Challenges in the diagnosis and management of multidrug-resistant gram-negative infections: Real-world evidence and experience

The diagnosis and treatment of multidrug-resistant (MDR) gram-negative bacteria in critically ill patients present many clinical challenges. Selection of appropriate antibiotic therapy in a timely manner requires patients’ comprehensive medical history, updated local knowledge of microbiological epidemiology, efficient use of diagnostic tools, and balancing of information from clinical trial data, real-world evidence (RWE), and guidelines.

In a symposium Pfizer organized in conjunction with the Asia Pacific Intensive Care Symposium (APICS), Professor David Paterson from the National University of Singapore discussed the importance of RWE in the antibiotic armamentarium, using ceftazidime-avibactam (CAZ-AVI, Zavicefta^®) as an example. Dr Asok Kurup, Consultant Infectious Diseases Physician at Mount Elizabeth Medical Centre, Singapore, explained how rapid diagnostics can guide treatment choices to improve patient outcomes in MDR gram-negative infections.

Importance of RWE in the antibiotic armamentarium
Prospective randomized controlled trials (RCTs) are the gold standard for assessing the effectiveness and safety of antibiotics. However, they are conducted under tightly-controlled settings and with highly-selected patient populations, which may limit the external validity and applicability of the findings. For this reason, RWE – derived from diverse clinical settings and which contained information about a broader cross-section of patients, including high-risk groups – may supplement RCT data.

“Types of RWE relevant for informing the choice of antibiotic include pragmatic randomized trials, large observational studies, case series or case reports, pre-use microbiological assessment, microbiological surveillance studies, and case series or case reports of emergence of resistance,” explained Paterson.

RCTs vs RWE for CAZ-AVI
“Regulatory RCTs have demonstrated the efficacy of CAZ-AVI in complicated urinary tract infections and acute pyelonephritis, complicated intra-abdominal infections (when combined with metronidazole), and nosocomial pneumonia, including ventilator-associated pneumonia). However, these trials had very few patients with carbapenem-resistant Enterobacterales (CRE),” said Paterson.

“The effectiveness of CAZ-AVI has been evaluated in numerous real-world studies,” he added. “CAZ-AVI showed high in vitro activity against ESBL, AmpC, KPC, and OXA-48-producing strains of Enterobacterales, as well as against majority of the strains of carbapenem-resistant Pseudomonas aeruginosa in these trials. RWE has also evaluated the clinical outcomes of CAZ-AVI vs polymyxin-based regimens for the treatment of CRE and carbapenemase-producing Enterobacterales (CPE).” [Clin Infect Dis 2018;66:163-71; J Antimicrob Chemother 2022;77:1452-1460]

The CAVICOR study
CAVICOR is an observational, retrospective study of 399 patients who received ≥48 h of CAZ-AVI or best available therapy (BAT) for documented CPE infections. CAZ-AVI was associated with improved survival compared with BAT, especially in patients with INCREMENT-CPE scores of >7 points (Figure 1). Additionally, treatment with CAZ-AVI was associated with more clinical improvement (21-day clinical cure; odds ratio [OR] 2.43, 95 percent confidence interval [CI], 1.16–5.12; p=0.02), microbiological eradication (OR, 0.40, 95 percent CI, 0.18–0.85; p=0.02), and fewer adverse events. [J Antimicrob Chemother 2022;77:1452-1460]

How rapid diagnostics guide treatment choices
Delays in appropriate antimicrobial therapy are associated with increased mortality in patients with severe bacterial infections, especially those infected with gram-negative pathogens. [Chest 2020;158:929-938] Thus, rapid detection of bacterial pathogens and determination of antimicrobial susceptibility profile is essential to facilitate timely administration of appropriate antibiotics. Multiplex polymerase chain reaction (PCR) technique, also known as syndromic testing, is a novel approach to rapid diagnosis of infectious diseases.

“Syndromic testing uses one test to simultaneously target multiple pathogens with overlapping signs and symptoms. It facilitates rapid multiplex PCR while preventing cross-contamination, and provides automated, user-friendly results on each target in the array,” explained Kurup. “If implemented correctly, syndromic panels have the potential to improve patient outcomes through improved clinical decision-making, optimized laboratory workflow, and enhanced antimicrobial stewardship.”

“The use of syndromic testing drastically reduces the time frame for empirical antimicrobial therapy and allows targeted therapy to be started much earlier than when using conventional cultures alone,” he added (Figure 2).

The use of a syndromic test could have prompted a change in therapy in about two-thirds of patients, either by expanding antimicrobial coverage or narrowing the antibiotic spectrum. [Cureus 2022;14(1):e21716.] Other potential benefits include reduced exposure to, and cost of, broad-spectrum antimicrobials, and reduced cost of other rapid diagnostic tests.

In another study, syndromic testing of patients presenting with respiratory infections decreased infection control isolation time by approximately 4 days vs routine testing in the ICU and in bone marrow transplant and respiratory wards. [Open Forum Infect Dis 2017;4(Suppl 1):S353]

“Molecular diagnostics may tend to be oversensitive, does not differentiate between live and dead organisms, or between contaminants and disease-causing pathogens. In addition, panels are not comprehensive and may not cover relevant organisms or resistant genes,” cautioned Kurup. “Importantly, syndromic testing should be conducted using the principles of diagnostic stewardship, and results should be interpreted within specific clinical contexts.”

Conclusion
·       While regulatory RCTs are great for assessing effectiveness and safety in highly targeted populations, RWE is necessary to evaluate the benefits of CAZ-AVI in treating CRE due to KPC or OXA-48, and carbapenem-resistant Pseudomonas aeruginosa.
·       Future RWE is needed to study the benefits of ‘early impact therapy’ with CAZ-AVI, assisted by rapid diagnostics.
·       Syndromic testing enables a more rapid time to optimize therapy, leading to improved patient outcomes. It reduces exposure to, and cost of, broad-spectrum antimicrobials and helps with infection prevention and control.