use cefiderocol for high resistant pseudomonas

This patient has multiple risk factors for the development of an infection with highly resistant gram-negative bacteria. Her most recent culture from her lower respiratory tract is growing a P aeruginosa with high-level resistance to β-lactam, cephalosporin, and carbapenem, as well as cephalosporin-β-lactamase inhibitor combination classes of antibiotics. At this point, cefiderocol should be initiated (choice D is correct).

Emerging resistance to antimicrobial therapy among gram-negative bacteria has led to limited therapeutic options. For most gram-negative bacteria with antimicrobial resistance, particularly through the extended-spectrum β-lactamases (ESBLs), the carbapenem class is the preferred antibiotic. However, during the last 5 years, the emergence of carbapenem-hydrolyzing β-lactamases (carbapenemases) and the emergence of porin channel mediated resistance (OprD) have reduced the susceptibility to carbapenem antibiotics. Two main groups of carbapenemases exist. Group A contains Klebsiella pneumoniae carbapenemase (KPC), the most clinically relevant strain in North America and the Middle East. KPC contains a carbapenemase that is transferred by plasmid and confers resistance to all β-lactam antibiotics. Group B carbapenemases require zinc for activity and thus are named "metallo-β-lactamases." These are most commonly found in the New Delhi metallo-β-lactamase (NDM-1) strain of K pneumoniae (common in Southeast Asia). P aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumannii, and other nonlactose-fermenting gram-negative rods develop resistance through the loss of a porin channel (eg, OprD), thus preventing the antibiotic from entering the cell (as opposed to ESBLs). Both of these mechanisms lead to class resistance with carbapenems and often carry resistance to most other newer antimicrobials as well (as with this case). For these highly resistant gram-negative bacteria, some older antimicrobials such as colistin and tigecycline may have activity. However, the side effect profile and poor clinical outcomes limit their use to salvage therapy only even if antimicrobial testing suggests susceptibility.

The development of a number of cephalosporin-β-lactamase inhibitor combinations, carbapenem-β-lactamase inhibitor combinations, and the cephalosporin cefiderocol provide more options for these highly resistant strains. Ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam will provide some expanded coverage of carbapenem-resistant P aeruginosa as well as a KPC. However, they do not provide coverage of the NDM-1 strain of K pneumoniae or the porin channel resistance of P aeruginosa, S maltophilia, and A baumannii. Ceftolozane-tazobactam provides excellent coverage of highly resistant P aeruginosa but does not cover KPC of the NDM-1 strain. In addition, there is emerging resistance to these newer cephalosporin-β-lactamase inhibitor and carbapenem-β-lacatamase inhibitor combinations, leading to few choices (as with this case). Cefiderocol is a newer siderophore cephalosporin that has broad activity against K pneumoniae (both KPS and NDM-1), P aeruginosa, S maltophilia, and A baumannii. It has a novel mechanism that allows for transport across membranes through the bacteria's iron transport mechanism, thus allowing it to evade porin channel deletion mechanisms of resistance. Additionally, it not hydrolyzed by the class A and B carbapenemases. Thus, this agent can provide coverage in cases in which the cephalosporin-β-lactamase inhibitor or carbapenem-β-lactamase inhibitor antimicrobials fail. Cefiderocol was used in this case, with improvement of symptoms within 7 days. Because this is a newer antimicrobial agent, some medical facilities may not readily carry this on formulary, and access may be limited.

The use of colistin may provide some coverage, but the toxicity (renal and optic nerve) is profound. Recent clinical trials suggest an increased mortality when colistin is used in highly resistant gram-negative infections (choice A is incorrect). Ceftazidime-avibactam was intermediate susceptibility in this case but even at high doses would not overcome the minimum inhibitory concentration enough to provide efficacy (choice B is incorrect). Ertapenem is a carbapenem that does not cover P aeruginosa, S maltophilia, and A baumannii and thus would have no activity (choice C is incorrect).1

Footnotes

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