Curr Infect Dis Rep (2017) 19:38
DOI 10.1007/s11908-017-0596-3
ANTIMICROBIAL DEVELOPMENT AND DRUG RESISTANCE (A PAKYZ, SECTION EDITOR)
Polymyxin Resistance in Gram-negative Pathogens
Pavithra Srinivas 1 & Kaitlyn Rivard 1
# Springer Science+Business Media, LLC 2017
Abstract
Purpose of Review The polymyxins are one of the last line
antimicrobial classes to retain activity against multidrug-
resistant Gram-negative bacilli. However, with the increased
use of polymyxins in recent years, reports of resistance have
also been increasing. We aimed to describe the mechanisms
and occurrence of polymyxin resistance in Gram-negative or-
ganisms and propose strategies to overcome resistance.
Recent Findings The most common mechanism of acquired
resistance to the polymyxins is via modification of the bacte-
rial outer membrane lipopolysaccharide. Global epidemiolog-
ical surveillance studies have reported the occurrence of poly-
myxin resistance to be most common in Enterobacteriaceae,
specifically Enterobacter species and Acinetobacter
baumannii. Prevalence of polymyxin-resistant Gram-negative
organisms varies significantly by geographical location.
Summary Emergence of polymyxin resistance is of great con-
cern, given the limited number of agents available to treat
infections caused by multidrug-resistant Gram-negative or-
ganisms. Strategies to mitigate the development of polymyxin
resistance include dose optimization and using polymyxin
agents in combination with other highly active antimicrobial
agents.
Keywords Colistin . Colistimethate sodium . Polymyxin B .
Multidrug-resistant gram-negative bacilli
This article is part of the Topical Collection on Antimicrobial
Development and Drug Resistance
* Pavithra Srinivas
srinivp2@ccf.org
1
Department of Pharmacy, Cleveland Clinic, 9500 Euclid Ave
(Hb-105), Cleveland, OH 44195, USA
Introduction
The emergence of multidrug-resistant (MDR) Gram-negative
organisms combined with the lack of novel antimicrobials has
been recognized worldwide as a significant concern [1]. MDR
organisms such as Acinetobacter baumannii and
Pseudomonas aeruginosa harbor multiple resistance mecha-
nisms, thereby limiting treatment options. The polymyxins,
colistin (polymyxin E), and polymyxin B remain one of the
last classes of antimicrobials to retain activity against these
MDR Gram-negative organisms [2]. The polymyxins are
lipopeptide antibiotics, isolated from the Gram-positive or-
ganism Paenibacillus polymyxa (previously Bacillus
polymyxa) in the 1940s, that exert bactericidal activity against
Gram-negative bacilli by disrupting the bacterial cell mem-
brane via both electrostatic and hydrophobic interactions. By
binding to the lipopolysaccharides (LPS) in the outer mem-
brane of Gram-negative bacilli, the positively charged poly-
myxin molecule interacts with the negatively charged phos-
phate groups on the lipid A moiety of the LPS, thereby
destabilizing the outer membrane. As a result of this destabi-
lization, the polymyxin molecule is able to insert its hydro-
phobic regions within the outer membrane causing further
membrane disruption and facilitating further uptake of poly-
myxins [3].
The polymyxins initially fell out of favor due to concerns
surrounding nephrotoxic and neurotoxic adverse effects.
However, with the emergence of MDR Gram-negative organ-
isms, there has been an increased utilization of these agents in
recent years [2]. Along with increased use of polymyxins,
there have also been increasing reports of resistance to the
polymyxins [4, 5, 6•, 7–9]. The purpose of this review is to
describe the mechanisms and occurrence of polymyxin resis-
tance in Gram-negative organisms and propose strategies to
overcome resistance.
38 Page 2 of 9
Mechanisms of Polymyxin Resistance
The most common mechanism for the development of resis-
tance to the polymyxins is via modification of the bacterial
outer membrane LPS. In this section, we describe the various
mechanisms involved in the development of polymyxin
resistance.
