Abstract
The increasing resistance of Gram-negative bacilli to a wide range of antibiotics has driven a return to colistin as the last resort in the treatment of severe infections. Given the stakes of colistin efficiency at both the individual level and generally, the manifestation and mechanisms of resistance to polymyxin E (also known as colistin) are now subject to careful monitoring and research. Recent findings from different parts of the world including Romania are reviewed and discussed in the light of ensuing challenges.
Keywords: Colistin; Gram-Negative Bacteria; Resistance Mechanisms and Detection
Colistin and Colistin Resistance
Colistin is a cationic polypeptide antibiotic from the polymyxin
family, which includes polymyxin E (colistin) and polymyxin B.
It was discovered in 1947 when it was isolated from the bacillus
Paenibacillus polymyxa subsp. colistinus [1,2]. Its main activity
mechanisms involve the displacement of calcium and magnesium
ions from lipopolysaccharides, leading to a disruption in the
permeability of the outer cellular membrane, as well as the inhibition
of the type II NADH-quinone oxidoreductases, which is a crucial
respiratory enzyme in the inner membrane of the Gram-negative
strains [3,4]. Polymyxin E exerts a swift and strong bactericidal
effect on Pseudomonas aeruginosa, Acinetobacter baumannii, and
most bacilli from the Enterobacterales family, except for Proteus
spp., Providencia spp., Serratia spp., Morganella spp., which are
naturally resistant to colistin [5]. Mutations and adaptation are
the most important mechanisms of bacterial acquired resistance
to polymyxin E. Because LPS is the major target of colistin it is
clearly that the first mechanisms of resistance will appear at this
level [5,6]. For Klebsiella pneumoniae strains, the modification of
the mgrB gene is the most important mechanism of resistance to
colistin [7].
Regarding A. baumannii strains, the alteration of the lpxA, lpxC
and lpxD genes determine inhibition of lipid A synthesis and, as
a consequence, colistin will lose the binding to bacterial cell [8].
Porin mutations and upregulation of efflux pump systems are
other possible mechanisms of resistance to colistin, which results of a combination of both [5]. Prior to 2015, resistance to colistin
was explained by means of chromosomal mutations, but then new
research uncovered genetic resistance that can be plasmid-mediated
[9]. Over the last years, for Escherichia coli and K. pneumoniae
strains have been reported plasmid mediated resistance genes, mcr,
which encodes phosphoethanolamine transferase [10]. Traditional
microbiology methods, as well as phenotyping and molecular
biology techniques, are some of the ways in which resistance to
colistin may be highlighted, the gold standard in this regard being
the broth microdilution test. Recent evidence and epidemiologic
studies have helped raise the alarm among the medical community
and add a shared sense of urgency to the conversation.
Evidence of Increasing Colistin Resistance
An extended study driven in Switzerland during 2011-2015
analyzed colistin-susceptibility for 10,824 strains (9,229 isolates
of E. coli and 1,595 isolates of K. pneumoniae) and the risk factors
for those proved to be colistin-resistant. 53 patients had colistinresistant
strains and the major risk factor was previous carbapenem
exposure [11]. Between 2013 and 2017 426 strains (18.5%) of
carbapenem resistant K. pneumoniae were isolated from several
healthcare settings from Serbia; 10.6% (a total of 45 clinical isolates)
of them were colistin resistant [12]. A study conducted in South
Africa in 2016-2017 revealed that colistin-resistant A. baumannii
happened as a consequence of the clonal spread. This was the
first report of this kind in that region. A possible explanation was
the presence of colistin-susceptible strains that were genetically
correlated in the same hospital, at the same time [13].
