REVIEW OF THERAPEUTICS

Colistin: Understanding and Applying Recent

Pharmacokinetic Advances
Jessica K. Ortwine,1 Keith S. Kaye,2,3 Jian Li,4 and Jason M. Pogue3,5*
1
Department of Pharmacy Services, Parkland Health and Hospital System, Dallas, Texas; 2Department of Internal
Medicine, Division of Infectious Diseases, Detroit Medical Center, Detroit, Michigan; 3Wayne State University
School of Medicine, Detroit, Michigan; 4Drug Delivery, Disposition and Dynamics, Monash Institute of
Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; 5Department of Pharmacy Services,
Sinai-Grace Hospital, Detroit Medical Center, Detroit, Michigan

Colistin, the most widely used polymyxin antibiotic, was originally introduced in the late 1950s before
the establishment of the present-day drug approval process. Originally shelved due to toxicity con-
cerns, colistin, in the form of its inactive prodrug colistin methanesulfonate, has undergone a renais-
sance in the past 15 years. Unfortunately, this is not because of an improved adverse-effect profile but
because colistin is among the only remaining antibiotics with activity against multidrug-resistant gram-
negative bacilli. Pharmacokinetic and pharmacodynamic data are limited to guide the appropriate use
of colistin; however, important advances have occurred over the past 5 years. Since its reintroduction,
published reports regarding colistin have produced discordant results in terms of both efficacy and
safety. Because the efficacy and toxicity of colistin are dose dependent, the impact of discordant dosing
recommendations cannot be understated. This review highlights the issues leading to differing and
often conflicting dosing recommendations, reviews the recent pharmacokinetic advances, and provides
recommendations for the optimal use of colistin.
KEY WORDS colistin, colistimethate, polymyxins, pharmacokinetics, pharmacodynamics.
(Pharmacotherapy 2014;**(**):**–**) doi: 10.1002/phar.1484

Colistin, the most widely used polymyxin
antibiotic, came to the market before the estab-
lishment of the present-day drug approval pro-
cess. As a result, limited pharmacokinetic (PK)
and pharmacodynamic (PD) data are available to
guide its appropriate use. Originally shelved due
to toxicity concerns, the polymyxins and, in
particular, colistin, have made a comeback in
recent years. Unfortunately, this is not because
of an improved adverse-effect profile but because
these drugs increasingly are the only remaining
antibiotics with activity against multidrug-resistant
gram-negative bacilli. In this review, we ana-
lyze recent PK/PD developments and make
*Address for correspondence: Jason M. Pogue, Clinical
Pharmacist, Infectious Diseases, Sinai-Grace Hospital,
Detroit Medical Center, 6071 West Outer Drive, Detroit,
MI 48235; e-mail: jpogue@dmc.org.
Ó 2014 Pharmacotherapy Publications, Inc.
recommendations on how to optimize the use of
this agent.
Since its reintroduction, published reports
regarding colistin, formulated as its prodrug colis-
tin methanesulfonate (CMS), also known as colis-
timethate, have produced discordant results in
terms of both efficacy and safety. One of the
primary reasons for this discordance is due to
the variability in the commercially available
CMS products. The similar-sounding Colomycin
(Forest Laboratories UK Limited, Dartford,
United Kingdom), primarily used in Europe, and
Coly-Mycin M Parenteral (Monarch Pharmaceuti-
cals, Inc., Bristol, TN), primarily used in the Uni-
ted States, are two of the available branded
formulations of CMS for injection. To add to the
confusion caused by similar names and despite
the fact that the vials contain the same product,
the labeling of each product describes the
contents in terms of different drug products (CMS
2 PHARMACOTHERAPY Volume **, Number **, 2014

for Colomycin and colistin base activity (CBA) for
Coly-Mycin M) and in different dosing units
(millions of international units (MU) of CMS,
milligrams of CMS, or milligrams of CBA).1, 2
The conversions among these units are as follows:
1 MU CMS = 80 mg CMS = 30 mg CBA.3 This
gets further complicated because the two package
insert dosing recommendations are inconsistent
with one another (Table 1). In a 70-kg patient,
the recommended daily dosage of Colomycin is
90–180 mg CBA (3–6 MU CMS),1 which is
roughly 50% lower than the recommended daily
dosage of Coly-Mycin M Parenteral (175–350 mg
CBA or 5.8–11.7 MU CMS),2 despite the contents
of the vials having the same product. Because the
efficacy and toxicity of colistin are dose depen-
dent, the impact of these discordant dosing
recommendations cannot be understated.
