Antimicrobial resistance is our biggest nightmare

2024 updated IDSA guidelines highlighted the previously considered standard practice to administer extended-infusion meropenem in combination with a second agent (polymyxins or aminoglycosides) for infections caused by CRE (Carbapenem resistant enterobacteracea) isolates with meropenem MICs as high as (8–16 µg/mL). However, trial data indicates increased mortality and excess nephrotoxicity associated with polymyxin or aminoglycoside-based regimens relative to newer β-lactam-β-lactamase inhibitor agents.

Therefore, the panel advises against the use of extended-infusion carbapenems with or without the addition of a second agent.

Instead we use the newer agents available in market as ceftazidime-avibactam/ meropenem-vaborbactam and imipenem-cilastatin-relebactam.

Single agent high dose tigecycline can also be used as long as it’s not urinary tract/bloodstream infection due to low serum and urine concentrations of tigecycline.

Tigecycline can be considered as alternative options for intra-abdominal infections, skin and soft tissue infections, osteomyelitis, and respiratory infections when optimal dosing is used (200mgLD,100mgMD).

But, keep in mind, trials suggested that tigecycline monotherapy is associated with higher mortality than alternative regimens

Note that, Polymyxin B and colistin are not suggested for the treatment of infections caused by CRE ( only uncomplicated CRE cystitis)

Combination antibiotic therapy (i.e., the use of a β-lactam agent in combination with an aminoglycoside, fluoroquinolone, tetracycline, or polymyxin) is not suggested bec. NO clinical data indicates that combination therapy prevents the emergence of resistance.

It’s important to mention that in case of the presence of NDM or MBL producing or OXA-48 Ceftazidime-avibactam should be in combination with aztreonam.

Aztreonam is not hydrolyzed by NDMs, it can be hydrolyzed by other β-lactamases that are often co-produced by NDM-producing isolates (e.g. ESBLs, KPCs, or OXA-48). Avibactam generally remains effective at inhibiting the activity of these other β-lactamases.

So, this might be crucial to hinder overuse of aztreonam and confirm the rationale behind its administration in combination with zavicefta.

Sadly, emergence of resistance of CRE isolates to the newer β-lactam agents occurred. Mutations in the KPC gene translating to amino acid changes in the KPC carbapenemase which leads to increased hydrolysis of ceftazidime. Changes in outer membrane permeability and efflux systems are the primary drivers of the emergence of resistance to meropenem/vaborbactam and imipenem-cilastatin-relebactam.

Accordingly, if a patient was recently treated with ceftazidime-avibactam and presents with a sepsis-like condition it is suggested to consider a different novel β-lactam agent at least until culture and AST data are available.

Moving on to CRAB (Carbapenem resistance Acinetobacter), ampicillin sulbactam in combination with a second agent such as (colistin) retreats from a first line agent to a preferable treatment option. Instead Sulbactam-durlobactam in combination with imipenem-cilastatin or meropenem is now a first line agent in CRAB infections.

Durlobactam reduces the likelihood of sulbactam hydrolysis by binding to and inhibiting β-lactamases so that sulbactam can successfully reach its PBP targets.

It’s found in the market by the name (Xacduro).

Trials tackling nebulised colistin for Pneumonia caused by CRAB has shown lack of clinical benefit. Aerosolized delivery of the prodrug of colistin to critically ill patients achieved high active drug levels in the epithelial lining fluid of the lungs, but not sufficient penetration and/or distribution throughout lung tissue to exert significant bactericidal activity.

In the end, we really need to be aware of this wave of antimicrobial resistance we’re facing nowadays and this is a quick reminder if you are a part of a healthcare team within a medical organization to start guiding therapeutic plans in a cautious and strategic manner to avoid further antibiotic misuse and resistance emergence.