes from a themed issue on Anti-infectives Edited by Sergio Sa´nchez Esquivel and Arnold L Demain

https://doi.org/10.1016/j.coph.2019.05.001 1471-4892/ã 2019 Elsevier Ltd. All rights reserved.

Introduction With the worrying rise of antimicrobial resistance globally, the need for developing new antibiotics is more pressing than ever. In order to remain ahead of the resistance curve, combining broad-spectrum antibiotics with enzyme inhibitors such as Diazabicyclooctanes (DBOs) have offered a route to overcoming resistance mechanisms exhibited primarily by carbapenemase-producing Gram-negative pathogens. Novel formulations of existing classes of antibiotics have proven to be another avenue for developing drugs that can overcome resistance pathogens, including methicillin resistant Staphylococcus aureus (MRSA). In addition, there are other miscellaneous novel antibacterials. In this review, we will be looking in to most of the very recently approved antibacterials, many in late stage of development and a few in pre-clinical stages of development, all deemed to be important in view of clinical use. However, this review will only be based on information obtained from literature published before 29.01.2019- the date of the initial submission of the www.sciencedirect.com

index manuscript. While the importance of sound antimicrobial stewardship is necessary in the battle against growing resistance, pharmaceutical companies need to be encouraged to invest in the antibiotic pipelines.

Combination antibiotics The struggle to discover and develop new classes of antibiotics has led to the reinvention of antibiotics already available to us. Combining broad-spectrum cephalosporins, carbapenems and beta-lactams with enzyme inhibitors in order to surmount resistance mechanisms has demonstrated real potential in the battle against antibiotic resistance. Ceftolozane-tazobactam

Ceftolozane-tazobactam is a new antibiotic approved by the FDA in December 2014 which is a cephalosporinbeta lactamase inhibitor combination. It is currently licensed for use in complicated UTI (cUTI), including acute pyelonephritis (PN) and complicated intra-abdominal infections (cIAI) [1]. Ceftolozane, being a cephalosporin is bactericidal by binding to penicillin binding proteins (PBPs) and thereby inhibiting cell wall synthesis. Combination of this drug with the beta-lactamase inhibitor tazobactam has demonstrated activity against multidrug resistant (MDR) Gram-negative pathogens. Tazobactam has a lesser affinity to PBPs but is an irreversible inhibitor of some beta lactamases. The organisms it is active against include Enterobacter cloacae, Escherichia coli, Klebsiella pneumonia, Klebsiella oxytoca, Proteus mirabilis, Pseudomonas aeruginosa, Bacteroides fragilis, Streptococcus anginosus, Streptococcus constellatus and Streptococcus salivarius [1]. In management of cIAI metronidazole should be added for anaerobic coverage [2]. Ceftolozane-tazobactam has proven in-vitro activity against producers of beta lactamases such as TEM, SHV and CTX-M but does not have activity against producers of carbapenemases KPC and MBL [1]. In a US study involving in-vitro surveillance of Gram-negative pathogens causing cUTI, ceftolozane-tazobactam was found to be more cost-effective than piperacillin-tazobactam [3]. Ceftazidime-avibactam

Ceftazidime-avibactam is a cephalosporin-beta-lactamase inhibitor combination drug which was approved recently for the same indications as ceftolozane-tazobactam. The beta-lactamase inhibitor avibactam is a diazabicyclooctane (DBO). DBOs are compounds which have cyclic boronic derivatives that inhibit beta-lactamase enzymes produced by resistant bacteria. The five-membered ring Current Opinion in Pharmacology 2019, 48:69–75