Pharmacokinetic Issues and Misunderstandings
Many of the PK issues and misunderstandings
stem from the fact that colistin is given in the
form of its inactive prodrug, CMS, rather than
the active moiety colistin.6 CMS is an unstable
compound that converts to colistin both in vivo
and in aqueous and biologic fluids ex vivo.7, 8
Historically, this conversion significantly limited
researchers’ abilities to obtain accurate PK/PD
data because CMS, if not promptly and properly
stored, continues to hydrolyze after blood sam-
ples are obtained, leading to falsely elevated
levels of colistin. The second obstacle that lim-
ited progress in this area was the fact that, until
recently, plasma concentrations of CMS and
formed colistin were not differentiated in the lit-
erature. In the early 2000s, high-performance
liquid chromatographic methods became avail-
able, allowing for quantitative assessment of
both compounds individually.9, 10 Before this, it
was understood that CMS was the prodrug of
colistin, but it was unknown how much each
component contributed to overall bacterial kill-
ing. These sampling and analyses issues are the
primary reasons why the package insert–based
dosing is inaccurate and why data prior to 2003
regarding the pharmacokinetics of “colistin” in
humans are invalid.
Modern Pharmacokinetic Data
As previously mentioned, the dosing recom-
mendations in the original package insert for
CMS was established when the drug first came to
market and were largely derived from both faulty
and insufficient PK evidence to support the rec-
ommendations. To help resolve these dosing dis-
crepancies, newer studies have undertaken the
task of providing accurate PK information to
help guide CMS/colistin dosing recommenda-
tions. A population PK model4 presented data
from 18 patients who received 3 MU of CMS
(90 mg CBA) every 8 hours and represents the
first significant breakthrough in our modern-day
understanding of colistin PK. Three extremely
important advances came from these data. First,
the authors showed that predicted maximum
serum concentrations, even with this dosage,
which was above the upper limit of the European
package insert dosage range recommendation,

Table 1. Colistin Dosing Recommendations

Dosing recommendations for Daily dose for a 70-kg patient with Clcr of
Source patients with normal renal function 70 ml/min (expressed in mg CBA)
Colomycin package insert1 ≤ 60 kg: 50,000 IU/kg/day in 3 divided 90–180 mg/day CBA in 3 divided doses
doses (maximum daily dose 75,000 IU/kg)
> 60 kg: 1–2 million IU (MU) 3 times/day
(maximum daily dose 6 MU)
Coly-Mycin M 2.5–5 mg CBA/kg/day in 2–4 divided doses 175–350 mg/day CBA in 2–4 divided doses
Parenteral package insert2 (maximum daily dose 300 mg CBA)
Plachouras et al4 Loading dose: 9–12 million IU 270–360 mg CBA loading dose + 135 mg
Maintenance dose: 4.5 million CBA every 12 h
IU every 12 hrs
Garonzik et al5 Loading dose: colistin Css,avg target 9 2.0 If Css,avg = 2.5 lg/ml: 300 mg CBA loading
9 ideal body weight (kg)a dose + 340 mg/day CBA in 3 divided doses
(maximum dose 300 mg CBA)
Maintenance dose: colistin Css,avg target
9 ([1.50 9 Clcr] + 30) in 2–3 divided dosesb
CBA = colistin base activity; Clcr = creatinine clearance; Css,avg = average steady-state concentration.
a
Use actual body weight if less than ideal body weight.
b
Clcr calculated by using actual body weight and normalized to body surface area (ml/min/1.73 m2).
 APPLYING COLISTIN PHARMACOKINETICS Ortwine et al
would be 0.6 lg/ml with the first dose and
2.3 lg/ml at steady state. When protein binding
of ~60% is taken into account,11, 12 these num-
bers for the first time brought into serious ques-
tion the appropriateness of the current
susceptibility breakpoint for colistin 2 lg/ml.13
Second, the half-life of colistin was determined
to be 14.4 hours showing that without a loading
dose it would take ~60 hours for colistin to
reach steady state. Finally, and perhaps most
concerning, the authors showed that hydrolysis
of CMS to active colistin in critically ill patients
was slow, with maximum concentrations occur-
ring ~7 hours after the dose.
