Colistin, together with polymyxin B, belongs to the group of polymyxin antibiotics
which were discovered in the 1940s and introduced into patient care in 1959, but their
clinical use was largely abandoned in the 1970s mainly due to concerns about their
potential to cause nephrotoxicity.[1] Over the last two decades, the emergence of gram-negative “superbugs” that are resistant
to essentially all contemporary antibiotics and the lack of newly developed antibacterials
have led to a resurgence in the use of the polymyxins.[2]
[3]
[4] Parenteral products of both polymyxins exist; of the two polymyxins, colistin is
more widely available around the world. For successful clinical use of any antibiotic,
dosage regimens need to be optimized to maximize bacterial killing and minimize emergence
of resistance and potential toxicity. This is important for any patient group but
particularly so for the critically ill as they are most at risk for high morbidity
and mortality.[5] In addition, the above statement is especially true for colistin because, as reviewed
below, it is an antibiotic with a narrow therapeutic window such that plasma concentrations
that increase the risk for nephrotoxicity are not far above those required for the
desired antibacterial effect.
Colistin was never subjected to modern drug development and regulatory approval procedures
which means that much of the information required to ensure its optimal use in patients
has been unavailable. The recent researcher-led redevelopment of colistin has resulted
in an improved understanding of its chemistry, parenteral formulations, pharmacokinetics
(PK), pharmacodynamics (PD), and toxicodynamics (TD).[3]
[6]
[7] A good understanding of all of these key characteristics is required to optimize
the clinical use of colistin and therefore these topics are briefly summarized below,
followed by a review of the current knowledge on how to optimally dose colistin in
critically ill patients.
Chemistry, Units of Dosage, and Formulations
Colistin is a cyclic polypeptide which is a cation at physiological pH. Being a fermentation
product it consists of several components, the major ones being colistin A and colistin
B.[8] It is administered parenterally (most often intravenously) and by inhalation as
its inactive prodrug colistin methanesulfonate (CMS, also known as colistimethate)
which has a lower potential for acute toxicity than colistin.[9]
[10] Conversion of CMS to colistin occurs in aqueous solutions both in vitro (e.g., water,
bacterial growth media) and in vivo (e.g., plasma, urine).[9]
[11]
[12] Indeed, the conversion is a prerequisite for antibacterial activity to be unmasked.
CMS products for parenteral and inhalational use are standardized to the in vitro
microbiological activity of colistin, but unfortunately labeling differs between geographic
regions.[2]
[13] Most notably in Europe, the United Kingdom, and India, CMS content and doses are
expressed as the number of international units (IU). In North and South America, Southeast
Asia, and Australia the amount in milligrams of colistin base activity (CBA) is used.
A dose of one million IU corresponds to approximately 30 mg of CBA (and approximately
80 mg of the chemical CMS). These different conventions (especially expression of
milligram amounts of two distinct entities) used for labeling and dosing have a great
potential to cause confusion in clinical practice resulting in medication errors and
serious consequences for patients.[13]
[14] Awareness of the different terminology is required in clinical practice, especially
when following recommendations in journal reports from different geographic regions.
