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Game Changers: New β‑Lactamase Inhibitor Combinations Targeting Antibiotic Resistance in Gram-Negative Bacteria Karen Bush* Biology Department, Indiana University Bloomington, 1001 E. Third Street, Bloomington, Indiana 47405, United States ABSTRACT: Recent regulatory approvals for the β-lactam inhibitor combinations of ceftazidime−avibactam and meropenem− vaborbactam have provided two novel therapeutic options for the treatment of multidrug-resistant infections caused by Gramnegative bacteria. Most importantly, these combination agents have satisfied an important medical need related to antibioticresistant Klebsiella pneumoniae that produce serine carbapenemases, especially the Klebsiella pneumoniae carbapenemase (KPC) enzymes. Both combinations contain non-β-lactam β-lactamase inhibitors of novel chemical classes not previously developed as antibacterial agents, the diazabicyclooctanes and cyclic boronic acid derivatives. Their rapid development and approval programs have spurred a number of similar inhibitor combinations that will need to differentiate themselves for commercial success. Gaps still exist for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa, Acinetobacter spp., and metallo-βlactamase-producing pathogens. Overall, the new β-lactamase inhibitor combinations have infused new life into the search for new antibacterial agents to treat multidrug-resistant bacteria.
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had become drugs of choice in hospitals struggling with ESBLs and cephalosporinases. Traditional BLIs including clavulanic acid and tazobactam could inhibit all these enzymes in isolated enzymes assays but were ineffective against intact bacteria that almost always produced multiple β-lactamases of different functional groups.5 Antibiotics in other structural classes were not reliably active against pathogens producing these enzymes, due to plasmid-encoded resistance determinants that traveled on the same genetic elements as the carbapenemase genes. The only efficacious agents for many patients infected with carbapenem-producing Enterobacteriaceae (CPE) were often colistin and tigecycline, drugs with unwanted side effects and a propensity to select for further resistance.6 Unfortunately, the emergence of CPE occurred at a time when the pharmaceutical industry was focused on treating methicillin-resistant Staphylococcus aureus (MRSA) and had diminished interest in Gram-negative infections. It was also a time when anti-infective research was falling out of favor in many large pharmaceutical companies, so that the appearance of a novel non-β-lactam BLI inhibitor was almost unnoticed. However, continued testing of avibactam with additional AmpC and KPC-producing pathogens demonstrated a broader range of inhibitory activity than originally realized. The DBO was effective in vitro in inhibiting serine β-lactamases from all molecular classes, including the class A ESBLs and KPCs, the class C plasmid-encoded AmpC cephalosporinases, and some class D OXA carbapenemases, but was not inhibitory against the less prevalent metallo-β-lactamases (MBLs), carbapenemases with zinc in the active site.7 Unlike the suicide inactivators clavulanic acid and tazobactam, avibactam was shown to be a tight-binding, long-lived, competitive inhibitor for most serine β-lactamases, thus releasing active inhibitor after binding to the target enzymes; only the KPC carbapenemases
any have reported that drug discovery efforts in the antimicrobial area of research over the past 15 years have been disastrous, and as a result, the medical community is lacking new drugs in the face of ever-increasing antibiotic resistance.1,2 This assertion is only partly accurate. It is true that successes have been limited when only drugs with novel mechanisms are considered. However, a notable success story can be told by the multiple companies that have capitalized upon a resurgence in interest in β-lactamase inhibitors (BLIs), beginning with an almost ignored set of BLIs first identified in the patent literature in 2003.3 At that time, BLI combinations had been used in clinical practice for 20 years. Inhibitors such as the clavam clavulanic acid (1) and the penicillanic acid sulfone tazobactam (2) (see Figure 1) served to protect companion penicillins from a limited set of deleterious βlactamases located in the periplasmic space of Gram-negative bacteria, thereby allowing the antibacterial agents to inactivate penicillin-binding proteins (PBPs) on the inner membrane, leading to cell death (Figure 2). The novel, non-β-lactam diazabicyclooctanes (DBOs), with avibactam (AVE1330A/ NXL104) (3) as the prototypical DBO (Figure 1), were initially regarded as providing incremental improvements in inhibitory activity compared to clavulanic acid and tazobactam when tested against the class A TEM-1 penicillinase and the P99 AmpC cephalosporinase.3 The reported activity against these classical β-lactamases did not inspire much enthusiasm among anti-infective research groups who regarded the inhibitor primarily as the starting point for a novel structural class of BLIs. However, the initial testing did not include studies with the rampant extended-spectrum β-lactamases (ESBLs) that were being reported, nor was the inhibitor tested against the newly emerging carbapenemases in multidrugresistant Gram-negative bacteria that were just beginning to cause major epidemics due to the production of the KPC (Klebsiella pneumoniae carbapenemase) enzymes.4 At the time, carbapenemase-producing bacteria were becoming prevalent in nosocomial settings; the carbapenems © XXXX American Chemical Society
Received: November 22, 2017
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DOI: 10.1021/acsinfecdis.7b00243 ACS Infect. Dis. XXXX, XXX, XXX−XXX
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Figure 1. Structures of β-lactamase inhibitors.
