Colistin: An
Update on the Antibiotic of the 21st Century
Silpak Biswas,
Jean-Michel Brunel, Jean-Christophe Dubus, Martine Reynaud-Gaubert, Jean-Marc
Rolain
Expert Rev Anti Infect Ther. 2012;10(8):917-934.
Abstract and Introduction
Abstract
The emergence of multidrug-resistant Gram-negative bacteria
that cause nosocomial infections is a growing problem worldwide. Colistin was
first introduced in 1952 and was used until the early 1980s for the treatment
of infections caused by Gram-negative bacilli. In vitro, colistin has
demonstrated excellent activity against various Gram-negative rod-shaped
bacteria, including multidrug-resistant Pseudomonas
aeruginosa, Acinetobacter
baumannii and Klebsiella pneumoniae.
Recent clinical findings regarding colistin activity, pharmacokinetic
properties, clinical uses, emerging resistance, toxicities and combination
therapy have been reviewed. Recent approaches to the use of colistin in
combination with other antibiotics hold promise for increased antibacterial efficacy.
It is probable that colistin will be the 'last-line' therapeutic drug against
multidrug-resistant Gram-negative pathogens in the 21st century.
Introduction
The emergence of multidrug-resistant (MDR) Gram-negative
bacteria in parallel with the lack of new antibacterial agents led scientists
to understand the importance of polymyxins.[1,2] There has recently been a tremendous increase in infections
caused by MDR Gram-negative bacteria, especially Pseudomonas aeruginosa,
Acinetobacter baumannii and Klebsiella
pneumoniae, and for these species, polymyxins
are often the only available active antibiotics.[1,3–9] Polymyxins
consist of polymyxins A–E, of which polymyxinB (PMB) and polymyxin E, or
colistin, are currently available in the market. When the use of β-lactam,
aminoglycoside or quinolone is ineffective, the polymyxins, especially
colistin, serve as the final alternative treatment.[4,10] Despite of a
daily selective pressure in patients receiving colistin by inhalation,
resistance to colistin is seldom observed.[11,12] In 2000, Littlewood et
al. in their review described the use
of colistin by inhalation in a Danish cystic fibrosis (CF) center for daily
maintenance therapy in 120 CF patients with chronic P. aeruginosa
lung infection since 1987. During this study, colistin-resistant strains were
only observed in 14patients (MIC: 100–400 µg/ml).[12]
Colistin became available for clinical use in the 1960s, but
was replaced in the 1970s with other antibiotics owing to its toxicity.[1,4,13]
There are two forms of colistin available in the market: colistin sulfate
(tablets or syrup for oral use and powder for topical use), which is also
available as an aqueous suspension solution for topical use in eyes and ears
(e.g., Coly-Mycin®S Otic), and colistin methanesulfonate (colistimethate sodium
[CMS]) for parenteral use.[2,14] Both of these forms can also be delivered by inhalation.[3] Colistin
methanesulfonate, or CMS, was largely replaced with aminoglycosides in the
1970s because of concern about its neurotoxicity and nephrotoxicity.[1,4,10,15]
Figure 1 represents the number of citations found in the
PubMed database from 1960 to the middle of 2011 using either the search phrase
'colistin' or 'colistin resistance'. This graph shows the trend in colistin
use, which has increased from the early 21st century, with a higher number of
publications on colistin, and it also shows the problem with colistin
resistance, with an increasing number of publications on this topic.
Figure 1.
Number of citations found in the PubMed database from 1960
to the middle of 2011 using either the term 'colistin' or 'colistin resistance'.
In recent years, colistin has attracted considerable
interest as an antibiotic for use against MDR strains. The aim of this review
is principally to discuss the antibacterial activity of colistin, mechanisms of
action and resistance, combination therapy and also its use for the treatment
of infections due to MDR Gram-negative infections in patients with or without
CF. Pharmacokinetic (PK) properties of colistin will be discussed in a short
section, as they are beyond the scope of this review. The review provide
updated information to enable clinicians to choose this drug for proper use as
a treatment option against pathogenic bacteria.