70 Anti-infectives

of the DBOs bears an amide ring that inhibits the active serine site of the beta-lactamase via a carbamylation reaction. DBOs potently inhibit Class A and C betalactamases which include KPC and others not inhibited by currently available beta-lactamase inhibitors which are beta lactams themselves (e.g. tazobactam) [4,5]. Avibactam is a DBO which has the broadest spectrum as a betalactamase inhibitor among the currently available ones [6]. Unfortunately, resistance to ceftazidime-avibactam has emerged [7]. Ceftazidime-avibactam was approved for use in cUTI and cIAI, and is active against Gram-negative bacteria comparable with ceftolozane-tazobactam but with efficacy against Providentia and Citrobacter spp. in addition. The addition of avibactam to ceftazidime protects the drug from beta-lactamase enzymes including TEM, SHV, CTX-M, KPC, AmpC and some OXA types. However, it does not offer significant activity against the MBL enzymes [1]. The enzyme OXA-48 can also be overcome by this combination antibiotic, and this may be attributable to both ceftazidime stability and inhibition by avibactam [8]. Meropenem-vaborbactam

In August 2017, meropenem-vaborbactam became the first carbapenem antibiotic combined with a beta-lactamase inhibitor to be approved via the FDA Fast Track programme. This was a result of the Generating Antibiotic Incentives Now (GAIN) act, after it was designated the status of a ‘qualified infectious disease product’. It is licensed for adults with cUTI including pyelonephritis caused by E. coli, K. pneumoniae and E. cloacae complex [9]. Vaborbactam (RPX7009) is a DBO and the drug has demonstrated in-vitro activity against nearly 99% of KPCproducing Enterobacteriaceae. Phase III clinical trials have shown its clinical efficacy, but there is no activity against MBL and OXA-48 [10,11]. New combinations of antibiotics coming through the development pipeline include aztreonam-avibactam, cefepime-zidebactam, cefepime-VNRX-5133, meropenem-nacubactam and ceftaroline-avibactam. Aztreonam-avibactam

Aztreonam is a monobactam which can be hydrolysed by many serine beta-lactamases (e.g. ESBL, KPC) but not MBLs produced by Gram-negative bacteria. The DBO avibactam, as mentioned earlier, is a potent beta-lactamase inhibitor. Combining the two has demonstrated activity against ESBL, KPC, AmpC and MBL beta-lactamases. Though the in-vitro activity of this combination was demonstrated at the beginning of this decade, clinical trials have been lagging for years [6,12]. Cefepime-zidebactam

The DBO zidebactam is a compound that binds to PBP2 of the bacterial cell wall. Although it does not inhibit Current Opinion in Pharmacology 2019, 48:69–75

MBL beta-lactamases, it demonstrates synergy with cefepime against some MBL producers through an enhancereffect, facilitating attack on different PBPs. As of August 2016, phase I clinical studies have been completed [13,14]. Meropenem-nacubactam

Meropenem-nacubactam has demonstrated in-vitro activity comparable to cefepime-zidebactam. Nacubactam is a DBO which demonstrates antibacterial activity via an enhancer effect with meropenem. It is, however, slightly less active against P. aeruginosa [6]. This drug is also ineffective against MBL beta-lactamases. Animal studies of the drug have shown promise in this as a potential new drug for cUTI caused by resistant Gram-negative bacteria [5]. Meropenem-nacubactam has not yet advanced to clinical trials. Cefepime-VNRX-5133

Cefepime-VNRX-5133 is a cephalosporin/boronate combination. Boronate VNRX-5133 is a novel, broad-spectrum and potent beta-lactamase inhibitor. This combination antibiotic has demonstrated enhancement of cefepime in in-vitro and preclinical in-vivo studies. Unlike vaborbactam, this boronate has shown good activity against MBLs and OXA-48 beta lactamases [6]. Ceftaroline-avibactam

Ceftaroline is a broad-spectrum cephalosporin which has anti-MRSA activity. It has been combined with the DBO avibactam to produce an antibiotic which can overcome Enterobacteriaceae which produce extended-spectrum beta-lactamases (ESBL). In-vitro studies have demonstrated good activity against ESBL (CTX-M types), KPC and AmpC [15]. Successful phase II trials have been conducted [1]. Table 1 summarises the combination antibiotics described above, along with a perspective of their developmental stages.

