New beta-lactam/beta-lactamase inhibitor combinations are reshaping the treatment landscape for multidrug-resistant Gram-negative infections. Yet innovation alone is not enough to support stewardship. Reporting from the BSAC New Agents conference, Gerry Hughes examines how expanding therapeutic options are forcing hospital pharmacists to rethink not only which agents to use, but when and how to deploy them.

Opening the recent British Society for Antimicrobial Chemotherapy (BSAC) New Agents Conference, its president Professor Andrew Seaton framed antimicrobial resistance (AMR) as a ‘supreme global threat’ requiring urgent clinical and scientific response.

In 2021, AMR was attributable to 1.14 million deaths globally. Across the UK, the picture is also concerning.

The English Surveillance Programme for Antimicrobial Utilisation and Resistance Report 2024 to 2025 describes how the burden of drug-resistant bacteraemia has risen steadily, increasing by 13.1% between 2019 and 2024.

Further data in the report outline how more than one in five bacteraemia episodes due to bacteria of public health importance are resistant to key antibiotics.

Enterobacterales dominate this burden, accounting for over 85% of antibiotic-resistant bloodstream infections. Escherichia coli remains the principal driver, responsible for approximately two-thirds of resistant cases over the past six years, while Klebsiella pneumoniae has shown the fastest rate of increase, rising by almost 40% since 2019. By contrast, Gram-positive bacteraemias have remained relatively stable over that time. 

During his BSAC New Agents session, Dr Colin Brown, infectious disease and medical microbiology consultant at the UK Health Security Agency, warned that this current epidemiological trajectory is one where ‘everything that we’re really worried about is not going in the right direction’.

He highlighted that AMR is not experienced evenly across society, disproportionately affecting deprived communities and vulnerable groups. Patients with cancer, for example, face substantially higher rates of Gram-negative infections, compounding already complex treatment pathways.

While resistance accelerates, the landscape of emerging antimicrobial agents remains fragile. Professor Seaton concluded his opening address by stating: ‘The pipeline is weak, and further innovation is needed to stimulate it.’  

For hospital pharmacists, AMR is becoming an everyday clinical constraint, placing renewed emphasis on the stewardship of both existing and emerging antimicrobial agents.

The BL/BLI pipeline for Gram-negative infections

With multidrug-resistant Gram-negative bacteria continuing to dominate the WHO Bacterial Priority Pathogens List, development efforts remain focused on beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations.

Cefepime/enmetazobactam exemplifies this strategy, as outlined by Professor Jim Spencer, professor of bacteriology at theUniversity of Bristol, during his talk on BL/BLIs.

Cefepime retains relative stability against hydrolysis by AmpC and OXA-48 enzymes, broadening its activity beyond earlier cephalosporin-based regimens.

According to Professor Spencer, it has added value as a carbapenem-sparing option for ESBL-producing Enterobacterales, including isolates that co-produce AmpC or OXA-48. Yet activity against Klebsiella pneumoniae carbapenemase (KPC) producers remains limited.

The introduction of avibactam marked what has been described as a step change that ‘really revolutionised the beta-lactamase inhibitor field’, according to Professor Spencer.

Its pairing with aztreonam is particularly impactful for metallo-beta-lactamase (MBL) producers: aztreonam is intrinsically stable to MBL-mediated hydrolysis, while avibactam inhibits co-produced beta-lactamases, together restoring activity across all four Ambler classes.

Similarly, sulbactam/durlobactam has emerged as a response to drug-resistant Acinetobacter baumannii, addressing class D oxacillinases, ‘filling an important gap in the therapeutic armamentarium’, Professor Spencer adds.

Vaborbactam, in combination with meropenem, extends activity against KPC and AmpC producers, though MBLs remain beyond reach.

‘New antibiotics save lives’

Shifting the focus from molecular innovation to clinical practice, Dr Ryan Shields, associate professor of medicine and infectious diseases at the University of Pittsburgh and co-director of the antimicrobial management program the University of Pittsburgh Medical Center, addressed what he termed the stewardship dilemma: how to balance timely access to life-saving agents while preserving their activity.