History & Discovery of Colistin
Polymyxin is an old class of cyclic polypeptide antibiotics
that was discovered in 1947 from Paenibacillus
polymyxa. it was formerly identified as Bacillus polymyxavar. colistinus. PMB and colistin (polymyxin E) are secondary metabolite
nonribosomal peptides produced by the soil bacteria P. polymyxa.[16–18] Colistin has been available since 1959 for the treatment of
infectious diseases caused by Gram-negative bacteria.[19] Colistin use
was restricted when the potentially less-toxic aminoglycosides and other
antipseudomonal agents became available. As a result, the use of colistin in
the treatment of infections caused by Gram-negative pathogens has declined from
the early 1970s to the early 2000s.[4,10]
Chemistry of Colistin
Colistin is a multicomponent polypeptide antibiotic that is
mainly composed of colistin A and colistin B. PMB and colistin (polymyxin E)
are secondary metabolite nonribosomal peptides that share a similar primary
sequence with the only difference being at position6, which is replaced by D-Phe
in PMB and D-Leu in colistin (Figure 2).
Figure 2.
Structure of polymyxin B and colistin. Polymyxin B and
colistin (polymyxin E) share a similar primary sequence with the only
difference being at position 6, in which D-Phe in polymyxin B is replaced by
and D-Leu in colistin.
Colistin sulfate and CMS are the two forms of colistin. CMS
is produced by the reaction of colistin with formaldehyde and sodium bisulfite,
which leads to the addition of a sulfomethyl group to the primary amines of
colistin.[20] Although CMS is the form administered parenterally, it
undergoes conversion invivo to form colistin, which is responsible for antibacterial
activity, and thus CMS should be considered as an inactive prodrug.[20,21]
The importance of the N-terminal fatty acyl segment for the
antimicrobial properties of polymyxins first became evident when polymyxin
nonapeptides were identified.[22] Although PMB and colistin nonapeptides lack any direct
antimicrobial activity, they possess the same ability to bind
lipopolysaccharide (LPS) with an important specificity and perturb the outer
membrane (OM) integrity to sensitize Gram-negative bacteria to hydrophobic
antibiotics that are not normally active.[22]
Previous studies of the Nα fatty acyl structure–activity relationships (SARs) of PMB
and colistin component peptides isolated from cultured strains did not provide
any clear and meaningful SAR data.[23] The most comprehensive Nα SAR data have been reported by Sakura and colleagues,[24,25] wherein
purified PMB or colistin were converted to nonapeptides by treatment with
S-ethyl trifluorothioacetate and used as the starting material.
Recently, Sakura and colleagues have reported a new series
of Nα analogs derived by acylation of the tetrakis (Nγ-Troc)-PMB or -colistin nonapeptides
with various hydrophobic acids and aliphatic or hydrophobic ring structures.[25] The Nα analogs were tested for their LPS
binding affinity and antimicrobial activity against Escherichia coli,
and Salmonella enterica and P.
aeruginosa. Thus, cyclohexylbutanoyl,
4-biphenylacetyl and 1-adamantaneacetyl-Nα analogs led to comparable activities with respect to the
parent compounds (PMB and colistin), with an improved LPS binding affinity.[26–28]
Tsubery et al. adopted a synthetic approach by using a combination of
solid-phase linear chain elongation methodology and subsequent cyclization
after release.[29] Owing to the presence of a long hydrophobic chain, [Ala]6-PMB
was expected to increase the potent antimicrobial activity; nevertheless,
neither of the oligoalanyl Nα analogs had significantly better activity than the control
product PMB. The N-terminus of the other pair was substituted with the
hydrophobic Fmoc group.[25,30,31] This result demonstrates that the hydrophobicity of the Nα substituent group greatly
influences the outcome antimicrobial activity and the inherent acute toxicity.