Articles for publication should use the recently recommended standardized terminology
in expressing CMS doses.[13]
Colistin Antibacterial Activity and Pharmacodynamics
CMS is an inactive prodrug and therefore it is essential that colistin is used in
in vitro studies, including measurement of minimum inhibitory concentration (MIC),
that investigate activity against bacterial strains.[9] Colistin is active against a range of gram-negative bacteria with most strains of
Pseudomonas aeruginosa, Klebsiella pneumonia, and Acinetobacter baumannii being susceptible, even strains that are multiresistant to other antibiotics.[15]
[16]
[17]
[18] The current susceptibility breakpoints for colistin are ≤ 2 mg/L for A. baumannii and Enterobacteriaceae, and ≤ 2 mg/L or ≤ 4 mg/L for P. aeruginosa.[19]
[20]
Although the ultimate mechanism of bacterial killing is still not known, the initial
bacterial target of colistin is the lipopolysaccharide (LPS) in the outer leaflet
of the outer membrane of gram-negative bacteria.[21] A key element in the interaction is electrostatic attraction of the positively charged
amine groups of colistin with negatively charged phosphate and carboxylate groups
on the lipid A and core-oligosaccharide of LPS. This electrostatic interaction enables
interaction of the fatty acyl tail and other hydrophobic regions of the colistin molecule
with hydrophobic domains of LPS. These electrostatic and hydrophobic interactions
are believed to weaken the packing of adjacent lipid A fatty acyl chains causing substantial
disruption and permeabilization of the outer membrane, including to colistin, a process
termed “self-promoted uptake”.[22] Subsequent steps in the killing action are not well defined and are subject to ongoing
investigation. Clearly, the initial interaction between colistin and LPS is analogous
to a “lock and key” arrangement and explains why colistin has very limited activity
against gram-positive bacteria. Not unexpectedly, most of the known mechanisms whereby
gram-negative bacteria develop resistance to colistin involve either chemical modification
of the phosphate groups of lipid A or elaboration of an outer membrane that lacks
LPS, both being changes that attenuate the initial electrostatic interaction between
colistin and the outer membrane.[21]
[23]
In vitro static and dynamic (the latter conducted in PK/PD models to mimic clinically
relevant fluctuating concentrations in patients) concentration time-kill studies have
demonstrated very rapid, concentration-dependent killing by colistin of multidrug-resistant
P. aeruginosa,[24]
[25]
[26]
[27]
[28] K. pneumonia,[29]
[30] and A. baumannii.[31]
[32]
[33]
[34] A common feature of such time-kill profiles is the regrowth of bacteria with enhanced
resistance to colistin. This regrowth is often related to the phenomenon of colistin
heteroresistance, which is the presence of a subpopulation of colistin-resistant bacteria
in an isolate that would be considered susceptible on the basis of MIC.[31] Following eradication of the predominant susceptible population, the colistin-resistant
subpopulation undergoes unopposed amplification. The rate and extent of killing of
P. aeruginosa in in vitro studies are considerably decreased at a high initial inoculum of 108 or 109 colony-forming units (CFU)/mL compared with a low initial inoculum of 106 CFU/mL.[35] At inocula of 108 and 109 CFU/mL, killing of susceptible bacterial populations was approximately 6-fold and
23-fold slower, respectively, compared with an inoculum of 106 CFU/mL. Clearly, the impact of the inoculum on the bactericidal activity of colistin
requires further examination. However, the results of the study above[35] imply that high-inoculum infections in patients may require more aggressive dosing.
Colistin combination therapy should be considered for such infections because the
risk of colistin-associated nephrotoxicity increases with plasma colistin concentrations
above ∼2.5–3 mg/L as revealed by recent PK/TD analyses.[36]
[37] However, as discussed in the next section, it is important to be aware of uncertainties
that surround the role of colistin combination therapy.
Recent studies in an in vitro PK/PD infection model against P. aeruginosa
[26] and in the “gold standard” mouse thigh infection model against P. aeruginosa
[38] and A. baumannii
[39] have demonstrated that the PK/PD index that best correlates with the antibacterial
activity of colistin is the ratio of the area under the concentration versus time
curve to the MIC. These studies[26]
[38]
[39] suggest that it is important to achieve an average steady-state plasma colistin
concentration of approximately 2 mg/L for isolates with MICs ≤ 1 mg/L. This finding
together with the relationship between plasma colistin concentration and risk of nephrotoxicity,[36]
[37] as discussed above, indicates that colistin is an antibiotic with a narrow therapeutic
window.
Activity of Colistin in Combination with Other Antibiotics
Studies conducted in in vitro static and dynamic infection models using clinically
relevant concentrations of colistin and various second antibiotics have provided evidence
for increased bacterial killing and decreased emergence of resistance with the use
of certain colistin combinations against P. aeruginosa, A. baumannii, and K. pneumoniae.[27]
[28]
[30]
[34]
[40] Not unexpectedly, the relative value of a combination may vary from bacterial strain
to strain.[41] Arguably, the most commonly tested second antibiotic has been a member of the carbapenem
class. A recent systematic review and meta-analysis of in vitro studies explored the
relative activity of colistin versus colistin plus carbapenem combinations.[42] In general, across several carbapenems and bacterial species, bactericidal effect
was enhanced and resistance emergence suppressed by the combination relative to the
use of colistin alone. Across all bacterial species, of the carbapenems examined doripenem
most consistently achieved synergy with colistin.[42]
Notwithstanding the growing evidence from in vitro studies for a beneficial effect
of colistin combinations, the situation remains unclear in regard to the role of colistin
combinations in patients. Very recently, an analysis was conducted of all clinical
studies (12 retrospective cohort studies or case series, 2 prospective observational
studies, and 2 randomized controlled trials [RCTs]) which compared colistin monotherapy
versus colistin-based combination therapy for the treatment of infections caused by
carbapenemase-producing or carbapenem-resistant gram-negative bacteria.[43] A requirement for inclusion in the analysis was that the original studies reported
quantitatively on the association between the treatment regimen and all-cause mortality.