Intrinsic Resistance
The polymyxins have no activity against anaerobes and
Gram-positive organisms, as they lack the presence of an
LPS containing outer cell membrane. A number of Gram-
negative organisms are naturally resistant to polymyxins, in-
cluding Brucella spp., Burkholderia cepacia complex,
Edwardsiella spp., Morganella morganii, Proteus spp.,
Providencia spp., and Serratia spp. The mechanism of this
natural resistance is hypothesized to be due to constitutive
gene expression resulting in the addition of cationic molecules
to the LPS, leading to decreased binding affinity at the poly-
myxin site of action on the LPS [10–12].
Modification of the LPS
Similar to naturally resistant Gram-negative pathogens, organ-
isms that are susceptible to polymyxins in vitro may acquire
mutations in cellular pathways that lead to modification of the
LPS. Modification primarily occurs via the addition of cation-
ic molecules, 4-amino-4-deoxy-L-arabinose (L-Ara4N), and
phosphoethanolamine (PEtN) to the lipid A or 3-deoxy-D-
mannooctulosonic acid (Kdo) components of the LPS.
The arnBCADTEF (also known as the pmrHFIJKLM) op-
eron and the pmrE operon, when activated, synthesize L-
Ara4N from uridine diphosphate glucuronic acid to be added
to the LPS [10, 11]. The arnBCADTEF and pmrE operons are
regulated by a pathway of two bacterial two-component sys-
tems (TCs), PhoP/PhoQ and PmrA/PmrB. Activation of the
PhoP/PhoQ TCs leads to activation of pmrD, which in turn
activates the PmrA/PmrB TCs. PmrA/PmrB then up-regulates
the arnBCADTEF and pmrE operons to synthesize L-Ara4N
for addition to the LPS [10, 11]. In some bacterial Gram-
negative species, such as Klebsiella spp., the PhoP/PhoQ
TCs can also directly activate the arnBCADTEF and pmrE
operons independent of pmrD and PmrA/PmrB [10]. MgrB
acts as negative feedback regulator for PhoP/PhoQ and sup-
presses the L-Ara4N synthesis pathway [13]. Mutations in any
of the aforementioned genes or TCs may lead to dysregulation
and overproduction of L-Ara4N synthesis. Additionally, envi-
ronmental stimuli can promote the activation of these systems
[3, 11]. Incorporation of the overproduced L-Ara4N into the
LPS leads to a net positive charge on the bacterial cell mem-
brane, impairing the ability of the polymyxins to bind to their
site of action.
Curr Infect Dis Rep (2017) 19:38
Synthesis of PEtN is also mediated through the PhoP/PhoQ
and PmrA/PmrB TC pathway. Once PmrA/PmrB is
expressed, pmrC (also known as eptA) and cptA (also known
as eptC) are activated to synthesize PEtN for addition to the
lipid A or Kdo components of the LPS [10, 11]. EptB (also
known as pagC) also results in modification of the LPS with
PEtN. MgrR acts as a negative feedback regulator for eptB.
Activation of mgrR by the PhoP/PhoQ TCs leads to repression
of eptB and decreased PEtN production [14]. Similar to the L-
Ara4N pathway, mutations in any of these genes or TCs may
lead to dysregulation and overproduction of PEtN, which
changes the charge of the LPS.
Additional methods for LPS modification have been dis-
covered including genes that result in acylation and
deacylation of lipid A (IpxM, pagL, IpxR), additional TCs
resulting in L-Ara4N synthesis and addition to the LPS
(colR/colS, cprR/cprS, parR/parS), and complete loss of the
LPS (IpxA, IpxC, IpxD) [10]. It is important to note that the
mechanism of LPS modification differs between Gram-
negative bacterial species.
Plasmid-mediated mcr-1 Gene
Modifications of the lipid A or Kdo components of the LPS in
Gram-negative organisms via the PmrA/PmrB, PhoP/PhoQ,
and mgrB/mgrR inactivation pathways are chromosomally
mediated, precluding the horizontal transfer of resistance
genes between bacterial generator species. However, recent
reports have identified a new colistin resistance gene, mcr-1,
encoding a PEtN transferase [10]. The mcr-1 gene was first
identified in commensal Escherichia coli isolates from food
animals in China during surveillance [15••]. However, within
months, dissemination of the gene in food animals in multiple
countries around the globe was reported [16]. Although most
mcr-1-mediated colistin resistance has been isolated in
carbapenem-susceptible organisms, the plasmid-mediated na-
ture of the gene raises concerns for inter-species transfer of
colistin resistance among Gram-negative organisms [10, 17].
