Abstract
Acinetobacter baumannii is an opportunistic pathogen associated with nosocomial and community infections of great clinical relevance. Its ability to rapidly develop resistance to antimicrobials, especially carbapenems, has re-boosted the prescription and use of polymyxins. However, the emergence of strains resistant to these antimicrobials is becoming a critical issue in several regions of the world because very few of currently available antibiotics are effective in these cases. This review summarizes the most up-to-date knowledge about chromosomally encoded and plasmid-mediated polymyxins resistance in A. baumannii. Different mechanisms are employed by A. baumannii to overcome the antibacterial effects of polymyxins. Modification of the outer membrane through phosphoethanolamine addition, loss of lipopolysaccharide, symmetric rupture, metabolic changes affecting osmoprotective amino acids, and overexpression of efflux pumps are involved in this process. Several genetic elements modulate these mechanisms, but only three of them have been described so far in A. baumannii clinical isolates such as mutations in pmrCAB, lpxACD, and lpsB. Elucidation of genotypic profiles and resistance mechanisms are necessary for control and fight against resistance to polymyxins in A. baumannii, thereby protecting this class for future treatment.
Similar content being viewed by others
Introduction
Acinetobacter baumannii is a Gram-negative, non-glucose-fermenting, oxidase-negative coccobacillus, most commonly related to healthcare-associated infections [1,2,3]. It is an opportunistic microorganism that causes several clinical complications in immunocompromised individuals such as pneumonia, bacteremia, meningitis, endocarditis, cellulitis, and urinary tract and soft-tissue infections [4,5,6]. In hospital settings, A. baumannii mainly affects patients in mechanical ventilation of intensive care units (ICUs). It is noteworthy that this microorganism has been responsible for one in five cases of ventilator-associated pneumonia in Europe [7] and 20% of ICUs infections in the USA [8].
The rapid capacity to develop antimicrobial resistance through various intrinsic and acquired mechanisms is notable in A. baumannii [2, 9, 10]. In British and American ICUs, more than 25 and 30% of A. baumannii isolates, respectively, are resistant to at least three classes of antimicrobials, being considered multidrug resistant (MDR) [11, 12]. Furthermore, in Asia and Eastern Europe countries, higher rates of resistance are observed, with 48 to 85% being MDR [13, 14]. In fact, A. baumannii is commonly associated with resistance to ureidopenicillins, cephalosporins (including extended-spectrum drugs), fluoroquinolones, aminoglycosides, and carbapenems [15, 16]. Carbapenems antibiotics are used as the primary option to treat severe MDR Gram-negative bacterial infections [15, 17]. However, carbapenemase-producing A. baumannii has increased rapidly on a global scale and are considered to be significant health threats. Thus, confronting the problem associated with carbapenem-resistant A. baumannii, the biomedical community has revived the use of polymyxins [9, 18, 19].
Isolated in 1947 as secondary metabolites of Paenibacillus polymyxa (anteriorly Bacillus polymyxa), the polymyxins showed a potent bactericidal effect against several Gram-negative species [20, 21]. They are a cyclic decapeptide consisting of a heptapeptide ring and a tripeptide side chain that attaches to a fatty acid. At physiological pH (7.2), five amino acid residues of the decapeptide portion are positively charged. Thus, the polymyxins can bind to the negative surface of lipopolysaccharide (LPS) that form the outer membrane (OM) of Gram-negative bacteria [21, 22]. After the ionic interaction, the fatty acid chain is inserted inside the OM, disrupting the bacterial membranes and resulting in cellular death [23]. In clinical settings, polymyxin B and colistin (polymyxin E) are frequently used; they have similar biological activities but differ structurally, with D-phenylalanine in polymyxin B replaced by D-leucine in colistin [24]. Until the 1960s, polymyxins had been the most popular therapeutic option for severe infections with Gram-negative bacteria, but their use has been restricted since 1970 because of the significant nephrotoxicity and neurotoxicity associated with prolonged treatment [25].
The re-boosted of polymyxin use increases the selective pressure that favors the resistant strains. Currently has already been reported low sensitivity to colistin and polymyxin B between Acinetobacter spp. [19], Pseudomonas spp., and Enterobacteriaceae species [26, 27] from several regions of the world. Also, has increased the frequency of infections caused by microorganisms intrinsically resistant to this class, such as Proteus spp. and Serratia spp. [28]. Moreover, the emergence of a plasmid-carried gene (mcr), associated with moderate colistin resistance, makes this scenario even more adverse [29]. Accordingly, the present review summarizes the most up-to-date knowledge about chromosomally encoded and plasmid-mediated polymyxins resistance in A. baumannii as well as characterizes the biochemical mechanisms that underlie this phenomenon.
Chromosomally encoded resistance to polymyxins in A. baumannii
Outer membrane changes
Gram-negative outer membrane (OM) is the molecular target of polymyxins action. Thus, alterations in this component can compromise the bactericidal effect and reduce the microorganism susceptibility to the drug in question [29,28,29,30,31,34]. The mechanisms underlying polymyxin resistance are complex, but in A. baumannii, the mutations that affect the OM stand out [35, 36]. Four different polymyxins resistance mechanisms have been previously reported to this species, being (i) modification of lipid A structure by the addition of phosphoethanolamine, (ii) complete loss of LPS via mutations in the genes that synthesize lipid A, (iii) reduction in the expression of cofactors involved in LPS synthesis, and (iv) downregulation of proteins that participate in the export and/or stabilization of OM precursors (Fig. 1).
The first mechanism is associated with mutations in pmrA and pmrB genes [31, 37,36,37,40]. They encode a two-component regulatory system that controls the expression of the pmrC gene, which encodes lipid A phosphoethanolamine transferase [38, 41], and of the pmrF operon, responsible for the expression of the enzymes involved in 4-deoxy-aminoarabinose biosynthesis (Ara4N) [15]. Modification of lipid A, a component of LPS, by the addition of Ara4N or/and phosphoethanolamine, protects the OM from binding and action of polymyxins [42]. The lipid A phosphates are esterified by these metabolites decreasing so the repulsion between adjacent LPS molecules into Gram-negatives OM. Hence, a more compact and lower negatively charged LPS layer is formed, which shows reduced sensitivity to the positively charged polymyxins [43]. However, it should be highlighted that Ara4N biosynthesis is not present in A. baumannii [24] and N. meningitidis [15] since the operon pmrF is absent in these species. Of note, N. meningitidis is intrinsically resistant to colistin, suggesting that pmrC modulation may be associated with polymyxin B and colistin resistance in A. baumannii [44].
