Next Article in Journal
A Ratiometric Fluorescent Probe Dye-Functionalized MOFs Integrated with Logic Gate Operation for Efficient Detection of Acetaldehyde
Next Article in Special Issue
Antimicrobial Potential of Scorpion-Venom-Derived Peptides
Previous Article in Journal
Study on Rapid Non-Destructive Detection Method of Corn Freshness Based on Hyperspectral Imaging Technology
Previous Article in Special Issue
Antibacterial Properties of Peptide and Protein Fractions from Cornu aspersum Mucus
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 29
Issue 13
10.3390/molecules29132969
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Colistin: Lights and Shadows of an Older Antibiotic

by
Erica Diani
1,
Gabriele Bianco
2,
Milo Gatti
3,
Davide Gibellini
1 and
Paolo Gaibani
1,*
1
Department of Diagnostic and Public Health, Microbiology Section, University of Verona, Strada Le Grazie 8, 37134 Verona, Italy
2
Department of Experimental Medicine, University of Salento, 73100 Lecce, Italy
3
Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy
*
Author to whom correspondence should be addressed.
Molecules 2024, 29(13), 2969; https://doi.org/10.3390/molecules29132969
Submission received: 29 May 2024 / Revised: 17 June 2024 / Accepted: 20 June 2024 / Published: 21 June 2024
(This article belongs to the Special Issue Development, Bioactivity, and Application of New Antimicrobial Peptides)
Browse Figures
Review Reports Versions Notes

Abstract

:
The emergence of antimicrobial resistance represents a serious threat to public health and for infections due to multidrug-resistant (MDR) microorganisms, representing one of the most important causes of death worldwide. The renewal of old antimicrobials, such as colistin, has been proposed as a valuable therapeutic alternative to the emergence of the MDR microorganisms. Although colistin is well known to present several adverse toxic effects, its usage in clinical practice has been reconsidered due to its broad spectrum of activity against Gram-negative (GN) bacteria and its important role of “last resort” agent against MDR-GN. Despite the revolutionary perspective of treatment with this old antimicrobial molecule, many questions remain open regarding the emergence of novel phenotypic traits of resistance and the optimal usage of the colistin in clinical practice. In last years, several forward steps have been made in the understanding of the resistance determinants, clinical usage, and pharmacological dosage of this molecule; however, different points regarding the role of colistin in clinical practice and the optimal pharmacokinetic/pharmacodynamic targets are not yet well defined. In this review, we summarize the mode of action, the emerging resistance determinants, and its optimal administration in the treatment of infections that are difficult to treat due to MDR Gram-negative bacteria.

1. Introduction

Antibiotic resistance represents a serious public health threat and is associated with millions of deaths annually [1]. Since the discovery of the first antimicrobial molecules, the emergence of novel traits of resistance to antimicrobials has been observed concomitantly [2]. It is well known that antimicrobial resistance is associated with the misuse and overuse of related drugs in different fields of applications (humans, animals and plants). Indeed, the presence of antimicrobial rich environments creates favorable conditions that allow the selection of resistant subpopulations in opposition to sensitive microorganisms [3].
With the diffusion of these drugs and the rapid increase in antimicrobial resistance, the development of microorganisms resistant to multiple antimicrobial classes of compounds has been subsequently observed [4]. The emergence of multidrug-resistant (MDR) microorganisms imposes different limitations on clinicians by reducing the available antimicrobial armamentarium. In the last years, the diffusion of MDR strains, especially Gram-negative bacteria, has been considered an urgent threat that requires a prompt response. To overcome these limitations, several strategies have been adopted, including new schemes of treatment combining antimicrobial molecules with no activity alone and the development of novel antimicrobial molecules [5,6]. At the same time, the revival of older antibiotics considered as last resort drugs has posed new prospective issues in the treatment of difficult-to-treat (DTR) infections due to MDR strains [5].
Colistin, also known as polymyxin E, is an old antimicrobial molecule that was discovered in the middle of the 19th century in Japan from a culture of the Paenibacillus polymyxa subspecies [7]. Colistin is a cyclic oligopeptide antimicrobial belonging to the class of polycationic antibiotics and it is active against most Gram-negative bacteria by binding to the lipopolysaccharide (LPS) of the outer cell membranes by electrostatic interaction. The linkage between colistin and the outer membrane created a disorganization of the outer membrane’s structure thus results in an alteration of the outer membrane and consequent intracellular content release and bacterial death [7].
In the last years, the renewal of older antibiotics such as colistin has created a new perspective in the treatment of DTR infections [6,8]. However, the emergence of new traits of resistance to this drug and its adverse toxic effects to mammalian cells has mitigated its use in clinical practice [6,7].
In this review, we discuss the principle of the mode of action, the emerging traits related to the resistance, and the use of colistin in clinical practice from pharmacological and clinical point of views. The main points discussed in this review are shown in Table 1.

2. Mechanisms of Action, Antibacterial Activity and Adverse Effects

2.1. Structure and Mode of Action

Colistin is an amphiphilic lipopeptide antibiotic, discovered in 1947 by Koyama [9,10]; it is produced by Paenibacillus polymyxa subspecies colistinus. Colistin, also called polymixyn E, is a member of the polymyxin family of antibiotics. In 1952, the first formulation in clinical use was a solution for intravenous administration that showed its bactericidal function against many Gram-negative bacteria, but not against Gram-positive, anaerobic bacteria or mycoplasmas. Due to its potent antibacterial activity against Gram-negative bacteria, colistin was initially considered a “miraculous molecule”. However, since the 1970s, its use in clinical practice has been mitigated due to its severe adverse effects [11]. The original molecule has been principally modified to reduce the nephrotoxicity effect, and two forms of colistin are clinically available for human treatment: colistin sulfate and colistin methanesulfonate, also called colistimethate sodium (prodrug form). Differences between these compounds are related to their use and toxicity. In particular, colistin sulfate is an active compound that is administered topically and orally, while colistimethate is used in formulations administered by parenteral and nebulization routes.
Colistin’s basic structure consists of a core region formed by a hydrophobic portion, which is a cyclic heptapeptide linked by a tripeptide bridge to the fatty acids. The colistin molecule is positively charged due to the presence of five diaminobutyric acid residues linked to the core [12]. The prodrug form differs from this structure due to the presence of methan-sulfonates linked to the diaminobutyric acids (Figure 1) [13].
It is noteworthy that the five diaminobutyric acid residues, which confer the positive charge to the molecule, play a determining role in the drug’s antibacterial effect, which is generally described with the Shai–Matsuzaki–Huang (SMH) model [14,15,16] and represented in Figure 2.
Colistin acts by competition with and the displacement of Ca2+ and Mg2+ from the negatively charged sulfate portion of the lipid A in the lipopolysaccharide molecule (LPS) of Gram-negative bacteria (Figure 2a). This ionic dislocation by colistin seems necessary for forming pore-like structures [17,18,19]. The loss of binding ions and their substitution with colistin molecules alters the tertiary structure of LPS, creating the possibility for colistin itself to insert its own portion of fatty acids into the membrane, definitively compromising the permeability of the outer membrane (Figure 2b). In addition, colistin acyl fat, inserted into the bilayer, alters the inner membrane stability, leading to bacterial membrane disruption and a bactericidal effect [20]. Colistin also plays a key role in preventing endotoxin-induced shock by binding to the lipide A portion [21]. This drug acts both at the surface and intracellular levels, in particular altering the vesicle–vesicle contact of bacterial cells. In brief, colistin crosses the membrane and causes the fusion of the inner leaflet of the outer membrane and the outer leaflet of the cytoplasmic membrane, disrupting the cytoplasmic bilayer, altering the osmotic balance, and leading to cell death [22,23] (Figure 2c). The antibacterial action of colistin was also reported at the molecular level, where it can induce oxidative stress and, consequently, DNA, protein, and lipid damage in bacteria through ROS production, being able to inhibit essential enzymes involved in the respiratory chain, such as the NADH-quinone oxidoreductase [24], leading to cell death.

2.2. Adverse Effects

Colistin treatment was dismissed in clinical use, principally due to its nephrotoxicity effect, which is lower for the prodrug form (i.e., colistin sodium methanesulfonate). Its adverse effects were principally due to its re-absorption by proximal tubule cells through an endocytotic process, mediated by megalin, and through facilitative transport by two transporters located in the apical cell membrane, the human peptide transporter 2 (PEPT2), and the carnitine/organic cation transporter 2 (OCTN2) [25,26]. The intracellular accumulation of colistin induces mitochondrial and endoplasmic reticulum stress, with consequent toxic cellular effects [27]. This mechanism leads to cellular lysis and acute tubular necrosis [28,29]. The incidence of colistin-induced acute kidney injury varies between 12.7 and 70% in intensive care unit patients [30,31,32,33]. A recent study by Kilic and colleagues demonstrated that the nephrotoxicity effect depends proportionally on the duration of treatment and is prevalent in older patients [28,34].
Due to the high lipid content of neuronal cells, colistin could also exert its action in these cells, and some patients (with an incidence of about 7% [34]) experienced neurological adverse effects, such as paresthesia, seizures, confusion, ataxia, and visual disturbances [35]. The mechanism by which colistin induces these effects is a non-competitive presynaptic myoneuronal blockade of acetylcholine release [36]. Its adverse effects on neuronal cells could be reverted by discontinuing the therapy.

2.3. In Vitro Antimicrobial Activity

The in vitro activity of colistin was tested with success on Acinetobacter baumannii, a large part of Enterobacteriales, and Pseudomonas aeruginosa [37]. In particular, for 106 non-duplicate isolates of A. baumannii, the authors reported a minimum inhibiting concentration of 0.5 μg/mL for MIC50 and of 1.0 μg/mL for MIC90 in monotherapy [37].
Walkty et al. [38] analyzed the colistin antibacterial activity exerted on 3480 isolates of Gram-negative bacilli from patients recruited over 2 years in 12 hospitals in Canada (CANWARD Study). In this study, the authors reported a MIC90 value ≤2 μg/mL against several clinically relevant Gram-negative bacilli, such as Escherichia coli (1732 isolates), Klebsiella spp. (515 isolates), Enterobacter spp., A. baumannii, and P. aeruginosa (561 isolates), including all 76 MDR P. aeruginosa isolates tested in the CANWARD Study.
A cross-sectional and descriptive study conducted on 52 MDR P. aeruginosa isolates, collected from urine, pus specimens and respiratory tract, reported a MIC50 value of 1.0 μg/mL and a MIC90 value of 3.0 μg/mL [39].
In the preceding years, several studies reported on the activity of colistin in combination other antimicrobial molecules. In particular, colistin, in combination with meropenem or tigecycline, showed synergistic activity against colistin-resistant KPC-producing K. pneumoniae [40]. In a study based on an in vitro checkerboard assay, Kheshti and coworkers [41] reported the good synergistic activity of colistin treatment in combination with ciprofloxacin, levofloxacin (5%—the lowest level), imipenem, meropenem, and ampicillin–sulbactam molecules and its higher synergism in combination with rifampin (55%) when tested on 20 isolates of A. baumanii.
A recent study [42] conducted on 219 K. pneumoniae isolates demonstrated the strong synergistic effects of minocycline and colistin on colistin-resistant and minocycline-intermediate or -resistant K. pneumoniae. This drug combination acts by disrupting the outer membrane (by colistin) without affecting the cytoplasmic membrane, allowing the entrance and accumulation of minocycline at the intracellular level.