The mcr-1 gene has also been reported in species of
Salmonella, Shigella, Klebsiella, and Enterobacter [10].
Amino acid sequencing of the mcr-1 gene has revealed a
close association with PEtN transferases (pmrC) found in
Paenibacillus spp., the bacteria that produces polymyxins.
Structural analysis of protein sequencing revealed the pres-
ence of two PEtN transferases, LptA from Neisseria
meningitidis and eptC (or cptA) from Campylobacter jejuni,
both of which are intrinsically resistant to polymyxins [15••].
Heteroresistance
Heteroresistance is defined as the presence of subpopulations
of resistant organisms in an isolate considered to be suscepti-
ble by standard testing methodologies. It is a poorly
Curr Infect Dis Rep (2017) 19:38
characterized phenomenon wherein a population of bacteria
with similar genotypes may exhibit variable phenotypic re-
sponses to an antimicrobial agent. Heteroresistance may also
be described as heterogeneous resistance, population-wide
variation of resistance, and heterogeneity of response to anti-
biotics. It was first described in 1947 for Haemophilus
influenzae, followed by Staphylococcus spp. in the 1970s,
and more recently for Gram-negative bacilli with polymyxins.
The clinical significance of heteroresistance is still unclear, but
the concern remains that the more resistant subpopulations
may be selected out during therapy [18].
Further complicating the phenomenon is the ability to mea-
sure heteroresistance in vitro. The gold standard for determin-
ing heteroresistance is a population analysis profile (PAP)
methodology, wherein a bacterial population is exposed to a
gradient of antibiotic concentrations and bacterial growth at
each concentration is quantified. The pitfalls of PAPs are that
they are labor intensive, time-consuming processes that may
not be suitable for clinical laboratories to perform [18].
Heteroresistance to colistin was first described in 2006
among clinical isolates of multidrug-resistant A. baumannii
that were reported as susceptible to colistin based on the min-
imum inhibitory concentration (MIC) [19]. The authors raised
concerns for rapid development of resistance and therapeutic
failure if colistin is used at suboptimal doses or as monother-
apy. A subsequent study attempted to associate colistin
heteroresistance in A. baumannii with prior colistin therapy
and demonstrated a significantly higher degree of
heteroresistance in isolates from patients with prior colistin
treatment [20]. Colistin and polymyxin B heteroresistance
have also been described in various other Gram-negative or-
ganisms (Table 1). However, the majority of the literature is
limited by small sample sizes, varying methodologies for de-
termining heteroresistance, and large variability in the rates of
heteroresistance detected [19–26].
Epidemiology of Polymyxin Resistance
The Clinical and Laboratory Standards Institute (CLSI) and
European Committee on Antimicrobial Susceptibility Testing
(EUCAST) have set the susceptibility breakpoint for colistin
and polymyxin B as ≤ 2 mg/L for A. baumannii and
P. aeruginosa and the epidemiological breakpoint as ≤ 2 mg/
L for Enterobacteriaceae [27, 28]. However, definitions of
resistance are slightly different between the CLSI and
EUCAST. The EUCAST guidelines consider any organism
with a colistin MIC > 2 mg/L to be resistant [28].
Alternatively, the CLSI guidelines provide organism-specific
resistance cutoffs. For A. baumannii, a colistin/polymyxin B
MIC ≥ 4 mg/L is considered resistant; for P. aeruginosa, a
colistin MIC ≥ 4 mg/L or a polymyxin B MIC ≥ 8 mg/L is
considered resistant; and for Enterobacteriaceae, a colistin
Page 3 of 9 38
MIC ≥ 4 mg/L meets the epidemiologic cutoff for resistance
[27]. As such, reported rates of colistin and polymyxin B
resistance range widely across the globe.
Acinetobacter baumannii
Global rates of polymyxin-resistant Acinetobacter spp.
have been steadily increasing since the first description
of a colistin-resistant strain in 1999. Reported rates of
colistin- and polymyxin B-resistant A. baumannii in the
worldwide SENTRY Antimicrobial Surveillance database
from 2001 to 2011 ranged from 0.9 to 3.3% [4, 5].