Function gain mutations in pmrA and/or pmrB are associated with high rates of colistin resistance in P. aeruginosa [45] and Salmonella spp. [46]. Adams et al. (2009) showed the first evidence that the PmrAB two-component system is involved in polymyxins resistance in A. baumannii. Initially, they found that the partial deletion of pmrB in a colistin-resistant (CoR) A. baumannii results in reversion to a colistin-sensitive (CoS) phenotype [31]. Arroyo et al. (2011) [38] demonstrated that partial removal of pmrC results in an increase in the sensitivity in CoR A. baumannii, with a decrease in polymyxin B minimum inhibitory concentration (MIC) from 4 to 0.25 μg mL−1. The positive regulation of pmrC induced by mutations in pmrAB is so efficient that specific genetic alterations affecting one or both genes generate a 26- to 292-fold increase in the level of pmrC expression.
Mass spectrometric analyses have confirmed that isolates with mutations in pmrAB showed the phosphoethanolamine addition in a hepta-acylated lipid A. However, according to Beceiro et al. (2011) [37] even with increased expression of pmrA (12.4-fold increase) and pmrB (6.8-fold increase) in CoR A. baumannii, the amount of the pmrC transcription may remains unchanged, suggesting that PmrAB-independent systems are associated with regulation of pmrC in A. baumannii. Also, little is known about the regulation of PmrAB two-component system in this species. In other Gram-negative bacilli, such as Salmonella enterica, Pseudomonas aeruginosa, and Klebsiella pneumoniae, the PmrAB two-component system is directly or indirectly modulated by the PhoPQ system [47]. However, the absence of the PhoPQ component in A. baumannii points to another regulatory factor [15]. Thus, more studies in the direction of elucidating the mechanism(s)/factor(s) that modulate the expression of the pmrA and pmrB genes, as well as those targeted to describing the regulation pmrAB-independent of pmrC gene, are important for understanding the dynamics of resistance to polymyxins in A. baumannii.
Resistance due to lipid A modifications by a mutation in PmrAB two-component system has a relatively low biologic cost, especially concerning A. baumannii virulence [48,47,50]. Additionally, the sensitivity patterns of amikacin, piperacillin-tazobactam, ciprofloxacin, azithromycin, cefepime, gentamicin, minocycline, tigecycline, ampicillin, and teicoplanin is similar between CoR-pmrB mutant and wild-type A. baumannii [48, 49]. CoR-pmrB mutant strains also develop cross-resistance to antimicrobial that constitutes the innate immune response of host cells, such as LL-37 and lysozyme [50]. These studies suggest that there is a low fitness burden associated with the development of polymyxins resistance via pmrAB mutation (Table 1) [19, 58].
The clinical importance of mutations in the pmrCAB operon has been demonstrated in several studies (Table 2) [18, 19, 37, 38, 40, 55, 56, 59,57,58,62]. Most clinical isolates have shown mutations in the pmrB, but mutations in pmrA and pmrC have also been observed. Substitutions represent the most frequent mutation type for all three proteins, with only two deletions (Δ32–35 and Δ160) [38] and one insertion (A163) [19] identified, both involving PmrB. The most frequent substitutions in PmrB were found to be P233S, P360Q, A226V, L208F, and A138T. However, one study revealed that CoS A. baumannii also carries substitutions in PmrB, such as A138T and A226V, suggesting that only these mutations may be unrelated to colistin resistance in this species [18]. In PmrA, a highly conserved mutation, with the substitution of proline by histidine at position 102, was observed in 14 isolates of CoR A. baumannii [55] and in one bacterium with resistance induced in vitro [31].
Moffatt et al. (2010) confirmed the resistance to polymyxins in A. baumannii attributed to the interference with OM synthesis [32]. They have found that a full inactivation of the lipid A biosynthetic genes—lpxA, lpxC, or lpxD—results in a complete loss of surface LPS in A. baumannii. Thus, the loss of LPS prevents the essential interaction between it and polymyxins, giving rise to very high colistin MICs. For example, a loss of LPS after the deletion at position 90 of LpxA protein showed a 130-fold increase in colistin MIC. In this context, the transformation of the A. baumannii mutant with a wild-type lpxA restored the CoS phenotype, reducing the MIC to 1 μg mL−1 [32]. Insertion sequences (IS) affecting the Lpx system have also been identified [51, 52]. The insertion of IS element Aba11 into lpxC and lpxA genes is associated with high resistance to colistin (MIC > 128 μg mL−1) [51] and polymyxin B (MIC > 32 μg mL−1) [53]. In addition, the presence of the ISAba125 element within lpxA in a strain with resistance induced by contact with polymyxin B in vitro was demonstrated in a recent study [52].
Contrasting with the mutations that affected the PmrAB two-component regulatory system, the LPS loss showed a high biologic cost, which limited its spread in clinical environments. The growth rate (μ) during the exponential phase, for example, was found to be significantly lower in ΔlpxA (μ = 0.85 ± 0.09), ΔlpxD (μ = 1.03 ± 0.09), and ΔlpxC (μ = 0.49 ± 0.03) A. baumannii in relation to the wild-type (μ = 1.56 ± 0.27) [54]. Similarly, strains with induced resistance to colistin yield less biomass at the end of 16 h of growth in Mueller-Hinton broth [49] and the capacity for adhesion and formation of biofilms is also compromised under static and dynamic conditions [56]. The virulence of A. baumannii lpxACD mutant is widely affected such shown by the viability of human lung alveolus cells (A546), which is significantly lower after exposure to strain wild-type. Similar results were obtained in in vivo infection models [48, 54]. Survival rates of mice [54] and invertebrates Caenorhabditis elegans [54] and Galleria mellonella [48] were found to be considerably lower after infection with wild-type or pmrAB mutants when compared with strains without LPS. Additionally, the loss of LPS alters the host’s immune response [63]. Exposure of RAW264.7 macrophages to LPS-deficient A. baumannii causes smaller activation of NF-κB and TNF-α [63], as well as increases the sensibility to organic antibacterial components, such as LL-37 [63] and lysozyme [64]. Indeed, it has been observed that MICs for teicoplanin, cefepime, azithromycin, amikacin, gentamicin, piperacillin/tazobactam, meropenem, ciprofloxacin, rifampicin, and vancomycin are considerably lowered after LPS loss in A. baumannii (Table 1) [32, 48, 64].
