Managing MDR gram-negative bacterial infections: Key lessons from 5 years of using ceftazidime-avibactam

The rapid emergence of multidrug-resistant (MDR) pathogens is a major and persistent global healthcare problem. In a Pfizer-sponsored symposium held during the 33rd European Congress of Clinical Microbiology & Infectious Diseases (ECCMID), experts shared lessons drawn from over half a decade of using ceftazidime-avibactam in the management of MDR gram-negative bacterial infections. Prof David Paterson from the National University of Singapore and Dr Maddalena Giannella from Bologna University, Italy chaired the session. 

Among the highlights were real-world evidence (RWE) with ceftazidime-avibactam and how it has shaped the anti-infective therapeutic landscape, the importance of early, appropriate treatment and its place in antimicrobial stewardship strategies, and the roles of microbiology and diagnostics in optimizing treatment strategies. 

Getting it right the first time in critically ill patients
“Getting it right refers to getting the right diagnosis, selecting the right antibiotic, giving it at the right time, and at the right dose,” said Professor Jan De Waele, intensivist at Ghent University Hospital, Belgium. “Selecting the right antibiotic is a challenge in the ICU. Not only is antimicrobial resistance more common, but patients are more vulnerable compared with the general wards. Besides susceptibility, we must consider the drug’s tolerability profile. We should avoid nephrotoxic drugs if possible.” 

“Delays in receiving appropriate therapy can have a great impact on patient outcomes,” he emphasized. Antimicrobial resistance was the cause of significant delays in adequate antimicrobial therapy in critically ill patients. Nonreceipt of initially appropriate antibiotic therapy predicted hospital mortality in studies. [Intensive Care Med 2023;49:178-190; Critical Care 2014;18:596] 

Moreover, irrespective of antimicrobial resistance, delayed appropriate therapy led to longer durations of antibiotic therapy and length of stay in the hospital, higher costs, lower likelihood of discharge to home, and greater likelihood of the composite mortality outcome. [Open Forum Infect Dis 2019;6:ofz194] 

“Risk stratification, knowledge about local ecology, and rapid diagnostics are essential for selecting the right antibiotic, in line with principles of antibiotic stewardship,” pointed out De Waele. “Recent β-lactam/β-lactamase inhibitor (BL/BLI) combinations, including ceftazidime-avibactam, can be used as directed therapy for MDR gram-negative bacteria (GNB) such as extended-spectrum β-lactamase (ESBL)-producing Enterobacterales, carbapenem-resistant Enterobacterales (CRE), or MDR Pseudomonas aeruginosa, or for empirical use in patients with severe infections at high risk of MDR GNB where baseline MDR-GNB prevalence is high.” 

Role of microbiology in guiding early appropriate treatment
“The clinical microbiologist plays important roles in providing knowledge on epidemiological data, including local surveillance data and antibiotic susceptibility data, in selecting laboratory diagnostics to deliver rapid and accurate microbiologic test results to enable selection of effective and targeted treatment, and in working collaboratively with the multidisciplinary team to optimize antibiotic therapy,” said Dr Louise Sweeney, Consultant Microbiologist at Manchester University, UK. 

The advent of recent BL/BLI combinations, of which ceftazidime-avibactam was the first, allowed the development of guidelines for the treatment of gram-negative antimicrobial-resistant infections. “This changed the practice landscape dramatically,” she noted. 

“Different screening methodologies for MDR pathogens vary in their sensitivity, specificity, cost and resource implications, and will have an impact on colonization data. These need to be carefully interpreted in the local context, while considering specific patient risk factors,” she added. 

Susceptibility testing is one of the key roles of a microbiologist. “There is a lot of heterogeneity in resistance mechanisms, and treatments should be selected accordingly (Table 1). We cannot use a BL/BLI empirically without considering the resistance mechanism,” cautioned Sweeney. 

RWE: 5 years with ceftazidime-avibactam
“Ceftazidime-avibactam was launched in Europe in 2017, heralding a new treatment option for MDR gram-negative bacterial infections,” recalled Paterson. “Its effectiveness has been evaluated in seven phase II and phase III randomized controlled clinical trials involving 2,024 patients and over 52 real-world studies involving 5,970 patients.” 