When stratified by geographic location, rates of poly-
myxin resistance have been higher in the US (0.8 to
4.8%) compared to Europe (0.4 to 2.7%), Latin
America (0.9 to 1.1%), and the Asia-Pacific (0.7 to
1.7%) regions [5, 6•]. Additionally, surveillance data
from 2006 to 2009 demonstrated higher rates of resis-
tance to polymyxin B among imipenem-non-susceptible
strains of A. baumannii (2.1%) in US hospitals, com-
pared to imipenem-susceptible strains (0.8%) [5]. Other
case reports from Europe have observed general rates of
colistin resistance in A. baumannii of < 7%, except two
reports from Bulgaria and Spain demonstrating rates of
16.7 and 19.1%, respectively [4, 29, 30]. Data from a
European surveillance network (EARS-Net) comprising
of 20 European countries from 2014 showed an overall
4% rate of polymyxin resistance in Acinetobacter spp.,
with the majority (80.1%) of them reported from Greece
and Italy [31].
On the other hand, heteroresistance rates to colistin in
A. baumannii have ranged from 14 to 100% in reports from
various parts of the world. Most of these reports were com-
prised of small sample sizes and varying testing methodolo-
gies, likely explaining the higher incidence and larger varia-
tion of reported rates [19–26]. The primary mechanism of
polymyxin resistance in A. baumannii is via mutations in the
PmrA/PmrB genes leading to the addition of PEtN to the
bacterial outer membrane LPS, as A. baumannii lacks the
arnBCADTEF and pmrE operons required to synthesize L-
Ara4N [3, 32].
Pseudomonas aeruginosa
Polymyxin resistance in P. aeruginosa is predominantly
developed by the addition of L-Ara4N to bacterial outer
membrane LPS, via PhoP/PhoQ-mediated activation of
arnBCADTEF [3, 32]. While the polymyxins have main-
tained excellent activity against P. aeruginosa over the
years, the increased use of inhaled colistin, particularly
in cystic fibrosis patients, has led to the emergence of
resistance [7]. SENTRY Antimicrobial Surveillance data
from US and European hospitals evaluated between 2009
38 Page 4 of 9 Curr Infect Dis Rep (2017) 19:38

Table 1 Prevalence of heteroresistance to colistin or polymyxin B among Gram-negative bacilli

Organism Antibiotic Detection of Year Comments Reference

heteroresistance

Acinetobacter baumannii Colistin 15/16 (93.7%) 2006 Some subpopulations were able to grow in the presence of up to [19]
200 μg/mL of colistin
Acinetobacter Colistin 19/19 (100%) 2008 Significantly higher degree of heteroresistance found among isolates [20]
baumannii-- from patients with previous colistin treatment. All isolates maintained
calcoaceticus complex colistin MICs > 16 mg/L after two passages on sheep blood plates
Acinetobacter baumannii Colistin 13/28 (46.4%) 2009 Case report of a patient with post-neurosurgical meningitis with [22]
development of colistin resistance during intrathecal treatment
Acinetobacter baumannii Colistin 1/7 (14%) 2007 All isolates maintained resistance to colistin after passaging on sheep [21]
Enterobacter cloacae 6/10 (60%) blood agar and retesting, suggesting resistance is induced upon
exposure to colistin rather than via a stable mutation
Enterobacter cloacae Polymyxin 8/8 (100%) 2013 In several isolates, the number of heteroresistant colonies was greater at [25]
B higher concentrations of polymyxin B (4–8 μg/mL) compared to
lower concentrations (0.5–2 μg/mL)
Carbapenemase-producing Colistin 12/16 (75%) 2011 All heteroresistant strains except one maintained colistin MICs [26]
Klebsiella pneumoniae > 8 mg/L after serial passages on colistin-free media
Pseudomonas aeruginosa Polymyxin 1/24 (4%) 2013 Rate of heterogeneous subpopulations with increased MICs to [24]
B polymyxin B but still < 2 mg/L were 37.5% (9/24)
Burkholderia cenocepacia Polymyxin – 2013 More resistant subpopulations of B. cenocepacia may communicate [23]
B high level resistance to less resistant cells

to 2012 have reported rates of colistin resistance in
P. aeruginosa around 0.3% [6•]. Worldwide reports of
polymyxin resistance rates in P. aeruginosa have similar-
ly ranged from 0.1 to 0.6% [5]. However, surveillance
data of P. aeruginosa isolates from Canadian hospitals
from 2008 to 2015 demonstrated overall colistin resis-
tance rates of 5.1%, with resistance rates in MDR and
extensively drug resistant (XDR) isolates ranging from
7.1 to 11.7%. One proposed reason for the higher rates
of colistin resistance reported is that patients with cystic
fibrosis and other conditions predisposing to multidrug
resistance were not excluded from the Canadian surveil-
lance database [8].