2.4. Antimicrobial Susceptibility Testing

The chemical structure of colistin and its cationic charge make the use of classical susceptibility tests, like E-tests and disc diffusion, difficult. To overcome this limitation and to provide a pharmacological alternative to the numerous multi-resistant bacterial species, classical diagnostic protocols have been modified, allowing the measurement of colistin susceptibility. Broth microdilution, the gold standard for colistin susceptibility test, is modified using a cation-adjusted Muller–Hinton broth without adding a surfactant [43,44]. Another method that has been approved by the CLSI for only Enterobactarales and Pseudomonas spp. is a broth disc elution, modified by Simner and colleagues [45]. The test, renamed as Colistin Broth Disc Elution (CBDE), is easier than the Broth microdilution and is based on analysis of the efficacy of a graded concentration of colistin (of 1,2,4 μg/mL) obtained from colistin disc elution in 10 mL of cation-adjusted Muller–Hinton broth, tested on a 0.5 Mc Farland of bacteria. EUCAST colistin breakpoints table, version 14.0, reports the following cut-off value for the detection of phenotypic resistance: an MIC of 2 mg/L for Enterobacterales and for Acinetobacter spp., and an MIC of 4 mg/L for P. aeruginosa.

3. Mechanisms of Colistin Resistance

A variety of mechanisms may be involved in the acquisition of colistin resistance in Gram-negative bacteria, and they can be summarized into four groups (Figure 3): the modification of LPS structures by chromosomal mutations (i), modification of LPS structures by acquisition of plasmids (ii), the loss of LPS structures (iii), and the overexpression of efflux pumps (iv).

3.1. Modification of LPS Structure by Chromosomal Mutations

A reduction in the negative charge of lipid A of LPS leads to the loss of electrostatic interactions with colistin and consequently to resistance [46]. Many genes and operons are involved in LPS modifications: (1) pmrC and pmrE genes and the pmrHFIJKLM operon, which promote the addition of phosphoethanolamine (PEtn) and/or 4-amino-4-deoxy-L-arabinose (L-Ara4N) to lipidA; (2) regulatory two-component systems such as PmrAB, PhoPQ, and crab; and (3) mgrB-negative regulator genes.
The addition of L-Ara4N and/or PEtn to lipidA changes the negative charge of the cell membrane by neutralizing the negatively charged phospholipids [47,48,49,50]. In detail, the addition of PEtn to the 1′- or 4′-phosphate group of lipid A is carried out by PmrC, a putative membrane protein with phosphoethanolamine transferase activity encoded by pmrABC operons [11,51,52,53,54]. The synthesis of L-Ara4N from uridine diphosphate glucuronic and its addition to lipid A is promoted by pmrHIJKLM operons (also called arnBCADTEF) and PmrE activity [51]. PmrB is a cytoplasmic membrane-bound protein which activates PmrA by phosphorylation, and PmrA in turns activates the regulation of the pmrABC and pmrHFIJKLM operons and the pmrE gene. Subsequently, these operons and genes lead to LPS modification by adding PEtn and L-Ara4N to lipid A [55]. Although the L-Ara4N modification of LPS has been described as a common mechanism of colistin resistance among Gram-negative bacteria (Klebsiella pneumoniae, Escherichia coli, Salmonella enterica, and Pseudomonas aeruginosa), it does not occur in Acinetobacter baumannii because it lacks all the genes required for L-Ara4N biosynthesis [51]. Alternatively, the addition of galactosamine to the 1′-phosphate position of lipid A, following activation of the sensor kinase PmrB, is associated with moderate levels of colistin resistance in A. baumannii [52].
The mutation of PmrA/PmrB results in the upregulation of the pmrABC and pmrFHIJKLM operons and pmrE gene. This leads to PEtN modification of lipid A, and in turn, results in colistin resistance. Several mutations have been reported in many Gram-negative bacteria, such as Salmonella enterica [56,57], K. pneumoniae [58,59,60], A. baumannii [61,62,63], P. aeruginosa [64,65], and E. coli [57,66,67].
The transcription of pmrFHIJKLM operons is also activated by the PhoPQ regulatory two-component system. PhoQ is a sensor kinase that promotes the expression of the regulator protein PhoQ, which promotes pmrFHIJKLM operon transcription via phosphorylation. Furthermore, PhoP indirectly activates pmrA through the PmrD connector protein, which subsequently activates the transcription of the pmrHFIJKLM operon. This then leads to the synthesis and transfer of PEtn to lipid A [11,49,50]. The mutation of the phoP/Q genes. which that leads to acquired colistin resistance, has been identified in K. pneumoniae and E. coli [68,69,70]. Higher polymyxin MICs have been observed in PhoQ-deficient P. aeruginosa mutants when additional alterations affected other regulatory two-component systems (CprRS and ColRS) [71].
More evidence has accumulated on the role played by mgrB, a gene encoding a small regulatory transmembrane protein that exerts negative feedback on the kinase activity of PhoQ [72]. The inactivation of mgrB leads to the activation of a phosphorylation cascade involving chain PhoQ, PhoP, PmrD and/or PmrAB. This finally triggers the expression of the pmrHIJKLM operon, resulting in LPS modification. The mutation of mgrB, including point mutations, deletions, nonsense, and insertion sequences (IS5-like, IS1F, ISKpn14, ISKpn13, IS10R), represents the most common mechanism of colistin resistance in clinical K. pneumoniae isolates [69,73,74,75,76,77]. The wide range of resistance levels showed by Gram-negative strains harbouring mutations in the genes pmrAB, phoPQ, or mgrB suggests a role for other genetic loci. Mutations in the CrrAB two-component system has been associated with increased levels of colistin resistance in strains of K. pneumoniae [74,78]. The mutation/inactivation of the crrB gene led to the activation of the pmrHFIJKLM operon and the pmrC and pmrE genes through the overexpression of the pmrAB operon [77,78]. Furthermore, various PEtn-coding genes, such as eptA (pmrC), eptB (pagC), and eptC (cptA), are able to add PEtn to LPS and can be involved in colistin resistance [79]. The overexpression of eptA has been associated with colistin resistance in A. baumannii [61,80]. Gerson et al. showed that mutations in the eptA gene (R127L and ISAba1 insertion) were associated with the overexpression of EptA and colistin resistance in A. baumannii [61].

3.2. Loss of LPS Structure

The complete loss of lipid A or the LPS core, leading to colistin resistance, has been observed in A. baumannii. The analysis of laboratory-induced colistin-resistant A. baumannii showed that the high level of resistance to colistin was caused by the inactivation of LPS biosynthesis genes lpxA, lpxC, lpxD, and lpsB [81]. Various nucleotide substitutions, deletions, and insertions that cause frameshifts or result in truncated proteins have been reported for in vitro mutants and clinical isolates [81,82,83,84]. Moreover, the disruption of lpxC and lpxD via the insertion of IS elements was described in colistin-resistant A. baumannii isolates [81,82,83,84,85,86]. Although LPS loss is an effective mechanism of colistin resistance, it has significant fitness costs, and this explains why these mutants are rarely encountered in the clinical setting [87].

3.3. Plasmid-Mediated Colistin Resistance

Since the first report of the mcr gene encoding for phosphoethanolamine transferase (mcr-1) in E. coli in China in 2015 [88], several reports worldwide have demonstrated the presence of mcr-1 and additional 9 families (mcr-2 to mcr-10), with more than 100 overall variants of different Gram-negative species distributed worldwide [11,49,50,51,52,53,89,90,91,92,93,94]. MCR is a member of the PETN enzyme family, located mainly in the bacteria plasmids, and its activity results in the modification of lipid A via PETN addition. The enzyme has a domain inserted into the inner membrane and a periplasmic C-terminal sulfatase catalytic domain.
In 2018, Partridge et al. proposed a nomenclature for mcr genes. Several variants were identified, especially for MCR-3 and MCR-1 [95]. MCR-1 and MCR-2 share 81% identity at the amino acid sequence level. Sequence identity suggests that these two variants originated from Moraxella spp. [89], with mcr-3, mcr-4, and mcr-7 coming from Aeromonas spp. and Shewanella frigidimarina, respectively [90,91,92,93].
The mcr-1 variant can be connected to various types of plasmids, including IncHI2, IncI2, IncX4, IncP, IncX, and IncFIP. The mcr-2 gene was detected on an IncX4 plasmid. The presence of insertion sequences (ISApl1, IS1595) on the genetic environment of mcr genes explains the possibility of their integration into bacterial chromosomes [94].
Plasmid-mediated colistin resistance represents the mechanism of greatest concern because of the ease of intra- and inter-species spread. Despite most of MCR-harboring microorganisms belonging to the Enterobacterales order, such as E. coli, Salmonella spp., and K. pneumoniae, several reports showed the presence of mcr-genes in non-fermenting Gram-negative species such as P. aeruginosa and A. baumannii complexes [96,97,98,99,100,101,102,103,104,105,106,107,108,109,110]. The mcr-1 gene is the most commonly detected in P. aeruginosa in both clinical [96,97,98,99] and animal settings [100,101,102,103], followed by mcr-5 [104,105]. In A. baumannii complex, the mcr-1 and mcr-4.3 are the major variants observed in clinical isolates from Asia and Europe [98,99,106,107,108,109]. Other mcr genes found in A. baumannii include mcr-2 and mcr-3 [110].

3.4. Overexpression of Efflux Pumps

The role of efflux pumps in colistin resistance is suggested by a few studies. Efflux pumps, such as the KpnEF and AcrAB, have been reported in Enterobactericeae. The ΔKpnEF mutants showed increased susceptibility to various cationic antimicrobial peptides such as colistin [111]. On the other hand, AcrAB is a part of the AcrAB–TolC complex and its overexpression has been observed in colistin-resistant E. coli, K. pneumoniae, and Salmonella strains [112,113,114].
The contribution of EmrAB efflux systems to colistin resistance in A. baumannii was shown by in vitro experiments with the ΔemrB mutant [115]. Moreover, the upregulation of the gene-encoding protein components of efflux pumps (adeI, adeC, emrB, mexB, and macAB) was also observed in colistin-resistant A. baumannii strains [83].
The overexpression of the efflux pumps MexXY (RND family) under exposure to ribosome-targeting antibiotics was found to correlate with the increased levels of colistin resistance in P. aeruginosa [116]. However, the heterogeneity of MexXY expression observed in clinical isolates of P. aeruginosa, showing variable levels of colistin resistance, suggested that the contribution of the efflux pumps to colistin resistance might also be related to other specific genetic backgrounds [117].
Further evidence of the role of efflux pumps in colistin resistance is the suppression of resistance by efflux pump inhibitor (EPI) and cyanide-3-chlorophenylhydrazone (CCCP) in A. baumannii, P. aeruginosa, K. pneumoniae, and S. maltophilia [118]. However, a possible explanation is that CCCP-mediated depolarization of the electrochemical gradient may restore the negative charge of the outer membrane and lead to increased susceptibility to colistin [48,118]. Furthermore, various studies suggested a complex regulatory relationship between the efflux pumps and their transcriptional regulators and LPS synthesis, transport, and modification [48].

