Challenges and strategies in the management of MDRO infections in Asia

Multidrug-resistant organisms (MDROs) are associated with a longer hospital stay, increased exposure to antimicrobial agents, and excess healthcare costs. Improved treatment and management strategies are urgently needed to curb the rising burden of MDROs in Asia. At a symposium organized by Pfizer in conjunction with the 18th Asia Pacific Congress of Clinical Microbiology and Infection (APCCMI 2021), experts discussed the role of rapid diagnostic testing and novel antibiotics in addressing MDRO infections, including practical solutions to maximize patient outcomes while minimizing the risk of antimicrobial resistance. The esteemed speakers were Professor Tobias Welte, Head, Department of Respiratory Medicine and Infectious Diseases, Hannover Medical School, Germany, and Dr Asok Kurup, Infectious Diseases Consultant at Mount Elizabeth Medical Centre, Singapore. Professor Balaji Veeraraghavan, Head of the Department of Clinical Microbiology, Christian Medical College and Hospital, Vellore, India, chaired the session.

Challenges and gaps in tackling AMR in the Asia-Pacific region
The Asia-Pacific region is highly vulnerable to the threats of antimicrobial resistance (AMR). “Densely populated cities may serve as huge reservoirs for the spread of drug-resistant pathogens. Inappropriate antibiotic use and a lack of antibiotic stewardship also contribute to AMR,” explained Kurup. 

There is a gap in the ability to reliably determine the AMR burden and impact of interventions, as standardized data collection and reporting processes are lacking. Many laboratories have limited infrastructure, expertise, and quality assurance. [BMJ 2017;358:j2291; Lancet Infect Dis 2011;11:692-701] 

Data suggest high rates of extended-spectrum β-lactamase (ESBL) producers among Escherichia coli (E. coli) isolates in Asia, as well as the widespread presence of carbapenem and polymyxin resistance among Klebsiella and E. coli. [J Travel Med 2017;24:S44; Int J Antimicrob Agents 2019;54:381-399] 

In the Asia-Pacific region, multidrug-resistant Pseudomonas aeruginosa (P. aeruginosa) has a prevalence of approximately 20 percent, while for carbapenem-resistant Enterobacteriaceae (CRE) it is about 12.8 percent. While CRE rates in North America have dropped since 2014, rates in Asia-Pacific continue to show a rising trend (Figure 1). [Open Forum Infect Dis 2019;6:S23-S33]

Importance of rapid diagnostics
“It is well-known that MDROs increase morbidity and mortality. The risk of death is up to two times higher in patients infected with MDR strains. Therefore, it is important to identify MDROs as early as possible to allow targeted treatment of these pathogens,” said Welte. [World Health Organization. Antimicrobial Resistance Global Report on Surveillance 2014] 

“One of the technologies for rapid diagnosis is the polymerase chain reaction (PCR) test. PCR has dramatically increased pathogen detection in critical care settings, and studies have demonstrated acceptable sensitivity. However, quantification is not possible with PCR, making it difficult to distinguish between colonization or infection that requires treatment,” said Welte. [Eur J Clin Microbiol Infect Dis 2019;38:1171-1178; Crit Care Med 2015;43:2283-2291] 

“In the future, whole pathogen sequencing may be the way to go,” said Welte. “It provides information about the pathogen, resistance patterns, and pathogenicity. Study results show it has enhanced performance compared with standard of care diagnostics. [Crit Care Med 2019;47:e394-e402] In addition, newer technologies such as shotgun metagenomics are now emerging. [Eur J Clin Microbiol Infect Dis 2019;38:1059-1070] Researchers are working to bring this technology to bedside,” he added.

Strategies for treatment of MDROs
“For severe infections in critical care settings, early and appropriate empirical antimicrobial treatment is essential to reduce mortality, followed by targeted treatment once microbiological results confirm the pathogen. The treatment approach may be based on resistance patterns,” said Welte. 

“For proper treatment decisions, knowledge of local epidemiology, understanding of institutional antibiograms and rapid diagnostics, as well as proper antibiotic stewardship, are ideally required,” advised Kurup. 

Role of newer antibiotics
Newer antibiotics for the treatment of MDROs include ceftolozane-tazobactam for MDR P. aeruginosa and ceftazidime-avibactam for Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria. [Int J Antimicrob Agents 2015;46:483-493; Crit Care 2020;24:383]

Ceftolozane-tazobactam was shown in the ASPECT-NP study to be noninferior to meropenem in both clinical cure and mortality in adults with nosocomial pneumonia, particularly for MDR and extensively drug-resistant (XDR) P. aeruginosa. [Lancet Infect Dis 2019;19:1299-1311] In a retrospective analysis, ceftolozane-tazobactam had higher cure rates and lower risk of acute kidney injury than colistin/aminoglycoside-based regimens for resistant P. aeruginosa infections. [Clin Infect Dis 2020;71:1799-1801]

Ceftazidime-avibactam was investigated in pivotal phase III studies, demonstrating clinical efficacy and noninferiority to carbapenem comparators in the treatment of complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), and nosocomial pneumonia, including ventilator-assisted pneumonia, and against ceftazidime-resistant Enterobacteriaceae and P. aeruginosa in cIAI or cUTI. [Clin Infect Dis 2016;63:6:754-762; Clin Infect Dis 2016;62:1380-1389; Lancet Infect Dis 2018;18:285-295; Lancet Infect Dis 2016;16:661-673]

Based on the evidence, the Infectious Diseases Society of America (IDSA) recommends ceftazidime-avibactam as a preferred option for carbapenem-resistant Enterobacterales in cUTI, as well as outside of the urinary tract (Table 1). [www.idsociety.org/practice-guideline/amr-guidance/]

Moving away from polymyxin-based regimens
The emergence of MDROs has prompted increased reliance on polymyxin therapy, which has demonstrated broad activity against Gram-negative bacteria. However, observational and randomized-controlled trial data have shown increased mortality and excess nephrotoxicity associated with polymyxin-based regimens relative to newer comparator agents, including ceftazidime-avibactam. [Antimicrob Agents Chemother 2017;61:e00883-17; Clin Infect Dis 2018;66:163-171; Int J Infect Dis 2017;59:118-123] 

“Even mild cases of nephrotoxicity have been linked to a variety of adverse outcomes, including increased in-hospital mortality and length of stay. Thus, the use of these agents should be avoided for the treatment of CRE infections, and alternative agents or combination with other antimicrobials should be considered,” Balaji pointed out.

Takeaways for clinicians
“MDR pathogens are a major risk factor for mortality. New and effective antibiotics, mainly ceftazidime-avibactam, cover MDR infection. Individualized therapy focusing on the suspected pathogen and the patient profile represents the future treatment for MDR infection,” said Welte.

“Understanding regional and local epidemiology, availability of institutional antibiogram, microbiology and laboratory support, and rapid diagnostics are elements which enable accurate and fast diagnosis. It is important to educate healthcare professionals on good antibiotic stewardship, which may include therapeutic drug monitoring and appropriate dosing and de-escalation strategies, to avoid clinical failure as well as minimize antibiotic resistance,” concluded Kurup.