New variants of classic antibiotics Further development of classic antibiotic classes has led to the discovery of entirely new drugs that confer benefit through activity against resistant bacteria. Examples of new agents described below include those originating from the beta-lactam (cephalosporin, monobactam), lipoglycopeptide, quinolone, tetracycline and aminoglycoside classes of antibiotics. Novel cephalosporins

Cefiderocol (S-649266) is the first siderophore-cephalosporin that has developed to late stage development. It chelates free iron and cefiderocol-iron complexes are actively transported across the outer membrane via the bacterial iron-transport system. It is stable against all the beta-lactamases, including carbapenemases, and www.sciencedirect.com

Newer antibiotics in the pipeline Gould, Gunasekera and Khan 71

Table 1 Novel combination antibiotics in pipeline Drug

Class/classes

Company

Phase of trial/approval

Indications

Ceftolozane/tazobactam

Cephalosporin-beta lactamase inhibitor (nonDBO) combination

Merck pharmaceuticals (Zerbaxa1)

cUTI including acute PN, cIAI

Ceftazidime/avibactam

Cephalosporin-beta lactamase inhibitor (DBO) combination

Allergan (Avycaz1) Pfizer (Zavicefta1)

Meropenem/vaborbactam

Carbapenem-DBO

The Medicines Company (Vabomere1)

Aztreonam/avibactam

Monobactam-DBO

Cefepime/zidebactam Meropenem/nacubactam Cefepime/VNRX-5133 Ceftaroline/avibactam

Cephalosporin-DBO Carbapenem/DBO Cephalosporin-boronate Cephalosporin-DBO

Allergan/ AztraZeneca-Pfizer Wockhardt Roche VenatoRx Allergan/ AztraZeneca-Pfizer

Approved by FDA in December 2014 Approved by EMA in July 2015 Approved by FDA in February 2015 Approved by EMA in June 2016 Approved by FDA Fast Track in August 2017 Approved by EMA in November 2018 Phase III Phase 1 Pre-clinical phase Pre-clinical phase Phase II

GN bacterial infections GN bacterial infections GN bacterial infections GN, GP (including MRSA) bacterial infections

cUTI including acute PN, cIAI, HAP and VAP caused by GN bacteria cUTI including acute PN, cIAI, HAP, VAP

GN bacterial infections

FDA = US Food and Drug Administration, EMA = European Medicines Agency, GN = Gram negative, GP = Gram positive.

hence overcomes the 3 main mechanisms of antibiotic resistance used by Gram-negative bacteria against betalactams as shown by in-vitro and in-vivo studies in animal models. This has led to it being described as the ‘Trojan Horse antibiotic’. Unfortunately, it does not possess activity against Gram-positive or anaerobic organisms [16]. A recent phase II non-inferiority trial demonstrated superiority to imipenem-cilastatin in a post-hoc analysis. This drug is awaiting the FDA’s fast track approval [16]. Novel monobactams

LYS-228 is a newer monobactam which is intrinsically stable to MBL beta-lactamases and also engineered to be stable to ESBLs, AmpC, OXA-48 like and KPC enzymes. However, no activity against P. aeruginosa is demonstrated. This novel drug is still in pre-clinical stages of its development [17,18]. Dalbavancin and oritavancin

Vancomycin has been a mainstay in the arsenal against Gram-positive organisms; however, vancomycin-intermediate and resistant strains of S. aureus and Enterococci demonstrate the need for new and improved glycopeptide antibiotics. Dalbavancin and Oritavancin are lipoglycopeptide antibiotics that have been around for a few years now, and their long half-lives have provided particular benefit in the treatment of infections in the outpatient setting [19]. These agents demonstrate activity against MRSA, coagulase-negative staphylococci and non-susceptible vancomycin-resistant daptomycin enterococci (VRE) [20]. Dalbavancin is inactive against VanA enterococci, but active against the VanB phenotype, while oritavancin has potent activity against both www.sciencedirect.com