“RWE studies provide valuable data in patient populations more representative of clinical practice compared with randomized clinical trials, though their interpretations may be limited by potential selection bias and unknown confounding factors,” said Dr Michele Bartoletti, infectious disease consultant, Humanitas University, Italy. 

Bartoletti highlighted several RWE studies comparing ceftazidime-avibactam with best available therapy (BAT) for infections caused by carbapenem-resistant Enterobacteriaceae and carbapenemase-producing Klebsiella pneumoniae, demonstrating significant reductions in mortality rates with ceftazidime-avibactam vs its comparators. [Antimicrob Agents Chemother 2021;61:e00883-17; Int J Infect Dis 2017;59:118-123; Clin Infect Dis 2018;66:163-171; Clin Infect Dis 2019;68:355-364; J Antimicrob Chemother 2022;77:1452-1460] 

In the CAVICOR study which was the largest comparative series of real-world data of patients with CPE infections treated with ceftazidime-avibactam or BAT, ceftazidime-avibactam had a lower 30-day mortality compared with BAT (Table 2). [J Antimicrob Chemother 2022;77:1452-1460] 

RWE data supports the use of ceftazidime-avibactam in adult patients with serious gram-negative infections and limited treatment options, including primary bacteremia, complicated skin and soft tissue infections, bone and joint infections and meningitis. In a systematic literature review of 73 relevant publications comprising 1,926 patients treated with ceftazidime-avibactam and 1,114 comparator/ control patients, the most common infections were carbapenem-resistant or carbapenemase-producing Enterobacterales (KPC and OXA-48 resistance mechanisms) and MDR P. aeruginosa. [Infect Dis Ther 2021;10:1989-2034] 

“In the past 5 years, we’ve acquired important additional information on the use of ceftazidime-avibactam. It is a preferred treatment option for KPC and OXA-48 producing carbapenemases, has a valid role in treating severe infections of P. aeruginosa, has proven effectiveness as a monotherapy, and is effective in treating high-risk patients with multiple comorbidities and immunocompromised patients,” summarized Bartoletti. 

Diagnostic tests to optimize treatment strategies
“Increasing antimicrobial resistance prevalence and heterogeneity also means empiric prescribing for patients with gram-negative infections may more frequently be incorrect,” said Dr Luke Moore, Infectious Disease Consultant and Microbiologist at Chelsea and Westminster Hospital, UK. “Owing to the epidemiological changes in beta-lactamase-producing pathogens over time, there is a need for rapid diagnostics that can identify molecular mechanisms of resistance to improve patient outcomes.” 

Back in 2017, diagnostics were primarily phenotypic, he added. “The COVID-19 pandemic brought a plurality of molecular mechanisms of diagnostics to the forefront. Syndromic diagnostic testing using novel, rapid, multiplexed molecular platforms represents a new opportunity for rapidly targeted antimicrobial therapy to improve patient outcomes and facilitate antibiotic stewardship.” 

“I am agnostic to the modality of diagnostic as long as it can give the right answer to the right patient at the right time,” Moore noted, sharing one study where rapid phenotypic antimicrobial susceptibility testing (AST) led to faster discontinuation of aminoglycosides and a shorter median time to starting an optimal antibiotic in bloodstream infections vs a conventional AST. [J Antimicrob Chemother 2022;77:771-781] 

“Rapid molecular diagnostics have increased in availability, utility, and repertoires and can enable earlier targeted antimicrobial therapy. By understanding where rapid tests are best conducted, and how results are integrated back into patient pathways, we can tackle the problem of resistant gram-negative infections,” he concluded. 

The preferred treatment option
“In view of the rise of carbapenem resistance, knowledge of whether a CRE clinical isolate is carbapenemase-producing and the specific carbapenemase that is produced, is important in guiding treatment decisions,” echoed Professor Ana Gales, Federal University of São Paulo, Brazil. 

“Ceftazidime-avibactam is a preferred treatment option for infections caused by CRE or P. aeruginosa with difficult-to-treat resistance. Polymyxins can be an alternative therapy in this population,” she summarized.