In this direction, few resistant isolates to polymyxins with genetic alterations involving lpx have been recovered (Table 2). In clinical strains, different molecular events, such as deletions, point mutations, or insertions, can inactivate any of the first three genes (lpxA, lpxC, and lpxD) in the lipid A biosynthetic pathway of A. baumannii. Substitutions are the most frequent genetic events in LpxC and LpxD [47, 55]. However, concerning lpxA, insertions (position 732) and deletions (position 776) related to low sensitivity to colistin and polymyxin B stand out. These mutations alter the size of primary sequences of proteins involved in LPS pathway, making them enzymatically inactive and unable to synthesize lipid A [9].
Recently, four more genes (lpsB, lptD, vacJ, and Locus of biotin synthesis) were shown to have a role to polymyxins resistance in A. baumannii (Table 1). These novel resistance mechanisms are poorly known, but some studies are trying to elicit their role in colistin and polymyxin B resistance in this Gram-negative bacillus. The lpsB gene contributes to the protection of A. baumannii from cationic antimicrobial peptides because it encodes the glycosyltransferase responsible for LPS structural ring synthesis [65, 66], which is directly associated with lower fluidity and higher osmotic resistance of the OM [67]. Time-kill curve study indicates that ΔlpsB -A. baumannii have higher sensitivity to LL-37 and colistin than the wild-type strain [30]. Also, the survival rate is lower after the pulmonary infection of animals with ΔlpsB strains [30]. These data suggest that mutations associated with overexpression of this gene may contribute to the resistance and virulence of A. baumannii. In clinical isolates, polymyxin resistance induced by mutations in LpsB has been described (Table 2) [55, 56]. Substitution of a histidine for a tyrosine at position 181 of LpsB was found in eight clinical isolates from Malaysia [55]. Another study revealed that the premature add of a stop codon in lpsB is also associated with high resistance to colistin (MIC 128 μg mL−1) but with a reduced ability to form biofilms [56].
The Lpt system component LptD, which is responsible for the insertion of LPS into the OM [57, 68], is also involved with polymyxins resistance in A. baumannii. Experimental removal of LptD results in moderate polymyxin B resistance, low virulence, and an increase of sensitivity to antibiotics non-polymyxins [57, 67]. The growth kinetics of ΔlptD -A. baumannii is characterized by an extensive log phase, a slower proliferation rate, a decrease in the exponential phase, and low cell density in the stationary phase [57]. Additionally, the sensitivity to fusidic acid, novobiocin, azithromycin, rifampicin, and ciprofloxacin were found to be higher in ΔlptD strains than in ΔlpxC [67]. The accumulation of LPS components into a bacterial cell in ΔlptD strains impairs the membrane stability and consequently reduces the fitness of A. baumannii. Consequently, the pharmacological inhibition of lpxC with the compound CHIR-090 as well as antagonism of enzymes β-ketoacyl-ACP synthases I and II by cerulenin, which is essential for the LPS biosynthesis, partially or completely recovered the fitness in lptD-mutant A. baumannii [57, 69].
A recent study has revealed that the loss of OM asymmetry is also involved in reducing the colistin susceptibility of A. baumannii. In several Gram-negatives species, the Vps/VacJ ATP-binding cassette (ABC) transporter system is proposed to function in maintaining the lipid asymmetry of OM, which ensures that the LPS remains on the outer face and phospholipids on the inner face [70]. Nhu et al. (2016) have shown that A. baumannii with a single mutation in VacJ (R166N) shows a highly colistin-resistant phenotype (MIC > 256 μg mL−1) [33]. However, several studies have shown that VacJ is essential for the virulence of Gram-negative pathogens such as Shigella flexneri [71, 72], Campylobacter lari [73], P. aeruginosa [74], Actinobacillus pleuropneumoniae [75], and Haemophilus parasuis [76]. Additionally, resistance to phenol in Pseudomonas putida [77], to paraquat in Campylobacter jejuni [78], to ceftriaxone in S. enterica serovar Typhimurium [79], and to tetracycline, chloramphenicol, and ciprofloxacin in P. aeruginosa [74] are mediated by vacJ. Nonetheless, due to the importance of virulence and resistance factor in several Gram-negative bacteria, VacJ may be necessary for the fitness of A. baumannii, but this remains to be elucidated.
The levels of biotin are also an essential factor related to the susceptibility to polymyxins in A. baumannii. It is an important co-factor of lipid metabolism, being that the acetyl-CoA carboxylase complex, which catalyzes the conversion of acetyl-CoA into malonyl-CoA, a rate-limiting step in fatty acid synthesis, only is active when binding to biotin [66]. Higher biotin levels cause increased production of lipid A and increase sensitivity to colistin. Thus, the removal of genes that synthesize this co-factor is related to a reduction in the sensitivity of A. baumannii to colistin [30]. Herein, it has been shown that the removal of the A1S_0807 locus, which contains genes responsible for the synthesis of biotin, significantly reduces the sensitivity of A. baumannii to colistin [30].
Changes in osmoprotective amino acid metabolism
Some amino acids such as proline, glycine, and aspartate are essential for the balance of solutes in prokaryotic cells. They participate as organic osmolytes and are biosynthesized to a higher degree after exposure of the bacterial cell to conditions of osmotic stress [80, 81]. Therefore, it is expected that quantitative modifications of these amino acids influence microbial sensitivity to compounds that induce osmotic fragility, such as polymyxins (Fig. 1).
According to Hood et al. (2013) [30], after colistin resistance induced in medium supplemented with NaCl (150 mM), A. baumannii shows a considerable reduction in the biosynthesis of osmoprotective amino acids. Possibly, this result is due to the negative regulation of genes involved in the production of proline from glutamate and in the metabolism of aspartate. On the other hand, mutations that compromise expression of the enzymes associated with aspartate catabolism, e.g., diaminobutyrate-2-oxoglutarate transaminase, may raise rates of resistance to colistin [30]. Additionally, it has been reported that alterations in genes that are related to biosynthetic feeder pathways of these amino acids, such as those involved in the maintenance of the tricarboxylic acid cycle, also contribute to colistin resistance [30]. Thus, an increase in the synthesis or a reduction in the catabolism of osmoprotective amino acids makes bacterial cells less susceptible to polymyxin-induced lysis (Table 1).