vancomycin-resistant S. aureus (VRSA) and VanA-type VRE [21]. Novel quinolones

There are a handful of novel quinolones being developed which are purported to offer improved efficacy over previous generations of quinolones, while supposedly boasting better tolerability and safety profile. Delafloxacin was approved in 2017 by the FDA for use in acute bacterial skin and skin structure infections (ABSSSI) and is available orally and intravenously. It has demonstrated non-inferiority to a vancomycin/aztreonam combination therapy, with an apparent favourable adverse event profile [22]. It has also shown activity against quinolone nonsusceptible isolates, including MRSA, and is therefore a new option for resistant infections [23]. Nemonoxacin is a non-fluorinated quinolone shown to have excellent invitro activity against most pathogens implicated in community acquired pneumonia (CAP), with efficacy and safety comparable to levofloxacin in that clinical context [24]. It also exhibits potent activity against MRSA and sexually transmitted diseases such as Chlamydia trachomatis and Neisseria gonorhhoeae [25]. Zabofloxacin is a quinolone that demonstrates non-inferiority to moxifloxacin in treatment of lower respiratory tract infection (LRTI) and is available orally and intravenously [26]. It is not active against MRSA or P. aeruginosa [27]. Finafloxacin is approved in the USA for treatment of otitis externa caused by S. aureus and P. aeruginosa, while showing potential promise for the management of ABSSSI, UTI, IAI and tuberculosis (TB) [28]. Lastly, avarafloxacin has shown comparable efficacy to linezolid in treatment of ABSSSI, and moxifloxacin in CAP [29]. Current Opinion in Pharmacology 2019, 48:69–75

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Novel tetracyclines

Omadacycline, a novel tetracycline, was approved in October 2018 by FDA. It was developed and studied for treatment of ABSSSI and CAP, as well as UTI. It has activity against MRSA, including strains resistant to traditional tetracyclines, macrolides and lincosamides and also shows in-vitro activity against VRE and Gram-negative organisms, making it a promising new agent for a multitude of community-acquired infections [30]. Approved in 2018, Eravacycline is a novel fluorocycline antibiotic being developed in both oral and intravenous preparations, which is active against Gram-positive and Gram-negative bacteria. This includes MDR variants such as MRSA, MDR Acinetobacter baumannii and Gram-negative bacteria expressing ESBL and KPC enzymes [31]. Indeed, at 24 hours, exposures of eravacycline equivalent to 1 g twice daily in a human, demonstrated antibacterial activity against MRSA [32]. Eravacycline has also shown promise in the treatment of complicated intra-abdominal infections, with the IGNITE 1 trial showing it to be noninferior to ertapenem [33]. It did not meet non-inferiority criteria for the treatment of cUTI, and this may be related to use of a lower dose compared to that administered in the cIAI trial [31]. Novel aminoglycosides

Aminoglycosides are broad spectrum antibiotics with potent activity mediated through inhibition of protein synthesis. This class of antibiotic was a fundamental antibacterial weapon till the 1980s, which saw the introduction of third-generation cephalosporins, carbapenems and fluoroquinolones offer less toxic and broader spectrums of coverage. In recent times, with the rise of resistance to these antibiotic classes, the aminoglycosides have provided a route towards tackling MDR pathogens [34]. The novel aminoglycoside plazomicin demonstrates broad spectrum activity against aerobic Gram-negative bacteria including ESBL and carbapenem-resistant Enterobacteriaceae as well as overcoming organisms that possess aminoglycoside-modifying enzymes (AME) [35]. It is not, however, active against the NDM-1 producing isolates due to ribosomal methyltransferases [31]. Plazomicin received FDA approval for the management of complicated UTI in 2018, but not in the context of bacteraemia where more data are needed. Just as with other aminoglycosides, plazomicin has a similar sideeffect profile, including nephrotoxicity, ototoxicity, neuromuscular blockade and foetal harm, and it is advised that therapeutic drug monitoring is used in patients with renal impairment [36]. Arbekacin is another aminoglycoside developed to overcome the action of AMEs and is a semi-synthetic derivative of kanamycin [37]. It is effective against strains of MRSA that possess AMEs which usually confer resistance to aminoglycosides [34]. In Japan it is widely utilised in the treatment of MRSA infection, including sepsis and pneumonia [38]. Current Opinion in Pharmacology 2019, 48:69–75

