Colistin is a cationic polypeptide antibiotic, a member of the polymyxin family of molecules. It was isolated for the first time in 1949 as a product of
As polymyxins are poorly absorbed from the digestive tract, orally administered polymyxins are only active on bacteria in the gastrointestinal system. Poly myxins do not diffuse well into tissues and do not penetrate the cerebrospinal fluid or the pleural and peritoneal cavity. Colistin has numerous side effects, including nephrotoxicity and neurotoxicity; therefore, it cannot be used in patients with renal failure (Kostowski and Herman 2010). The levels of nephrotoxicity and neurotoxicity were the reason for its discontinued use in human medicine after 1970 (Tullu and Dhariwal 2013).
In medicine, two physical forms of colistin are available, colistin sulphate (CS) for oral and topical use, and colistin methanesulphonate (CMS) for parenteral use (Kwa et al. 2005; Li et al. 2005). Nephrotoxicity and neurotoxicity are dose-dependent (Ordooei Javan et al. 2015). Risk factors for nephrotoxicity include colistin plasma levels > 2.5–3 g/l, concomitant administration of other nephrotoxic drugs (such as anti-inflammatory drugs, vancomycin and aminoglycosides), the advanced age of patient, and severity of the disease (rates of nephrotoxicity 14–53%) (Kwon et al. 2010; Pogue et al. 2011). Neurotoxicity is reversible and manifests itself, among others, in the form of peripheral and facial paresthesia, dizziness/vertigo, weakness, visual disturbances, and ataxia (4–6% of patients) (Koch-Weser et al. 1970; Spapen et al. 2011). Colistin methanesulphonate has no antimicrobial activity and acts as a colistin pro-drug that does not bind to plasma proteins. After parenteral administration, approximately 20% of CMS is hydrolyzed to colistin. This is an important feature in reducing toxicity, especially nephrotoxicity (Falagas et al. 2005). When given intravenously, a large portion of CMS is eliminated mainly through the kidneys by glomerular filtration and tubular secretion, which allows the use of CMS in urinary tract infections (Kostowski and Herman 2010). The intravenous (IV) form of the drug may also be administered by inhalation (Li et al. 2005). Inhaled colistin is used for treating pneumonia and ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) Gram-negative microorganisms, while it is also used prophylactically in patients with cystic fibrosis. Colistin also causes the release of histamine and serotonin by monocytes, which can lead to acute respiratory failure; therefore, care is needed when administering this drug in the form of an aerosol (Dzierżanowska 2018).
In the last 20 years, the emergence of MDR Gram-negative bacilli has led to polymyxins B and E being used once again, as a “salvage” therapy in the patients with CRE (carbapenems-resistant
Bacteria acquire resistance to colistin as a result of mutations and adaptation mechanisms. Different molecular mechanisms are associated with colistin resistance in Gram-negative bacteria; there are, among others, changes in the two-component systems:
Bacterial colistin resistance may be coded on transposable genetic elements (mostly plasmids with the
The
Recently, Carroll et al. (2019) have described the
Colistin is used for treating infections with carbapenem-resistant
Moreover, the development of outbreaks by colistin-resistant Gram-negative bacilli producing carbapenemases is a great problem (Antoniadou et al. 2007; Marchaim et al. 2011; Monaco et al. 2014; Olaitan et al. 2014a; Parisi et al. 2015; Jayol et al. 2016; Gundogdu et al. 2018). In 2013, the colistin resistance rate has risen to an average of over 30% of CRE isolates, including Italy, Spain, and Greece, and constituted accordingly 43, 31, and 20.8%, respectively (ECDC 2014; Monaco et al. 2014; Pena et al. 2014; Meletis et al. 2015). The increased mortality is also related to infections with colistin-resistant strains (Capone et al. 2013). Colistin resistance makes the choice of antimicrobial agents difficult, and the use of therapeutic options for colistin-resistant MDR isolates depends on the sensitivity phenotype of the isolates, the infection type and site, antimicrobial PK/PD properties, and potential side effects (Petrosillo et al. 2019).
