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REVIEW 10.1111/j.1469-0691.2011.03734.

Colistin: new lessons on an old antibiotic

D. Yahav1,2, L. Farbman1,2, L. Leibovici1,2 and M. Paul2,3


1) Internal Medicine E, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, 2) Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv and
3) Unit of Infectious Diseases, Rabin Medical Centre, Beilinson Hospital, Petah Tikva, Israel

Abstract

Colistin has been re-introduced into clinical practice for the treatment of carbapenem-resistant Gram-negative bacteria. Studies in the
last decade attempted to reconstruct the path that present-day medications undergo prior to clinical use. In this review, we summarize
the results of recent clinical studies. Colistin was associated with lower mortality than no effective treatment and higher unadjusted
mortality than b-lactams in non-randomized clinical studies. However, it was administered to sicker patients with carabapenem-resistant
bacteria. Overall, nephrotoxicity rates were not higher with colistin in these studies, and colistin-induced nephrotoxicity is reversible in
most patients. The emergence of colistin resistance has been described in high-use settings. Synergy with carbapenem, rifampin and
other antibiotics has been reported in vitro. Randomized controlled trials are ongoing or in planning to assess this and other aspects of
colistin use in clinical practice.

Keywords: Colistin, multidrug-resistant bacteria, nephrotoxicity, polymyxins, ventilator-associated pneumonia


Article published online: 20 November 2011
Clin Microbiol Infect 2012; 18: 18–29

Corresponding author: D. Yahav, Internal Medicine E, Rabin


Medical Centre, Beilinson Hospital, Petah Tikva 49100, Israel
E-mail: dafna.yahav@gmail.com

Introduction mechanism of action [6]. The initial target of the antimicrobial


activity of polymyxins is the lipopolysaccharide (LPS) compo-
The polymyxin group of polypeptide antibiotics, discovered in nent of the outer membrane [7,8]. The polymyxins have a
the 1940s, were among the first antibiotics with significant strong positive charge and a hydrophobic acyl chain that give
activity against Gram-negative bacteria [1,2]. Polymyxin E (colis- them a high binding affinity for LPS molecules. They interact
tin) and polymyxin B are the main antibiotics of this group and electrostatically with these molecules and competitively displace
the only polymyxins used clinically. Following reports on neph- divalent cations from them, causing disruption of the membrane
rotoxicity and neurotoxicity in the 1970s, they were largely [9]. The result of this process is an increase in the permeability
replaced by other antibiotics [3,4]. In the last two decades, the of the cell envelope, leakage of cell contents, and, subsequently,
paucity of novel antibiotics with which to treat drug-resistant cell death [10,11]. Some authors argue that interaction with
infections, especially those caused by Gram-negative pathogens, membranes is indeed a part of the action of polymyxins, but is
has led to their reconsideration as a therapeutic option [5]. The not actually the lethal event [9]. The exact mechanism by which
current review focuses on colistin, rather than polymyxin B, the polymyxins induce bacterial killing is still unknown, and mul-
because of its wider use in current clinical practice. tiple bacterial cell targets may be involved [12–14]. Polymyxins
also bind to the lipid A portion of LPS and, in animal studies,
block many of the biological effects of endotoxin [15].
Mechanism of Action
Spectrum of Activity and Resistance
Most investigations have been conducted with polymyxin B,
which is regarded as a model polymyxin. Colistin has a similar Colistin’s in vitro activity includes most aerobic Gram-negative
structure to polymyxin B, and is believed to have an identical rods, except for Neisseria, Proteus, Serratia, Providencia, Brucella