Efflux pumps
In A. baumannii, four categories of efflux pumps are related to antimicrobial resistance, including resistance-nodulation-division (RND), major facilitator (MF), multidrug-toxic compound extrusion (MATE), and small multidrug resistance (SMR) families [82,77,84]. The ErmAB protein, an efflux pump belonging to the MF family, has been attributed to MDR in several Enterobacteriaceae [85,80,87]. Some strains of E. coli that harbor plasmids containing genes emrA and emrB show high resistance to antimicrobial detergents [86, 87]. Since polymyxins have amphipathic characteristics and behave similarly to other biological detergents, there is a possibility that this system may be implicated in resistance to the antimicrobials in question (Fig. 1).
To clarify the relationship between the efflux system and the polymyxin resistance in A. baumannii, a study has conducted a genomic analysis and revealed the presence of four pairs of genes named emrA-like/emrB-like in this species. It is noteworthy that the removal of sequence emrB-like results in increased sensitivity to colistin in A. baumannii, with a reduction in the MIC in a dilution. Time-kill curve studies have also revealed that the loss of emrAB is associated with worse survival of A. baumannii after 4 h in plates containing 1 μg mL−1 of polymyxin B [34]. In support to the evidence for the role of the EmrAB efflux system in resistance to polymyxins in A. baumannii, a strain with laboratory-induced resistance showed a 1.6-fold increase in the expression level of emrB-like [34]. These data validate the involvement of EmrAB-like efflux pumps in the decrease of sensitivity to polymyxins in A. baumannii; however, the clinical importance of this mechanism remains to be elucidated.
In some microorganisms such as Pseudomonas putida, the ttg2C gene encodes an efflux pump involved in tolerance to toluene [88]. A recent work showed that in A. baumannii with colistin resistance induced in vitro, the substitution of asparagine by methionine at position 104 in Ttg2C is associated with high resistance (MIC > 256 μg mL−1) [33]. This result suggests that ttg2C may encode other transporters and promotes efflux of polymyxins, but further research is needed to test whether these antibiotics are in fact substrates of this efflux system.
Plasmid-mediated resistance to polymyxins in A. baumannii
Resistance to colistin in A. baumannii was originally chromosomal, which limits its rapid distribution and dissemination [30,29,32]. However, a plasmid-borne gene, called mcr-1, was identified in Escherichia coli of animal, human, and environmental origin from China in 2015 [29]. Subsequently mcr-1.2, mcr-2, mcr-3, mcr-4, and mcr-5 variants were also identified [89,84,85,86,93].
The mcr genes encode a phosphoethanolamine transferase that leads low to moderate polymyxin resistance (MIC from 4 to 16 μg mL−1) [15]. Structurally, the N-terminal region of the enzyme encoded by mcr is inserted into the inner membrane, while its C-terminal domain continues into the periplasmic space. The latter process allows the addition of phosphoethanolamine resulting from the cleavage of phosphatidylethanolamine in the 3-deoxy-d-manno-octulosonic acid residue of LPS [94, 95].
The diversity of plasmids harboring mcr described in Enterobacteriaceae on different continents shows high potential for dissemination of this gene [30]. By the time of this review, mcr has been identified in E. coli, K. pneumoniae, Salmonella spp., Shigella sonnei, Klebsiella (anteriorly Enterobacter) aerogenes, Enterobacter cloacae, Cronobacter sakazakii, Kluyvera ascorbata, Citrobacter freundii, and Moraxella spp. [96,90,91,99], but in vitro studies also revealed the possibility of gene acquisition from K. pneumoniae to P. aeruginosa by transformation [100]. In A. baumannii, there is still no report of mcr-positive isolates but, the rapid dissemination of this gene as well as the real possibility of non-glucose-fermenting Gram-negative bacilli (e.g., P. aeruginosa) to acquire mcr from Enterobacteriaceae suggest that this is only a matter of time [33]. Thus, the intensification of surveillance studies is imperative for control of the dissemination of mcr and for protection of the class of polymyxins, which are still an important therapeutic option for the treatment of A. baumannii extremely-drug-resistant (XDR) infections [15].
Conclusion remarks
Currently, polymyxin-resistant A. baumannii represents less than 1% of clinical isolates, but they pose a significant challenge to public health authorities [101]. Polymyxins are the last pharmacological resource available to treat infections caused by XDR A. baumannii. Unfortunately, lineages with low sensitivity to polymyxins have increased in many parts of the world, especially in Europe, Asia, and South America [2, 19]. This fact suggests that the loss of polymyxins to drug resistance seems to be inevitable in the future. Although chromosomal mutations mediate the polymyxin resistance in A. baumannii, the emergence of plasmid-mediated mcr, which may be transferable between bacterial species and increasing rates of polymyxin resistance in carbapenem-resistant bacteria, is of great concern. Although our understanding of the mechanisms and occurrence of polymyxin resistance has increased in recent years, we know very little about the impact of the different mechanism in the clinic. Thus, reinforcing the detection of polymyxin-resistant isolates must be encouraged so that we can better understand the impacts of each mechanism and outline more effective control measures in each case.
