DiazabicyclooctaneEdit
Diazabicyclooctane (DBO) is a family of non-β-lactam beta-lactamase inhibitors designed to restore the effectiveness of β-lactam antibiotics against bacteria that produce β-lactamases. The DBO scaffold supports potent inhibition of several clinically important serine β-lactamases, broadening the activity of partner antibiotics against resistant Gram-negative pathogens. The most familiar clinical members are avibactam and relebactam, which are combined with established β-lactams to treat complicated infections. Other DBOs such as nacubactam and zidebactam are in development or early clinical testing, reflecting ongoing efforts to expand the reach of this class.
In clinical practice, diazabicyclooctane inhibitors are used to protect co-administered β-lactam antibiotics from hydrolysis by targeted enzymes. The combinations CEFTAZIDIME–AVIBACTAM and IMIPENEM–RELEBACTAM (with cilastatin) are the best-known examples. These products are written in the literature and on labels as ceftazidime-avibactam (brand names such as Avycaz) and Recarbrio for the imipenem–cilastatin–relebactam combination. In addition, avibactam forms the backbone of research programs aimed at pairing with other β-lactams to cover broader resistance landscapes, including combinations with aztreonam to address certain metallo-β-lactamase producers.
Overview of mechanism and structure
Structure and binding: DBO inhibitors are built around a diazabicyclooctane framework that mimics aspects of the β-lactam core without being a classic β-lactam antibiotic. This scaffold enables tight, time-limited interactions with active sites of serine β-lactamases, resulting in a covalent but reversible acyl-enzyme complex that shields the enzyme from hydrolyzing the partner β-lactam. The net effect is to preserve the integrity of the antibiotic long enough to exert its bactericidal action.
Target spectrum: The inhibitors are active against many class A, class C, and some class D β-lactamases, extending the usefulness of drugs such as ceftazidime and imipenem against organisms that would otherwise degrade them. They generally do not inhibit most metallo-β-lactamases (class B), though combinations with other agents (for example, aztreonam) can sometimes resolve specific resistance gaps.
Notable members: The clinically used DBOs include avibactam and relebactam. Other examples in development or early clinical stages include nacubactam and zidebactam, which aim to broaden spectrum or add additional antibacterial activity.
Relation to other β-lactamase inhibitors: DBOs are distinct from boronic acid or sulfonamide–based inhibitors and occupy a niche by delivering broad β-lactamase coverage with reversible covalent interaction, enabling protection of a wide range of β-lactam partners.
Clinical use and pharmacology
Approved combinations and indications: The combination of ceftazidime with avibactam provides activity against many Enterobacterales and Pseudomonas aeruginosa isolates that produce ESBLs or certain carbapenemases. The imipenem–cilastatin–relebactam combination expands activity against β-lactamase–producing Gram-negative pathogens, with particular utility against AmpC-producing organisms and certain carbapenemase producers.
Pharmacokinetics and administration: These inhibitors are administered intravenously alongside their partner β-lactams. Pharmacokinetic properties are tailored to achieve effective concentrations at the site of infection, with dosing and infusion schedules adjusted for organ function as appropriate. Metabolic and excretory pathways are primarily renal in character for these agents, guiding dose adjustments in patients with renal impairment.
Clinical impact: By restoring the activity of cephalosporins and carbapenems against resistant bacteria, DBOs contribute to improved clinical outcomes in subsets of complicated urinary tract infections, intra‑abdominal infections, pneumonia, and other serious infections where β-lactamase–mediated resistance limits conventional therapy.
Spectrum of activity and limitations
Coverage enabled by DBOs: The inhibitors extend the activity of partner β-lactams against many organisms that produce class A (for example, KPC-type enzymes), class C (AmpC) and some class D β-lactamases. This includes many strains of healthcare-associated pathogens where resistance would otherwise compromise treatment.
Gaps and resistance: DBOs do not reliably inhibit most metallo-β-lactamases (MBLs, such as NDM, VIM, and IMP). In practice, clinicians sometimes pair with aztreonam to address MBL producers, leveraging aztreonam’s relative stability to MBLs while avibactam inhibits accompanying ESBLs and AmpC enzymes. However, this strategy has limitations and is not universally effective across all isolates.
Resistance evolution: Bacteria can adapt to DBO-containing regimens through various routes, including upregulation or mutation of target β-lactamases, alternative resistance mechanisms, or changes in permeability. Emergence of variants that reduce susceptibility to avibactam or relebactam has been described in surveillance and clinical settings, highlighting the ongoing need for stewardship and surveillance.
Resistance, safety, and stewardship
Safety profile: As with other β-lactam therapies, adverse events are generally related to the β-lactam component and the patient’s comorbidities. Hypersensitivity, gastrointestinal effects, and potential impacts on the microbiome are considerations that accompany broad-spectrum β-lactam use.
Stewardship implications: The introduction of DBO inhibitors is closely tied to antibiotic stewardship. While these agents expand therapeutic options, their use must be guided by susceptibility data to minimize selection pressure and preserve activity. Stewardship programs aim to allocate these drugs to cases where they are most needed and most likely to succeed.
Policy and access considerations: The development of DBO inhibitors reflects a broader push to revive antibiotic pipelines through a combination of private investment and regulatory pathways. Market-driven incentives, intellectual-property protections, and targeted funding for antibiotic innovation intersect with debates about drug pricing, access, and sustainability. Proponents of market-based approaches argue they incentivize robust R&D, while critics advocate for subsidies or “pull incentives” to ensure ongoing development and equitable access. In this domain, DBOs illustrate the balance between encouraging innovation and ensuring that life-saving therapies reach the patients who need them.
Research developments and future directions
Next-generation DBOs: Ongoing research seeks to broaden activity against resistant pathogens, improve pharmacokinetic properties, and reduce the likelihood of resistance development. Agents such as nacubactam and zidebactam illustrate continuing efforts to diversify the DBO class and extend therapeutic reach, including potential dual-action mechanisms that couple β-lactamase inhibition with direct antibacterial effects.
Combination strategies: Beyond the classic ceftazidime–avibactam pairing, researchers are exploring combinations with additional partners, alternative dosing strategies, and adjunctive therapies to further suppress resistance emergence and treat hard-to-manage infections.
Global health considerations: The spread of β-lactamase–producing organisms is a global challenge. The role of DBO inhibitors in antimicrobial stewardship, infection control, and hospital practice is intertwined with policy, surveillance, and access initiatives that shape how these drugs are used in diverse health-care settings.