ª2011 The Authors


Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases
CMI Yahav et al. Colistin: new lessons on an old antibiotic 19

and Edwardsiella species, Pseudomonas mallei, and Burkholderia methate sodium (colistin sulphomethate sodium, colistin
cepacia [1,16]. It causes rapid bacterial killing in a concentra- methanesulphonate). Colistimethate sodium is a prodrug
tion-dependent manner [2]. It has in vitro activity against some [36]. In aqueous solution, colistimethate sodium undergoes
multidrug-resistant (MDR) Gram-negative pathogens, including spontaneous hydrolysis to the active form colistin [20]. Co-
Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella listimethate sodium is administered parenterally, intrave-
pneumoniae, [17] and Stenotrophomonas maltophilia. P. aerugin- nously, or intramuscularly, as it is less toxic than colistin
osa susceptibility and A. baumannii susceptibility are defined as sulphate [37]. The intramuscular injection, which is rarely
MICs of £4 and £2 mg/L colistin sulphate, respectively, accord- used in clinical practice, may cause severe local pain, and
ing to the European Committee on Antimicrobial Susceptibility absorption is variable. Colistin sulphate is administered either
Testing [18], and as an MIC of £2 mg/L for both bacteria orally (for bowel decontamination, without absorption) or
according to the CLSI [19]. Colistin has no activity against topically (for the treatment of bacterial skin infections) [1].
Gram-positive bacteria, all cocci, and anaerobes [1,20]. It has Both colistimethate sodium and colistin can be given via inha-
also been reported to be potentially active against several lation, but colistin may result in a higher frequency of bron-
mycobacterial species, including Mycobacterium tuberculosis [1]. choconstriction than colistimethate sodium (see below).
Rates of colistin resistance have been relatively low, proba- Colistimethate sodium can also be administered by the intra-
bly because of its infrequent use. Nevertheless, resistance has thechal or intraventricular routes [1]. Colistimethate sodium
recently been identified in several Gram-negative bacterial spe- is hydrolysed in aqueous solutions to colistin in a concentra-
cies. Ko et al. [21] identified a high rate of colistin/polymyxin tion-dependent manner, so it should be administered shortly
resistance in A. baumannii strains belonging to subgroups II and after reconstitution to avoid the toxicity associated with
III in Korea, on the basis of rpoB gene analysis. Heteroresis- colistin [38].
tance to colistin (i.e. the presence of colistin-resistant subpop- There are two common commercially available parenteral
ulations within a microbial population that is susceptible formulations of colistimethate sodium [20]. Colomycin injec-
according to its MIC) in MDR A. baumannii has been reported tion, which is manufactured and used in Europe, is provided
in 23–100% of clinical isolates in few studies, but the clinical in vials containing 500 000, 106 or 2 ·106 international units
relevance of this heteroresistance was not investigated [22– (IU) of colistimethate sodium. An IU of colistin is defined as
24]. Heteroresistance to colistin has also been recently the minimal concentration that inhibits the growth of Escheri-
detected in other species, including K. pneumoniae [25,26] and chia coli 95 I.S.M in 1 mL of broth at pH 7.2 [39], and 106 IU
P. aeruginosa [27]. The emergence of colistin-resistant K. pneu- is considered to be equivalent to 80 mg of colistimethate
moniae has been described following widespread use of colistin sodium [40]. Coly-Mycin M Parenteral, which is manufac-
[28]. Resistance of P. aeruginosa to colistin is a growing prob- tured and used in the USA, contains 150 mg of ‘colistin base
lem [29,30], and has been described most commonly in activity’ per vial, equivalent to 360 mg of colistimethate
patients with cystic fibrosis (CF) who have received aerosol- sodium per vial and to 4.5 ·106 IU of colistimethate sodium
ized colistin therapy [31,32]. The most common mechanism of [20]. The need for uniform dosing of colistimethate sodium
colistin resistance is modification of LPS [33]. Several other is obvious, and this would avoid confusion. As there is no
mechanisms have been suggested, most of which involve direct relationship between IUs determined in vitro and the
changes in the outer membrane [20,33]. An efflux pump/potas- pharmacodynamics of colistimethate sodium in vivo, it has
sium system may also be associated with resistance to poly- been suggested that the use of milligrams of colistimethate
myxin B [34]. Paenibacillus polymyxa subspecies colistinus, the sodium is preferable [41]. The doses of colistimethate
organism that produces colistin, also produces colistinase, sodium used for systemic infections in adults range widely,
which inactivates colistin. However, enzymatic resistance of between 240 and 720 mg daily (i.e. 3–9 ·106 IU/day), in two
bacteria to colistin has not been reported in clinical practice to four divided doses. The pharmacokinetics of intravenous
[1]. Recently, colistin resistance mediated by complete loss of colistin are discussed extensively by Couet et al. [42] in this
LPS production has been described in A. baumannii strains [35]. issue.
Penetration of colistin through the blood–brain barrier to
the central nervous system (CNS) is poor, and is estimated
Formulations, Dosage, and Route of
to be approximately 5% [43]. In different studies, enhance-
Administration
ment of penetration during meningitis and inflammation has
been reported to range between none [44] and 25–67%
There are two forms of colistin available: colistin sulphate [45,46]. In a review of case reports, the doses of colistimet-
and the commercially available parenteral formulation colisti- hate sodium used in intrathecal or intraventricular adminis-

