How to treat infections caused by organisms with NDM (New Delhi metallo-beta-lactamase) and OXA-48 (oxacillinase-48) genes that confer carbapenem resistance?

From the Guidelines

Treating infections caused by organisms with NDM and OXA-48 genes requires combination antimicrobial therapy, with ceftazidime/avibactam plus aztreonam being the preferred treatment for metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE) 1. The recommended approach typically involves using two or more active agents, with combinations of polymyxins (colistin or polymyxin B), tigecycline, aminoglycosides, and high-dose carbapenems forming the backbone of treatment. Some key points to consider in the treatment of these infections include:

• The use of ceftazidime/avibactam plus aztreonam for MBL-producing CRE, as supported by a recent observational study showing lower 30-day mortality compared to other antibiotics active in vitro 1.
• The potential use of cefiderocol as an alternative option for infections caused by MBL-producing CRE, although the strength of recommendation is conditional due to low certainty of evidence 1.
• The importance of source control through drainage of abscesses or removal of infected devices, as well as regular monitoring of renal function when using nephrotoxic agents like colistin and aminoglycosides.
• Treatment duration typically ranges from 7-14 days depending on infection site and clinical response, with the goal of minimizing morbidity, mortality, and improving quality of life 1. It is essential to note that the treatment of infections caused by organisms with NDM and OXA-48 genes should be individualized based on the specific infection site, underlying comorbidities, and initial response to therapy, with a focus on minimizing adverse outcomes and improving patient outcomes 1.

From the FDA Drug Label

Tigecycline inhibits protein translation in bacteria by binding to the 30S ribosomal subunit and blocking entry of amino-acyl tRNA molecules into the A site of the ribosome. Resistance To date there has been no cross-resistance observed between tigecycline and other antibacterials. Tigecycline is less affected by the two major tetracycline-resistance mechanisms, ribosomal protection and efflux Additionally, tigecycline is not affected by resistance mechanisms such as beta-lactamases (including extended spectrum beta-lactamases), target-site modifications, macrolide efflux pumps or enzyme target changes (e.g. gyrase/topoisomerases).

Treatment of Infections Caused by NDM and OXA-48 Genes

• Tigecycline may be effective against some gram-negative bacteria, including those with extended-spectrum beta-lactamases (ESBLs)
• However, there is no direct information in the provided drug labels that specifically addresses the treatment of infections caused by organisms with NDM and OXA-48 genes that confer carbapenem resistance.
• The use of tigecycline or colistin for the treatment of such infections cannot be directly concluded from the provided information 2, 3.

From the Research

Treatment Options for NDM and OXA-48 Producing Organisms

• The treatment of infections caused by organisms with NDM and OXA-48 genes that confer carbapenem resistance is challenging due to limited antibiotic options 4, 5.
• Ceftazidime-avibactam is considered a viable treatment option for OXA-48 producers, while colistin remains a second-line option if in vitro susceptibility is demonstrated 5.
• For NDM producers, ceftazidime-avibactam and aztreonam combination or cefiderocol can be used, although higher cefiderocol MICs against NDM producers are a concern 5.
• Aztreonam-avibactam provides hope for the treatment of NDM producers, but more research is needed to confirm its efficacy 5.

Antibiotic Resistance and Mechanisms

• OXA-48-type β-lactamases confer resistance to penicillin and carbapenem antibiotics, with variants emerging that hydrolyze expanded-spectrum oxyimino-cephalosporins 6.
• NDM-1 carbapenemase typically confers complete aminoglycoside resistance due to the presence of 16S rRNA methylases 7.
• The activity of colistin, fosfomycin, and tigecycline is unrelated to the isolates' carbapenem resistance mechanisms, making them potential treatment options 7.

Combination Therapy and Novel Antibiotics

• Combination antimicrobial therapy with agents exhibiting synergy may be beneficial for treating NDM and OXA-48 producing organisms 4.
• Novel antibiotics, such as ceftolozane-tazobactam, are being developed to combat carbapenem-resistant Gram-negative bacteria, including those producing NDM and OXA-48 8.
• Strict implementation of antibiotic stewardship and in-time isolation cohorts are crucial in limiting the spread of carbapenem-resistant Gram-negative bacteria and alleviating the worsening trends of resistance 8.