In 2011, one report5 significantly enhanced
our PK understanding for critically ill patients by
using data from 105 patients across a wide range
of renal function. Pivotal findings from this
study included both important advances of our
understanding of the PK of CMS and colistin
(described later), as well as confirmations of the
data from the study cited earlier4 regarding the
need for a loading dose and that conventional
dosing yields concentrations in the 2.0–2.5-lg/ml
range. The authors demonstrated that a large
proportion of CMS was cleared before conversion
to the active drug and that the resultant colistin
concentrations were both low and highly variable
(~20-fold variation in levels were observed,
despite only ~6-fold variation in dosage adminis-
tered). Of importance, the authors also showed
that despite not being renally eliminated itself,
colistin levels were elevated in patients with
renal insufficiency, presumably due to decreased
elimination of CMS, allowing a subsequently
higher proportion of CMS to be hydrolyzed to
active colistin. This finding confirmed the need
for dosage adjustments for patients with renal
insufficiency. Using these data, the authors
developed the first scientifically based dosage
regimens and devised a dosing equation for
both loading and maintenance doses (Table 1),
depending on the target colistin steady-state con-
centration. They also provided recommendations
for patients with various degrees of renal dys-
function including those on intermittent hemodi-
alysis and continuous renal replacement therapy.
Understanding and Using the Recently
Developed Dosing Equation
After giving the patient a onetime loading
dose of 5 mg/kg CBA based on actual or ideal
body weight, whichever is lower (maximum
dose 300 mg CBA), the authors proposed the
3
following equation for determining the mainte-
nance dose with creatinine clearance (Clcr)
normalized to body surface area:
Maintenance dose (mg of CBA) = colistin Css,avg
target 9 ([1.50 9 Clcr] + 30)5
To first implement this equation, the clinician
needs to determine the target colistin steady-state
concentration (Css, avg). The authors suggest an
average target concentration of 2.5 lg/ml, which
would equate to a free concentration of ~1.0 lg/ml.
This target was suggested as a compromise
between efficacy and toxicity because the mean
total colistin concentration observed in patients in
this PK analysis was 2.36 lg/ml, which was asso-
ciated with 48% patients having a greater than
50% increase in serum creatinine concentration.
These toxicity rates are in concordance with a
recent report14 that showed rates of nephrotoxi-
city of 65–85% with trough concentrations greater
than 2.2 lg/ml. With a free colistin concentration
target of 1.0 lg/ml, the free area under the
unbound colistin concentration-versus-time curve
over 24 hours (fAUC0–24) would be 24 lg•hour/
ml given the “flat” plasma concentration versus
time profiles of formed colistin.4, 5 It is imperative
for the clinician to understand that, based on
neutropenic mouse thigh infection models in both
Pseudomonas aeruginosa and Acinetobacter bauman-
nii, this exposure would only reliably be associ-
ated with a 2-log10 kill in bacterial burden for
organisms with a minimum inhibitory concentra-
tion (MIC) of up to 0.5 lg/ml and that for organ-
isms with an MIC of 1 lg/ml, a 1-log10 kill is
more likely.15, 16 For organisms with an MIC of
2 lg/ml (the current susceptibility breakpoint) or
above, minimal kill would be expected, highlight-
ing the controversy around the current break-
point. It is important to note that the Sanford
Guide recommends a target concentration of
3.5 lg/ml, which would equate to an fAUC0–24 of
34 lg•hour/ml.17 Given the high rates of neph-
rotoxicity discussed earlier when trough con-
centrations were significantly lower than this,
coupled with the knowledge that toxicity is dose
dependent, we would not recommend this
higher target concentration because the safety of
the doses required to reach that concentration
has not been sufficiently studied. In addition,
true bactericidal activity (3-log10 kill) remains
unlikely even with that exposure.15, 16 There-
fore, we question if there is any bang for
your buck, so to speak, in going higher with the
target concentration.
In addition, these data suggest that in spite
of U.S. package insert recommendations, the
4 PHARMACOTHERAPY Volume **, Number **, 2014
Table 2. Impact of Using the Cockcroft-Gault Equation with Ideal Body Weight or with Actual Body Weight Normalized
to Body Surface Area on Calculated Creatinine Clearance and Subsequent Colistin Maintenance Dose Recommendation
Using the Colistin Dosing Equation Derived by Garonzik et al5 in a Hypothetical Patienta
Calculated creatinine Colistin maintenance dose
Weight used Resultant Cockcroft-Gault equation clearance (ml/min) recommendation (mg/day CBA)
Use ideal body weight 53 273
ð140  age)  IBW
72  Scr
Use actual body weight 70 338
corrected for BSA
ð140  age)  TBW 1:73

72  Scr BSA
BSA = body surface area; CBA = colistin base activity; IBW = ideal body weight; Scr = serum creatinine concentration; TBW = total body
weight.
a
Patient characteristics were as follows: 54-year-old male; height = 67 inches; weight = 128 kg; IBW = 66.1 kg; Scr = 1.5 mg/dl;
BSA = 2.45 m2; colistin minimum inhibitory concentration for organism = 1 lg/ml; target colistin concentration 2.5 lg/ml.