4. Pharmacokinetic/Pharmacodynamic Features

According to several pieces of preclinical evidence, the free area under the concentration-to-time curve to minimum inhibitory concentration ratio (fAUC/MIC) was defined as the best pharmacokinetic/pharmacodynamic (PK/PD) target for achieving colistin efficacy in infections caused by P. aeruginosa and A. baumannii [119]. In a neutropenic murine thigh and lung infection model aimed against three P. aeruginosa strains, Dudhani et al. [120] found that the fAUC/MIC ratio was the best PK/PD index, correlating with colistin efficacy in both thigh (R2 = 0.87) and lung infection models (R2 = 0.89). The colistin fAUC/MIC targets required to achieve 1-log and 2-log kills against the three strains were 15.6 to 22.8 and 27.6 to 36.1, respectively, in the thigh infection model, whereas a fAUC/MIC ratio ranging from 12.2 to 16.7 and from 36.9 to 45.9 in the lung infection model was found to achieve 1-log and 2-log kills [120]. In a neutropenic murine thigh and lung infection model aimed against three A. baumannii strains (of which two were colistin heteroresistant), Dudhani et al. [121] reported that the fAUC/MIC ratio was the best PK/PD index, correlating with colistin efficacy in both the thigh (R2 = 0.90) and lung infection model (R2 = 0.80). The colistin fAUC/MIC targets required to achieve stasis and 1-log kill against the three strains were 1.89–7.41 and 6.98–13.6 in the thigh infection model, respectively, and 1.57–6.52 and 8.18–42.1, respectively, in the lung infection model [121]. Notably, these colistin PK/PD targets, acting against P. aeruginosa and A. baumannii, were consistent with those retrieved in a recent murine thigh and lung infection model [122]. Indeed, the fAUC/MIC ratio was confirmed as the best PK/PD target for predicting colistin efficacy, with fAUC/MIC ratios of 7.4–13.7 and 7.4–17.6 required for achieving 2-log kills against Pseudomonas aeruginosa and A. baumannii strains of, respectively [122]. It should be noted that these PK/PD targets could only be attained in two P. aeruginosa strains and in one A. baumannii strain in the lung infection model, even at the highest colistin dose tolerated [122].
For Enterobacterales, an in vitro model investigated the best PK/PD target of colistin efficacy against three K. pneumoniae strains exhibiting MIC values of 0.5, 1, and 4 mg/L, respectively [123]. The fAUC/MIC ratio emerged as the best PK/PD target for colistin efficacy, with an fAUC/MIC ≥25 being more predictive for a bactericidal effect [123]. Notably, this PK/PD target may be attained at standard colistin doses of 9 MU in 100%, 5–70%, and 0% of K. pneumoniae isolates, showing MIC values of 0.5, 1, and 2 mg/L, respectively [123]. These findings may suggest on the one hand the need to revise the current colistin clinical breakpoint against Enterobacterales, and on the other hand the potential relevance of implementing a therapeutic-drug-monitoring (TDM)-guided approach for personalizing colistin dosage.
It should be noted that evidence investigating the relationship between optimal PK/PD target attainment for colistin retrieved in preclinical studies and clinical outcomes is currently limited. A prospective observational study investigated the relationship between PK/PD target attainment of colistin and microbiological/clinical outcomes in nine patients affected by multidrug-resistant (MDR) Gram-negative infections (eight caused by A. baumannii and one by K. pneumoniae) [124]. After the fifth colistin dose of 2 MU, the AUC0–8/MIC ranged from 35.5 to 126. Although no significant relationship between AUC/MIC ratio and microbiological/clinical cure was found, a positive trend was observed at logistic regression (p = 0.28) [124]. A prospective observational study, including 33 patients affected by urinary tract infections and/or pyelonephritis caused by extremely drug-resistant P. aeruginosa, reported no significant difference in the fAUC/MIC ratio between cases exhibiting favourable clinical outcomes and those with clinical failure (21.5 vs. 47.4; p = 0.85) or in the proportion of attainment of an AUC/MIC ratio ≥60 mg/L (32.3% vs. 50.0%; p = 0.99) [125]. Undergoing multivariate analysis, the average steady-state colistin concentration showed a trend towards statistical significance for acute kidney injury occurrence (OR 4.36; 95%CI 0.86–20.0; p = 0.07—Sorlí et al., 2019) [125].
Studies assessing colistin penetration into different sites of infection are reported in Table 2. Currently, data are only available for the lungs, central nervous system (CNS), and eye (Table 1). Specifically, a prospective observational study investigating the epithelial lining fluid (ELF) penetration of intravenous colistin, administered at a dosage of 2 MU every 8 h in 13 critically ill patients affected by ventilator-associated pneumonia, reported undetectable colistin concentrations in ELF [126].
A prospective observational study including five critically ill patients assessed colistin penetration into cerebrospinal fluid (CSF) administered intravenously at a dosage of 2–3 MU every 8 h [127]. The colistin CSF-to-plasma ratio was 0.05, with the absolute concentrations retrieved in CSF allowing the attainment of optimal PK/PD targets, but only against P. aeruginosa and A. baumannii strains, showing an MIC value up to 0.06 mg/L [127]. In regard to ocular penetration, currently, only a preclinical animal model has assessed this issue in twenty rabbits receiving intravenous colistin at a dosage of 5 mg/kg [128]. Overall, absolute colistin concentrations were extremely low in.
Aqueous humor and undetectable in vitreous humor in most of the included cases [128].
Overall, these findings strongly support the implementation of alternative agents in the case of deep-seated infections, especially given the limited colistin penetration rate in lung and CSF and the failure in attaining optimal PK/PD targets. Notably, these findings may be expected according to the physicochemical and PK features of colistin, namely its hydrophilic properties, large molecular weight, and limited volume of distribution [129].

5. Future Prospectives

Several strategies have been proposed for contrasting the emergence and diffusion of antibiotic-resistance. Since the discovery of the first antimicrobial molecules, several groups aimed to evaluate the in vitro activity of different antimicrobial combinations due to their potentially promising results, especially against multidrug-resistant clinical isolates. In particular, recent studies demonstrated that colistin in combination with different antimicrobial molecules (i.e., rifampicin, meropenem, etc.) exerted potent synergy in vitro against MDR also including colistin-resistant strains [40,130]. However, the discordance of the different in vitro results and the prognostic utility of the synergy tests in the clinical practice still remain controversial [131].
In the last years, the revival of old microbiological techniques such as the serum bactericidal titres (SBTs) has been proposed for monitoring the antibiotic treatment of multidrug-resistant Gram-negative infections [132]. Indeed, SBT is the only laboratory test that integrates drug pharmacodynamics, host pharmacokinetics, and synergistic or antagonistic interactions of antimicrobial combinations into a single index of antimicrobial activity [132]. Recent study demonstrated the high bactericidal activity in serum of patients treated with colistin in association with meropenem rather than other combinations [133]. Although SBT appears to be a promising surrogate PK/PD marker for assessing antimicrobial treatment of Gram-negative infections, the predictive value of the SBT still remains poorly defined, as does the standardization of a more rapid SBT testing method [132].
Novel techniques have been proposed to fight the emergence of antimicrobial resistance, especially among MDR strains. An example is the phenylboronic acid (PBA)-installed micellar nanocarriers, incorporating different antimicrobials that have shown promising in vitro and in vivo results [134]. Recently, Huang and co-workers on a study based on PBA-functionalized micelle loaded with vancomycin and curcumin demonstrated the ability to eradicate drug-resistant bacteria in vitro and in vivo due to the synergism of the two drugs [134]. However, further studies are needed to confirm the results obtained by this novel application.
Lastly, meta-organic framework (MOF)-loaded biohybrid magnetic microrobots have been proposed as an alternative strategy for non-antibiotic bacterial killing [135]. This strategy uses the gradual release of metal ions to cause damage to the bacterial membrane, thus resulting in the efficient killing of bacteria. Although this novel methodology could be considered a promising strategy for treating infections due to MDR strains, further studies are necessary to confirm its clinical utility.

6. Conclusions

In the last years, the renewed use of older antimicrobial molecules has revolutionized the treatment of infections due to MDR-GN microorganisms. At the same time, novel approaches, including therapeutic drug monitoring (TDM), for the personalization of the antimicrobial dosage of the different antimicrobial molecules and new therapeutic schemes of treatment, designed by combining antibiotics with limited antimicrobial activity, have revolutionized the treatment of infections due to MDR pathogens.
The clinical usage of colistin alone and in combination with other antimicrobials with scarce and/or limited antimicrobial activity has recently reinvented its role in clinical practice [136,137]. Also, considering the limited antimicrobial options against these pathogens, colistin was defined as the “last-hope resource” for the treatment of DTR infections, especially among critical-ill patients [8]. In this context, the further application of colistin in clinical practice could be utilized in the treatment of emerging pathogens with novel traits of resistance, considering the limited antimicrobial options available.
Conversely, the adverse toxic effects and the limited tissue penetrations in different anatomical districts prompted us to mitigate its role in the clinical setting by limiting its use [1]. In addition, the widespread use of colistin-resistant strains [2,3] poses a serious limitation in terms of the issue of this molecule, especially in light of the new antimicrobial molecules developed recently, possessing high bactericidal activity against MDR microorganisms (i.e., cefiderocol, ceftazidime/avibactam, meropenem/vaborbactam, etc.).

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflicts of interest.

