Treatment options for K. pneumoniae, P. aeruginosa and A. baumannii co-resistant to carbapenems, aminoglycosides, polymyxins and tigecycline: an approach based on the mechanisms of resistance to carbapenems

Abstract

The management of carbapenem-resistant infections is often based on polymyxins, tigecycline, aminoglycosides and their combinations. However, in a recent systematic review, we found that Gram-negative bacteria (GNB) co-resistant to carbapanems, aminoglycosides, polymyxins and tigecycline (CAPT-resistant) are increasingly being reported worldwide. Clinical data to guide the treatment of CAPT-resistant GNB are scarce and based exclusively on few case reports and small case series, but seem to indicate that appropriate (in vitro active) antimicrobial regimens, including newer antibiotics and synergistic combinations, may be associated with lower mortality. In this review, we consolidate the available literature to inform clinicians dealing with CAPT-resistant GNB about treatment options by considering the mechanisms of resistance to carbapenems. In combination with rapid diagnostic methods that allow fast detection of carbapenemase production, the approach proposed in this review may guide a timely and targeted treatment of patients with infections by CAPT-resistant GNB. Specifically, we focus on the three most problematic species, namely Klebsiella pneumoniae , Pseudomonas aeruginosa and Acinetobacter baumannii . Several treatment options are currently available for CAPT-resistant K. pneumonia . Newer β-lactam-β-lactamase combinations, including the combination of ceftazidime/avibactam with aztreonam against metallo-β-lactamase-producing isolates, appear to be more effective compared to combinations of older agents. Options for P. aeruginosa (especially metallo-β-lactamase-producing strains) and A. baumannii remain limited. Synergistic combination of older agents (e.g., polymyxin- or fosfomycin-based synergistic combinations) may represent a last resort option, but their use against CAPT-resistant GNB requires further study.

Treatment Options for <em>K. pneumoniae</em>, <em>P. aeruginosa</em> and <em>A. baumannii</em> Co-resistant to Carbapenems, Aminoglycosides, Colistin and Tigecycline. An Approach Based on the Mechanisms of Resistance to Carbapenems

“…The frequency of carbapenemase-negative carbapenem-resistant K. pneumoniae is also highly variable in different countries and continents [8,28,32]. Porin mutations or efflux pump overexpression (often combined with the production of other betalactamases) appear to be responsible for the resistance in carbapenemase-negative K. pneumoniae [34][35][36][37].…”

“…On the other hand, options for MBL-producing K. pneumoniae are limited. The novel β-lactam-βlactamase inhibitor combinations, including ceftazidime/avibactam [56], ceftolozane/tazobactam [74], meropenem/vaborbactam [75] and imipenem/relebactam [52], are inactive against MBL-producing GNB [76]. In contrast, the combination of aztreonam with avibactam may restore activity against MBL-producing isolates [57,77], because aztreonam is not hydrolyzed by MBLs and avibactam effectively inhibits other beta-lactamases (ESBL, KPC and OXA-48) that can hydrolyze aztreonam.…”

“…Other potential options for CACT-resistant K. pneumoniae include eravacycline, fosfomycin and cefiderocol. Eravacycline is more potent compared to tigecycline, and may be active against some tigecycline-resistant strains (especially considering the current EUCAST susceptibility breakpoint for tigecycline) [87,88] . Successful use of fosfomycin against extensively drugresistant K. pneumoniae has been reported in small case series, often in combination with other antimicrobials [89,90].…”

“…Both are less prone to outer membrane permeability changes (porin loss/ efflux pumps) and neither is affected by AmpC (ceftolozane is stable against AmpC and avibactam restores the activity of ceftazidime by inhibition of AmpC) [97,98]. Therefore, both ceftazidime/avibactam and ceftolozane/tazobactam remain highly active (81-92% [97,[99][100][101][102]) against non-MBL carbapenem-resistant P. aeruginosa, but susceptibility may be much lower (41-48% [42,99]) in isolates co-resistant to multiple anti-pseudomonal beta-lactams (ceftazidime, piperacillin/tazobactam and cefepime). Generally, ceftolozane/tazobactam appears to be more potent than ceftazidime/avibactam in noncarbapenemase producing P. aeruginosa [97,98], and has been used successfully against ventilator-associated pneumonia by CACT-resistant P. aeruginosa [103].…”

Carbapenem-Resistant Klebsiella pneumoniae Clinical Isolates: In Vivo Virulence Assessment in Galleria mellonella and Potential Therapeutics by Polycationic Oligoethyleneimine

“…Very few treatment options are available for patients infected with K. pneumoniae producing KPC or OXA-48-like carbapenemases and are often limited to administration of multiple antibiotic therapies and to colistin [ 17 , 18 ]. In the light of this, in this study, we report the use of a polycationic synthetic oligomer, linear oligoethyleneimine hydrochloride (L-OEI-h), as an antimicrobial agent for the treatment of K. pneumonia KPC(+) and OXA-48(+) bacterial infections.…”