Using Molecular Diagnostics to Develop Therapeutic Strategies for Carbapenem-Resistant Gram-Negative Infections

Abstract

Infections caused by multidrug-resistant Gram-negative organisms have become a global threat. Such infections can be very difficult to treat, especially when they are caused by carbapenemase-producing organisms (CPO). Since infections caused by CPO tend to have worse outcomes than non-CPO infections, it is important to identify the type of carbapenemase present in the isolate or at least the Ambler Class (i.e., A, B, or D), to optimize therapy. Many of the newer beta-lactam/beta-lactamase inhibitor combinations are not active against organisms carrying Class B metallo-enzymes, so differentiating organisms with Class A or D carbapenemases from those with Class B enzymes rapidly is critical. Using molecular tests to detect and differentiate carbapenem-resistance genes (CRG) in bacterial isolates provides fast and actionable results, but utilization of these tests globally appears to be low. Detecting CRG directly in positive blood culture bottles or in syndromic panels coupled with bacterial identification are helpful when results are positive, however, even negative results can provide guidance for anti-infective therapy for key organism-drug combinations when linked to local epidemiology. This perspective will focus on the reluctance of laboratories to use molecular tests as aids to developing therapeutic strategies for infections caused by carbapenem-resistant organisms and how to overcome that reluctance.

Molecular Epidemiology, Risk Factors and Clinical Outcomes of Carbapenem-Nonsusceptible Enterobacter cloacae Complex Infections in a Taiwan University Hospital

“…Aside from the carbapenem, several novel antibiotics, such as ceftazidime-avibactam, ceftozolanetazobactam, cefepime-zidebactam, meropenem-vaborbactam, cefiderocol and eravacycline have been developed to treat multidrug-resistant organisms but many of them have limited activity against strains bearing class B metallo-lactamases (MBLs) such as IMP. Therefore, using novel rapid molecular/ lateral flow infectious disease diagnostic tools such as Xpert ® Carba-R test (Cepheid, Sunnyvale, CA, USA), Biofire FilmArray panels (Biomerieux, Nürtingen, Germany) or NG-Test Carba 5 (NG Biotech, Guipry, France) to identify the type of carbapenemase present in the carbapenem nonsusceptible isolate is important for optimizing antibiotics therapy [34,35].…”

Characterization of Carbapenemase- and ESBL-Producing Gram-Negative Bacilli Isolated from Patients with Urinary Tract and Bloodstream Infections

“…bla OXA-237 is another carbapenemase found in Acinetobacter species; however, one that is derived from the bla OXA-134 group. The proliferation of carbapenemase genes seen among Acinetobacter species in the United States is important for clinical microbiologists to recognize since many laboratories do not test Acinetobacter species for carbapenemases, presuming that the carbapenem resistance is efflux-mediated [ 28 ]. Furthermore, beta-lactam/beta-lactamase combination drugs with activity against Acinetobacter isolates producing class D beta-lactamases are now available [ 29 ].…”

The diagnostic accuracy of the GeneXpert ESBL- ampC prototype assay for rapid PCR-based detection of extended-spectrum beta-lactamase genes directly from urine

“…In this way, the use of carbapenems can be limited to those patients without alternative antimicrobial options, thus avoiding the use of carbapenems in patients without ESBL-producing bacteria. Using PCR to identify resistance genes to guide antimicrobial treatment is common for distinguishing methicillin-resistant Staphylococcus aureus from methicillin-susceptible S. aureus in blood cultures using the mecA gene ( 7 ), for detecting mutations associated with rifampin resistance in Mycobacterium tuberculosis ( 8 ), and as part of multiple syndromic panels ( 9 ). This approach can improve patient care and reduce the selective pressure that leads to further development of antimicrobial resistance.…”