References
Lăzureanu V, Poroșnicu M, Gândac C, Moisil T, Bădițoiu L, Laza R, Musta V, Crisan A, Marinesco AR (2016) Infection with Acinetobacter baumannii in an intensive care unit in the Western part of Romania. BMC Infect Dis 16:24–28
Bardbari AM, Arabestani MR, Karami M, Keramat F, Aghazadeh H, Alikhani MY, Bagheri KP (2018) Highly synergistic activity of melittin with imipenem and colistin in biofilm inhibition against multidrug-resistant strong biofilm producer strains of Acinetobacter baumannii. Eur J Clin Microbiol Infect Dis. https://doi.org/10.1007/s10096-018-3189-7
Daitch V, Akayzen Y, Abu-Ghanem Y, Eliakim-Raz N, Paul M, Leibovici L, Yahav D (2018) Secular trends in the appropriateness of empirical antibiotics treatment in patients with bacteremia: a comparison between three prospective cohorts. Eur J Clin Microbiol Infect Dis. https://doi.org/10.1007/s10096-018-3190-1
Bergogne-Berezin E, Towner KJ (1996) Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev 9:148–165
Sebeny PJ, Riddle MS, Petersen K (2008) Acinetobacter baumannii skin and soft-tissue infection associated with war trauma. Clin Infect Dis 47:444–449
Sturiale M, Corpina C, Sturiale L (2016) Endocarditis due to Acinetobacter baumannii. Int J Cardiol 209:161–163
Koulenti D, Lisboa T, Brun-Buisson C, Krueger W, Macor A, Sole-Violan J, Diaz E, Topeli A, DeWaele J, Carneiro A, Martin-Loeches I, Armaganidis A, Rello J, EU-VAP/CAP Study Groupm (2009) Spectrum of practice in the diagnosis of nosocomial pneumonia in patients requiring mechanical ventilation in European intensive care units. Crit Care Med 37:2360–2368
Vincent J-L, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, Moreno R, Lipman J, Gomersall C, Sakr Y, Reinhart K, EPIC II Group of Investigators (2009) International study of the prevalence and outcomes of infection in intensive care units. JAMA 302:2323–2329
Selasi GN, Nicholas A, Jeon H, Lee YC, Yoo JR, Heo ST, Lee JC (2015) Genetic basis of antimicrobial resistance and clonal dynamics of carbapenem-resistant Acinetobacter baumannii sequence type 191 in a Korean hospital. Infect Genet Evol 36:1–7
El-Mahdy TS, Al-Agamy MH, Al-Qahtani AA, Shibl AM (2016) Detection of blaOXA-23-like and blaNDM-1 in Acinetobacter baumannii from the Eastern Region, Saudi Arabia. Microb Drug Resist 23:115–121
Livermore DM, Hill RLR, Thomson H, Charlett A, Turton JF, Pike R, Patel BC, Manuel R, Gillespie S, Barrett SP, Cumberland N, Twagira M, C-MRAB Study Group (2010) Antimicrobial treatment and clinical outcome for infections with carbapenem- and multiply-resistant Acinetobacter baumannii around London. Int J Antimicrob Agents 35:19–24
Lockhart SR, Abramson MA, Beekmann SE, Gallagher G, Riedel S, Diekema DJ, Quinn JP, Doern GV (2009) Antimicrobial resistance among gram-negative bacilli causing infections in intensive care unit patients in the United States between 1993 and 2004. J Clin Microbiol 45:3352–3359
Jean SS, Hsueh PR (2011) High burden of antimicrobial resistance in Asia. Int J Antimicrob Agents 37:291–295
Gaynes R, Edwards JR, National Nosocomial Infections Surveillance System (2005) Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect 41:848–854
Jeannot K, Bolard A, Plésiat P (2017) Resistance to polymyxins in Gram-negative organisms. Int J Antimicrob Agents 49:526–535
Rossi F, Girardello R, Cury AP, Di Gioia TSR, Almeida-Junior JN, Duarte AJS (2017) Emergence of colistin resistance in the largest university hospital complex of São Paulo, Brazil, over five years. Braz J Infect Dis 21:98–101
Georgis M (2016) Carbapenem resistance: overview of the problem and future perspective therapeutic advances in infectious diseases. Ther Adv Infect Dis 3:15–21
Oikonomou O, Sarrou S, Papagiannitsis CC, Georgiadou S, Mantzarlis K, Zakynthinos E, Zakynthinos E, Dalekos GN, Petinaki E (2015) Rapid dissemination of colistin and carbapenem resistant Acinetobacter baumannii in Central Greece: mechanisms of resistance, molecular identification, and epidemiological data. BMC Infect Dis 15:1–6
Bakour S, Olaitan AO, Ammari H, Touati A, Saoudi S, Saoudi K, Rolain JM (2014) Emergence of colistin- and carbapenem-resistant Acinetobacter baumannii ST2 2015 clinical isolate in Algeria: first case report. Microb Drug Resist 21:279–285
Hancock REW, Chapple DS (1999) Peptide antibiotics. Antimicrob Agents Chemother 43:1317–1323
Viehman JA, Nguyen MH, Doi Y (2014) Treatment options for carbapenem-resistant and extensively drug-resistant Acinetobacter baumannii infections. Drugs 74:1315–1333
Lynn WA, Golenbock DT (1992) Lipopolysaccharide antagonists. Immunol Today 13:271–276
Clausell A, Garcia-Subirats M, Pujol M, Busquets MA, Rabanal F, Cajal Y (2007) Gram-negative outer and inner membrane models: insertion of cyclic cationic lipopeptides. J Phys Chem Biol 111:551–563
Vardakas KZ, Falagas ME (2017) Colistin versus polymyxin B for the treatment of patients with multidrug-resistant Gram-negative infections: a systematic review and meta-analysis. Int J Antimicrob Agents 49:233–238
Velkov T, Roberts KD, Nation RL, Thompson PE, Li J (2013) Pharmacology of polymyxins: new insights into an ‘old’ class of antibiotics. Future Microbiol 8:711–724
Pellegrino FLPC, Teixeira LM, Carvalho MGS, Nouér SA, Oliveira MP, Sampaio JLM, Freitas AD, Ferreira ALP, Amorim ELT, Riley LW, Moreira BM (2002) Occurrence of a multidrug-resistant Pseudomonas aeruginosa clone in different hospitals in Rio de Janeiro, Brazil. J Clin Microbiol 40:2420–2424