References

  1. Salam, M.A.; Al-Amin, M.Y.; Salam, M.T.; Pawar, J.S.; Akhter, N.; Rabaan, A.A.; Alqumber, M.A.A. Antimicrobial Resistance: A Growing Serious Threat for Global Public Health. Healthcare 2023, 11, 1946. [Google Scholar] [CrossRef]
  2. Hutchings, M.I.; Truman, A.W.; Wilkinson, B. Antibiotics: Past, Present and Future. Curr. Opin. Microbiol. 2019, 51, 72–80. [Google Scholar] [CrossRef]
  3. Urban-Chmiel, R.; Marek, A.; Stępień-Pyśniak, D.; Wieczorek, K.; Dec, M.; Nowaczek, A.; Osek, J. Antibiotic Resistance in Bacteria—A Review. Antibiotics 2022, 11, 1079. [Google Scholar] [CrossRef]
  4. Muteeb, G.; Rehman, M.T.; Shahwan, M.; Aatif, M. Origin of Antibiotics and Antibiotic Resistance, and Their Impacts on Drug Development: A Narrative Review. Pharmaceuticals 2023, 16, 1615. [Google Scholar] [CrossRef]
  5. Walsh, C.T.; Wencewicz, T.A. Prospects for New Antibiotics: A Molecule-Centered Perspective. J. Antibiot. 2014, 67, 7–22. [Google Scholar] [CrossRef]
  6. Gaibani, P.; Giani, T.; Bovo, F.; Lombardo, D.; Amadesi, S.; Lazzarotto, T.; Coppi, M.; Rossolini, G.M.; Ambretti, S. Resistance to Ceftazidime/Avibactam, Meropenem/Vaborbactam and Imipenem/Relebactam in Gram-Negative MDR Bacilli: Molecular Mechanisms and Susceptibility Testing. Antibiotics 2022, 11, 628. [Google Scholar] [CrossRef]
  7. El-Sayed Ahmed, M.A.E.-G.; Zhong, L.-L.; Shen, C.; Yang, Y.; Doi, Y.; Tian, G.-B. Colistin and Its Role in the Era of Antibiotic Resistance: An Extended Review (2000–2019). Emerg. Microbes Infect. 2020, 9, 868–885. [Google Scholar] [CrossRef]
  8. Mondal, A.H.; Khare, K.; Saxena, P.; Debnath, P.; Mukhopadhyay, K.; Yadav, D. A Review on Colistin Resistance: An Antibiotic of Last Resort. Microorganisms 2024, 12, 772. [Google Scholar] [CrossRef]
  9. Koyama, Y. A New Antibiotic “Colistin” Produced by Spore-Forming Soil Bacteria. J. Antibiot. 1950, 3, 457–458. [Google Scholar]
  10. Stansly, P.G.; Schlosser, M.E. Studies on Polymyxin: Isolation and Identification of Bacillus polymyxa and Differentiation of Polymyxin from Certain Known Antibiotics. J. Bacteriol. 1947, 54, 549–556. [Google Scholar] [CrossRef]
  11. Hamel, M.; Rolain, J.-M.; Baron, S.A. The History of Colistin Resistance Mechanisms in Bacteria: Progress and Challenges. Microorganisms 2021, 9, 442. [Google Scholar] [CrossRef]
  12. Bergen, P.J.; Li, J.; Rayner, C.R.; Nation, R.L. Colistin Methanesulfonate Is an Inactive Prodrug of Colistin against Pseudomonas Aeruginosa. Antimicrob. Agents Chemother. 2006, 50, 1953–1958. [Google Scholar] [CrossRef]
  13. Ehrentraut, S.F.; Muenster, S.; Kreyer, S.; Theuerkauf, N.U.; Bode, C.; Steinhagen, F.; Ehrentraut, H.; Schewe, J.-C.; Weber, M.; Putensen, C.; et al. Extensive Therapeutic Drug Monitoring of Colistin in Critically Ill Patients Reveals Undetected Risks. Microorganisms 2020, 8, 415. [Google Scholar] [CrossRef]
  14. Matsuzaki, K. Why and How Are Peptide–Lipid Interactions Utilized for Self-Defense? Magainins and Tachyplesins as Archetypes. Biochim. Biophys. Acta (BBA)-Biomembr. 1999, 1462, 1–10. [Google Scholar] [CrossRef]
  15. Shai, Y. Mechanism of the Binding, Insertion and Destabilization of Phospholipid Bilayer Membranes by α-Helical Antimicrobial and Cell Non-Selective Membrane-Lytic Peptides. Biochim. Biophys. Acta (BBA)-Biomembr. 1999, 1462, 55–70. [Google Scholar] [CrossRef]
  16. Yang, L.; Weiss, T.M.; Lehrer, R.I.; Huang, H.W. Crystallization of Antimicrobial Pores in Membranes: Magainin and Protegrin. Biophys. J. 2000, 79, 2002–2009. [Google Scholar] [CrossRef]
  17. Cai, Y.; Lee, W.; Kwa, A.L. Polymyxin B versus Colistin: An Update. Expert Rev. Anti Infect. Ther. 2015, 13, 1481–1497. [Google Scholar] [CrossRef]
  18. Trimble, M.J.; Mlynárčik, P.; Kolář, M.; Hancock, R.E.W. Polymyxin: Alternative Mechanisms of Action and Resistance. Cold Spring Harb. Perspect. Med. 2016, 6, a025288. [Google Scholar] [CrossRef]
  19. Andrade, F.F.; Silva, D.; Rodrigues, A.; Pina-Vaz, C. Colistin Update on Its Mechanism of Action and Resistance, Present and Future Challenges. Microorganisms 2020, 8, 1716. [Google Scholar] [CrossRef]
  20. Velkov, T.; Thompson, P.E.; Nation, R.L.; Li, J. Structure−Activity Relationships of Polymyxin Antibiotics. J. Med. Chem. 2010, 53, 1898–1916. [Google Scholar] [CrossRef]
  21. Falagas, M.E.; Kasiakou, S.K.; Saravolatz, L.D. Colistin: The Revival of Polymyxins for the Management of Multidrug-Resistant Gram-Negative Bacterial Infections. Clin. Infect. Dis. 2005, 40, 1333–1341. [Google Scholar] [CrossRef]
  22. Kaye, K.S.; Pogue, J.M.; Tran, T.B.; Nation, R.L.; Li, J. Agents of Last Resort. Infect. Dis. Clin. N. Am. 2016, 30, 391–414. [Google Scholar] [CrossRef]
  23. Gurjar, M. Colistin for Lung Infection: An Update. J. Intensive Care 2015, 3, 3. [Google Scholar] [CrossRef]
  24. Deris, Z.Z.; Akter, J.; Sivanesan, S.; Roberts, K.D.; Thompson, P.E.; Nation, R.L.; Li, J.; Velkov, T. A Secondary Mode of Action of Polymyxins against Gram-Negative Bacteria Involves the Inhibition of NADH-Quinone Oxidoreductase Activity. J. Antibiot. 2014, 67, 147–151. [Google Scholar] [CrossRef]
  25. Lu, X.; Chan, T.; Xu, C.; Zhu, L.; Zhou, Q.T.; Roberts, K.D.; Chan, H.-K.; Li, J.; Zhou, F. Human Oligopeptide Transporter 2 (PEPT2) Mediates Cellular Uptake of Polymyxins. J. Antimicrob. Chemother. 2016, 71, 403–412. [Google Scholar] [CrossRef]
  26. Visentin, M.; Gai, Z.; Torozi, A.; Hiller, C.; Kullak-Ublick, G.A. Colistin Is Substrate of the Carnitine/Organic Cation Transporter 2 (OCTN2, SLC22A5). Drug Metab. Dispos. 2017, 45, 1240–1244. [Google Scholar] [CrossRef]
  27. Gai, Z.; Samodelov, S.; Kullak-Ublick, G.; Visentin, M. Molecular Mechanisms of Colistin-Induced Nephrotoxicity. Molecules 2019, 24, 653. [Google Scholar] [CrossRef]
  28. Kilic, I.; Ayar, Y.; Ceylan, İ.; Kaya, P.K.; Caliskan, G. Nephrotoxicity Caused by Colistin Use in ICU: A Single Centre Experience. BMC Nephrol. 2023, 24, 302. [Google Scholar] [CrossRef]
  29. Nation, R.L.; Li, J. Colistin in the 21st Century. Curr. Opin. Infect. Dis. 2009, 22, 535–543. [Google Scholar] [CrossRef]
  30. Akajagbor, D.S.; Wilson, S.L.; Shere-Wolfe, K.D.; Dakum, P.; Charurat, M.E.; Gilliam, B.L. Higher Incidence of Acute Kidney Injury with Intravenous Colistimethate Sodium Compared with Polymyxin B in Critically Ill Patients at a Tertiary Care Medical Center. Clin. Infect. Dis. 2013, 57, 1300–1303. [Google Scholar] [CrossRef]
  31. Dalfino, L.; Puntillo, F.; Ondok, M.J.M.; Mosca, A.; Monno, R.; Coppolecchia, S.; Spada, M.L.; Bruno, F.; Brienza, N. Colistin-Associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study. Clin. Infect. Dis. 2015, 61, 1771–1777. [Google Scholar] [CrossRef]
  32. Özkarakaş, H.; Köse, I.; Zincircioğlu, Ç.; Ersan, S.; Ersan, G.; Şenoğlu, N.; Köse, Ş.; Erbay, R.H. Risk Factors for Colistin-Associated Nephrotoxicity and Mortality in Critically Ill Patients. Turk. J. Med. Sci. 2017, 47, 1165–1172. [Google Scholar] [CrossRef]
  33. Petrosillo, N.; Giannella, M.; Antonelli, M.; Antonini, M.; Barsic, B.; Belancic, L.; Inkaya, A.C.; De Pascale, G.; Grilli, E.; Tumbarello, M.; et al. Clinical Experience of Colistin-Glycopeptide Combination in Critically Ill Patients Infected with Gram-Negative Bacteria. Antimicrob. Agents Chemother. 2014, 58, 851–858. [Google Scholar] [CrossRef]
  34. Falagas, M.E.; Kasiakou, S.K.; Tsiodras, S.; Michalopoulos, A. The Use of Intravenous and Aerosolized Polymyxins for the Treatment of Infections in Critically Ill Patients: A Review of the Recent Literature. Clin. Med. Res. 2006, 4, 138–146. [Google Scholar] [CrossRef]
  35. Spapen, H.; Jacobs, R.; Van Gorp, V.; Troubleyn, J.; Honoré, P.M. Renal and Neurological Side Effects of Colistin in Critically Ill Patients. Ann. Intensive Care 2011, 1, 14. [Google Scholar] [CrossRef]
  36. Kubikowski, P.; Szreniawski, Z. The Mechanism of the Neuromuscular Blockade by Antibiotics. Arch. Int. Pharmacodyn. Ther. 1963, 146, 549–560. [Google Scholar]
  37. Wang, Y.; Li, H.; Xie, X.; Wu, X.; Li, X.; Zhao, Z.; Luo, S.; Wan, Z.; Liu, J.; Fu, L.; et al. In Vitro and in Vivo Assessment of the Antibacterial Activity of Colistin Alone and in Combination with Other Antibiotics against Acinetobacter baumannii and Escherichia coli. J. Glob. Antimicrob. Resist. 2020, 20, 351–359. [Google Scholar] [CrossRef]
  38. Walkty, A.; DeCorby, M.; Nichol, K.; Karlowsky, J.A.; Hoban, D.J.; Zhanel, G.G. In Vitro Activity of Colistin (Polymyxin E) against 3480 Isolates of Gram-Negative Bacilli Obtained from Patients in Canadian Hospitals in the CANWARD Study, 2007–2008. Antimicrob. Agents Chemother. 2009, 53, 4924–4926. [Google Scholar] [CrossRef]