Due to the increasing role of colistin in the treatment of human infections with MDR bacteria, the resistance to this antibiotic should be carefully monitored. The use of colistin in human medicine is assumed to be a cause for the occurrence of colistin resistance in Enterobacterales, particularly in
Ceftazidime/avibactam, as a combination of β-lactam and β-lactamases inhibitor, plays an important role in the treatment of MDR
The combination of meropenem with vaborbactam is the new antimicrobial agent active against KPC-positive
It is highly important to develop phenotypic tests capable of detecting the colistin resistance in Gram-negative rods. Until recently, there was no consensus as to the methodology for colistin susceptibility testing. The disc diffusion method and gradient tests proved to be unreliable due to the poor diffusion of colistin in agar (Galani et al. 2008; Behera et al. 2010; Dafopoupolu et al. 2015; Chew et al. 2017; Vasoo 2017; Giske and Kahlameter 2018). Therefore, disk diffusion and gradient diffusion are not valid techniques for the determination of susceptibility to polymyxins.
In 2016, both EUCAST and the Clinical and Laboratory Standards Institute (CLSI) recommended the International Standard Organization (ISO) 20776 standard broth dilution method for testing of the MIC values of colistin (CLSI 2016; EUCAST 2016). However, the reference broth microdilution method is difficult to apply in routine microbiological diagnostics. The EUCAST does not recommend the use of automated systems to determine the phenotype of bacterial sensitivity such as Vitek 2, (bioMerieux, France), BD Phoenix (Becton Dickinson, USA), as well as Walk-Away (Beckman Coulter, USA) for the analysis of the sensitivity of Gram-negative bacilli to colistin. This is because these systems have fairly limited accuracy in determining colistin MIC, particularly in the range of 2–4 mg/l when compared to the reference method (Nordmann et al. 2016b; Bosacka et al. 2018; Matuschek et al. 2018b; Lellouche et al. 2019).
The literature data indicate the usefulness of several commercially available systems that are based on the broth microdilution method, such as the MIC-Strip Colistin (Merlin,Germany), Microlatest MIC Colistin (Erba Lachema, Czech Republic), Sensitest Colistin (Liofilchem, Italy), and MIC COL (Diagnostics, Slovakia) for the evaluation of the sensitivity of Enterobacterales and non-fermenting rods to colistin (Nordmann et al. 2016b; Matuschek et al. 2018a; Bosacka et al. 2018; Lellouche et al. 2019). Members of colistin-resistant bacilli are usually correctly categorized as resistant using the above-mentioned methods (Chew et al. 2017; Poirel et al. 2017). An increasing number of recent reports point to the heterogeneity of strains detected
The innovatory technique for the identification of colistin resistance is the Rapid Polymyxin NP (Nordmann/Poirel) test. It was developed by the Nordmann’s group for the colistin susceptibility testing in Enterobacterales (Nordmann et al. 2016b). Currently, the rese archers are underway to use this test for the detection of colistin resistance in non-fermenting bacilli. The Rapid Polymyxin NP test detects fermentation of glucose associated with bacterial growth in the presence of a defined concentration of polymyxin E or B; the presence of acid metabolites is evidenced by the change in the pH and the indicator (red phenol) color from orange to yellow. The sensitivity and specificity of the test are highly comparable to the reference broth microdilution method (99.3 and 95.4%, respectively). This test is easy to perform and provides a result in less than 2 hours (Nordmann et al. 2016b).
Chromogenic media are commonly used for screening; they allow the growth of sought bacteria as properly colored colonies. The first agar medium for detecting colistin-resistant Gram-negative rods from bacterial cultures and rectal swab samples was the SuperPolymyxin screening medium (Nordmann et al. 2016a); the commercial version of this medium is SuperPolymyxin medium (ELITechGroup, Puteaux, France) for detecting colistin-resistant Enterobacterales strains, including these with the low MIC values (mg/l) that harbor the
The chromogenic method is based on the dilution in agar, although EUCAST does not recommend this procedure for the determination of bacterial susceptibility to colistin, as the threshold of the detectability increases with the growth of the bacterial inoculum (Matuschek et al. 2018b). However, Turlej-Rogacka et al. (2018) reported that when compared to broth dilution methods, the method of the dilution in agar yields more accurate results in the evaluation of the colistin MIC values (Turlej-Rogacka et al. 2018). Behera and colleagues (2010) confirmed the high correlation of results between the reference method and the agar dilution method (Behera et al. 2010; Dafopouolu et al. 2015). The greatest challenge in colistin handling is its binding to plastic (Humphries 2015; Matuschek et al. 2018b). According to the above-mentioned authors, the agar dilution method significantly reduces the phenomenon of colistin-plastic binding, and the MICs results obtained with this method are characterized by a high accuracy (Behera et al. 2010; Humphries 2015; Matuschek et al. 2018).