Sampaio LM, Gales AC (2016) Antimicrobial resistantace in Enterobacteriaceae in Brazil: focus a β-lactamase and polymyxins. Braz J Microbiol 47:31–37
Chen CY, Chen YH, Lu PL, Lin WR, Chen TC, Lin CY (2012) Proteus Mirabilis urinary tract infection and bacteremia: risk clinical presentation, and outcomes. J Microbiol Immunol Infect 45:228–236
Liu YY, Wang Y, Walsh TR, Yi LX, Zhang R, Spencer J, Doi Y, Tian G, Dong B, Huang X, Yu LF, Gu D, Ren H, Chen X, Lv L, He D, Zhou H, Liang Z, Liu JH, Shen J (2016) Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study. Lancet Infect Dis 16:161–168
Hood MI, Becker KW, Roux CM, Dunman PM, Skaar EP (2013) Genetic determinants of intrinsic colistin tolerance in Acinetobacter baumannii. Infect Immun 81:542–551
Adams MD, Nickel GC, Bajaksouzian S, Lavender H, Murthy AR, Jacobs MR, Bonomo RA (2009) Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component system. Antimicrob Agents Chemother 53:3628–3634
Moffatt JH, Harper M, Harrison P, Hale JD, Vinogradov E, Seemann T, Henry R, Crane B, Michael F, Cox AD, Adler B, Nation RL, Li J, Boyce JD (2010) Colistin resistance in Acinetobacter baumannii is mediated by complete loss of lipopolysaccharide production. Antimicrob Agents Chemother 54:4971–4977
Nhu NTK, Riordan DW, Nhu TDH, Thanh DP, Thwaites G, Lan NPH, Wren BW, Baker S, Stabler RA (2016) The induction and identification of novel colistin resistance mutations in Acinetobacter baumannii and their implications. Sci Rep 6:1–10
Lin M-F, Lin Y-Y, Lan C-Y (2017) Contribution of EmrAB efflux pumps to colistin resistance in Acinetobacter baumannii. J Microb Feb 55:130–136
Loho T, Dharmayanti A (2015) Colistin: an antibiotic and its role in multiresistant Gram-negative infections. Acta Med Indones 47:157–168
Velkov T, Thompsom PE, Nation RL, Li J (2010) Structure-activity relationships of polymyxin antibiotics. J Med Chem 53:1898–1916
Beceiro A, Llobet E, Aranda J, Bengoechea JA, Doumith M, Hornsey M, Dhanji H, Chart H, Bou G, Livermore DM, Woodford N (2011) Phosphoethanolamine modification of lipid A in colistin-resistant variants of Acinetobacter baumannii mediated by the pmrAB two-component regulatory system. Antimicrob Agents Chemother 55:3370–3379
Arroyo LA, Herrera CM, Fernandez L, Hankins JV, Trent MS, Hancock RE (2011) The pmrCAB operon mediates polymyxin resistance in Acinetobacter baumannii ATCC17978 and clinical isolates through phosphoethanolamine modification of lipid A. Antimicrob Agents Chemother 55:3743–3751
Lean SS, Yeo CC, Suhaili Z, Thong KL (2016) Comparative genomics of two ST195 carbapenem-resistant Acinetobacter baumannii with different susceptibility to polymyxin revealed underlying resistance mechanism. Front Microbiol. https://doi.org/10.3389/fmicb.2015.01445
Rolain JM, Diene SM, Kempf M, Gimenez G, Robert C, Raoult D (2015) Real-time sequencing to decipher the molecular mechanism of resistance of a clinical pan-drug-resistant Acinetobacter baumannii isolate from Marseille, France. Antimicrob Agents Chemother 57:592–596
Raetz CRH, Reynolds CM, Trent MS, Bishop RE (2007) Lipid A modification systems in Gram-negative bacteria. Annu Rev Biochem 76:295–329
Olaitan AO, Morand S, Rolain J-M (2014) Mechanisms of polymyxin resistance: acquired and intrinsic resistance in bacteria. Front Microbiol. https://doi.org/10.3389/fmicb.2014.00643
Delcour AH (2009) Outer membrane permeability and antibiotic resistance. Biochim Biophys Acta 1794:808–816
Tzeng YL, Ambrose KD, Zughaier S, Zhou X, Miller YK, Shafer WM, Stephens DS (2005) Cationic antimicrobial peptide resistance in Neisseria meningitidis. J Bacteriol 187:5387–5396
Moskowitz SM, Ernst RK, Miller SI (2004) PmrAB, a two-component regulatory system of Pseudomonas aeruginosa that modulates resistance to cationic antimicrobial peptides and addition of aminoarabinose to lipid A. J Bacteriol 186:575–579
Murray SR, Ernst RK, Bermudes D, Miller SI, Low KB (2007) PmrA(Con) confers pmrHFIJKL-dependent EGTA and polymyxin resistance on msbB Salmonella by decorating lipid A with phosphoethanolamine. J Bacteriol 189:5161–5169
Mitrophanov AY, Jewett MW, Hadley TJ, Groisman EA (2008) Evolution and dynamics of regulatory architectures controlling polymyxin B resistance in enteric bacteria. PLoS Genet 4:1–11
Wand ME, Bock LJ, Bonney LC, Sutton JM (2015) Retention of virulence following adaptation to colistin in Acinetobacter baumannii reflects the mechanism of resistance. J Antimicrob Chemother 70:2209–2216
Mu X, Wang N, Li X, Shi K, Zhou Z, Yu Y, Hua X (2016) The effect of colistin resistance-associated mutations on the fitness of Acinetobacter baumannii. Front Microbiol 7:1–8
Napier BA, Burd EM, Satola SW, Cagle SM, Ray SM, McGann P, Pohl J, Lesho EP, Weiss DS (2013) Clinical use of colistin cross-resistance to host antimicrobials in Acinetobacter baumannii. MBio 4:1–5
Moffatt JH, Harper M, Adler B, Nation RL, Li J, Boyce JD (2011) Insertion sequence ISAba11 is involved in colistin resistance and loss of lipopolysaccharide in Acinetobacter baumannii. Antimicrob Agents Chemother 55:3022–3024
Girardello R, Visconde M, Cayô R, Figueiredo RC, Mori MA, Lincopan N, Gales AC (2016) Diversity of polymyxin resistance mechanisms among Acinetobacter baumannii clinical isolates. Diagn Microbiol Infect Dis 87:37–44
Lim TP, Ong RT, Hon PY, Hawkey J, Holt KE, Koh TH, Leong ML, Teo JQ, Tan TY, Ng MM, Hsu LY (2015) Multiple genetic mutations associated with polymyxin resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 59:7899–7902
