Mechanisms of antimicrobial resistance in Gram-negative bacilli

Ruppé et al. Ann. Intensive Care (2015) 5:21 DOI 10.1186/s13613-015-0061-0 Open Access REVIEW Mechanisms of antimicrobial resistance in Gram‑negative bacilli Étienne Ruppé1, Paul‑Louis Woerther2 and François Barbier3* Abstract The burden of multidrug resistance in Gram-negative bacilli (GNB) now represents a daily issue for the management of antimicrobial therapy in intensive care unit (ICU) patients. In Enterobacteriaceae, the dramatic increase in the rates of resistance to third-generation cephalosporins mainly results from the spread of plasmid-borne extended-spectrum beta-lactamase (ESBL), especially those belonging to the CTX-M family. The efficacy of beta-lactam/beta-lactamase inhibitor associations for severe infections due to ESBL-producing Enterobacteriaceae has not been adequately evaluated in critically ill patients, and carbapenems still stands as the first-line choice in this situation. However, carbapenemase-producing strains have emerged worldwide over the past decade. VIM- and NDM-type metallo-betalactamases, OXA-48 and KPC appear as the most successful enzymes and may threaten the efficacy of carbapenems in the near future. ESBL- and carbapenemase-encoding plasmids frequently bear resistance determinants for other antimicrobial classes, including aminoglycosides (aminoglycoside-modifying enzymes or 16S rRNA methylases) and fluoroquinolones (Qnr, AAC(6′)-Ib-cr or efflux pumps), a key feature that fosters the spread of multidrug resistance in Enterobacteriaceae. In non-fermenting GNB such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia, multidrug resistance may emerge following the sole occurrence of sequential chromosomal mutations, which may lead to the overproduction of intrinsic beta-lactamases, hyper-expression of efflux pumps, tar‑ get modifications and permeability alterations. P. aeruginosa and A. baumannii also have the ability to acquire mobile genetic elements encoding resistance determinants, including carbapenemases. Available options for the treatment of ICU-acquired infections due to carbapenem-resistant GNB are currently scarce, and recent reports emphasizing the spread of colistin resistance in environments with high volume of polymyxins use elicit major concern. Keywords: Enterobacteriaceae, Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia, Antimicrobial resistance, Extended-spectrum beta-lactamase, Carbapenemase, Colistin, Intestinal microbiota, Intensive care unit Background The burden of antimicrobial resistance in Gram-negative bacilli (GNB) is a daily challenge to face for intensive care unit (ICU) physicians. Indeed, GNB are responsible for 45–70% of ventilator-associated pneumonia (VAP) [1], 20–30% of catheter-related bloodstream infections [2], and commonly cause other ICU-acquired sepsis such as surgical site or urinary tract infections (UTI) [3]. In such situations, the timely administration of adequate antibiotic coverage is a crucial determinant of patient outcome, *Correspondence: francois.barbier@chr‑orleans.fr 3 Medical Intensive Care Unit, La Source Hospital - CHR Orléans, Orléans, France Full list of author information is available at the end of the article especially when criteria for severe sepsis are present [4]. Nevertheless, alarming resistance rates are now reported worldwide, and rising trends may elicit concerns for the coming years [2, 3, 5–9]. Almost exclusively restricted to the hospital setting till the beginning of the century, this issue increasingly applies for patients with healthcareassociated [10, 11] and even community-acquired infections [12–14]. Enterobacteriaceae and non-fermenting GNB (Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia) account for the major part of the problem [15]. Antimicrobial resistance in GNB results from the expression of antibiotic-inactivating enzymes and nonenzymatic mechanisms [16]. Both may be intrinsically © 2015 Ruppé et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Ruppé et al. Ann. Intensive Care (2015) 5:21 expressed by a given species (chromosomal genes), or acquired by a subset of strains as a consequence of two distinct albeit not mutually exclusive genetic events: 1. Mutations in chromosomal genes resulting in an increase in the expression of intrinsic resistance mechanisms (either antibiotic-inactivating enzymes or efflux pumps), permeability alterations by loss of outer membrane porins, or target modifications; 2. Horizontal transfers of mobile genetic elements (MGEs) carrying resistance genes, most notably plasmid-encoding beta-lactamases, aminoglycosides-modifying enzymes (AMEs), or non-enzymatic mechanisms such as Qnr for fluoroquinolone resistance in Enterobacteriaceae. Since these plasmids commonly bear multiple resistance determinants, a single plasmid conjugation may suffice to confer a multidrug resistance phenotype to the recipient strain. The mechanisms of antimicrobial resistance in GNB may interfere with several facets of antibiotic stewardship Page 2 of 15 algorithms in critically ill patients, including the choice of empirical regimen, available options for de-escalation, and the management of clinical failure due to the emergence of resistance under therapy [17, 18]. In this concise review, we sought to summarize the current knowledge on resistance mechanisms and epidemiologic trends in the main clinically relevant species belonging to Enterobacteriaceae and non-fermenting GNB, and make the connection with the use of antimicrobial therapy in the ICU. Review Current trends in the global epidemiology of multidrug‑resistant GNB Each given ICU has its own bacterial ecology, which may fluctuate owing to antibiotic use policies, patient recruitment and sporadic outbreaks. Yet, data from large surveillance networks yield a general overview of resistance rates in GNB causing ICU-acquired infections (Table 1). Following a decade of steady rise [19], rates of resistance to third-generation cephalosporins (3GC) in Enterobacteriaceae are now constantly above 10% and may reach 70% Table 1 Rates of antimicrobial resistance in Gram-negative bacilli responsible for hospital-acquired infections Study/surveillance network INICC [3] SENTRY [9] ANSRPRG [8] EARS-NET [5] Geographic area International (36 countries) International (Europe/USA) International (Asia) International (Europe) Study years 2004–2009 2009–2011 2008–2009 2013 Setting ICU ICU ICU/non-ICU ICU/non-ICU Pneumonia Bloodstream infections Type of hospital-acquired infections Catheter-related infections and ventila‑ All (pooled) t (...truncated)