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Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
20 Clinical Microbiology and Infection, Volume 18 Number 1, January 2012 CMI

tration for meningitis ranged between 3.2 and 40 mg time to nephrotoxicity was not reported in most studies.
(40 000–500 000 IU) per day [47]. The paucity of data pre- Four studies reported that most cases occurred within the
vents an analysis of the association between dosing and first week of treatment [59,61–63]. Studies monitoring
treatment success. In a pharmacokinetic (PK) study, a daily patients for up to 1–3 months after treatment demonstrated
dose of 4.8 mg (60 000 IU) of intraventricular colistimethate reversibility of renal failure in at least 88% of patients
sodium resulted in a trough colistin cerebrospinal fluid level [54,58,60]. Overall, rates of nephrotoxicity are probably
of 2.2 mg/L, whereas regimens of 2.4 mg (30 000 IU) every lower today than those observed in old studies [4]. Explana-
12 h or 4.8 mg (60 000 IU) every 12 h led to a trough con- tions for the lower toxicity include fewer chemical impurities
centration of >5 mg/L (the target MIC is >2 mg/L) (Cusato in colistimethate sodium, better intensive-care unit (ICU)
et al., 21st ECCMID, 2011, Abstract P814). monitoring, and avoidance of co-administration of other
Distribution to the biliary tract, pleural fluid and joint fluid nephrotoxic drugs [66,67]. Recent observations have sug-
is considered to be similarly poor [48]. A prospective study gested that, at least in CF patients, colistimethate sodium
conducted in 13 critically ill adult patients found that the may actually be less nephrotoxic than aminoglycosides [68].
intravenous administration of 480 mg (6 ·106 IU) of colisti- Neurotoxicity is less common than nephrotoxicity. Clini-
methate sodium per day resulted in suboptimal plasma con- cal manifestations include dizziness, muscle weakness, pares-
centrations of colistin, which were undetectable in thesias, partial deafness, visual disturbances, vertigo,
bronchoalveoalar lavage fluid [49]. Another study in two crit- confusion, hallucinations, seizures, ataxia, and neuromuscular
ically ill patients demonstrated good penetration into lung blockade. Paresthesias constitute the most common clinical
tissue and called for further studies [50]. Differences in manifestation, being reported in approximately 27% of cases
results were explained by dilutional effects and colistimethate with the use of intravenous colistimethate sodium. Neuro-
sodium intravenous dosage. Trials assessing the pharmacoki- toxic effects are usually mild, and resolve after prompt dis-
netics of colistin (plasma levels and concentrations in pulmo- continuation of the antibiotic [67].
nary epithelial lining fluid) are ongoing [51,52]. Apnoea and respiratory failure, which are feared complica-
tions of neuromuscular blockade, have not been reported
with intravenous colistimethate sodium in the recent litera-
Toxicity
ture [67], but a case has been described when intravenous
administration was combined with inhaled colistimethate
Nephrotoxicity is one of the commonly observed adverse sodium [69]. Other adverse events of inhaled colistimethate
effects following intravenous administration of colistimethate sodium may include bronchospasm and hypersensitivity pneu-
sodium. In studies comparing treatment with colistimethate monitis [70], but recent studies in critically ill patients with-
sodium with or without other antibiotics vs. other antibiotic out CF have not demonstrated these adverse events [71–
regimens, nephrotoxicity was significantly higher with colisti- 79].
methate sodium (or polymyxin B) in six studies, similar to
that with comparators in five (two of which claimed no
Clinical Experience with Intravenous
events), and lower in two (Table 1). Rates of nephrotoxicity
Colistimethate Sodium
in recent studies designed to assess this outcome have ran-
ged from 6% to 14% in some [53–57] and from 32% to 55%
in others [58–63]. The wide range of nephrotoxicity rates Treatment with colistimethate sodium has been described
can be at least partly explained by different definitions of worldwide in the last decade. Table 1 summarizes compara-
renal failure (see Table S1). Some studies used any of the tive and non-comparative clinical studies assessing colistimet-
RIFLE criteria (risk, injury, failure, loss, and end-stage kidney hate sodium and polymyxin B. Most studies reported on
disease) [64], some used the threshold of failure or above, MDR A. baumannii and P. aeruginosa infections. A few recent
and others defined renal failure as creatinine >2 mg/dL. Risk studies have also reported on carbapenem-resistant K. pneu-
factors for nephrotoxicity found in different studies included moniae infections. Non-comparative studies described series
older age [59,62], pre-existing renal insufficiency [65], hypo- of patients treated with colistimethate sodium (Table 1), and
albuminaemia [60], and concomitant use of non-steroidal concluded that outcomes were acceptable, considering the
anti-inflammatory drugs [60] or vancomycin [62]. Higher severity of infection and underlying patient illnesses. All but
dosing is associated with renal failure, with some studies one were retrospective, and colistimethate sodium was usu-
identifying the total cumulative dose as predictive of renal ally administered in combination with other antibiotics. The
failure [4,57,58], and others the daily dose [59,62,63]. The most common source of infection was pneumonia (usually