Beceiro A, Moreno A, Fernández N, Vallejo JA, Aranda J, Adler B, Harper M, Boyce JD, Bou G (2014) Biological cost of different mechanisms of colistin resistance and their impact on virulence in Acinetobacter baumannii. Antimicrob Agents Chemother 58:518–526
Lean SS, Suhaili Z, Ismail S, Rahman NI, Othman N, Abdullah FH, Jusoh Z, Yeo CC, Thong KL (2014) Prevalence and genetic characterization of carbapenem- and polymyxin-resistant Acinetobacter baumannii isolated from a tertiary hospital in Terengganu, Malaysia. ISRN Microbiol 2014:1–9
Dafopoulou K, Xavier BB, Hotterbeekx A, Janssens L, Lammens C, Dé E, Goossens H, Tsakris A, Malhotra-Kumar S, Pournaras S (2015) Colistin-resistant Acinetobacter baumannii clinical strains with deficient biofilm formation. Antimicrob Agents Chemother 60:1892–1895
Bojkovic J, Richie DL, Six DA, Rath CM, Sawyer WS, Hu Q, Dean CR (2015) Characterization of an Acinetobacter baumannii lptD deletion strain: permeability defects and response to inhibition of lipopolysaccharide and fatty acid biosynthesis. J Bacteriol 198:731–741
Durante-Mangoni E, Del Franco M, Andini R, Bernardo M, Giannouli M, Zarrilli R (2015) Emergence of colistin resistance without loss of fitness and virulence after prolonged colistin administration in a patient with extensively drug-resistant Acinetobacter baumannii. Diagn Microbiol Infect Dis 82:222–226
Rolain JM, Roch A, Castanier M, Papazian L, Raoult D (2011) Acinetobacter baumannii resistant to colistin with impaired virulence: a case report from France. J Infect Dis 204:1146–1147
Pournaras S, Poulou A, Dafopoulou K, Chabane YN, Kristo I, Makris D, Hardouin J, Cosette P, Tsakris A, Dé E (2014) Growth retardation, reduced invasiveness, and impaired colistin-mediated cell death associated with colistin resistance development in Acinetobacter baumannii. Antimicrob Agents Chemother 58:828–832
Mavroidi A, Likousi S, Palla E, Katsiari M, Roussou Z, Maguina A, Platsouka ED (2015) Molecular identification of tigecycline- and colistin-resistant carbapenemase-producing Acinetobacter baumannii from a Greek hospital from 2011 to 2013. J Med Microbiol 64:993–997
Valencia R, Arroyo LA, Conde M, Aldana JM, Torres MJ, Fernández-Cuenca F, Garnacho-Montero J, Cisneros JM, Ortíz C, Pachón J, Aznar J (2009) Nosocomial outbreak of infection with pan-drug resistant Acinetobacter baumannii in a tertiary care university hospital. Infect Control Hosp Epidemiol 30:257–263
Moffatt JH, Harper M, Mansell A, Crane B, Fitzsimons TC, Nation RL, Li J, Adler B, Boyce JD (2013) Lipopolysaccharide-deficient Acinetobacter baumannii shows altered signaling through host Toll-like receptors and increased susceptibility to the host antimicrobial peptide LL-37. Infect Immun 81:684–689
García-Quintanilla M, Carretero-Ledesma M, Moreno-Martínez P, Martín-Peña R, Pachón J, McConnell MJ (2015) Lipopolysaccharide loss produces partial colistin dependence and collateral sensitivity to azithromycin, rifampicin and vancomycin in Acinetobacter baumannii. Int J Antimicrob Agents 46:696–702
Luke NR, Sauberan SL, Russo TA, Beanan JM, Olson R, Loehfelm TW, Cox AD, Michael F, Vinogradov EV, Campagnari AA (2010) Identification and characterization of a glycosyltransferase involved in Acinetobacter baumannii lipopolysaccharide core biosynthesis. Infect Immun 78:2017–2023
Whitfield C, Trent MS (2014) Biosynthesis and export of bacterial lipopolysaccharides. Annu Rev Biochem 83:99–128
Kabanov DS, Prokhorenko IR (2010) Structural analysis of lipopolysaccharides from Gram-negative bacteria. Biochemistry (Mosc) 75:383–404
Schmidt J, Patora-Komisarska K, Moehle K, Obrecht D, Robinson JA (2013) Structural studies of β-hairpin peptidomimetic antibiotics that target LptD in Pseudomonas sp. Bioorg Med Chem 21:5806–5810
Li X, Gu Y, Dong H, Wang W, Dong C Trapped lipopolysaccharide and LptD intermediates reveal lipopolysaccharide translocation steps across the Escherichia coli outer membrane. Sci Rep 5:1–8
Malinverni JC, Silhavy TJ (2009) An ABC transport system that maintains lipid asymmetry in the Gram-negative outer membrane. Proc Natl Acad Sci U S A 106:8009–8014
Carpenter CD, Cooley BJ, Needham BD, Fisher CR, Trent MS, Gordon V, Payne SM (2014) The Vps/VacJ ABC transporter is required for intercellular spread of Shigella flexneri. Infect Immun 82:660–669
Suzuki T, Murai T, Fukuda I, Tobe T, Yoshikawa M, Sasakawa C (1994) Identification and characterization of a chromosomal virulence gene, vacJ, required for intercellular spreading of Shigella flexneri. Mol Microbiol 11:31–41
Takaku C, Sekizuka T, Tazumi A, Moore JE, Millar BC, Matsuda M (2009) Campylobacter lari: molecular and comparative analyses of the virulence-associated chromosome locus J (vacJ) gene homologue, including the promoter region. Br J Biomed Sci 66:85–92
Shen L, Gao X, Wei J, Chen L, Zhao X, Li B, Duan K (2012) PA2800 plays an important role in both antibiotic susceptibility and virulence in Pseudomonas aeruginosa. Curr Microbiol 65:601–609
Xie F, Li G, Zhang W, Zhang Y, Zhou L, Liu S, Wang C (2016) Outer membrane lipoprotein VacJ is required for the membrane integrity, serum resistance and biofilm formation of Actinobacillus pleuropneumoniae. Vet Microbiol 183:1–8
Zhao L, Gao X, Liu C, Lv X, Jiang N, Zheng S (2017) Deletion of the vacJ gene affects the biology and virulence in Haemophilus parasuis serovar 5. Gene 603:42–53
Santos PM, Benndorf D, Sá-Correia I (2004) Insights into Pseudomonas putida KT2440 response to phenol-induced stress by quantitative proteomics. Proteomics 4:2640–2652