Figure 2. In Gram-negative bacteria, access to penicillin-binding proteins (PBPs) by β-lactam antibiotics is blocked by β-lactamases (Bla) that inactivate the antibiotics in transit to their killing targets. Addition of a β-lactamase inhibitor (BLI) prevents the β-lactamase from destroying the antibiotic that can proceed to its PBP target, resulting in cell death.
combined with a companion β-lactam can select for resistance to the combination in a single step.8 In addition to the DBOs, a second family of novel βlactamase inhibitors has emerged, on the basis of a set of classical cyclic boronic acid-derived molecules studied as basic research tools for more than the past 35 years.9 Vaborbactam (5, Figure 1), the first of these inhibitors to progress to late stage clinical development, binds covalently to the active site serine in many serine β-lactamases, most notably the class A ESBLs and KPC enzymes and the class C cephalosporinases,9 thus providing a fourth structural class of BLIs, beyond clavulanic acid, the penicillanic acid sulfones, and the DBOs. This molecular diversity is encouraging, as it is less likely for inhibitors in the different classes to be cross-resistant due to mutations in the target enzymes. In August 2017, the first boronic acid inhibitor combination, vaborbactam combined with the carbapenem meropenem, was approved for clinical use by the FDA. Because of the medical need to treat CPE, both the avibactam and vaborbactam combinations were given expedited drug approvals on the basis of limited clinical data. Few patients infected with KPC-producing Enterobacteriaceae were treated with either of these combinations during their pivotal registration trials on which approvals were based. However, in a retrospective, nonrandomized study from the University of Pittsburgh Medical Center, patients with carbapenem-resistant K. pneumoniae bacteremia who were treated with the ceftazidime−avibactam combination had higher clinical success rates (P = 0.006) and survival (P = 0.01) compared to patients treated with other regimens. 10 In addition, the triple combination of ceftazidime−avibactam together with aztreonam has been used successfully to treat a patient infected with an MBL-producing Stenotrophomonas maltophilia.11
could bind covalently and then hydrolyze the inhibitor, following a long residence time on the enzyme. The combination of avibactam with ceftazidime was first approved by the FDA in 2015 and then by the EMA in 2016, with the expectation that it would be used extensively to treat KPCproducing bacteria. As an indication of the importance of this agent, the FDA approved the combination on the basis of two Phase 2 studies in complicated urinary tract infections and complicated intraabdominal infections, an unprecedented action in recent antibacterial history. The initial labeling restriction, for use in patients who had limited or no alternative treatment options, was lifted by the FDA a year later, after Phase 3 data for the same indications were reviewed. Although this combination promises effective therapy against most CPE, excluding MBL-producing pathogens, the combination of avibactam with aztreonam has been shown in vitro to be inhibitory against many clinical isolates that produce MBLs, due to the stability of aztreonam to hydrolysis by these carbapenemases.7 This combination is currently in Phase 2 clinical trials. As a variety of DBOs was synthesized by various medicinal chemists, a pleasant surprise was observed. Some of these inhibitors had multiple mechanisms of action, including high affinity for penicillin-binding protein 2 (PBP2) in Gramnegative bacteria, thus contributing to antibacterial activity on their own in enteric bacteria, as well as in P. aeruginosa or Acinetobacter for some analogs. The first of these “dual agent” DBOs was nacubactam (4, Figure 1), now under development in a combination with meropenem.7 Currently, at least six DBOs are in development, with at least five DBO combinations having entered clinical trials.7 At this time, all the DBOs have been paired with approved β-lactams, including cephalosporins, carbapenems, or the monobactam aztreonam. In vitro, DBOs B
DOI: 10.1021/acsinfecdis.7b00243 ACS Infect. Dis. XXXX, XXX, XXX−XXX