By 2017, up to 8.5% of strains were found to be colistinresistant
(2.4% for K. pneumoniae), the highest reported incidence
being in Greece and Italy [14]. One year later, the World Health
Organization elevated polymyxins to the level of criticallyimportant
antimicrobial agents, recommending that colistin be
used only in the treatment of infections with Gram-negative bacilli
already multidrug-resistant [15]. During 2011-2018, Macesic, et
al. [16] identified 665 patients with carbapenem-resistant and
106 patients with colistin-resistant K. pneumoniae strains. In 48%
patients the first K. pneumoniae polymyxin-resistant isolate was
linked to an infection of the respiratory tract. Consecutively to the
detection of colistin-resistant K. pneumoniae the 7-day and 30-day
all-cause mortality rates raised from 13% and 32%, respectively,
to 15% and 38%, respectively. The mechanisms of polymyxin
resistance were heterogenous, leading to the conclusion that, in
most occasions, polymyxin-resistant strains emerge after colistin
treatment rather than clonal dissemination.
According to a recent study, no fewer than 590 strains of
colistin-resistant K. pneumoniae were identified in six countries:
438 in Turkey, 86 in Iran, 24 in Saudi Arabia, 31 in the United
Arab Emirates, 5 in Kuwait, 3 in Israel, and another 3 in Lebanon,
between 2013 and 2018. The mgrB gene was found to be involved
in the resistance mechanism [17]. In another study from 2020, in
Turkey, from a total of 150 strains of Enterobacterales isolated in
pediatric patients suffering from infections, 41% were resistant
to carbapenems and 15% to colistin. The reported risk factors
for colistin resistance in these cases were mechanical ventilation,
urinary catheterization, and the associated pathology of necrotizing
enterocolitis [18]. The presence of the gene mcr-1 and colistin
resistance were monitored over a 5-year period (2014-2019) in
patients infected with carbapenem-resistant Enterobacterales
strains, who were administered colistin as part of their treatment.
At the beginning, the incidence of strains carrying the mcr-1 gene
was low (0.41%), but then it began to rise (1.38%), especially
once colistin was introduced. This pointed to the hypothesis that
polymyxin E was responsible for triggering the mcr-1 gene. The fact
that the colistin minimal inhibitory concentration increased from
<2 mg/L in 80% of the strains to 2 mg/L in 100% of the strains in a
relatively short amount of time was yet another reason of concern
[19].
In India, by 2020, 2499 strains of Klebsiella spp. were isolated
from urine, sputum, broncho-alveolar lavage, blood culture and pus,
in patients hospitalized in intensive care unit; 8.75% of colistinresistant
Klebsiella spp. were isolated from blood specimens,
4.26% from urine samples and 4.4% from sputum [20]. Another
recent study highlighted the risk factors for patients with colistinresistant
Enterobacterales and identified some particular mutations
associated with some of the strains isolated. From a total number
of 16.373 isolates, 103 were colistin-resistant Enterobacterales
strains. The main risk factors associated were: age >55 years and
prescription of an antibiotic for no longer than 90 days. The main
mutations that were identified from 33 strains, 8 were from E. coli
isolates (mcr-1/mcr-1.1 and pmrA/B mutations) and 8 from K.
pneumoniae (mgrB and pmrA mutations). Regarding Enterobacter
species the mutations were not related to colistin resistant
phenotype [21].
Colistin Resistance in Romania
In Romania, in 2015, the presence of four colistin-resistant K. pneumoniae strains with identical PFGE profiles (Pulse-field Gel Electrophoresis) was reported in the cardiac intensive care unit at a university hospital in North-Eastern Romania. Fortunately, they did not produce carbapenemases [22]. However, in a recent study on patients with urinary tract infections, approximately 30% of K. pneumoniae isolates were found to be colistin-resistant and to produce wide-spectrum beta-lactamases [23]. Close monitoring and additional studies are needed in order to attain a more comprehensive understanding of the phenomenon and plan accordingly before the problem aggravates.
Conclusion
The increasing prevalence of multidrug-resistant strains has substantial, far-reaching negative implications for the entire world. The still excessive use of antibiotics and their diminishing effectiveness can limit treatment options to colistin, which we now know is not invulnerable. Invasive medical procedures and prolonged hospitalization can further contribute to the risk of developing resistance to this life-saving medication. In countries like Romania, where data is still scarce but sufficiently concerning, more research and communication need to be conducted with an adequate sense of urgency.
Conflict of Interest
The authors declare no conflict of interest.
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