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Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
CMI

TABLE 1 . Results of clinical studies assessing intravenous colistimethate sodium (CMS); studies are sorted by design (comparative or not and prospective/retrospective)
and publication year

Study Antibiotics assessed Concomitant Infecting Bacteraemia Pneumonia Mortality Treatment Renal failure
Location years Design (no. of episodes) antibiotic bacteriaa (%) (%) (%) failure (%)b

Comparative
Spain [125] 1997–2001 Prospective comparative 21 CMS vs. 14 imipenem ) A 10 vs. 14 100 vs. 100 62 vs. 64 43 vs. 43 24 vs. 42
(non-matched)
Argentina [126] 2000–2004 Prospective comparative 55 CMS vs. 130 other + A, P 16 vs. 19 53 vs. 66 29 vs. 26 15 vs. 17 0 vs. 0
(non-matched)
Tunisia [127] 2003–2005 Retrospective matched 60 CMS vs. 60 imipenem ) A, P 100 35 vs. 25 75 vs. 72 0 vs. 0
cohort
USA [128] 2001–2004 Retrospective comparative 31 CMS vs. 64 other + P 45 vs. 34 55 vs. 47 61 vs. 47 48 vs. 66 23 vs. 22
(non-matched)
Argentina [129] 2001–2004 Retrospective comparative 31 CMS vs. 30 ) A, P 3.2 vs. 6.7 100 51.6 vs. 45.1 6.5 vs. 6.7
(non-matched) imipenem–meropenem
Thailand [130] 2005–2006 Prospective comparative 78 CMS vs. 15 inappropriatec + A, P 11.5 colistin 69 colistin 46.2 vs. 80 19.2 vs. 73.3 30.8 vs. 66.7
(non-matched)
Brazil [131] 1996–2004 Retrospective comparative 82 polymyxin B, + A 40 vs. 53 34 vs. 39 77 vs. 64 37 vs. 34 26 vs. 26
(non-matched) 85 ampicillin–sulbactam
Greece [132] NS Quasi-randomized 15 CMS vs. 13 ) A NS 100 33.3 vs. 30 26.6 vs. 23 33 vs. 15.3
ampicillin–sulbactam
South Africa [133] 2003–2005 Retrospective comparative 32 CMS vs. 32 tobramycin ) A 31 vs. 31 72 vs. 88 50 vs. 28.1 19.4 vs. 8.7
(non-matched)
Israel [81] 2006–2009 Prospective comparative 200 CMS vs. 295 other + A, K, P, other 46 vs. 43 49 vs. 44 39 vs. 29 15.5 vs. 7
(non-matched)
Croatia [134] 2002–2006 Retrospective matched 26 CMS vs. 26 other + P 84 vs. 69 – 11 vs. 11 23.1 vs. 34.6 11 vs. 0
cohort
c
Korea [135] 2000–2007 Retrospective comparative 31 CMS vs. 39 inappropriate + A 100 41.9 vs. 30 35.5 vs. 38.5 50 vs. 28.5
Yahav et al.