Enterobacteriaceae
Among the Enterobacteriaceae, Klebsiella spp. is the
most common genus associated with polymyxin resis-
tance. However, recent surveillance data from 2009 to
2012 has also demonstrated high polymyxin resistance
rates in Enterobacter spp., ranging from 13.6 to 15%, in
US and European hospitals. Rates of polymyxin resis-
tance in Klebsiella spp. have been reported at 2.7 and
3.6%, in the US and European regions, respectively,
while resistance rates in E. coli have been significantly
lower at 0.3 and 0.1%, respectively. Extended-spectrum
beta-lactamase producing (ESBL) Klebsiella spp. and
E. coli have demonstrated higher rates of resistance to
polymyxins—11.5% in ESBL Klebsiella spp. and 1.4%
in ESBL E. coli from US hospitals and 7.8% in ESBL
Klebsiella spp. and 0.7% in ESBL E. coli from European
hospitals [6•]. In a recent global surveillance program of
19,719 isolates of Enterobacteriaceae collected between
2012 and 2013 from 39 countries, the highest rates of
polymyxin resistance occurred in Enterobacter asburiae
(39.1%), Enterobacter cloacae (3%), and Klebsiella
pneumoniae (2.4%) isolates. Regional distribution of
polymyxin resistance was similar worldwide—Europe
(1.8%), Latin America (1.5%), Middle East-Africa
(1.4%), North America (1.3%), and Asia-Pacific (1.3%).
Alarmingly, polymyxin resistance was significantly
higher in carbapenemase-producing Enterobacteriaceae,
with rates nearing 12%, suggesting a strong association
between the presence of a carbapenemase and decreased
activity of polymyxin against these isolates.
K. pneumoniae was the most common polymyxin-resis-
tant, carbapenemase-producing species [9].
While most Enterobacteriaceae develop resistance to the
polymyxins via chromosomal modifications to the outer mem-
brane LPS, the predominant pathway utilized is organism spe-
cific. For example, Klebsiella spp. rely more on the addition of
L-Ara4N to the lipid A via mutations in the mgrB negative
feedback regulator of PhoP/PhoQ, whereas E. coli develops
resistance via the addition of PEtN to the LPS core due to
mutations in the mgrR negative feedback regulator and eptB
[10, 32]. More recently, the plasmid mediated mcr-1 gene has
also been implicated in colistin-resistance among E. coli [17].
The first report of a pathogenic E. coli harboring the mcr-1 gene
was identified in the urine culture of a patient in Pennsylvania
in April 2016 [33]. Since then, the mcr-1 gene has been
Curr Infect Dis Rep (2017) 19:38
identified in human isolates from eight additional states in the
USA as well as in case reports from Italy and Egypt [34–36].
Therapeutic Approaches to Combating Polymyxin
Resistance
The two polymyxin agents used in clinical practice, colistin
and polymyxin B, share similarities in mechanism of action
and spectrum of activity. They differ structurally only in one
amino acid and in commercial availability. Colistin is com-
mercially available as the inactive prodrug, colistimethate so-
dium (CMS), which requires activation in vivo via hydrolysis.
Polymyxin B, on the other hand, is available as the active
sulfate salt form, which begets significant pharmacokinetic
differences in vivo [37]. Both agents are available as parenter-
al formulations; however, availability of each agent varies by
country. For example, some countries such as Japan and South
Africa do not have access to either of the polymyxins, whereas
in Europe and Australia, the CMS formulation is the only
commercially available product. In the USA and a number
of other countries, both formulations are available [3, 37].
The pharmacokinetic/pharmacodynamic (PK/PD) parame-
ter best associated with polymyxin activity is the fractional
area under the curve of the drug over the MIC of the organism
(fAUC/MIC). It is proposed that the average steady-state con-
centration (Css,avg) of drug should be greater than or equiva-
lent to the pathogen’s MIC to ensure optimal antibacterial
activity [38, 39]. Therefore, based on CLSI and EUCAST
susceptibility breakpoints, it would prudent to target a colistin
or polymyxin B plasma Css,avg of at least 2 mg/L empirically,
until confirmation of pathogen MICs.