The analysis revealed that there was no difference in mortality between colistin alone
and colistin/carbapenem combination therapy in any of the individual studies or when
they were pooled. Pooling the only two RCTs showed similar mortality for colistin
monotherapy versus colistin/rifampicin combination therapy. However, the authors of
the analysis indicated that numerous sources of bias in the original studies existed,
including the following: the retrospective nature of most of the studies; differences
between the monotherapy and combination groups in regard to the nature and severity
of infection; small sample sizes; appropriateness of the initial empirical antibiotic
treatment; and the inclusion in some studies of multiple noncolistin antibiotics in
the combination group.[43] Additional limitations include the following: the use of dosage regimens of colistin
and/or the second antibiotic that were not optimized based upon PK/PD principles;
lack of measurement of plasma concentrations of colistin in both groups to gauge the
equivalence of exposure to colistin; failure to stratify outcomes based on the site
and/or severity of illness; and, the administration of antibiotics other than the
index second antibiotic to patients in both the so-called colistin “monotherapy” group
and the combination group. Clearly, given ethical and practical considerations, it
is much more difficult to study colistin combinations in patients in the absence of
potentially confounding effects than it is in a preclinical model where much tighter
control over the experimental conditions is possible. Well designed and adequately
powered RCTs are needed to define the role of colistin combination therapy. Two such
RCTs (see NCT01732250 and NCT01597973 at ClinicalTrials.gov) are currently underway
to compare colistin/carbapenem combination therapy versus colistin monotherapy for
invasive infections caused by carbapenem-resistant gram-negative bacteria.
Pharmacokinetics of CMS and Formed Colistin: General Considerations
To optimize dosing of CMS/colistin, a good understanding of the PK of CMS and colistin
is essential. Considerable progress has been made in this field since the beginning
of the redevelopment of colistin and many reports of preclinical and clinical studies
are available.[44]
[45]
[46]
[47]
[48]
[49]
[50] It is important to be aware that “old” PK data (certainly the information generated
before the start of the 21st century) based on CMS/colistin concentrations determined
by microbiological assays are invalid due to the ongoing conversion of CMS to colistin
during the incubation period of the assay.[6] Despite this, PK data based on these outdated and erroneous findings are still included
in product information and package inserts.[2]
[51] This review will only consider PK data determined by high-performance liquid chromatography
or liquid chromatography-tandem mass spectrometry methods that are capable of separately
quantifying CMS and formed colistin in biological fluids.
The inactive prodrug (CMS) and formed colistin (the active antibacterial) have very
different PK ([Fig. 1]).[2]
[52] CMS is eliminated mainly via the kidneys, by glomerular filtration and there may
also be a component of tubular secretion.[45] Because in a renally healthy individual the renal clearance of CMS is much greater
than its conversion clearance to colistin, only approximately 20% (or less) of a CMS
dose is converted in vivo to the active entity colistin.[2]
[52] Not only is the extent of conversion very low, but also the rate of conversion is
slow.[48]
[50] Thus, CMS is a highly inefficient prodrug, and the clinical consequences of these
characteristics for therapeutic use in critically ill patients will be discussed in
the following section. In contrast, renal excretion plays a minor role in the overall
elimination of formed colistin because following glomerular filtration colistin is
subject to very extensive tubular reabsorption ([Fig. 1]).[2]
[3]
[7]
[44] The reabsorptive trafficking of colistin through renal tubular cells is almost certainly
linked to its propensity to cause nephrotoxicity.