  39. Gill, M.M.; Rao, J.U.; Kaleem, F.; Hassan, A.; Khalid, A.; Anjum, R. In Vitro Efficacy of Colistin against Multi-Drug Resistant Pseudomonas Aeruginosa by Minimum Inhibitory Concentration. Pak. J. Pharm. Sci. 2013, 26, 7–10. [Google Scholar]
  40. Gaibani, P.; Lombardo, D.; Lewis, R.E.; Mercuri, M.; Bonora, S.; Landini, M.P.; Ambretti, S. In Vitro Activity and Post-Antibiotic Effects of Colistin in Combination with Other Antimicrobials against Colistin-Resistant KPC-Producing Klebsiella Pneumoniae Bloodstream Isolates. J. Antimicrob. Chemother. 2014, 69, 1856–1865. [Google Scholar] [CrossRef]
  41. Kheshti, R.; Pourabbas, B.; Mosayebi, M.; Vazin, A. In Vitro Activity of Colistin in Combination with Various Antimicrobials against Acinetobacter baumannii Species, a Report from South Iran. Infect. Drug Resist. 2018, 12, 129–135. [Google Scholar] [CrossRef]
  42. Brennan-Krohn, T.; Grote, A.; Rodriguez, S.; Kirby, J.E.; Earl, A.M. Transcriptomics Reveals How Minocycline-Colistin Synergy Overcomes Antibiotic Resistance in Multidrug-Resistant Klebsiella Pneumoniae. Antimicrob. Agents Chemother. 2022, 66, e0196921. [Google Scholar] [CrossRef]
  43. Rout, B.; Dash, S.K.; Sahu, K.K.; Behera, B.; Praharaj, I.; Otta, S. Evaluation of Different Methods for in Vitro Susceptibility Testing of Colistin in Carbapenem Resistant Gram-Negative Bacilli. Access Microbiol. 2023, 5, 000595.v3. [Google Scholar] [CrossRef]
  44. Clinical and Laboratory Standards Institute (CLSI). Performance and Standards for Antimicrobial Susceptibility Testing. In CLSI Supplement M100; CLSI: Wayne, PA, USA, 2018. [Google Scholar]
  45. Simner, P.J.; Bergman, Y.; Trejo, M.; Roberts, A.A.; Marayan, R.; Tekle, T.; Campeau, S.; Kazmi, A.Q.; Bell, D.T.; Lewis, S.; et al. Two-Site Evaluation of the Colistin Broth Disk Elution Test to Determine Colistin In Vitro Activity against Gram-Negative Bacilli. J. Clin. Microbiol. 2019, 57, e01163-18. [Google Scholar] [CrossRef]
  46. Needham, B.D.; Trent, M.S. Fortifying the Barrier: The Impact of Lipid A Remodelling on Bacterial Pathogenesis. Nat. Rev. Microbiol. 2013, 11, 467–481. [Google Scholar] [CrossRef] [PubMed]
  47. Novović, K.; Jovčić, B. Colistin Resistance in Acinetobacter baumannii: Molecular Mechanisms and Epidemiology. Antibiotics 2023, 12, 516. [Google Scholar] [CrossRef]
  48. Ding, Y.; Hao, J.; Xiao, W.; Ye, C.; Xiao, X.; Jian, C.; Tang, M.; Li, G.; Liu, J.; Zeng, Z. Role of Efflux Pumps, Their Inhibitors, and Regulators in Colistin Resistance. Front. Microbiol. 2023, 14, 1207441. [Google Scholar] [CrossRef]
  49. Aghapour, Z.; Gholizadeh, P.; Ganbarov, K.; Bialvaei, A.Z.; Mahmood, S.S.; Tanomand, A.; Yousefi, M.; Asgharzadeh, M.; Yousefi, B.; Samadi Kafil, H. Molecular Mechanisms Related to Colistin Resistance in Enterobacteriaceae. Infect. Drug Resist. 2019, 12, 965–975. [Google Scholar] [CrossRef]
  50. Zhang, H.; Srinivas, S.; Xu, Y.; Wei, W.; Feng, Y. Genetic and Biochemical Mechanisms for Bacterial Lipid A Modifiers Associated with Polymyxin Resistance. Trends Biochem. Sci. 2019, 44, 973–988. [Google Scholar] [CrossRef]
  51. Olaitan, A.O.; Morand, S.; Rolain, J.-M. Mechanisms of Polymyxin Resistance: Acquired and Intrinsic Resistance in Bacteria. Front. Microbiol. 2014, 5, 643. [Google Scholar] [CrossRef]
  52. Pelletier, M.R.; Casella, L.G.; Jones, J.W.; Adams, M.D.; Zurawski, D.V.; Hazlett, K.R.O.; Doi, Y.; Ernst, R.K. Unique Structural Modifications Are Present in the Lipopolysaccharide from Colistin-Resistant Strains of Acinetobacter baumannii. Antimicrob. Agents Chemother. 2013, 57, 4831–4840. [Google Scholar] [CrossRef] [PubMed]
  53. Falagas, M.E.; Rafailidis, P.I.; Matthaiou, D.K. Resistance to Polymyxins: Mechanisms, Frequency and Treatment Options. Drug Resist. Updates 2010, 13, 132–138. [Google Scholar] [CrossRef] [PubMed]
  54. Ly, N.S.; Yang, J.; Bulitta, J.B.; Tsuji, B.T. Impact of Two-Component Regulatory Systems PhoP-PhoQ and PmrA-PmrB on Colistin Pharmacodynamics in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2012, 56, 3453–3456. [Google Scholar] [CrossRef] [PubMed]
  55. Gunn, J.S. The Salmonella PmrAB Regulon: Lipopolysaccharide Modifications, Antimicrobial Peptide Resistance and More. Trends Microbiol. 2008, 16, 284–290. [Google Scholar] [CrossRef] [PubMed]
  56. Olaitan, A.O.; Dia, N.M.; Gautret, P.; Benkouiten, S.; Belhouchat, K.; Drali, T.; Parola, P.; Brouqui, P.; Memish, Z.; Raoult, D.; et al. Acquisition of Extended-Spectrum Cephalosporin- and Colistin-Resistant Salmonella Enterica Subsp. Enterica Serotype Newport by Pilgrims during Hajj. Int. J. Antimicrob. Agents 2015, 45, 600–604. [Google Scholar] [CrossRef] [PubMed]
  57. Quesada, A.; Porrero, M.C.; Téllez, S.; Palomo, G.; García, M.; Domínguez, L. Polymorphism of Genes Encoding PmrAB in Colistin-Resistant Strains of Escherichia coli and Salmonella enterica Isolated from Poultry and Swine. J. Antimicrob. Chemother. 2015, 70, 71–74. [Google Scholar] [CrossRef] [PubMed]
  58. Cannatelli, A.; Di Pilato, V.; Giani, T.; Arena, F.; Ambretti, S.; Gaibani, P.; D’Andrea, M.M.; Rossolini, G.M. In Vivo Evolution to Colistin Resistance by PmrB Sensor Kinase Mutation in KPC-Producing Klebsiella Pneumoniae Is Associated with Low-Dosage Colistin Treatment. Antimicrob. Agents Chemother. 2014, 58, 4399–4403. [Google Scholar] [CrossRef]
  59. Cheng, Y.-H.; Lin, T.-L.; Pan, Y.-J.; Wang, Y.-P.; Lin, Y.-T.; Wang, J.-T. Colistin Resistance Mechanisms in Klebsiella Pneumoniae Strains from Taiwan. Antimicrob. Agents Chemother. 2015, 59, 2909–2913. [Google Scholar] [CrossRef] [PubMed]
  60. Jayol, A.; Poirel, L.; Brink, A.; Villegas, M.-V.; Yilmaz, M.; Nordmann, P. Resistance to Colistin Associated with a Single Amino Acid Change in Protein PmrB among Klebsiella pneumoniae Isolates of Worldwide Origin. Antimicrob. Agents Chemother. 2014, 58, 4762–4766. [Google Scholar] [CrossRef]
  61. Gerson, S.; Betts, J.W.; Lucaßen, K.; Nodari, C.S.; Wille, J.; Josten, M.; Göttig, S.; Nowak, J.; Stefanik, D.; Roca, I.; et al. Investigation of Novel PmrB and EptA Mutations in Isogenic Acinetobacter baumannii Isolates Associated with Colistin Resistance and Increased Virulence In Vivo. Antimicrob. Agents Chemother. 2019, 63, e01586-18. [Google Scholar] [CrossRef]
  62. Park, Y.K.; Choi, J.Y.; Shin, D.; Ko, K.S. Correlation between Overexpression and Amino Acid Substitution of the PmrAB Locus and Colistin Resistance in Acinetobacter baumannii. Int. J. Antimicrob. Agents 2011, 37, 525–530. [Google Scholar] [CrossRef] [PubMed]
  63. Dahdouh, E.; Gómez-Gil, R.; Sanz, S.; González-Zorn, B.; Daoud, Z.; Mingorance, J.; Suárez, M. A Novel Mutation in PmrB Mediates Colistin Resistance during Therapy of Acinetobacter baumannii. Int. J. Antimicrob. Agents 2017, 49, 727–733. [Google Scholar] [CrossRef] [PubMed]
  64. Moskowitz, S.M.; Brannon, M.K.; Dasgupta, N.; Pier, M.; Sgambati, N.; Miller, A.K.; Selgrade, S.E.; Miller, S.I.; Denton, M.; Conway, S.P.; et al. PmrB Mutations Promote Polymyxin Resistance of Pseudomonas Aeruginosa Isolated from Colistin-Treated Cystic Fibrosis Patients. Antimicrob. Agents Chemother. 2012, 56, 1019–1030. [Google Scholar] [CrossRef] [PubMed]
  65. Owusu-Anim, D.; Kwon, D.H. Differential Role of Two-Component Regulatory Systems (phoPQ and pmrAB) in Polymyxin B Susceptibility of Pseudomonas aeruginosa. Adv. Microbiol. 2012, 2, 31–36. [Google Scholar] [CrossRef] [PubMed]
  66. Olaitan, A.O.; Morand, S.; Rolain, J.-M. Emergence of Colistin-Resistant Bacteria in Humans without Colistin Usage: A New Worry and Cause for Vigilance. Int. J. Antimicrob. Agents 2016, 47, 1–3. [Google Scholar] [CrossRef] [PubMed]
  67. Wang, C.-H.; Siu, L.K.; Chang, F.-Y.; Tsai, Y.-K.; Lin, Y.-T.; Chiu, S.-K.; Huang, L.-Y.; Lin, J.-C. A Novel Deletion Mutation in PmrB Contributes to Concurrent Colistin Resistance in Carbapenem-Resistant Escherichia Coli Sequence Type 405 of Clinical Origin. Antimicrob. Agents Chemother. 2020, 64, e00220-20. [Google Scholar] [CrossRef] [PubMed]
  68. Jayol, A.; Nordmann, P.; Brink, A.; Poirel, L. Heteroresistance to Colistin in Klebsiella Pneumoniae Associated with Alterations in the PhoPQ Regulatory System. Antimicrob. Agents Chemother. 2015, 59, 2780–2784. [Google Scholar] [CrossRef] [PubMed]
  69. Olaitan, A.O.; Diene, S.M.; Kempf, M.; Berrazeg, M.; Bakour, S.; Gupta, S.K.; Thongmalayvong, B.; Akkhavong, K.; Somphavong, S.; Paboriboune, P.; et al. Worldwide Emergence of Colistin Resistance in Klebsiella Pneumoniae from Healthy Humans and Patients in Lao PDR, Thailand, Israel, Nigeria and France Owing to Inactivation of the PhoP/PhoQ Regulator MgrB: An Epidemiological and Molecular Study. Int. J. Antimicrob. Agents 2014, 44, 500–507. [Google Scholar] [CrossRef]