maintenance dose of CMS should not be based
on weight because the equation only includes
target colistin concentrations and Clcr. We
believe it is crucial to point out two important
caveats. First, the median (range) weight in this
study was 59.1 (30.0–106.4) kg.5 Therefore,
applying these algorithms to the obese popula-
tion requires further clinical PK/PD studies. In
addition, if you use this equation for your
patients, it is important to highlight that Clcr in
this study was calculated by using actual body
weight corrected to body surface area in Clcr
equations. On average, in obese patients, using
actual body weight normalized to body surface
area leads to a significantly larger Clcr than
when using ideal body weight in Clcr equations
and therefore significantly larger doses
(Table 2).
Finally, the authors suggest dividing the daily
dose into three doses in patients with normal
renal function. This dosing schema was based
on a rat model comparing regimens equivalent
to once/day and twice/day dosing in humans,
which resulted in development of more severe
and diverse renal lesions among the group that
received the equivalent of once/day colistin
administration,18 and on an in vitro PK/PD
model study suggesting that dividing the daily
dose into an every-8-hour regimen decreases the
emergence of colistin resistance.19 Although lim-
itations to these data exist, we feel at the current
time that this strategy is reasonable.
What Are the Important Lessons Learned from
These Newer Pharmacokinetic Data?
If we accept the reasonable conclusion that
the target colistin concentration should be
2.5 lg/ml, it becomes immediately apparent that
this is likely to be unachievable in certain
patient populations, specifically in patients with
normal to good renal function or obesity. The
authors explicitly state that when Clcr is greater
than 70 ml/minute, the equation gives doses for
which the safety is unknown (e.g., the daily
maintenance dose for a target concentration of
2.5 lg/ml and a Clcr of 70 ml/minute is 338 mg
CBA). Although in our clinical practice we
occasionally go above this daily dose, multiple
publications have suggested there is a signifi-
cant increase in toxicity with a daily dose above
5 mg/kg of ideal body weight,20, 21 whereas
there are no data equating this to improved
efficacy. As we previously stated, to use this
equation in obese patients, actual body weight
normalized to body surface area must be used
in Clcr determinations. This will often give a
Clcr more than 70 ml/minute, even in the set-
ting of moderate renal insufficiency, which
leads to the same problem (i.e., requirement of
high doses with unknown safety) stated ear-
lier above in nonobese patients without renal
dysfunction.
In addition, the clinician must remember that
a target colistin concentration of 2.5 lg/ml
equates to an area under the curve (AUC)0–24 of
60 lg•hour/ml (fAUC0–24 of ~24 lg•hour/ml)
and is only associated with, at best, a static
effect for MIC values of 0.5–2.0 lg/ml.
The current clinical PK and animal PK/PD
findings, when taken together, suggest that the
susceptibility breakpoints for colistin warrant
revisiting due to practical limitations in achiev-
ing adequate in vivo colistin exposure and are a
primary reason why many experts recommend
the use of combination therapy.
 APPLYING COLISTIN PHARMACOKINETICS Ortwine et al
How Should I Dose and Use the Drug in My
Patients?