Fig. 1 Schematic diagram of the pharmacokinetic pathways for colistin methanesulfonate (CMS)
and colistin. The thickness of the arrows indicates the relative magnitude of the
respective clearance pathways when kidney function is normal. After administration
of CMS, extensive renal excretion of the prodrug occurs with some of the excreted
CMS converting to colistin within the urinary tract. Adapted with permission from
Nation et al.[52]
Pharmacokinetics of CMS and Formed Colistin in Critically Ill Patients: Implications
for Dosing
Initially, PK following intravenous administration of CMS will be considered. Subsequently,
consideration will be given to administration of CMS directly to sites such as the
lungs and the central nervous system. There has been only one brief report relating
to three pediatric patients who ranged in age from 1.5 months to 14 years,[53] and therefore the studies reviewed below relate to critically ill adult patients.
Intravenous Administration of CMS
The first report on the PK of intravenous CMS and the colistin formed from it in a
critically ill patient, with plasma concentrations measured using specific chromatographic
methods, was by Li et al.[54] The patient was receiving continuous venovenous hemodiafiltration as part of management
of multiorgan failure. Because the product information for CMS provided no information
to guide dosage selection for such a patient, the patient was administered intravenously
2.5 mg CBA per kg every 48 hour. This was a regimen that had been proposed in a review
on antibiotic dosing in patients receiving continuous renal replacement therapy, although
there was no supporting data for the suggested dosage regimen.[55] The report of Li et al[54] demonstrated that both CMS and colistin were cleared by the renal replacement modality.
As a consequence of the extracorporeal clearance and the inappropriately low daily
dose of CMS, plasma concentrations of colistin were substantially lower than 1 mg/L,
the MIC of the infecting organism, for almost 90% of the 48-hour dosage interval.
Unfortunately, the patient did not survive. This case report sent a strong signal
of the need for PK information to assist clinicians when selecting dosage regimens
of CMS for various categories of critically ill patients.
Two subsequent small studies reported the steady-state plasma concentrations of formed
colistin, but not CMS, following intravenous administration of CMS to critically ill
patients, all of whom had creatinine clearance greater than about 50 mL/min.[56]
[57] Patients were administered either 3 million IU (approximately 90 mg CBA) every 8
hours[56] or 2 million IU (approximately 60 mg CBA) every 8 hours.[57] Concern was expressed by the authors of both reports about the relatively low plasma
colistin concentrations achieved in the patients. In these two studies, it was not
possible to identify any patient factors that influenced the steady-state plasma colistin
concentrations achieved. This was most likely due to the small number of patients
(n = 14 and 13) included in the respective studies and the fact that all patients had
creatinine clearance values greater than 46 and 96 mL/min.[56]
[57]
The PK of both CMS and formed colistin were investigated in two clinical studies involving
a total of 28 critically ill patients who received intravenously 1 to 3 million IU
(approximately 30–90 mg CBA) every 8 hours and most of whom had moderate-to-good renal
function (creatinine clearance range 24–214 mL/min).[48]
[58] These and other studies[48]
[50]
[58] identified a significant problem that may arise if CMS regimens are not initiated
with a loading dose. Because of the slow conversion of CMS to colistin mentioned above
and the long half-life of formed colistin, in the absence of a loading dose of CMS
plasma concentrations of colistin (the active antibacterial) rise slowly over the
first 2 to 3 days of therapy. In the study of Plachouras et al,[48] a loading dose was not administered and plasma colistin concentrations were generally
below 1 mg/L after the first dose ([Fig. 2], panel B). The long delay in achieving plasma colistin concentrations that are likely
to be effective is of concern given the link between timely initiation of appropriate
antibiotic therapy and clinical outcome in critically ill patients.[59]
[60] Thus, a loading dose of CMS at the initiation of therapy is advised.
Fig. 2 Plasma concentrations of colistin methanesulfonate (CMS) (panels A and C) and formed
colistin (panels B and D) in individual critically ill patients after the administration
of the first dose of CMS (left panels) and the fourth dose of CMS (right panels).
The dose of CMS was 3 million IU (∼90 mg colistin base activity [CBA]) every 8 hours
in all except one patient who received 2 million IU (∼60 mg CBA) every 8 hours. Adapted
with permission from Plachouras et al.[48]
In the two studies mentioned above,[48]
[58] plasma concentrations of CMS and colistin were also measured across a dosage interval
at steady state. While accumulation had occurred relative to concentrations after
the first dose, the plasma colistin concentrations across the dosage interval at steady
state in several patients were less than 2 mg/L ([Fig. 2], panel D). The authors expressed concern that the steady-state plasma concentrations
of colistin were low in relation to current MIC breakpoints.[48] The steady-state data along with those collected after the initial dose of CMS were
pooled across the two studies and subjected to population PK analysis.[58] The clearance of the prodrug CMS was 13.1 L/h, its renal clearance was similar to
creatinine clearance and the terminal half-life was 2.2 hours. The half-life of formed
colistin was considerably longer at 18.5 hours. A comprehensive search for patient
covariates (e.g., body weight, renal function) that may influence the disposition
of CMS and/or colistin was conducted by the authors. However, no covariates were identified,
most likely because of the small sample size (total of 28 patients across the two
studies) and only 3 of these patients had a creatinine clearance less than 50 mL/min.