  70. Nordmann, P.; Jayol, A.; Poirel, L. Rapid Detection of Polymyxin Resistance in Enterobacteriaceae. Emerg. Infect. Dis. 2016, 22, 1038–1043. [Google Scholar] [CrossRef]
  71. Gutu, A.D.; Sgambati, N.; Strasbourger, P.; Brannon, M.K.; Jacobs, M.A.; Haugen, E.; Kaul, R.K.; Johansen, H.K.; Høiby, N.; Moskowitz, S.M. Polymyxin Resistance of Pseudomonas aeruginosa PhoQ Mutants Is Dependent on Additional Two-Component Regulatory Systems. Antimicrob. Agents Chemother. 2013, 57, 2204–2215. [Google Scholar] [CrossRef]
  72. Lippa, A.M.; Goulian, M. Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide. PLoS Genet. 2009, 5, e1000788. [Google Scholar] [CrossRef]
  73. Cannatelli, A.; Giani, T.; D’Andrea, M.M.; Di Pilato, V.; Arena, F.; Conte, V.; Tryfinopoulou, K.; Vatopoulos, A.; Rossolini, G.M. MgrB Inactivation Is a Common Mechanism of Colistin Resistance in KPC-Producing Klebsiella Pneumoniae of Clinical Origin. Antimicrob. Agents Chemother. 2014, 58, 5696–5703. [Google Scholar] [CrossRef]
  74. Wright, M.S.; Suzuki, Y.; Jones, M.B.; Marshall, S.H.; Rudin, S.D.; van Duin, D.; Kaye, K.; Jacobs, M.R.; Bonomo, R.A.; Adams, M.D. Genomic and Transcriptomic Analyses of Colistin-Resistant Clinical Isolates of Klebsiella Pneumoniae Reveal Multiple Pathways of Resistance. Antimicrob. Agents Chemother. 2015, 59, 536–543. [Google Scholar] [CrossRef] [PubMed]
  75. Cannatelli, A.; D’Andrea, M.M.; Giani, T.; Di Pilato, V.; Arena, F.; Ambretti, S.; Gaibani, P.; Rossolini, G.M. In Vivo Emergence of Colistin Resistance in Klebsiella Pneumoniae Producing KPC-Type Carbapenemases Mediated by Insertional Inactivation of the PhoQ/PhoP MgrB Regulator. Antimicrob. Agents Chemother. 2013, 57, 5521–5526. [Google Scholar] [CrossRef] [PubMed]
  76. Lopez-Camacho, E.; Gomez-Gil, R.; Tobes, R.; Manrique, M.; Lorenzo, M.; Galvan, B.; Salvarelli, E.; Moatassim, Y.; Salanueva, I.J.; Pareja, E.; et al. Genomic Analysis of the Emergence and Evolution of Multidrug Resistance during a Klebsiella Pneumoniae Outbreak Including Carbapenem and Colistin Resistance. J. Antimicrob. Chemother. 2014, 69, 632–636. [Google Scholar] [CrossRef]
  77. Poirel, L.; Jayol, A.; Bontron, S.; Villegas, M.-V.; Ozdamar, M.; Turkoglu, S.; Nordmann, P. The MgrB Gene as a Key Target for Acquired Resistance to Colistin in Klebsiella Pneumoniae. J. Antimicrob. Chemother. 2015, 70, 75–80. [Google Scholar] [CrossRef] [PubMed]
  78. Cheng, Y.-H.; Lin, T.-L.; Lin, Y.-T.; Wang, J.-T. Amino Acid Substitutions of CrrB Responsible for Resistance to Colistin through CrrC in Klebsiella Pneumoniae. Antimicrob. Agents Chemother. 2016, 60, 3709–3716. [Google Scholar] [CrossRef]
  79. Baron, S.; Hadjadj, L.; Rolain, J.-M.; Olaitan, A.O. Molecular Mechanisms of Polymyxin Resistance: Knowns and Unknowns. Int. J. Antimicrob. Agents 2016, 48, 583–591. [Google Scholar] [CrossRef]
  80. Trebosc, V.; Gartenmann, S.; Tötzl, M.; Lucchini, V.; Schellhorn, B.; Pieren, M.; Lociuro, S.; Gitzinger, M.; Tigges, M.; Bumann, D.; et al. Dissecting Colistin Resistance Mechanisms in Extensively Drug-Resistant Acinetobacter baumannii Clinical Isolates. mBio 2019, 10, e01083-19. [Google Scholar] [CrossRef]
  81. Moffatt, J.H.; Harper, M.; Harrison, P.; Hale, J.D.F.; Vinogradov, E.; Seemann, T.; Henry, R.; Crane, B.; St. Michael, F.; Cox, A.D.; et al. Colistin Resistance in Acinetobacter Baumannii Is Mediated by Complete Loss of Lipopolysaccharide Production. Antimicrob. Agents Chemother. 2010, 54, 4971–4977. [Google Scholar] [CrossRef]
  82. Carretero-Ledesma, M.; García-Quintanilla, M.; Martín-Peña, R.; Pulido, M.R.; Pachón, J.; McConnell, M.J. Phenotypic Changes Associated with Colistin Resistance Due to Lipopolysaccharide Loss in Acinetobacter baumannii. Virulence 2018, 9, 930–942. [Google Scholar] [CrossRef] [PubMed]
  83. Boinett, C.J.; Cain, A.K.; Hawkey, J.; Do Hoang, N.T.; Khanh, N.N.T.; Thanh, D.P.; Dordel, J.; Campbell, J.I.; Lan, N.P.H.; Mayho, M.; et al. Clinical and Laboratory-Induced Colistin-Resistance Mechanisms in Acinetobacter baumannii. Microb. Genom. 2019, 5, e000246. [Google Scholar] [CrossRef] [PubMed]
  84. Lean, S.-S.; Yeo, C.C.; Suhaili, Z.; Thong, K.-L. Comparative Genomics of Two ST 195 Carbapenem-Resistant Acinetobacter Baumannii with Different Susceptibility to Polymyxin Revealed Underlying Resistance Mechanism. Front. Microbiol. 2016, 6, 1445. [Google Scholar] [CrossRef] [PubMed]
  85. Moffatt, J.H.; Harper, M.; Adler, B.; Nation, R.L.; Li, J.; Boyce, J.D. Insertion Sequence IS Aba11 Is Involved in Colistin Resistance and Loss of Lipopolysaccharide in Acinetobacter baumannii. Antimicrob. Agents Chemother. 2011, 55, 3022–3024. [Google Scholar] [CrossRef]
  86. Kamoshida, G.; Yamada, N.; Nakamura, T.; Yamaguchi, D.; Kai, D.; Yamashita, M.; Hayashi, C.; Kanda, N.; Sakaguchi, M.; Morimoto, H.; et al. Preferential Selection of Low-Frequency, Lipopolysaccharide-Modified, Colistin-Resistant Mutants with a Combination of Antimicrobials in Acinetobacter baumannii. Microbiol. Spectr. 2022, 10, e0192822. [Google Scholar] [CrossRef] [PubMed]
  87. Beceiro, A.; Moreno, A.; Fernández, N.; Vallejo, J.A.; Aranda, J.; Adler, B.; Harper, M.; Boyce, J.D.; Bou, G. Biological Cost of Different Mechanisms of Colistin Resistance and Their Impact on Virulence in Acinetobacter baumannii. Antimicrob. Agents Chemother. 2014, 58, 518–526. [Google Scholar] [CrossRef] [PubMed]
  88. Liu, Y.-Y.; Wang, Y.; Walsh, T.R.; Yi, L.-X.; Zhang, R.; Spencer, J.; Doi, Y.; Tian, G.; Dong, B.; Huang, X.; et al. 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. 2016, 16, 161–168. [Google Scholar] [CrossRef] [PubMed]
  89. Kieffer, N.; Nordmann, P.; Poirel, L. Moraxella Species as Potential Sources of MCR-Like Polymyxin Resistance Determinants. Antimicrob. Agents Chemother. 2017, 61, e00129-17. [Google Scholar] [CrossRef] [PubMed]
  90. Xavier, B.B.; Lammens, C.; Ruhal, R.; Kumar-Singh, S.; Butaye, P.; Goossens, H.; Malhotra-Kumar, S. Identification of a Novel Plasmid-Mediated Colistin-Resistance Gene, Mcr-2, in Escherichia coli, Belgium, June 2016. Eurosurveillance 2016, 21, 30280. [Google Scholar] [CrossRef]
  91. Yin, W.; Li, H.; Shen, Y.; Liu, Z.; Wang, S.; Shen, Z.; Zhang, R.; Walsh, T.R.; Shen, J.; Wang, Y. Novel Plasmid-Mediated Colistin Resistance Gene Mcr-3 in Escherichia coli. mBio 2017, 8, e00543-17. [Google Scholar] [CrossRef]
  92. Carattoli, A.; Villa, L.; Feudi, C.; Curcio, L.; Orsini, S.; Luppi, A.; Pezzotti, G.; Magistrali, C.F. Novel Plasmid-Mediated Colistin Resistance Mcr-4 Gene in Salmonella and Escherichia Coli, Italy 2013, Spain and Belgium, 2015 to 2016. Eurosurveillance 2017, 22, 30589. [Google Scholar] [CrossRef] [PubMed]
  93. Borowiak, M.; Fischer, J.; Hammerl, J.A.; Hendriksen, R.S.; Szabo, I.; Malorny, B. 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. 2017, 72, 3317–3324. [Google Scholar] [CrossRef] [PubMed]
  94. Zurfluh, K.; Tasara, T.; Poirel, L.; Nordmann, P.; Stephan, R. Draft Genome Sequence of Escherichia coli S51, a Chicken Isolate Harboring a Chromosomally Encoded Mcr-1 Gene. Genome Announc. 2016, 4, e00796-16. [Google Scholar] [CrossRef] [PubMed]
  95. Partridge, S.R.; Di Pilato, V.; Doi, Y.; Feldgarden, M.; Haft, D.H.; Klimke, W.; Kumar-Singh, S.; Liu, J.-H.; Malhotra-Kumar, S.; Prasad, A.; et al. Proposal for Assignment of Allele Numbers for Mobile Colistin Resistance (Mcr) Genes. J. Antimicrob. Chemother. 2018, 73, 2625–2630. [Google Scholar] [CrossRef] [PubMed]
  96. Nitz, F.; de Melo, B.O.; da Silva, L.C.N.; de Souza Monteiro, A.; Marques, S.G.; Monteiro-Neto, V.; de Jesus Gomes Turri, R.; Junior, A.D.S.; Conceição, P.C.R.; Magalhães, H.J.C.; et al. Molecular Detection of Drug-Resistance Genes of BlaOXA-23-BlaOXA-51 and Mcr-1 in Clinical Isolates of Pseudomonas Aeruginosa. Microorganisms 2021, 9, 786. [Google Scholar] [CrossRef]
  97. Abd El-Baky, R.M.; Masoud, S.M.; Mohamed, D.S.; Waly, N.G.; Shafik, E.A.; Mohareb, D.A.; Elkady, A.; Elbadr, M.M.; Hetta, H.F. Prevalence and Some Possible Mechanisms of Colistin Resistance Among Multidrug-Resistant and Extensively Drug-Resistant Pseudomonas aeruginosa. Infect. Drug Resist. 2020, 13, 323–332. [Google Scholar] [CrossRef] [PubMed]
  98. Shabban, M.; Fahim, N.A.E.; Montasser, K.; El Magd, N.M.A. Resistance to Colistin Mediated by Mcr-1 among Multidrug Resistant Gram Negative Pathogens at a Tertiary Care Hospital, Egypt. J. Pure Appl. Microbiol. 2020, 14, 1125–1132. [Google Scholar] [CrossRef]