Appropriate utilization of the polymyxins is key to over-
coming or preventing polymyxin resistance. A thorough un-
derstanding of the PK/PD properties of the polymyxins is
needed to determine the appropriate agent to use in a given
situation (when both formulations are available), select an
appropriate dose, and use effectively in combination with oth-
er antimicrobial agents.
Polymyxin Agent Selection
Colistin’s commercial availability as the prodrug form, CMS,
presents challenges in its ability to rapidly and reliably reach
target steady-state plasma concentrations. Once administered,
CMS undergoes slow and variable hydrolysis into colistin,
leading to delayed achievement of therapeutic concentrations
of active drug [37, 40]. CMS has a relatively short half-life (2–
3 h) and undergoes rapid renal elimination, whereas the active
colistin has a longer half-life (14 h) and is eliminated via non-
renal pathways. Due to its rapid renal clearance, it is estimated
that only 20–25% of CMS is converted to colistin systemical-
ly in patients with normal renal function, thereby delaying
Page 5 of 9 38
achievement of clinically significant plasma concentrations.
However, this rapid renal elimination results in high urinary
concentrations of colistin, as CMS continues to be converted
to active drug in the urine. Furthermore, significant inter-
patient variability in plasma colistin Cssavg in the tenfold range
raises additional concerns for achieving drug concentrations
that are both effective and safe, due to the narrow therapeutic
window of colistin and increased risk of nephrotoxicity at
concentrations > 2.5 mg/L [40–42••].
Polymyxin B, on the other hand, can rapidly achieve
desired plasma concentrations with less inter-patient var-
iability, in the range of only three- to fourfold at various
renal functions, due to being administered as the active
drug [37, 42••, 43]. However, polymyxin B is eliminated
via non-renal mechanisms and does not achieve thera-
peutic concentrations in the urinary tract.
Despite pharmacokinetic differences between CMS
and polymyxin B, clinical comparisons of efficacy and
toxicities are limited. Most studies comparing colistin
and polymyxin B have focused on nephrotoxicity, with
efficacy outcomes being secondary. Furthermore, these
studies have been retrospective and limited in sample
size. Oliveira and colleagues were the first to compare
clinical outcomes between colistin and polymyxin B in
82 patients and concluded that both agents were compa-
rable with regard to nephrotoxicity and efficacy [44].
Other comparative studies have also observed no signif-
icant differences in in-hospital and 30-day mortality
rates between colistin and polymyxin B, although differ-
ences in nephrotoxicity outcomes have varied [45–48].
While clinical efficacy may not be significantly differ-
ent, recent reports of nephrotoxicity may favor the use
of polymyxin B over colistin. Although literature com-
paring nephrotoxicity rates between colistin and poly-
myxin B are limited to six studies, rates of acute kidney
injury (AKI) reported have ranged widely from 25 to
60% with CMS and 21–41% with polymyxin B
[44–49]. Studies performed more recently have reported
higher rates of AKI compared to older studies, likely a
reflection of updated, more aggressive dose recommen-
dations for colistin and polymyxin B.
As such, we recommend that polymyxin B be considered
over CMS for the treatment of serious systemic infections
given its more reliable pharmacokinetic profile. However,
due to the inability of polymyxin B to achieve adequate con-
centrations in the urine, CMS may still be considered for uri-
nary tract infections [37, 43]. Additionally, colistin remains
the preferred agent for inhalation therapy due to reports
of bronchoconstriction with inhaled polymyxin B [50]. If
polymyxin B is unavailable, CMS may still be considered
for systemic infections. Regardless of which agent is uti-
lized, dose-optimization is essential to minimize the de-
velopment of resistance.
38 Page 6 of 9 Curr Infect Dis Rep (2017) 19:38

Dosing Optimization recommendations are supported by a limited amount of liter-

Since the polymyxins were developed before the Food and
Drug Administration (FDA) developed standards for approval
of new drugs, they did not undergo rigorous evaluation of
dosing for efficacy and safety. As such, variations exist in
colistin dosing recommendations between the FDA, the
European Medicines Agency (EMA), and population
pharmacokinetics-based data [42••, 51, 52]. The FDA recom-
mends weight-based dosing determined by ideal body weight
and adjusted for renal function. The EMA recommends a flat
CMS dose based on a calculated Cockroft-Gault creatinine
clearance, along with a loading dose for critically ill patients.