Ultimately, the question remains: Which of
these many dosing options available should be
used? Unfortunately, the clinical impact of higher
or more aggressive dosing on efficacy still remains
unclear, and PK/PD targets as a function of infec-
tion type warrant further exploration. Two studies
that appeared to show a dose-efficacy response
with “higher dosing” both used 9 MU/day of CMS
(270 mg CBA),22, 23 which is lower than doses
commonly used in the United States (300 mg/day
of CBA in a 60-kg patient), and they did not eval-
uate efficacy relative to the colistin MIC for the
pathogen. Alternatively, another analysis showed
poor outcomes even when using up to 10 mg/kg/
day (maximum 600 mg) of CBA.24 If we choose
to dose based on the U.S. package insert, the ques-
tion of what dosing weight to use in obesity
remains, and, as previously discussed, data5 sug-
gest that weight (in the form of an increased Clcr)
will increase the required CMS dose. Of impor-
tance, however, this needs to be balanced against
the finding that using dosing weights other than
ideal body weight with the U.S. dosing schemes
will increase both the CMS dose and the risk of
toxicity.20, 21
When determining what to do, in the end, we
need to come back to the important finding that
even with the most aggressive of these dosing
regimens, our likely obtainable colistin concen-
trations are relatively low and likely to result in
bacteriostatic effects. When these relatively low
exposures are combined with the known hetero-
resistance to colistin in multidrug-resistant
gram-negative bacilli25–27 and the impressive
synergy seen in vitro, the role of combination
therapy with other active or synergistic agents
becomes increasingly important. Because the
data with imipenem show synergy even with
subtherapeutic (0.5 9 MIC) concentrations of
colistin,27 we promote a more conservative
approach to dosing the drug, regardless of dos-
ing strategy used, to maximize efficacy and mini-
mize nephrotoxicity. After the patient receives
a loading dose, this conservative approach
includes maintenance dosing strategies such as
capping the dose in the equation presented
earlier5 at roughly 340 mg/day as the authors
suggest, dosing on ideal body weight with the
U.S. package insert, or administering a fixed dose
of 9 MU CMS as currently done by many Euro-
peans in patients with normal renal function,
with subsequent dosage reductions in patients
5
with renal insufficiency. Although this will
undoubtedly lead to subtherapeutic concentra-
tions in some types of infection scenarios, we
question whether “therapeutic” colistin concen-
trations are even possible in some situations
and therefore stress combination therapy and
safety. Of importance, despite the theoretical
advantages of combination therapy, the efficacy
data in patients comparing colistin monothera-
py versus combination therapy have been
inconclusive to this point, with no evident con-
sistent advantage. Two ongoing randomized
controlled trials (one of which is blinded) com-
paring colistin versus a colistin-meropenem
combination should help shed light on this
important question. Although combination
therapy makes sense, it is important in this era
of increasing drug resistance that we ensure
combination therapy equates to improved
outcomes and that there are no detrimental
ecological impacts of increased exposure to the
synergistic (or active) second agents, most
notably, the carbapenems.
References
1. Forest Laboratories UK Limited. Colomycin [package insert].
Dartford, Kent, U.K.; 2012.
2. Monarch Pharmaceuticals, Inc. Coly-Mycin M Parenteral
[package insert]. Bristol, TN; 2006.
3. Nation RL, Li J, Cars O, et al. Consistent global approach on
reporting of colistin doses to promote safe and effective use.
Clin Infect Dis 2014;58:139–41.
4. Plachouras D, Karvanen M, Friberg LE, et al. Population
pharmacokinetic analysis of colistin methanesulfonate and
colistin after intravenous administration in critically ill patients
with infections caused by Gram-negative bacteria. Antimicrob
Agents Chemother 2008;53:3430–6.
5. Garonzik SM, Li J, Thamlikitkul V, et al. Population pharma-
cokinetic of colistin methanesulfonate and formed colistin in
critically ill patients from a multicenter study to provide dos-
ing suggestions for various categories of patients. Antimicrob
Agents Chemother 2011;55:3284–94.
6. Bergen PJ, Li J, Rayner CR, Nation RL. Colistin methanesulfo-
nate is an inactive prodrug of colistin against Pseudomonas
aeruginosa. Antimicrob Agents Chemother 2006;50:1953–8.
7. Li J, Milne RW, Nation RL, et al. Pharmacokinetics of colistin
methanesulphonate and colistin in rats following an intrave-
nous dose of colistin methanesulphonate. J Antimicrob Che-
mother 2004;53:837–40.
8. Li J, Milne RW, Nation RL, et al. Stability of colistin and
colistin methanesulphonate in aqueous media and plasma as
determined by high-performance liquid chromatography. Anti-
microb Agents Chemother 2003;47:1364–70.
9. Li J, Milne RW, Nation RL, et al. Simple method for assaying
colistin methanesulfonate in plasma and urine using high-
performance liquid chromatography. Antimicrob Agents
Chemother 2002;46:3304–7.
10. Li J, Milne RW, Nation RL, et al. A simple method for the
assay of colistin in human plasma, using pre-column derivati-
zation with 9-fluorenylmethyl chloroformate in solid-phase
extraction cartridges and reversed-phase high-performance
liquid chromatography. J Chromatogr B Biomed Sci Appl
2001;761:167–75.