Garonzik et al[50] reported the results of the largest study thus far on the PK of CMS and colistin
in critically ill patients. The study population was 105 patients, including 89 not
on renal replacement who had a large range of renal function (creatinine clearance
3–169 mL/[min·1.73 m2]), 12 on intermittent hemodialysis and 4 on continuous renal replacement therapy.
The daily dose of intravenous CMS was at the discretion of the treating medical team.
Across all patients the daily dose ranged from 75 to 410 mg CBA (approximately 2.5–13.7
million IU) with a median of 200 mg CBA (approximately 6.67 million IU), and achieved
an average plasma colistin concentration at steady state (Css,avg) of 0.48 to 9.38 mg/L (median 2.36 mg/L)([Fig. 3], panel B). That is, the approximately 5.5-fold range in the daily dose of CMS resulted
in approximately 20-fold range in the Css,avg of colistin in plasma. Initial graphical analysis of the data suggested the likelihood
that renal function, along with daily dose of CMS, was an important contributor to
the wide range of plasma colistin concentrations observed ([Fig. 4]). Also, evident from these graphs was that administration of a daily dose of CMS
at the upper limit of the currently approved dosage range (300 mg CBA/d) was unable
to reliably achieve a Css,avg of colistin in plasma of 2 mg/L. As noted above, this concentration may be considered
as a reasonable target based upon translation of current evidence from PK/PD studies
in animal infection models[38]
[39] and given that PK/TD analyses indicate that the risk of nephrotoxicity in critically
ill patients increases substantially as plasma colistin concentrations exceed approximately
2.5 to 3 mg/L.[36]
[37] Thus, in patients with relatively good renal function (>∼80 mL/min), combination
therapy should be considered, particularly if the MIC for the infecting organism is
toward the upper end of the current breakpoint range.[50]
Fig. 3 Plasma concentration versus time profiles of the prodrug colistin methanesulfonate
(CMS) (panel A) and formed colistin (panel B) across a dosage interval at steady state
in 105 critically ill patients (89 not on renal replacement, 12 on intermittent hemodialysis,
and 4 on continuous renal replacement therapy). Physician-selected CMS dosage intervals
ranged from 8 to 24 hour and hence the interdosing blood sampling interval spanned
the same range. Reproduced with permission from Garonzik et al.[50]
Fig. 4 Relationship of physician-selected daily dose of CMS (expressed as colistin base
activity [CBA]) (panel A) and the resultant steady-state plasma colistin concentration
(panel B) with creatinine clearance in 105 critically ill patients. Reproduced with
permission from Garonzik et al.[50]
As the study of Garonzik et al[50] comprised a large number of patients, including those with very low renal function,
population PK analysis was able to identify creatinine clearance as a patient covariate
that influenced the PK of both CMS and formed colistin. Because the prodrug (CMS)
is predominantly cleared by renal excretion ([Fig. 1]) it is easy to understand that its total body clearance declines with decreasing
kidney function. It may be more difficult to understand the impact of declining renal
function on the disposition of formed colistin given that renal excretion is a very
small contributor to its overall elimination from the body. The explanation lies in
the relatively complex interplay of the dispositions of CMS and colistin. In a patient
with good kidney function, only a small fraction of each dose of CMS is converted
to colistin ([Fig. 1]). However, with declining renal function, a progressively larger fraction of each
CMS dose is converted to the active antibacterial. Thus, the apparent clearance of
colistin decreases in parallel with creatinine clearance. Not unexpectedly, creatinine
clearance was the patient factor included in the algorithm developed by the authors
to calculate the CMS daily maintenance dose needed to generate a desired target steady-state
plasma concentration of formed colistin in a patient not receiving renal replacement
therapy.[50]
Reflected by the data in [Fig. 4], at a given creatinine clearance there was a very large degree of interpatient variability
(up to ∼10-fold) in the apparent clearance of colistin and consequently in the CMS
daily dose to achieve a desired steady-state plasma colistin concentration. The interpatient
variability in the plasma colistin concentration achieved at a certain creatinine
clearance and daily dose of CMS serves to complicate the clinical use of CMS, particularly
since colistin has a narrow therapeutic window. Because of this wide interpatient