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As might be expected, resistance has emerged in a small fraction of patients treated with the avibactam combination as studied in some depth in three patients from at the Pittsburgh Medical Center.12 Interestingly, the D179Y mutation in the Ωloop of a KPC-3 enzyme variant from the Pittsburgh hospital was identical to a mutation identified by Livermore et al. in their in vitro resistance selection studies with KPC-3.13 This mutation, alone or together with a second mutation, T243M, rendered KPC-3-producing strains more resistant to ceftazidime and ceftazidime−avibactam but more susceptible to meropenem.12 Other resistance mechanisms involving avibactam combinations were identified in a small reservoir of naturally occurring isolates that had the insertion of four amino acids into PBP3 of E. coli; these strains had elevated ceftazidime, ceftaroline, or aztreonam MICs in the presence of avibactam, as a result of lower affinity of these β-lactams for PBP3, their major killing target in Gram-negative bacteria.14 At this time, no patient-associated mutations due to the use of the meropenem−vaborbactam combination have been reported. However, KPC-producing strains overexpressing the AcrAB efflux pump and lacking both outer membrane porins OmpK35 and OmpK36, exhibited reduced susceptibility to both meropenem and meropenem−vaborbactam when tested in vitro.9 All of these resistance mechanisms, due to mutations that affect primarily the β-lactam partner and not the inhibitor itself, have implications for the future. Although the potentiating BLI activity of the inhibitors may be preserved, resistance mechanisms targeting the same accompanying cephalosporin, carbapenem, or monobactam will affect all combinations with that particular β-lactam. Currently, at least four BLI combinations are being developed with oxyiminocephalosporins as partners, and at least three with accompanying carbapenems,7 setting up the potential for cross-resistance among the different combinations. Development of new β-lactam combinations currently represents one of the most active areas of antibacterial research, generally addressing the medical need posed by infections caused by CPE. The relatively rapid approvals of the avibactam and vaborbactam combinations have provided the medical community with new therapeutic options to treat these infections. In addition, these actions have energized companies to continue working on anti-infective agents that may treat unmet medical needs. The question remains to be answered as to how many of these new agents and BLI combinations will be medically and commercially viable. As past experience has shown us, antibiotics in new classes that looked highly promising throughout clinical trials have not always delivered the breakthroughs that were anticipated. The first, or second, drugs in a class are not always the most successful. With antibiotics, rapid emergence of resistance can mean that backup molecules or combinations may be needed to continue to fill medical needs. Current gaps remain for therapies to treat infections caused by multidrug-resistant P. aeruginosa and Acinetobacter spp. or organisms that produce MBL- or OXA-48producing pathogens. In addition, unexpected toxicities can arise for agents that were approved on the basis of limited clinical data. The new β-lactam combinations have re-energized the infectious disease arena and are encouraging entries to the antibacterial armamentarium to treat serious carbapenemresistant infections. However, additional agents will continue to need to be added to our medicine bags as resistance inevitably will increase, in spite of the addition of novel, exciting, and unique antimicrobial agents.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Karen Bush: 0000-0002-7843-2474 Author Contributions
This manuscript was conceived by, researched by, and written by Karen Bush, Department of Biology, Indiana University, Bloomington, IN 47405. Notes
The author declares the following competing financial interest(s): K.B. has served as a consultant or as a member of a Scientific Advisory Board for Achaogen, Allecra, Entasis, Fedora, Forma Therapeutics, Gladius, Melinta, Merck, Roche, Shionogi, Tetraphase, The Medicines Company, and WarpDrive. She has received research funding from Achaogen, Actavis, Merck, and Tetraphase. This manuscript was prepared with no input from any of these organizations.
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ABBREVIATIONS BLI, β-lactamase inhibitor; DBO, diazabicyclooctane; CPE, carbapenem-producing Enterobacteriaceae; ESBL, extendedspectrum β-lactamase; KPC, Klebsiella pneumoniae carbapenemase; MBL, metallo-β-lactamase
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REFERENCES
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DOI: 10.1021/acsinfecdis.7b00243 ACS Infect. Dis. XXXX, XXX, XXX−XXX