  99. Hameed, F.; Khan, M.A.; Muhammad, H.; Sarwar, T.; Bilal, H.; Rehman, T.U. Plasmid-Mediated Mcr-1 Gene in Acinetobacter Baumannii and Pseudomonas Aeruginosa: First Report from Pakistan. Rev. Soc. Bras. Med. Trop. 2019, 52, e20190237. [Google Scholar] [CrossRef]
  100. Martins, E.; Maboni, G.; Battisti, R.; da Costa, L.; Selva, H.L.; Levitzki, E.D.; Gressler, L.T. High Rates of Multidrug Resistance in Bacteria Associated with Small Animal Otitis: A Study of Cumulative Microbiological Culture and Antimicrobial Susceptibility. Microb. Pathog. 2022, 165, 105399. [Google Scholar] [CrossRef]
  101. Ahmed, Z.S.; Elshafiee, E.A.; Khalefa, H.S.; Kadry, M.; Hamza, D.A. Evidence of Colistin Resistance Genes (Mcr-1 and Mcr-2) in Wild Birds and Its Public Health Implication in Egypt. Antimicrob. Resist. Infect. Control 2019, 8, 197. [Google Scholar] [CrossRef]
  102. Tartor, Y.H.; Gharieb, R.M.A.; Abd El-Aziz, N.K.; El Damaty, H.M.; Enany, S.; Khalifa, E.; Attia, A.S.A.; Abdellatif, S.S.; Ramadan, H. Virulence Determinants and Plasmid-Mediated Colistin Resistance Mcr Genes in Gram-Negative Bacteria Isolated from Bovine Milk. Front. Cell. Infect. Microbiol. 2021, 11, 761417. [Google Scholar] [CrossRef] [PubMed]
  103. Javed, H.; Saleem, S.; Zafar, A.; Ghafoor, A.; Bin Shahzad, A.; Ejaz, H.; Junaid, K.; Jahan, S. Emergence of Plasmid-Mediated Mcr Genes from Gram-Negative Bacteria at the Human-Animal Interface. Gut Pathog. 2020, 12, 54. [Google Scholar] [CrossRef] [PubMed]
  104. Fujihara, H.; Yamazoe, A.; Hosoyama, A.; Suenaga, H.; Kimura, N.; Hirose, J.; Watanabe, T.; Futagami, T.; Goto, M.; Furukawa, K. Draft Genome Sequence of Pseudomonas Aeruginosa KF702 (NBRC 110665), a Polychlorinated Biphenyl-Degrading Bacterium Isolated from Biphenyl-Contaminated Soil. Genome Announc. 2015, 3, e00517-15. [Google Scholar] [CrossRef]
  105. Snesrud, E.; Maybank, R.; Kwak, Y.I.; Jones, A.R.; Hinkle, M.K.; McGann, P. Chromosomally Encoded Mcr-5 in Colistin-Nonsusceptible Pseudomonas Aeruginosa. Antimicrob. Agents Chemother. 2018, 62, e00679-18. [Google Scholar] [CrossRef]
  106. Martins-Sorenson, N.; Snesrud, E.; Xavier, D.E.; Cacci, L.C.; Iavarone, A.T.; McGann, P.; Riley, L.W.; Moreira, B.M. A Novel Plasmid-Encoded Mcr-4.3 Gene in a Colistin-Resistant Acinetobacter baumannii Clinical Strain. J. Antimicrob. Chemother. 2020, 75, 60–64. [Google Scholar] [CrossRef] [PubMed]
  107. Fan, R.; Li, C.; Duan, R.; Qin, S.; Liang, J.; Xiao, M.; Lv, D.; Jing, H.; Wang, X. Retrospective Screening and Analysis of Mcr-1 and BlaNDM in Gram-Negative Bacteria in China, 2010–2019. Front. Microbiol. 2020, 11, 121. [Google Scholar] [CrossRef] [PubMed]
  108. Kalová, A.; Gelbíčová, T.; Overballe-Petersen, S.; Litrup, E.; Karpíšková, R. Characterisation of Colistin -Resistant Enterobacterales and Acinetobacter Strains Carrying Mcr Genes from Asian Aquaculture Products. Antibiotics 2021, 10, 838. [Google Scholar] [CrossRef]
  109. Bitar, I.; Medvecky, M.; Gelbicova, T.; Jakubu, V.; Hrabak, J.; Zemlickova, H.; Karpiskova, R.; Dolejska, M. Complete Nucleotide Sequences of Mcr-4.3-Carrying Plasmids in Acinetobacter Baumannii Sequence Type 345 of Human and Food Origin from the Czech Republic, the First Case in Europe. Antimicrob. Agents Chemother. 2019, 63, e01166-19. [Google Scholar] [CrossRef]
  110. Al-Kadmy, I.M.S.; Ibrahim, S.A.; Al-Saryi, N.; Aziz, S.N.; Besinis, A.; Hetta, H.F. Prevalence of Genes Involved in Colistin Resistance in Acinetobacter baumannii: First Report from Iraq. Microb. Drug Resist. 2020, 26, 616–622. [Google Scholar] [CrossRef]
  111. Srinivasan, V.B.; Rajamohan, G. KpnEF, a New Member of the Klebsiella Pneumoniae Cell Envelope Stress Response Regulon, Is an SMR-Type Efflux Pump Involved in Broad-Spectrum Antimicrobial Resistance. Antimicrob. Agents Chemother. 2013, 57, 4449–4462. [Google Scholar] [CrossRef]
  112. Warner, D.M.; Levy, S.B. Different Effects of Transcriptional Regulators MarA, SoxS and Rob on Susceptibility of Escherichia Coli to Cationic Antimicrobial Peptides (CAMPs): Rob-Dependent CAMP Induction of the MarRAB Operon. Microbiology 2010, 156, 570–578. [Google Scholar] [CrossRef] [PubMed]
  113. Koutsolioutsou, A.; Peña-Llopis, S.; Demple, B. Constitutive SoxR Mutations Contribute to Multiple-Antibiotic Resistance in Clinical Escherichia coli Isolates. Antimicrob. Agents Chemother. 2005, 49, 2746–2752. [Google Scholar] [CrossRef] [PubMed]
  114. Parra-Lopez, C.; Baer, M.T.; Groisman, E.A. Molecular Genetic Analysis of a Locus Required for Resistance to Antimicrobial Peptides in Salmonella Typhimurium. EMBO J. 1993, 12, 4053–4062. [Google Scholar] [CrossRef] [PubMed]
  115. Lin, M.-F.; Lin, Y.-Y.; Lan, C.-Y. Contribution of EmrAB Efflux Pumps to Colistin Resistance in Acinetobacter Baumannii. J. Microbiol. 2017, 55, 130–136. [Google Scholar] [CrossRef] [PubMed]
  116. Poole, K.; Lau, C.H.-F.; Gilmour, C.; Hao, Y.; Lam, J.S. Polymyxin Susceptibility in Pseudomonas Aeruginosa Linked to the MexXY-OprM Multidrug Efflux System. Antimicrob. Agents Chemother. 2015, 59, 7276–7289. [Google Scholar] [CrossRef] [PubMed]
  117. Goli, H.R.; Nahaei, M.R.; Ahangarzadeh Rezaee, M.; Hasani, A.; Samadi Kafil, H.; Aghazadeh, M. Emergence of Colistin Resistant Pseudomonas Aeruginosa at Tabriz Hospitals, Iran. Iran. J. Microbiol. 2016, 8, 62–69. [Google Scholar]
  118. Ni, W.; Li, Y.; Guan, J.; Zhao, J.; Cui, J.; Wang, R.; Liu, Y. Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria. Antimicrob. Agents Chemother. 2016, 60, 3215–3218. [Google Scholar] [CrossRef] [PubMed]
  119. Bergen, P.J.; Li, J.; Nation, R.L. Dosing of Colistin—Back to Basic PK/PD. Curr. Opin. Pharmacol. 2011, 11, 464–469. [Google Scholar] [CrossRef]
  120. Dudhani, R.V.; Turnidge, J.D.; Coulthard, K.; Milne, R.W.; Rayner, C.R.; Li, J.; Nation, R.L. Elucidation of the Pharmacokinetic/Pharmacodynamic Determinant of Colistin Activity against Pseudomonas aeruginosa in Murine Thigh and Lung Infection Models. Antimicrob. Agents Chemother. 2010, 54, 1117–1124. [Google Scholar] [CrossRef]
  121. Dudhani, R.V.; Turnidge, J.D.; Nation, R.L.; Li, J. FAUC/MIC Is the Most Predictive Pharmacokinetic/Pharmacodynamic Index of Colistin against Acinetobacter baumannii in Murine Thigh and Lung Infection Models. J. Antimicrob. Chemother. 2010, 65, 1984–1990. [Google Scholar] [CrossRef]
  122. Cheah, S.-E.; Wang, J.; Nguyen, V.T.T.; Turnidge, J.D.; Li, J.; Nation, R.L. New Pharmacokinetic/Pharmacodynamic Studies of Systemically Administered Colistin against Pseudomonas aeruginosa and Acinetobacter baumannii in Mouse Thigh and Lung Infection Models: Smaller Response in Lung Infection. J. Antimicrob. Chemother. 2015, 70, 3291–3297. [Google Scholar] [CrossRef] [PubMed]
  123. Tsala, M.; Vourli, S.; Georgiou, P.-C.; Pournaras, S.; Tsakris, A.; Daikos, G.L.; Mouton, J.W.; Meletiadis, J. Exploring Colistin Pharmacodynamics against Klebsiella Pneumoniae: A Need to Revise Current Susceptibility Breakpoints. J. Antimicrob. Chemother. 2018, 73, 953–961. [Google Scholar] [CrossRef]
  124. Gautam, V.; Shafiq, N.; Mouton, J.; Malhotra, S.; Kaur, S.; Ray, P. Pharmacokinetics of Colistin in Patients with Multidrug-Resistant Gram-Negative Infections: A Pilot Study. Indian J. Med. Res. 2018, 147, 407. [Google Scholar] [CrossRef] [PubMed]
  125. Sorlí, L.; Luque, S.; Li, J.; Campillo, N.; Danés, M.; Montero, M.; Segura, C.; Grau, S.; Horcajada, J.P. Colistin for the Treatment of Urinary Tract Infections Caused by Extremely Drug-Resistant Pseudomonas aeruginosa: Dose Is Critical. J. Infect. 2019, 79, 253–261. [Google Scholar] [CrossRef]
  126. Imberti, R.; Cusato, M.; Villani, P.; Carnevale, L.; Iotti, G.A.; Langer, M.; Regazzi, M. Steady-State Pharmacokinetics and BAL Concentration of Colistin in Critically Ill Patients After IV Colistin Methanesulfonate Administration. Chest 2010, 138, 1333–1339. [Google Scholar] [CrossRef] [PubMed]
  127. Markantonis, S.L.; Markou, N.; Fousteri, M.; Sakellaridis, N.; Karatzas, S.; Alamanos, I.; Dimopoulou, E.; Baltopoulos, G. Penetration of Colistin into Cerebrospinal Fluid. Antimicrob. Agents Chemother. 2009, 53, 4907–4910. [Google Scholar] [CrossRef] [PubMed]
  128. Ozcimen, M.; Ozcimen, S.; Sakarya, Y.; Sakarya, R.; Goktas, S.; Alpfidan, I.; Erdogan, E. Ocular Penetration of Intravenously Administered Colistin in Rabbit Uveitis Model. J. Ocul. Pharmacol. Ther. 2014, 30, 681–685. [Google Scholar] [CrossRef] [PubMed]