Finally, N-terminal modifications of PMB nonapetide have been shown to possess
high antibacterial activity and significantly reduced toxicity.[29]
Dosage of CMS/Colistin Base
The dosage of intravenous CMS recommended by the
manufacturers in the USA is 2.5–5 mg/kg (31,250–62,500 IU/kg) per day, divided
into two to four equal doses.[1] Dosage adjustments are recommended for patients with
mild-to-moderate renal dysfunction. Specifically, when the serum creatinine
level is 1.3–1.5, 1.6–2.5 or ≥2.6 mg/dl, the recommended dosage of intravenous
colistin for serious infections is 2 million IU every 12, 24 or 36 h,
respectively.[32] For patients with renal failure that necessitates dialysis,
the recommended intravenous dosages of CMS are 2–3 mg/kg after each
hemodialysis treatment and 2 mg/kg daily during peritoneal dialysis.[33,34] The two most
common commercially available parenteral formulations of CMS are Colomycin
(Dumex-Alpharma A/S, Copenhagen, Denmark) and Coly-Mycin (Parkedale
Pharmaceuticals, NY, USA). It has been reported that the recommended daily dose
of Coly-Mycin (400–800 mg) is almost double that of Colomycin (240–480 mg) for
patients with normal renal function and bodyweight of 60 kg. This difference
has important implications for therapeutic doses.[3]
It should be noted that that there is a substantial
difference in the recommended doses of the European and US products. The dosage
recommended by the manufacturers in the UK is 4–6 mg/kg (50,000–75,000 IU/kg)
per day, in three divided doses for adults and children with bodyweights of ≤60
kg and 80–160 mg (1–2 million IU) every 8 h for those with bodyweights of
>60 kg. When colistin is given by inhalation, the dosage recommended by the
manufacturers in the UK is 40 mg (500,000 IU) every 12 h for patients with
bodyweights of ≤40 kg and 80 mg (1 million IU) every 12 h for patients with
bodyweights of >40 kg.[1]
Pure colistin base has been assigned a potency of 30,000
IU/mg, and CMS has a potency of 12,500 IU/mg. Thus, recommendations regarding
dosing should clearly refer to colistin base and CMS to avoid possible
confusion.[35]
CMS is mostly administered for 10–14 days. Dose regimens
varied considerably. Doses were adjusted for renal function depending on serum
creatinine levels or creatinine clearance. Colistin PKs are different in
critically ill patients and they have fluctuations in renal clearance. Many
authors reported the administration of CMS at a dose of 3MIU every 8 h,
especially in critically ill patients with normal renal function.[34,36–38]
PK Properties of Colistin
As details about PK properties of colistin base and CMS are
beyond the scope of this review article, the authors will give a short note on
PK properties. Interested readers should refer to the recent reviews on this
topic.[21,35,39]
CMS is an inactive prodrug of colistin that exhibits a low
level of protein binding. CMS is a prodrug that is hydrolyzed after intravenous
administration to produce active colistin (formed colistin).[20] After
administration of CMS, colistin appears in plasma rapidly.[20]
Initial PK studies on colistin base and CMS relied on
bioassays,[40] which are still used in some places. Chromatographic
procedures using HPLC[41] or liquid chromatography–tandem mass spectrometry[42,43] have only been
developed relatively recently and used by several groups in order to complete a
series of major modern PK studies.
An initial PK study in rats, using a novel specific HPLC
assay, was conducted in 2003 after direct intravenous administration of CMS.
The derived clearance value 0.010 ± 0.008 ml/min/kg was much lower than the
expected renal clearance by glomerular filtration.[44] This low renal
clearance suggested extensive tubular reabsorption, which was later confirmed
by the same group.[45] More recently, a dose-ranging PK study was conducted by
Marchand et al. using a new liquid chromatography–tandem mass spectrometry
assay.[46] They reported that the PKs of CMS and formed colistin
appear linear following the intravenous administration of CMS to rats over a
range of doses, generating clinically relevant plasma concentrations.
Previously, Li et al. developed a sensitive HPLC method to determine colistin
levels in plasma.[47] This HPLC method is very useful to measure colistin
sulfate.
Recent studies demonstrate that the PK properties of
colistin base and CMS are different in critically ill and CF patients. In 2008,
Markou et al. published PK data of the colistin in critically ill
patients using a chromatographic assay.[36] In this study, CMS dosage regimens administered to these
critically ill adult patients were associated with suboptimal Cmax/MIC
ratios for many strains of Gram-negative bacilli. Markou et al.[36] and Imberti et
al.[48] reported plasma colistin Cmax at a steady state
of 1.15–5.14 mg/l and 0.68–4.65 mg/l, respectively, in critically ill patients
with moderate-to-good renal function. Li et
al. reported that CF patients
administered intravenous CMS had a range of peak plasma concentrations (Cmax)
of formed colistin of 1.2–3.1 mg/l at steady state.[49] Another PK
study in critical care patients was published in 2009 by Plachouras et al..[37] The colistin
base elimination half-life was much longer than that of CMS.[50] Very recently,
Garonzik et al. described the effects of CMS and formed colistin in 105
critically ill patients.[51] Among these patients, some were on hemodialysis and some
were undergoing continuous renal replacement therapy. This study discusses the
problem and lack of study of CMS dosing, in addidtion, this population PK
analysis suggests the traditional CMS doses are often suboptimal.[51] Plachouras et al. also found
that with standard dosing it will take 2–3 days before the steady-state
concentration of colistin is obtained for a typical individual.[37] Aforementioned
studies by Plachouras et al.[37] and Garonzik et al.[51] provide suggestions on higher dosing of CMS and formed
colistin in critically ill patients based on their population PK study. The
very recent study by Dalfino et al. provided some insight into the high colistin dosage
prescribed for critically ill patients.[52] In total, 28 infectious cases due to A. baumannii (46.4%), K.