Arbekacin has also been studied as an inhaled option in management of VAP caused by P. aeruginosa [39]. Again, it shares the side effect profile and potential toxicities associated with other aminoglycosides. Novel macrolides

Solithromycin is a new fluoroketolide fourth generation macrolide drug which inhibits bacterial protein synthesis at translation level as it binds to the 23S ribosomal RNA. Phase II and III trials have been conducted and shown that it is non-inferior to moxifloxacin and active against common agents causing CAP. However, FDA or EMA approval is yet to be obtained after further trials on safety, particularly with regard to hepatic involvement [40]. Table 2 summarises the new variants of classic antibiotics mentioned above, with a perspective of their developmental stages.

Other potential antibiotics Lefamulin

The pleuromutilin class of antibiotic was first produced in the 1950s and has been utilised in veterinary medicine in the form of tiamulin and valnemulin. Retapamulin was the first of this class approved for use in humans in the treatment of impetigo and is only available in topical formulation [41]. Lefamulin is a semi-synthetic pleuromutilin antibiotic that has been granted Qualified Infectious Disease Product and Fast Track designation by the FDA for the management of CAP and would be available as both oral and intravenous formulations [42]. It inhibits protein synthesis by binding to the 50S ribosomal subunit, and is active against MRSA, VRE and penicillinnon-susceptible Streptococcus pneumoniae [43]. Lefamulin has shown microbiological and clinical efficacy comparable to vancomycin in the treatment of ABSSSI [44]. LEAP 1 and LEAP 2 are a couple of phase III noninferiority trials that have shown lefamulin to be as effective as moxifloxacin +/ linezolid in the management of bacterial CAP [45,46]. Iclaprim

Iclaprim is a bacterial dihydrofolate reductase inhibitor that is not yet approved but shows promise in studies of its use against ABSSSI and nosocomial pneumonia caused by Gram-positive bacteria including MRSA, while also demonstrating coverage of Gram-negative bacteria such as Haemophilus influenzae and Moraxella catarrhalis [47]. Fatty acid synthesis inhibitors

Inhibition of fatty acid synthesis has provided an avenue for the development of new antibiotics. Debio 1452 is a Fab1 inhibitor that has demonstrated significant activity against staphylococcal pathogens, including MRSA strains, and is being developed for treatment of ABSSSI and osteomyelitis [48]. CG400549 is another Fab1 inhibitor under development for use against staphylococcal www.sciencedirect.com

Newer antibiotics in the pipeline Gould, Gunasekera and Khan 73

Table 2 Novel variants of classic antibiotics in pipeline Drug

Class/classes

Company

Phase of trial/approval

Indications

Cefiderocol

Catechol cephalosporin

Shionogi

cUTI by GN bacteria

LYS-228 Dalbavancin

Monobactam Lipoglycopeptide

Novartis Allergan/Actavis

Oritavancin

Lipoglycopeptide

Delafloxacin

Fluoroquinolone

Developed by Eli Lilly initially now rights with The Medicines Company Melinta

Phase II Impending FDA Fast Track approval Pre-clinical phase FDA approval May 2014, EMA approval March 2015 FDA approval August 2014, EMA approval January 2015

Nemonoxacin

Non-fluorinated quinolone

TaiGen

Zabofloxacin

Fluoroquinolone

Dong Wha

FDA approval June 2017, EMA product-specific waiver approved in April 2018 Phase III results awaited; FDA granted QIDP/fast track approval Awaiting phase III trials