Garénaux A, Guillou S, Ermel G, Wren B, Federighi M, Ritz M (2008) Role of the Cj1371 periplasmic protein and the Cj0355c two-component regulator in the Campylobacter jejuni NCTC 11168 response to oxidative stress caused by paraquat. Res Microbiol 159:718–726
Hu WS, Lin JF, Lin YH, Chang HY (2009) Outer membrane protein STM3031 (Ail/OmpX-like protein) plays a key role in the ceftriaxone resistance of Salmonella enterica serovar Typhimurium. Antimicrob Agents Chemother 53:3248–3255
Métris A, George SM, Ropers D (2017) Piecewise linear approximations to model the dynamics of adaptation to osmotic stress by food-borne pathogens. Int J Food Microbiol 240:63–74
Sleator RD, Hill C (2002) Bacterial osmoadaptation: the role of osmolytes in bacterial stress and virulence. FEMS Microbiol Rev 26:49–71
Opazo AC, Mella SM, Domínguez MY, Bello HT, González GR (2009) Multi-drug efflux pumps and antibiotic resistance in Acinetobacter baumannii. Rev Chil Infectol 26:1–5
Vila J, Martí S, Sánchez-Céspedes J (2007) Porins, efflux pumps and multidrug resistance in Acinetobacter baumannii. J Antimicrob Chemother 59:1210–1215
Coyne S, Courvalin P, Périchon B (2011) Efflux-mediated antibiotic resistance in Acinetobacter spp. Antimicrob Agents Chemother 55:947–953
Rensch U, Nishino K, Klein G, Kehrenberg C (2014) Salmonella enterica serovar Typhimurium multidrug efflux pumps EmrAB and AcrEF support the major efflux system AcrAB in decreased susceptibility to triclosan. Int J Antimicrob Agents 44:179–180
Furukawa H, Tsay JT, Jackowski S, Takamura Y, Rock CO (1993) Thiolactomycin resistance in Escherichia coli is associated with the multidrug resistance efflux pump encoded by emrAB. J Bacteriol 175:3723–3729
Lomovskaya O, Lewis K (1992) Emr, an Escherichia coli locus for multidrug resistance. Proc Natl Acad Sci U S A 89:8938–8942
Roma-Rodrigues C, Santos PM, Benndorf D, Rapp E, Sá-Correia I (2010) Response of Pseudomonas putida KT2440 to phenol at the level of membrane proteome. J Proteome 73:1461–1478
Simoni S, Morroni G, Brenciani A, Vincenzi C, Cirioni O, Castelletti S, Varaldo PE, Giovanetti E, Mingoia M (2017) Spread of colistin resistance gene mcr-1 in Italy: characterization of the mcr-1.2 allelic variant in a colistin-resistant blood isolate of Escherichia coli. Diagn Microbiol Infect Dis. https://doi.org/10.1016/j.diagmicrobio.2017.12.015
AbuOun M, Stubberfield EJ, Duggett NA, Kirchner M, Dormer L, Nunez-Garcia J, Randall LP, Lemma F, Crook DW, Teale C, Smith RP, Anjum MF (2017) mcr-1 and mcr-2 variant genes identified in Moraxella species isolated from pigs in Great Britain from 2014 to 2015. J Antimicrob Chemother 72:2745–2749
Yin W, Li H, Shen Y, Liu Z, Wang S, Shen Z, Zhang R, Walsh TR, Shen J, Wang Y (2017) Novel plasmid-mediated colistin resistance gene mcr-3 in Escherichia coli. MBio. https://doi.org/10.1128/mBio.00543-17
Carattoli A, Villa L, Feudi C, Curcio L, Orsini S, Luppi A, Pezzotti G, Magistrali CF (2017) Novel plasmid-mediated colistin resistance mcr-4 gene in Salmonella and Escherichia coli, Italy 2013, Spain and Belgium, 2015 to 2016. Euro Surveill. https://doi.org/10.2807/1560-7917.ES.2017.22.31.30589
Borowiak M, Fischer J, Hammerl JA, Hendriksen RS, Szabo I, Malorny B (2017) Identification of a novel transposon-associated phosphoethanolamine transferase gene, mcr-5, conferring colistin resistance in d-tartrate fermenting Salmonella enterica subsp. enterica serovar Paratyphi B. J Antimicrob Chemother 72:3317–3324
Poirel L, Jayol A, Nordmann P (2017) Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 30:557–596
Reynolds CM, Kalb SR, Cotter RJ, Raetz CR (2005) A phosphoethanolamine transferase specific for the outer 3-deoxy-d-manno-octulosonic acid residue of Escherichia coli lipopolysaccharide. Identification of the eptB gene and Ca2+ hypersensitivity of an eptB deletion mutant. J Biol Chem 280:21202–21211
Caniaux I, Van Belkum A, Zambardi G, Poirel L, Gros MF (2017) MCR: modern colistin resistance. Eur J Clin Microbiol Infect Dis 36:415–420
Li X-P, Fang L-X, Jiang P, Pan D, Xia J, Liao X-P, Liu YH, Sun J (2017) Emergence of the colistin resistance gene mcr-1 in Citrobacter freundii. Int J Antimicrob Agents 49:786–787
Kieffer N, Nordmann P, Poirel L (2017) Moraxella species as potential sources of MCR-like polymyxin-resistance determinants. Antimicrob Agents Chemother. https://doi.org/10.1128/AAC.00129-17
Liu BT, Song FJ, Zou M, Hao ZH, Shan H (2017) Emergence of colistin resistance gene mcr-1 in Cronobacter sakazakii producing NDM-9 and in Escherichia coli from the same animal. Antimicrob Agents Chemother 61:1444–1446
Stoesser N, Mathers AJ, Moore CE, Day NP, Crook DW (2016) Colistin resistance gene mcr-1 and pHNSHP45 plasmid in human isolates of Escherichia coli and Klebsiella pneumoniae. Lancet Infect Dis 16:285–286
Gales AC, Jones RN, Sader HS (2011) Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006–2009). J Antimicrob Chemother 66:2070–2074
Acknowledgements
We thank UFSJ/PPGCF for the availability of bibliographic support. W.G.L. is grateful to Fundação de Amparo à Pesquisa de Minas Gerais (FAPMIG) for a graduate fellowship.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Rights and permissions
About this article
Cite this article
Lima, W.G., Alves, M.C., Cruz, W.S. et al. Chromosomally encoded and plasmid-mediated polymyxins resistance in Acinetobacter baumannii: a huge public health threat. Eur J Clin Microbiol Infect Dis 37, 1009–1019 (2018). https://doi.org/10.1007/s10096-018-3223-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10096-018-3223-9