The COLR medium uses the borderline colistin concentrations that allow qualification of the strains studied as susceptible or resistant. This chromogenic medium is a qualitative method of Enterobacterales detection and does not allow the determination of the colistin MIC values against the bacterial strains analyzed. As such, it should only be regarded as a screening test. On the other hand, in treating the infections caused by colistin-resistant bacteria, the clinical interpretation is significant. This entails the categorization of colistin resistance rather than the determination of the specific MIC value since maximum dosages of the medication are prescribed independently of precise susceptibility levels. However, the MIC values are important in monitoring the increase in the resistance to colistin observed in the intestinal bacteria.
Other new-generation methods have been developed recently to detect colistin-resistant strains: the loop-mediated isothermal amplification (LAMP) for nucleic acid detection (Zou et al. 2017), and a microarray CT103XL (Bernasconi et al. 2017). Zou et al. (2017) showed that the LAMP test is ten times more sensitive than the conventional PCR and confirmed its usefulness for the detection of the
Colistin sulphate has also been widely and heavily used for decades in veterinary medicine for the treatment of intestinal infections in pigs, poultry, and cattle, which were caused by Enterobacterales strains, mainly
In Asian countries, the use of antibiotics, particularly colistin, in animal husbandry also takes place on a large scale. China is one of the world’s largest users of colistin in agriculture; over 11 thousand tons of colistin is being used (QYResearch Medical Research Centre 2015). Considering this upward trend, the consumption of colistin in Chinese agriculture is estimated to reach more than 16 thousand tons in 2021 (QYResearch Medical Research Centre 2015). China remains the largest user of colistin in agriculture worldwide. In the Red River Delta region of Vietnam, colistin was also used as a feed additive for growth promotion in pig production (Kim et al. 2013). This was a cause of concern because colistin is an unapproved antibiotic for growth promotion in Vietnam (MARD 2006; 2009). These facts illustrate the sheer scale of antibiotic consumption in animal and poultry husbandry.
Alarming data on the use of antibiotics in veterinary medicine, in particular colistin, has led to efforts to limit their use. The different monitoring systems for the use of antibiotics in animals and the surveillance of resistance to antibiotics were established in European countries (BTK 2015; Borck Høg et al. 2017; SDa Autoriteit Diergenesmiddelen 2018; SWEDRES/SVARM 2018; MARAN 2019). In 2015, Nunan and Young (2015) reported that antibiotics, particularly colistin, should not be routinely used as prophylactics in animal farms in the United Kingdom (UK). The authors added that colistin accounted for only 0.2% of all antibiotics that were used in breeding in the UK and was only used by veterinarians to treat sick animals (EMA/CVMP 2010; Nunan and Young 2015; Catry et al. 2015).
In a national report on antibiotics consumption in the Australian pig industry, Jordan et al. (2009) found that colistin was not used during the study period in the production of pigs.
Until recently, there were no recommendations on the need of conducting the screening tests to find the carriage of colistin-resistant bacteria, but under a ‘One Health’ perspective, it is necessary to monitor the colistin resistance among Gram-negative bacteria in veterinary and human medicine. Currently, at least in the veterinarian sector in Germany, screening for colistin resistance is recommended and carried out routinely, and efforts are being made to implement colistin screening also for human isolates. It, therefore, seems justified to develop a chromogenic agar medium for detecting colistin-resistant rods directly from clinical material other than stools and rectal swabs, e.g. samples from the lower respiratory tract or urine samples.
There are progressively more and more reports on the culture of the colistin-resistant Enterobacterales strains from vegetables and fruits samples (Liu et al. 2014; Jones-Dias et al. 2016; Luo et al. 2017). A study by Zhon et al. (2017) showed that water, where live bacteria may have come from the excrements, can be the source of plant contamination with Gram-negative bacilli (Zhon et al. 2017). Jung et al. (2014) analyzed the relationship between the plant food production chain and the incidence of foodborne disease outbreaks, and the consumption of contaminated raw vegetables has been linked with these outbreaks (Jung et al. 2014). Liu et al. (2014) studied the samples of vegetables (carrots, pak choi, green peppers, and leaf lettuce) from supermarkets or farmers’ markets in nine provinces of China; about 4% of the vegetable samples (3.6%) carried one or more the
Zurfuh et al. (2016) reported the presence of the plasmid-borne
The resistance of Gram-negative rods to colistin, including Enterobacterales, is a serious public health problem. The colistin use in animal husbandry and agriculture has an impact on the spread of colistin resistance (Catry et al. 2015). The