Nation and colleagues also recommend initiating colistin ther-
apy with a loading dose; however, they recommend a CMS
dosing equation that incorporates the target Css,avg and renal
function to derive a dose [42••, 53••]. To complicate matters
further, CMS dosing is expressed in different units depending
on the region of the world, international units (IU), or colistin
base activity (CBA). One million IUs of CMS is equivalent to
approximately 30-mg CBA.
Comparisons of the three colistin dosing recommendations
(FDA, EMA, and Nation et al.) and their respective probabil-
ities of achieving target PK/PD parameters for various MICs
have demonstrated that all three dosing schemes would per-
form well when treating a pathogen with a colistin MIC of
0.5 mg/L (Table 2) [40, 42••, 53••]. However, with rising
colistin MIC, the ability to achieve a Css,avg ≥ 1 mg/L in
patients with normal renal function (CrCl > 80 ml/min) drops
significantly, likely due to the rapid clearance of CMS pre-
cluding conversion to active colistin in vivo. In patients with
impaired renal function (CrCl < 80 ml/min), FDA dosing rec-
ommendations often fail to achieve target Css,avg ≥ 2 mg/L,
whereas dosing regimens proposed by the EMA and Nation
et al. are able to reasonably achieve appropriate Css,avg.
Polymyxin B, on the other hand, is administered in its
active form and drug clearance is not impacted by renal func-
tion. While dosing of polymyxin B is less ambiguous than
CMS, it is important to note that polymyxin B dosing
ature. Similar to CMS, dosing for polymyxin B may be
expressed in terms of IUs or mg—10,000 IUs is equivalent
to 1 mg of polymyxin B. The FDA-recommended polymyxin
B dose is 1.5–2.5 mg/kg/day, calculated from total body
weight and divided every 12 h [43]. Although the product
package insert recommends a dose reduction in patients with
renal impairment, recent pharmacokinetic data has suggested
that polymyxin B doses are better scaled by total body weight
rather than renal function [54]. Sandri et al. also attempted to
provide guidance regarding optimal polymyxin B dosing in
their pharmacokinetic analysis of 24 patients. Based on Monte
Carlo simulations of polymyxin B exposures for various dos-
ing regimens, the regimen with the highest probability of tar-
get fAUC/MIC and Css,avg concentrations was a 2.5-mg/kg
loading dose followed by 1.5 mg/kg every 12 h. However,
as seen with colistin, for pathogens with MICs ≥ 2 mg/L, the
probability of target fAUC/MIC and Css,avg attainment was
significantly lower [54]. Therefore, combination antimicrobial
therapy is warranted in patient populations with decreased
likelihood of achieving goal colistin/polymyxin B concentra-
tions, such as patients with good renal function or infections
with organisms with MICs > 0.5 mg/L.
At this time, there is no “one size fits all” dosing recom-
mendation for the polymyxins, as more data are needed to
truly understand the best dose to maximize efficacy and min-
imize toxicity. We recommend consideration of the pathogen
MIC, patient-specific factors, and evaluation of the most up-
dated literature to determine the optimal dosing regimen for
either agent for a given patient.