Highlighting composite data drawn from multiple studies dating back to 2017, Professor Shields outlined the mortality benefit associated with ceftazidime/avibactam and meropenem/vaborbactam.

Referring specifically to infections caused by KPC-producing organisms, and when compared with older BL/BLIs, he framed the message simply as: new antibiotics save lives.

During his BSAC New Agents conference session, he advocated that antimicrobial stewardship programmes should consider moving beyond a narrow emphasis on restriction and instead promote the rational, evidence-based use of newer therapies.

Antimicrobial stewardship through optimised drug delivery

Hospital pharmacists will be accustomed to ensuring antibiotics are delivered within their licensed remits, with standard dosing regimens and adjustment where required for special populations. However, Professor Shields challenged that approach somewhat and described scenarios where alternative approaches may be required.

As time-dependent beta-lactams, drugs such as ceftazidime/avibactam require sustained exposure above the minimum inhibitory concentration. ‘You should always be giving beta-lactams over prolonged infusion if you can,’ was the clear advice offered by Professor Shields.

He cited a large Italian multicentre study of patients with KPC-producing Klebsiella pneumoniae infections, where mortality was lower among those receiving ceftazidime/avibactam by prolonged infusion.

Paradoxically, mortality was higher in those undergoing renal dose adjustment – a finding that challenges standard assumptions. Conventional renal dosing strategies are largely derived from stable chronic kidney disease populations, yet severe infection can be accompanied by transient kidney injury. In this context, dose reductions may risk underexposure.

Further evidence suggests that aggressive attainment of pharmacokinetic-pharmacodynamic targets, supported by intensive therapeutic drug monitoring and multidisciplinary oversight, is protective not only against microbiological failure but also against subsequent resistance development.

Professor Shields went on to caution that patients with pneumonia require careful management. He advised that this population tends to be heterogenous, unwell, frequently ventilated and with labile renal function, making effective drug delivery challenging.

Compounding this is the reduced penetration of BL/BLIs to lung tissue, which can be inactivated by pulmonary surfactants and can provide residence for multi drug resistance pathogens.

Timely deployment of new agents

Many hospital antimicrobial stewardship programmes follow agent restriction, in accordance with international best practice. But if newer BL/BLI combinations confer survival benefit, withholding them may not represent optimal care, Professor Shields argued, particularly where rapid diagnostics are not quick enough or may not exist for certain pathogens.

Nowhere is this tension clearer than with Pseudomonas aeruginosa as there is no single rapid diagnostic test on each of its possible resistance mechanisms. Furthermore, this organism possesses a large accessory genome and remarkable adaptive capacity, enabling it to select for resistance more rapidly than many other pathogens.

Clinical data are sobering. In a recent evaluation of ceftazidime/avibactam and ceftolozane/tazobactam for Pseudomonas aeruginosa infections, resistance emerged in approximately one in five patients during therapy.

Professor Shields added the caveat that deploying antibiotics such as these for resistant Pseudomonas aeruginosa often occurs after other options have been exhausted.

He asked: ‘Are we really putting these agents in the best position to be successful if we’re only reserving them for salvage scenarios in organisms that are already highly evolved and have many underlying mechanisms of resistance?’

Calling for a different way of thinking about antibiotic treatment for these difficult to manage infections, he added: ‘We have to shift then, the clinical decision away from potentially earlier detection and maybe earlier differences in treatment selection.’

Future stewardship evolution

The message emerging from the BSAC New Agents conference was not simply that new antibiotics work, but that their success is conditional on several factors, including early pathogen detection, optimised drug exposure and strategic positioning of such drugs within treatment pathways.

Difficult-to-treat Gram-negative infections will require more than choosing the right agent. Hospital pharmacists will need to continually adapt to rethink not just which agents are chosen, but when and how to use them.

In the era of expanding but fragile therapeutic options, stewardship must evolve from cautious gatekeeping to strategic, evidence-driven antimicrobial drug deployment.