variability in PK, clinicians are encouraged to use therapeutic drug monitoring (TDM)
when available to assist in titration of the daily maintenance dose of CMS to achieve
the desired steady-state plasma concentration of colistin.[52]
Of the 105 critically ill patients in the report of Garonzik et al,[50] 16 were receiving renal replacement therapy at the time of initiating the CMS regimen
(12 intermittent hemodialysis and 4 continuous renal replacement). These renal replacement
modalities were shown to have a substantial impact on the plasma colistin concentration
achieved from a given daily dose of CMS; this was in agreement with reports from case
studies and case series.[54]
[61]
[62]
[63]
[64]
[65]
[66] There are two reasons why renal replacement therapy has such a substantial impact
on dosage requirements of CMS. First, the circulating plasma concentrations of CMS
are considerably higher than those of formed colistin ([Figs. 2] and [3]) and therefore a significant proportion of the material dialyzed out of the patient
is in the form of CMS, before there has been an opportunity for conversion to colistin
in the body. Second, as noted above, colistin is subject to very extensive carrier-mediated
tubular reabsorption in the kidney[44] but a renal replacement cartridge has no corresponding mechanism to return to the
circulation compounds, such as CMS and colistin, which have passively diffused into
dialysate. As a result of the efficient extracorporeal clearance of CMS/colistin,
dosage regimens of CMS for such patients must be carefully chosen. Garonzik et al[50] by way of population PK modeling were able to propose a daily maintenance dose of
CMS to achieve a desired steady-state plasma concentration of formed colistin in patients
receiving intermittent hemodialysis. The algorithm that was developed for designing
dosage regimens for patients on intermittent hemodialysis included administration
of a supplemental dose of CMS after the dialysis session to replace CMS and colistin
that had been cleared by dialysis. These authors also developed a CMS dosage algorithm
to achieve a desired plasma concentration of formed colistin in patients receiving
continuous renal replacement therapy.[50]
The study of Garonzik et al[50] also developed an algorithm for calculating a loading dose of CMS to be administered
to patients whether they are, or are not, receiving renal replacement therapy at the
initiation of therapy. The loading dose algorithm was based upon body weight being
a covariate on the volume of distribution of CMS. Alternatively, a nonweight-based
loading dose may be used.[67] The loading and maintenance doses proposed by Garonzik et al are the first scientifically
based regimens for CMS/colistin.[50] The study went on to recruit a total of 230 critically ill patients and therefore
the interim dosing suggestions[50] are not reproduced here as they will be updated based upon the final population
PK/PD analysis of the data.
There is very little information on the extent to which colistin distributes into
important extravascular infection sites (e.g., cerebrospinal fluid [CSF], lungs) following
intravenous administration of CMS. Concentrations of formed colistin in CSF are very
low compared with those in plasma.[53]
[68]
[69] In a similar way, following intravenously administered CMS the concentrations of
formed colistin in sputum of patients with cystic fibrosis[70] and in bronchoalveolar lavage (BAL) fluid from critically ill patients[57] are very low relative to concomitant plasma concentrations. In relation to the latter
study, it should be noted that BAL is an approximate 100-fold dilution of epithelial
lining fluid (ELF) and given the limit of quantification of the assay for colistin
in BAL the result of that study requires cautious interpretation. However, the current
data overall suggest limited penetration of formed colistin into CSF and lung fluids
following intravenous administration of CMS.
Administration of CMS Directly to the Central Nervous System and Lungs
It is axiomatic that bacterial killing by an antibiotic at an extravascular infection
site requires achievement of adequate concentrations of the antibiotic at that site.
CMS is commonly administered to critically ill patients for the treatment of ventilator-associated
pneumonia and less commonly for the treatment of infections within the central nervous
system. However, as reviewed briefly in the last paragraph of the section above, the
emerging data suggest that following intravenous administration of CMS the concentrations
of formed colistin achieved in CSF and lung fluids are very low.