Combination Therapy
Various pharmacokinetic and clinical evaluations have asso-
ciated colistin or polymyxin B monotherapy with suboptimal
outcomes. An in vitro pharmacodynamics study of polymyxin
B against four strains of P. aeruginosa demonstrated a signif-
icant reduction in bactericidal activity with a high inoculum
and selective amplification of resistant subpopulations at 24 h

Table 2 Percent of patients achieving goal Css,avg by dosing strategy [42••, 53••]

CrCl (mL/min) FDA dosing EMA dosing Nation et al. dosing

Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg Css,avg
0.5 1 2 4 0.5 1 2 4 0.5 1 2 4

≥ 80 > 90% 60–70% 20–30% 0–10% 100% 70–80% 30–40% 0–10% 100% 70–80% 30–40% 0–10%
50–< 80 100% > 90% 60% 0–10% 100% 100% > 90% 20–30% 100% > 90% 80–90% 0–10%
30–< 50 100% > 90% 50% 0–10% 100% 100% 90% 40–50% 100% 100% 80–90% 20–30%
< 30 > 90% 50–60% 0–10% 0–10% 100% 100% 80–90% 30–40% 100% > 90% 80–90% 20–30%

Shaded region indicates suboptimal probability of target Css,avg attainment

FDA Food and Drug Administration, EMA European Medicines Agency, CrCl creatinine clearance, Css,avg average steady-state concentration
Curr Infect Dis Rep (2017) 19:38
with clinical dose equivalents of polymyxin B [55]. As men-
tioned previously, population pharmacokinetic modeling has
suggested that colistin may best be used as part of a highly
active combination due to the inability to achieve adequate
plasma concentrations, especially in patients with moderate
to good renal function and/or for organisms with an MIC
≥ 1 mg/L [40].
Given the high rates of colistin resistance in
Enterobacteriaceae and reports of colistin heteroresistance in
A. baumannii, combination therapy with a polymyxin and an
additional agent may be considered in order to avoid develop-
ment of resistance or isolation of resistant subpopulations dur-
ing therapy. The selection of the antimicrobial agent to be used
in combination with colistin or polymyxin B should be based
upon data regarding synergistic activity of the combination.
The most common antimicrobials evaluated in combination
with the polymyxins are the carbapenems. A time-kill study
of various dosing strategies of polymyxin B in combination
with doripenem demonstrated rapid and extensive bacterial
killing within 24 h and was sustained over 10 days when
aggressive dosing regimens for polymyxin with doripenem
were used [56]. A systematic review of in vitro synergy of
polymyxins and carbapenems against Gram-negative bacteria
demonstrated high rates of synergistic activity with the com-
bination, especially for A. baumannii, as well as less resistance
development [57].
The clinical benefits of polymyxin combination ther-
apy are mostly limited to retrospective studies. In a ret-
rospective analysis of colistin monotherapy versus com-
bination therapy in critically ill patients with MDR
Gram-negative pneumonia, Parchem and colleagues
demonstrated significant improvements in microbiologi-
cal cure rates with combination therapy; however, no
difference in clinical cure was observed [58]. Other an-
timicrobial agents that have been evaluated in combina-
tion with polymyxins include rifampicin and fosfomycin.
Studies comparing colistin monotherapy to a combina-
tion of colistin and rifampicin have not demonstrated
significant microbiological or clinical benefits of the
combination [59, 60]. A preliminary study of colistin
versus a combination of colistin and intravenous
fosfomycin failed to show any clinical benefits from
the combination against carbapenem-resistant
A. baumannii infections [61]. As such, the addition of
rifampicin or fosfomycin to polymyxin therapy is not
routinely recommended. A multicenter randomized con-
trolled trial comparing colistin monotherapy to colistin
plus meropenem for severe infections caused by
carbapenem-resistant Gram-negative infections is cur-
rently underway [62]. Based on promising in vitro data,
we recommend that colistin or polymyxin B be consid-
ered in combination with highly active bactericidal
agents such as carbapenems. With the introduction of
Page 7 of 9 38
newer beta-lactam/beta-lactamase inhibitor combination
agents (i.e., ceftolozane/tazobactam and ceftazidime/
avibactam), further studies are needed to evaluate the
effects of combining these agents with polymyxins.
Conclusion
Polymyxins are one of the last remaining antimicrobial classes
with activity against multi-drug resistant Gram-negative path-
ogens. Of great concern is the emergence of polymyxin-resis-
tance, particularly the plasmid-mediated mcr-1 gene, which
may be transferable between bacterial species and increasing
rates of polymyxin resistance in carbapenem-resistant
Enterobacteriaceae (CRE). As our understanding of the
mechanisms and occurrence of polymyxin resistance grows,
so must our understanding of how to best optimize the use of
these agents including polymyxin agent selection, dosing op-
timization, and use in combination regimens.
Acknowledgments We thank Elizabeth Neuner, PharmD for assisting
with technical editing, language editing, and proofreading of this
manuscript.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflicts of
interest.
Human and Animal Rights This article does not contain any studies
with human or animal subjects performed by any of the authors.
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