Finafloxacin

Fluoroquinolone

MerLion/Alcon

FDA approval December 2014

Avarofloxacin

Fluoroquinolone

Awaiting phase III trials

Omadacycline Eravacycline

Tetracycline Fluorocycline

PPD, Inc initially, currently rights acquired by Actavis Paratek Tetraphase

Plazomicin Arbekacin

Aminoglycoside Aminoglycoside

Archaogen Meiji Seika

Solithromycin

Macrolide (fluoroketolide)

Cempra

FDA approval October 2018 FDA approval August 2018, EMA approval July 2018 FDA approval June 2018 Approved for systemic use in Japan; FDA: In clinical phase trials Awaiting further phase III trials

GN bacterial infections ABSSSI, including MRSA ABSSSI, including MRSA, VRE

ABSSSI, including MRSA

CAP, ABSSSI, including MRSA

GP and GN infections, excluding MRSA, Enterocococcus and Pseudomonas Acute otitis externa caused by Pseudomonas and S. aureus GP and GN bacteria, including Neisseria gonorrhoeae, MRSA, drug-resistant S. pneumoniae ABSSSI, CAP, including MRSA cIAI cUTI MRSA, pneumonia, MDR GN bacteria CAP

FDA = US Food and Drug Administration, EMA = European Medicines Agency, GN = Gram negative, GP = Gram positive.

infections and is being studied currently for use in management of ABSSSI caused by MRSA [49]. Topoisomerase inhibitors

Zoliflodacin is an experimental drug which inhibits bacterial topoisomerases which has demonstrated its efficacy in inhibition of Neisseria gonorrhoeae [50]. Phase II trials of its use as a single dose treatment for uncomplicated urogenital and rectal gonorrhoea have shown promise [50]. Novel peptidomimetics

Murepavadin (POL7080) is a novel peptidomimetic drug targeting outer membrane protein of P. aeruginosa. It is a promising drug for treatment of HAP and VAP caused by MDR P. aeruginosa infections currently in phase III trials and the first in its class to be developed [51].

Conclusion Antimicrobial resistance is inevitable. Bacteria will continue to evolve new resistance mechanisms to counteract available treatments. Although it may come across as www.sciencedirect.com

scare-mongering, the global threat of antibiotic resistance truly does run the risk throwing the world back into a preantibiotic era where routine surgeries and minor infections will once again become life threatening. In order to tackle this growing problem, sound antimicrobial stewardship to protect our present arsenal of drugs must also be combined with research and development of new antibiotics. The frightening scarcity of new antibiotics has largely been driven by a lack of financial incentives for drug companies in this area of pharmaceutical development. Antibiotics are generally used for a short period of time, meaning the financial return they provide fails to cover for the cost of their production. In its recently published five-year national action plan for tackling antimicrobial resistance, the UK government acknowledges the poor commercial returns on offer from developing new antibiotics, despite the massive advantage they would offer to society at large. This plan suggests a ‘pay or play’ strategy which would entail imposing an antibiotic investment charge on the pharmaceutical sector, so that companies would choose to either pay a charge or invest in antimicrobial resistance research and Current Opinion in Pharmacology 2019, 48:69–75

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development. Moreover, ‘de-linking’ the price paid for antimicrobials from the volumes sold may go some way to encouraging investment into new therapies. Global cooperation and collaboration, combined with significant political will, must be encouraged if we are to combat the problem of antimicrobial resistance. Without this, stewardship measures to preserve our current collection of drugs will simply delay an inevitable doomsday scenario where infectious diseases become incurable.

Conflicts of interest statement Professor Ian M Gould: Consultancy/lecture fees received from the following companies: MSD, AstraZeneca, Bayer, Pfizer, Basilea. Lecture fees received from the following companies: Sanofi, Norma Hellas, Xellia. Consultancy fees received from the following companies: Achaogen, Gilead. Dr Chathuri Gunasekera — none. Dr Ali Khan — none.

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