Two recent studies, the first in patients with cystic fibrosis[70] and the second in mechanically ventilated critically ill patients,[71] have demonstrated the substantially higher colistin concentrations that can be achieved
in sputum and ELF, respectively, following inhalational delivery of CMS, compared
with intravenous administration. Following pulmonary administration of CMS the extent
of absorption into the systemic circulation was minimal and the plasma concentrations
of formed colistin were very low.[70]
[71] It was possible in the study in cystic fibrosis patients to calculate the pulmonary
targeting advantage of inhalational administration (i.e., the relative values for
inhalational versus intravenous administration of CMS of the ratio of colistin concentration
in sputum to that in plasma).[70] There was a massive targeting advantage with inhalational administration, indicating
the potential to achieve more effective bacterial killing in the lungs while sparing
the kidneys. The role of inhalational administration of CMS, possibly combined with
a suitable intravenous regimen, in critically ill patients warrants further investigation.
Intrathecal or intraventricular administration of CMS appears to be a generally effective
and safe treatment for ventriculitis/meningitis caused by gram-negative bacteria.[72]
[73]
[74]
[75] A much lower dose is administered by these routes than is typically administered
intravenously. Because of the relatively small volume into which the intrathecal or
intraventricular dose is delivered and the relatively slow turnover of CSF, it is
possible to achieve CSF colistin concentrations very much higher than is possible
with intravenous administration of a far larger dose.[53]
[68]
[69] One would expect plasma colistin concentrations following intrathecal or intraventricular
administration of CMS to be very low, although there appear to be no data to substantiate
this. It can be noted, however, that colistin-associated nephrotoxicity appears to
occur rarely following these routes of delivery to the CNS.[72]
[74] There may be benefit in concomitant administration of intravenous CMS.
Take-Home Messages
The following are some key points for those using colistin in critically ill patients
to keep in mind:
-
How is colistin administered? Colistin is administered intravenously and by inhalation as its inactive prodrug
CMS (also known as colistimethate). CMS must be converted to colistin in the body.
Care is needed to avoid confusion arising from the different conventions used to label
vials and specify doses.
-
What plasma concentration is appropriate for intravenous administration? Based upon current evidence, a plasma colistin concentration of 2 mg/L is a reasonable
target value for isolates with MICs ≤ 1 mg/L, and minimizes the risk of nephrotoxicity.
-
Should I consider colistin combination therapy? It is prudent to consider combination therapy for infections where the causative
organism has an MIC > 1 mg/L or when there is a high-inoculum or deep-seated infection
(e.g., in lungs), especially in patients with moderate-to-good renal function, although
the clinical benefit of colistin combinations remains unproven.
-
Do I need to administer an intravenous loading dose? Yes, because CMS is relatively slowly converted to colistin in the body and it may
take many hours to achieve steady-state plasma concentrations without a loading dose.
-
Do I need to adjust the daily maintenance dose if the patient has renal impairment? The plasma concentrations of colistin achieved from a given intravenous daily dose
are influenced by kidney function. The recently developed dosing algorithm provides
a means to tailor the daily dose.
-
Does renal replacement therapy have implications for selection of intravenous dosage
regimens? Yes, CMS and colistin are efficiently removed from the body by both intermittent
hemodialysis and continuous renal replacement therapy. The recently developed dosage
algorithms for such patients allow calculation of dosage regimens and of the size
of a supplemental dose to be administered after each intermittent hemodialysis session.
-
Is there a potential benefit of using TDM to assist optimizing therapy? Yes, colistin has a narrow therapeutic window and plasma concentrations are subject
to marked interpatient variability, even at a given creatinine clearance and daily
dose of intravenous CMS. TDM is recommended if it is available.
-
Should I consider administration directly to the lungs or CNS for infections in those
sites? Intrathecal or intraventricular administration of CMS is able to generate concentrations
of colistin in CSF that are very much higher than can be achieved with intravenous
administration, and the treatment appears to be safe and effective. Similarly, inhalational
delivery of CMS generates concentrations of colistin in lung fluids that are substantially
higher than is possible after intravenous administration, with negligible plasma concentrations.
The potential benefits (more effective bacterial killing in lung and sparing of the
kidneys) are attractive, but remain to be proven.
In summary, over the last decade or so, considerable progress has been made in understanding
how to optimize the clinical use of colistin in critically ill patients. However,
as identified in this article, answers are still required for several important questions.