  129. Li, J.; Nation, R.L.; Turnidge, J.D.; Milne, R.W.; Coulthard, K.; Rayner, C.R.; Paterson, D.L. Colistin: The ReEmerging Antibiotic for Multidrug-Resistant Gram-Negative Bacterial Infections. Lancet Infect. Dis. 2006, 6, 589–601. [Google Scholar] [CrossRef] [PubMed]
  130. Brennan-Krohn, T.; Kirby, J.E. Synergistic Combinations and Repurposed Antibiotics Active against the Pandrug-Resistant Klebsiella pneumoniae Nevada Strain. Antimicrob. Agents Chemother. 2019, 63, e01374-19. [Google Scholar] [CrossRef]
  131. Doern, C.D. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J. Clin. Microbiol. 2014, 52, 4124–4128. [Google Scholar] [CrossRef]
  132. Zaghi, I.; Gaibani, P.; Campoli, C.; Bartoletti, M.; Giannella, M.; Ambretti, S.; Viale, P.; Lewis, R.E. Serum bactericidal titres for monitoring antimicrobial therapy: Current status and potential role in the management of multidrug-resistant Gram- negative infections. Clin. Microbiol. Infect. 2020, 26, 1338–1344. [Google Scholar] [CrossRef] [PubMed]
  133. Gaibani, P.; Lombardo, D.; Bartoletti, M.; Ambretti, S.; Campoli, C.; Giannella, M.; Tedeschi, S.; Conti, M.; Mancini, R.; Landini, M.P.; et al. Comparative serum bactericidal activity of meropenem-based combination regimens against extended-spectrum beta-lactamase and KPC-producing Klebsiella pneumoniae. Eur. J. Clin. Microbiol. Infect. Dis. 2019, 38, 1925–1931. [Google Scholar] [CrossRef]
  134. Gu, B.; Cai, J.; Peng, G.; Zhou, H.; Zhang, W.; Zhang, D.; Gong, D. Metal organic framework-loaded biohybrid magnetic microrobots for enhanced antibacterial treatment. Colloids Surf. A Physicochem. Eng. Asp. 2024, 685, 133295. [Google Scholar] [CrossRef]
  135. Huang, F.; Cai, X.; Hou, X.; Zhang, Y.; Liu, J.; Yang, L.; Liu, Y.; Liu, J. A dynamic covalent polymeric antimicrobial for conquering drug-resistant bacterial infection. Exploration 2022, 2, 20210145. [Google Scholar] [CrossRef] [PubMed]
  136. Papazachariou, A.; Tziolos, R.N.; Karakonstantis, S.; Ioannou, P.; Samonis, G.; Kofteridis, D.P. Treatment Strategies of Colistin Resistance Acinetobacter baumannii Infections. Antibiotics 2024, 13, 423. [Google Scholar] [CrossRef]
  137. Girometti, N.; Lewis, R.E.; Giannella, M.; Ambretti, S.; Bartoletti, M.; Tedeschi, S.; Tumietto, F.; Cristini, F.; Trapani, F.; Gaibani, P.; et al. Klebsiella pneumoniae bloodstream infection: Epidemiology and impact of inappropriate empirical therapy. Medicine 2014, 93, 298–309. [Google Scholar] [CrossRef]
Molecules 29 02969 g001
Figure 1. Colistin prodrug structure. Two-dimensional representation of colistin methanesulfonate molecule highlighted the five methanesulfonate groups (inside the purple dotted circles) responsible for the difference between active compound and its colistimethate sodium (prodrug) form. This 2D representation was performed with MolView v2.4 online tool (https://molview.org/ accessed on 1 January 2024).
Figure 1. Colistin prodrug structure. Two-dimensional representation of colistin methanesulfonate molecule highlighted the five methanesulfonate groups (inside the purple dotted circles) responsible for the difference between active compound and its colistimethate sodium (prodrug) form. This 2D representation was performed with MolView v2.4 online tool (https://molview.org/ accessed on 1 January 2024).
Molecules 29 02969 g001
Molecules 29 02969 g002
Figure 2. Colistin mechanism of action and SMH model. Schematic representation of colistin’s effect on Gram-negative bacteria. (a) Colistin drug acts by competition with Ca2+ and Mg2+ ions, causing their displacement and leading to (b) formation of pores. Colistin goes through the peptidoglycan barrier reaching the inner membrane where it acts by displacing Ca2+ and Mg2+ ions. All the structural alteration, induced by colistin action on membranes or colistin intracellular accumulation, leads to cell death (c). The three-dimensional model of colistin was generated with MolView v2.4 online tool (https://molview.org/ accessed on 1 January 2024). This figure was created in BioRender.com.
Figure 2. Colistin mechanism of action and SMH model. Schematic representation of colistin’s effect on Gram-negative bacteria. (a) Colistin drug acts by competition with Ca2+ and Mg2+ ions, causing their displacement and leading to (b) formation of pores. Colistin goes through the peptidoglycan barrier reaching the inner membrane where it acts by displacing Ca2+ and Mg2+ ions. All the structural alteration, induced by colistin action on membranes or colistin intracellular accumulation, leads to cell death (c). The three-dimensional model of colistin was generated with MolView v2.4 online tool (https://molview.org/ accessed on 1 January 2024). This figure was created in BioRender.com.
Molecules 29 02969 g002
Molecules 29 02969 g003
Figure 3. Mechanism of resistance to colistin. Schematic representation of principal colistin resistance mechanisms among Gram-negative bacteria: (i) modification of LPS structure mediated by chromosomal mutation; (ii) modification of LPS structure mediated by plasmid-resistance; (iii) loss of LPS structure; (iv) overexpression of efflux pumps.
Figure 3. Mechanism of resistance to colistin. Schematic representation of principal colistin resistance mechanisms among Gram-negative bacteria: (i) modification of LPS structure mediated by chromosomal mutation; (ii) modification of LPS structure mediated by plasmid-resistance; (iii) loss of LPS structure; (iv) overexpression of efflux pumps.
Molecules 29 02969 g003
Table 1. Principal points discussed in this review.
Table 1. Principal points discussed in this review.
Insight Into the Mechanism of ActionActivity Against Gram-Negative BacteriaInteraction with Lipid A of LPSBacteria Death Induced by Altering Permeability Outer Membrane Bacteria Death Induced by Oxidative StressBacteria Death Induced by Inhibiting Bacteria Respiration Enzymes
Insight into the mechanism of resistanceChromosomal resistance Plasmid resistance
Reduction in LPS negative charge (i.e., pmrHIJKLM operon)Loss of Lipid A (i.e., Lpx byosinthesis)Overexpression of efflux pumps (i.e., AcrAB–TolC complex) Modification of Lipid A structure (i.e., mcr gene)
Insight into pharmacokinetic/pharmacodynamic propertiesfAUC/MIC represent the best PK/PD target for colistin
Table 2. Colistin penetration and assessment of PK/PD target attainment in different sites of infection.
Table 2. Colistin penetration and assessment of PK/PD target attainment in different sites of infection.
Site of
Infection		Study DesignNumber of PatientsSettingDoseAbsolute Tissue ConcentrationsAbsolute Plasmatic ConcentrationsPenetration Rate
(AUCtissue/AUCplasma)		PK/PD Target AttainmentRef.
LungProspective observational13ICU
VAP		2 MU q8h IVUndetectableCmin 1.03 ± 0.69 mg/L
AUC/MIC ratio 17.3 ± 9.3
(for MIC = 2 mg/L)		0.00Suboptimal in ELF[126]
CSFProspective observational5ICU2–3 MU q8h IVCmin 0.47 mg/L
AUC 0.53 mg·h/L		Cmin 9.26 mg/L
AUC 10.4 mg·h/L		0.05Optimal PK/PD target attainment only for P. aeruginosa and A. baumannii strains exhibiting MIC values up to 0.06 mg/L[127]
OcularPreclinical rabbit uveitis model20Uveitis induced after endotoxin injection5 mg/kg IVAqueous humor
0.62 ± 0.07 (at 0.5 h)
0.45 ± 0.05 (at 3 h)
0.38 ± 0.08 (at 6 h)
Vitreous humor
0.02 ± 0.01 (at 3 h)		9.84 ± 2.0 (at 0.5 h)
0.93 ± 0.07 (at 3 h)
0.24 ± 0.08 (at 6 h)		0.07
(aqueous humor at 0.5 h)
0.48
(aqueous humor at 3 h)
1.58
(aqueous humor at 6 h)
0.02
(vitreous humor at 3 h)		Not assessable[128]
AUC: area under concentration-to-time curve; Cmin: trough concentrations; CSF: cerebrospinal fluid; ELF: epithelial lining fluid; ICU: intensive care unit; IV: intravenous; MIC: minimum inhibitory concentration; PK/PD: pharmacokinetic/pharmacodynamic; VAP: ventilator-associated pneumonia.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Diani, E.; Bianco, G.; Gatti, M.; Gibellini, D.; Gaibani, P. Colistin: Lights and Shadows of an Older Antibiotic. Molecules 2024, 29, 2969. https://doi.org/10.3390/molecules29132969

AMA Style

Diani E, Bianco G, Gatti M, Gibellini D, Gaibani P. Colistin: Lights and Shadows of an Older Antibiotic. Molecules. 2024; 29(13):2969. https://doi.org/10.3390/molecules29132969

Chicago/Turabian Style

Diani, Erica, Gabriele Bianco, Milo Gatti, Davide Gibellini, and Paolo Gaibani. 2024. "Colistin: Lights and Shadows of an Older Antibiotic" Molecules 29, no. 13: 2969. https://doi.org/10.3390/molecules29132969

APA Style

Diani, E., Bianco, G., Gatti, M., Gibellini, D., & Gaibani, P. (2024). Colistin: Lights and Shadows of an Older Antibiotic. Molecules, 29(13), 2969. https://doi.org/10.3390/molecules29132969

Article Metrics

Back to TopTop