POLYMYXINS

Amanda Chamieh PGY IV

• a group of polypeptide antibiotics that consists of 5 chemically different
compounds (polymyxins A–E) discovered in 1947
• discovered in 1949 and was nonribosomally synthesized by Bacillus polymyxa
subspecies colistinus
• Only polymyxin B and polymyxin E (colistin) used in clinical practice
• Colistin was initially used therapeutically in Japan and in Europe during the 1950s
and in the United States in the form of colistimethate sodium in 1959
• intravenous formulations of colistin and polymyxin B were gradually abandoned in
the early 1980s because of toxicities
• Subsequently,the intravenous use of colistin was mainly restricted during the past
2 decades for MDR GN in cystic fibrosis
Structure
• Cationic cyclic decapeptide linked to fatty acid chain by amide
• AA’s: D-leucine, L-threonine, L-g-y-diaminobutyric acidlinked to FA residue
• Colistin A: 6-methyloctanoic acid; Colistin B: 6-methyl-eptanoic acid
• 2 commercial forms:
• Colistin sulfate (PO/syrup/powder)
• Colistimethat sodium –less potent but less toxic (IV/IM/IH)
Mechanism of Action
• Targets bacterial cell membrane
• Electrostatic interactions between cationic polypeptide and anionic LPS->deranged cell
membrane, displaces Ca++ and Mg++

• Anti-endotoxin activity by neutralizing LPS when binding to lipid A moiety

Spectrum of Action
• Bactericidal activity against most GN aerobic bacilli, including Acinetobacter
species, pseudomonas, klebsiella, Enterobacter, Ecoli, salmonella, shigella,
citrobacter, Yersinia, morganella, heamophilus, some stenotrophomonas
• Inherent resistance: pseudomonas mallei, burkholderia cepacia, proteus,
providencia, serratia, edwardsiella, Brucella
Mechanism of Resistance
• Chromosomally mediated by regulation of pmrA/B,PhoP/PhoQ regulator
• Plasmid mediated –mcr-1, mcr1.2, mcr 2
Plasmid Mediated
• Acquisition of foreign DNA in GN organisms, mcr genes
• Ecoli, Kp, Shigella sonnei, Salmonella enterica
• 1st in China Nov 2015->
• mcr-1 in 5 different continents from colonized+infected humans,food,farm+ wild
animals
• Mcr-2 bovine+porcine isolated Ecoli from Belgium
• However this was traced back to 1980’s in chicken
mcr genes
• Encode phosphoethanolamine transferases
• Mcr-1 and mcr -2 share 80.65% AA at sequence level
• Promote resistane like in intrinsice resistance
• Located on transferable plasmids that easily propagate by conjugation among
ecoli
• And can transform to Kp and Pseudo by in vitro transformation
• SENTRY Survery in 2014 and 2015 showed 44%Kp, 0.4% Ecoli from Europe,latin
America, north America,asia pacific are coli resistant MIC>4
Adaptive resistance of colistin
• pH changes
• Cationic peptides present (Urine vs blood)
• aim of the current study was to investigate the prevalence of the plasmid-
mediated colistin resistance gene mcr-1 and phenotypic colistin resistance among
ESBL-producing E. coli among these isolates.
• In 2012, 1000 participants from 18 villages in three counties (338, 315 and 347
persons participated from each county,respectively) of different socioeconomic
status in Shandong Province provided faecal samples with ESwabTM (Copan,
Brescia, Italy) and responded to a questionnaire.
• 706 unique ecoli esbl isolates out of 411 participants; screened for mcr-1
• 25 isolates (3.5%) from 20 persons (4.9%) were positive for the mcr-1 gene.
• The prevalence by person in the three counties was 4.0% (n = 6/151), 3.2% (n =
3/95) and 6.7% (n = 11/165) respectively; the differences were not statistically
significant (P = 0.37).
• No parameter was significantly associated with mcr-1 carriage.
• The colistin MIC was determined for all isolates
• Carriage rate of 4.9% of ESBL Ecoli with mrc-1 among non-hospitalized patients
living in rural areas in china in 2012
• annual prevalence of mcr-1 among E. coli isolated from chicken in eight provinces
in China and showed an increase in prevalence from 5.2% in 2009 to 30.0% in 2014
and also found the gene in an isolate from chicken fromthe 1980s
• These data indicate that mcr-1 likely was selected for in animal farming and later
transferred to humans, a process that is likely still ongoing
• Stool samples collected from healthy individuals in Laos, Thailand in 2012
• Stool samples from patietns in France from 2012-2013
• Stool samples from 2 hopsitals in Nigeria
• screening for col R by BD cepacia medium, screening for col S by MacConkey
agar
• Then chocolate agar if pinkish on cepacia medium and LF->MALDI-TOF/MS for
identification
• Healthy individuals
• Laos 19011/190 CRKP (5.8%)
• Thailand 21214/212 (6.6%)
• Patients
• france 328 6 CRKp, 2 K.oxytoca col R (2.4%)
• Nigeria 139 1 CRKP
• 29/34 col R are co-colonized CSKp
• Most of CRKP isolates were susceptible to most antimicrobials other than coli
• Significant clonal colonization both by CRKP and CSKP in patients while healthy
individuals strains are multiclonal, suggesting that risk of selection of cloncal CRKP
very high in pateitns if treated with colistin
• according to the last report of the Brazil-ian Health Surveillance Agency (ANVISA),
Klebsiella pneumoniae is the third pathogen isolated from patients admitted to
intensive care units – ICU (13.8%), followed by Acinetobacterspp. (11.8%), and
Pseudomonas spp. (10.1%).
• Carbapenem resistance among Acinetobacter species increased from 30% to 70%
from 2010 to 2014
• Restrospective evaluation from databases of microbiology labs between 2010-
2014
• From 2010->2014: 33,765 GN that were tested for col R
• Enterobacteriaceae 49% (16,533)
• Pseudomonas 29% (9,786)
• Acinetobacter 22% (7,446)

• 4% col R 1346/33,765 have MIC 2- to >32

• Enterobacteriacea 7% col R (1159)
• Acineto 1.4 % (102)
• Pseudomonas 0.9 % (85)
• Trend of increasing colistin resistance among enterobacteriacea from 6.6% (111) in
2010 to 9.4% (383) in 2014
• 21.5 % of colR are carbapenem sensitive
• Enterobacteriacea 21.1% (244)
• Acineto 22.5% (23)
• Pseudomonas 27.1% (23)
• Determine a carriage rate in healthy and sick individuals
• Colonization vs infection
• How many col R are carbapenem S