pneumoniae (46.4%) and P. aeruginosa
(7.2%) were analyzed in this study. The CMS dosing schedule was based on a
loading dose of 9 MU, and a 9 MU twice-daily fractioned maintenance dose,
titrated on renal function. Clinical cure was observed in 82.1% of cases. The
result shows that in severe infections by colistin-only susceptible
Gram-negative bacteria, the high-dose extended interval CMS regimen has a high
efficacy without significant renal toxicity.
Mode of Action of Colistin
The bacterial cell membrane is the initial site of action
for colistin.[1,2,10] Colistin binds to LPSs and phospholipids in the outer cell
membrane of Gram-negative bacteria. It competitively displaces divalent cations
(Ca2+ and Mg2+) from the phosphate groups of membrane lipids, which leads
to disruption of the outer cell membrane, leakage of intracellular contents and
bacterial death (Figure 3).[1,3,10,13,15,53,54]
Figure 3.
Antimicrobial mode of action of polymyxin against
Gram-negative bacterial membranes. LPS: Lipopolysaccharide.
With electron microscopic examination, previous studies
showed the bacterial cytoplasmic membrane to be partially damaged and part of
the cytoplasmic material released in fibrous forms through cracks.[55] Hydrophilic
antibiotics such as rifampicin, carbapenems, glycopeptides and tetracyclines
can work synergistically owing to the disruption of membrane integrity by
colistin.[56] Some reports showed that polymyxins act through an
alternative mode of action, other than acting on bacterial cell membrane.[57,58] Therefore, the
exact mechanism(s) by which colistin ultimately kill bacterial cells is still
unknown.
Antibacterial Activity of Colistin &
Mechanisms of Resistance
Susceptibility
Breakpoints
Susceptibility breakpoints for colistin have been developed
in France, Germany and the UK that are very conflicting to each other. The
breakpoints for susceptibility are based on colistin sulfate. The French
Society for Microbiology has selected ≤2 mg/l as the susceptibility breakpoint
and >2 mg/l as the resistance breakpoint for Enterobacteriaceae,
while the British Society for Antimicrobial Chemotherapy has selected ≤4 mg/l
for the susceptibility breakpoint and ≥8 mg/l for the resistance breakpoint.[4,10,59,60]
The Clinical and Laboratory Standards Institute (CLSI) has
recently revised the colistin interpretative criteria for Acinetobacter
spp. as resistance breakpoints (≥ 4 mg/l), which is different from those
recommended for P. aeruginosa (≥8 mg/l) and other non-Enterobacteriaceae as the cutoff to define resistance,[61,62] while the
European breakpoints published by the European Committee on Antimicrobial
Susceptibility Testing for Acinetobacter spp. (susceptible [S] ≤ 2 mg/l, resistant [R] > 2 mg/l)
and for Pseudomonas spp. (S ≤ 4 mg/l, R > 4 mg/l). Moreover, there are no
polymyxin breakpoints established for Enterobacteriaceae by the CLSI. Regarding disc diffusion testing, the CLSI
recommends susceptibility breakpoints only for P. aeruginosa
(10-µg colistin disc; R ≤10 mm, S ≥11 mm). The disc diffusion is not a reliable
technique for determining the susceptibility of Acinetobacter
spp. to polymyxins. Guidelines for colistin disc susceptibility testing have
also been published by the French Society for Microbiology and the British
Society for Antimicrobial Chemotherapy.[59,60,301] More clinical data will be needed to define the optimal
susceptibility breakpoints, and the results must be influenced by the
antimicrobial susceptibility techniques employed in the respective studies.