6 PHARMACOTHERAPY Volume **, Number **, 2014
11. Mohamed AF, Karaiskos I, Plachouras D, et al. Application of
a loading dose of colistin methanesulfonate in critically ill
patients: population pharmacokinetics, protein binding, and
prediction of bacterial kill. Antimicrob Agents Chemother
2012;56:4241–9.
12. Sandri AM, Landersdorfer CB, Jacob J, et al. Population phar-
macokinetics of intravenous polymyxin B in critically ill
patients: implications for selection of dosage regimens. Clin
Infect Dis 2013;57:524–31.
13. Clinical and Laboratory Standards Institute. Performance
standards for antimicrobial susceptibility testing: 24th informa-
tional supplement. CLSI M100-S24. Wayne, PA: Clinical Labo-
ratory Standards Institute.
14. Sorli L, Lugue S, Grau S, et al. Trough colistin plasma level is
an independent risk factor for nephrotoxicity: a prospective
observational cohort study. BMC Infect Dis 2013;13:380.
15. Dudhani RV, Turnidge JD, Coulthard K, et al. Elucidation of
the pharmacokinetic/pharmacodynamics determinant of colis-
tin activity against Pseudomonas aeruginosa in murine thigh
and lung infection models. Antimicrob Agents Chemother
2010;54:1117–24.
16. Dudhani RV, Turnidge JD, Nation RL, et al. fAUC/MIC is the
most predictive pharmacokinetic/pharmacodynamics index of
colistin against Acinetobacter baumanii in murine thigh and lung
infection models. J Antimicrob Chemother 2010;65:1984–90.
17. Gilbert DN, Moellering RCJr, Eliopoulos GM, Chambers HF,
Saag MS, eds. The Sanford guide to antimicrobial therapy,
43rd ed. Sperryville, VA: Antimicrobial Therapy; 2013.
18. Wallace SJ, Li J, Nation RL, et al. Subacute toxicity of
colistin methanesulfonate in rats: comparison of various
intravenous dosage regimens. Antimicrob Agents Chemother
2008;52:1159–61.
19. Bergen PJ, Li J, Nation RL, et al. Comparison of once-, twice-
and thrice-daily dosing of colistin on antibacterial effect and
emergence of resistance: studies with Pseudomonas aeruginosa
in an in vitro pharmacodynamic model. J Antimicrob Chemo-
ther 2008;61:636–42.
20. Deryke CA, Crawford AJ, Uddin N, et al. Colistin dosing and
nephrotoxicity in a large community teaching hospital. Anti-
microb Agents Chemother 2010;54:4503–5.
21. Pogue JM, Lee J, Marchaim D, et al. Incidence of and risk fac-
tors for colistin-associated nephrotoxicity in a large academic
health system. Clin Infect Dis 2011;53:879–84.
22. Dalfino L, Puntillo F, Mosca A, et al. High-dose, extended-
interval colistin administration in critically ill patients: is this
the right dosing strategy? A preliminary study Clin Infect Dis
2012;54:1720–6.
23. Falagas ME, Rafailidis PI, Ioannidou E, et al. Colistin therapy
for microbiologically documented multidrug-resistant Gram-
negative bacterial infections: a retrospective cohort study of
258 patients. Int J Antimicrob Agents 2010;35:194–9.
24. Kalin G, Alp E, Coskun R, et al. Use of high-dose IV and
aerosolized colistin for the treatment of multidrug-resistant
Acinetobacter baumanii ventilator-associated pneumonia: do we
really need this treatment? J Infect Chemother 2012;18:872–
7.
25. Li J, Rayner CR, Nation RL, et al. Heteroresistance to colistin
in multidrug-resistant Acinetobacter baumannii. Antimicrob
Agents Chemother 2006;50:2946–50.
26. Meletis G, Tzampaz E, Sianou E, et al. Colistin heteroresis-
tance in carbapenemase-producing Klebsiella pneumoniae. J An-
timicrob Chemother 2011;66:946–7.
27. Bergen PJ, Forrest A, Bulitta JB, et al. Clinically relevant
plasma concentrations of colistin in combination with imipe-
nem enhance pharmacodynamics activity against multidrug-
resistant Pseudomonas aeruginosa at multiple inocula. Antimic-
rob Agents Chemother 2011;55:5134–42.