Antibacterial Activity
Colistin is mostly active against Gram-negative clinical
isolates. Colistin is active against species of Enterobacteriaceae.[4,10,15]
The nonfermentative Gram-negative bacteria P.
aeruginosa and Acinetobacter
species are naturally susceptible.[63–65] Colistin is also active against Haemophilus influenzae,
E. coli, Salmonella spp., Shigella spp., Klebsiella spp., Legionella
pneumophila, Aeromonas spp., Citrobacter spp. and Bordetella
pertussis. Campylobacter species vary in susceptibility to colistin.[2,4,66–68]describes
the antimicrobial activity of colistin against pathogenic bacteria from
clinical isolates in different countries.
Table 1. Antimicrobial
activity of colistin against pathogenic bacteria from clinical isolates showing
proportion of susceptible and resistant isolates in different studies conducted
in countries (starting from recent years).
BSAC: British Society of Antimicrobial Chemotherapy
guidelines; CLSI: Clinical and Laboratory Standard Institute; DIN: German
Deutsches Institut für Normung; EUCAST: European Committee on Antimicrobial
Susceptibility Testing; SENTRY: Antimicrobial surveillance program including
Asia-Pacific, Europe, Latin America and the USA/Canada; S/R: Proportion of
susceptible (S) and resistant (R) isolates.
Natural or Intrinsic
Resistance
The pathogenic Neisseria spp., Moraxella
catarrhalis, Helicobacter
pylori, Proteus
mirabilis, Serratia
marcescens, Morganella
morganii, Chromobacterium and Brucella species are naturally resistant to colistin.[10,69–72]
Isolates of Inquilinus, Pandoraea and Burkholderia associated with CF are also intrinsically resistant to
colistin.[73–76] In Proteus mirabilis, Burkholderia
cepacia and Chromobacterium violaceum,
polymyxin resistance has been associated with the changes in lipid A.[72,77]
Acquired Resistance
There are very limited data on acquired resistance to
colistin or other polymyxins. Pitt et
al. found that 3.1% of 417 CF patient
isolates of P. aeruginosa from 17 hospitals in the UK had MICs higher than 4 mg/l
(the British Society for Antimicrobial Chemotherapy breakpoint).[78] In a CF center
in southern Germany, 15.3% of 229 non-mucoid P.aeruginosa strains and 3.2% of 156 mucoid P.aeruginosa
strains had MIC values to colistin sulfate above 2 mg/l.[65] Some studies
found inhaled colistin to be responsible for the resistance to colistin in P. aeruginosa
from CF patients.[78–80] In Salmonella spp. and E. coli, acquired resistance to polymyxin is linked with the
substitution of phosphate groups in LPS.[81,82]
Heteroresistance
Against Polymyxins
In 2006, Li et
al. first reported the presence of
heteroresistance against polymyxins in isolates of A. baumannii.[83] They observed
that resistant subpopulations existing in the inocula justified the early
development of resistance. Moreover, regrowth was observed at 24 h after an
early concentration-dependent killing. The recent SENTRY study reported the
prevalence of colistin heteroresistance in MDR A.baumannii
clinical isolates from different countries in Asia, Africa and Oceania.[84] Although the
heteroresistance to colistin in A.
baumannii has been described previously,[83,85] theclinical
significance of colistin heteroresistance in A.
baumannii has not been determined yet.[86]
Mechanisms of
Resistance
There are two mechanisms of polymyxin resistance. The
mechanism of colistin resistance was studied by selecting invitro colistin
resistance derivatives of the MDR isolates and the drug-susceptible strain
using escalating concentrations of colistin in liquid culture. Most of the
reported mechanisms were described in isolates in which development of
polymyxin resistance had occurred after in
vitro exposure (adaptive mechanism).
Regrowth of bacterial isolates with colistin monotherapy was observed in in vitro studies.[83,87–89]
Earlier, Gunderson et al. reported regrowth of two MDR isolates of P. aeruginosa
with colistin concentrations of up to 200 mg/l.[87] On the other
hand, regrowth of A. baumannii[90] and K. pneumoniae[88] has been reported in static time-kill studies utilizing
colistin concentrations up to 64 times higher than the MIC.
The most common mechanisms of resistance to colistin are
modifications to LPS, the initial site of action of colistin.[10,15] LPS is an
immunogenic glycolipid that constitutes most of the outer leaflet of the OM of
Gram-negative bacteria.
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