(non-matched)
Brazil [136] 2004–2009 Retrospective comparative 45 polymyxin B vs. 88 other + P 100 37.8 vs. 33 66.7 vs. 28.4 24.4 vs. 4.5
(non-matched)
Non-comparative
Brazil [65] 1993–1994 Prospective 60 CMS – A, P 15 33 37 42 37
USA [137] 1999–2000 Retrospective 60 polymyxin B + A, P 8 65 20 14
Greece [138] NS NS 30 CMS + A, P 42 58 47 37 14
USA [105] 1996–2003 Retrospective 26 CMS + P 31 69 61 35
Spain [55] 1995–2006 Retrospective 60 CMS + A, P, K, others 60 26.7 28.3 10.9
Spain [139] 1997–2006 Retrospective 121 CMS + P 13.2 16.5 16.5 28.1 8.3
India [140] 2006–2007 Retrospective 45 polymyxin B + A, P 11 52 4
Taiwan [56] 2006–2008 Retrospective 115 CMS + A, P, K, others 71 27.8 49 14
Greece [54,80,141] 2000–2007 Retrospective 258 CMS + A, P, K 12.8 60 34.9 20.9 10

NS, not stated.


a
A, Acinetobacter spp., P, Pseudomonas aeruginosa; K, Klebsiella pneumoniae.
b
Definitions of renal failure in individual studies are provided in Table S1.
c
Antibiotics to which infecting bacteria were resistant.
Colistin: new lessons on an old antibiotic

Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
ª2011 The Authors
21
22 Clinical Microbiology and Infection, Volume 18 Number 1, January 2012 CMI

ventilator-associated pneumonia (VAP)), and all-cause mortal- with inappropriate antibiotics given to bacteria susceptible
ity ranged between 20% and 52%. In the largest cohort, only to colistin. As previously, the most common source of
which included 258 patients, 60% of patients had pneumonia, infection was pneumonia (median of 62% patients), and most
and the in-hospital mortality rate was 34.9% [80]. In a single patients treated with colistimethate sodium were concomi-
prospective older study, colistimethate sodium was adminis- tantly treated with other antibiotics, although the infecting
tered as monotherapy, and the mortality rate was 37% [65]. bacteria were frequently susceptible only to colistin. The
Twelve comparative prospective or retrospective clinical comparative all-cause mortality results are summarized in
studies were identified (Table 1). Most compared treatment Fig. 1. One small quasi-randomized trial, two retrospective
with colistimethate sodium against Gram-negative bacteria studies using some type of matching procedure and four pro-
resistant to all other antibiotics with b-lactams (usually car- spective non-matched comparative studies showed no differ-
bapenems) given according to the antibiotic susceptibilities of ence or a higher mortality rate with colistimethate sodium,
the infecting bacteria. Two compared colistimethate sodium with a pooled OR for death of 1.40 (95% CI 1.07–1.84),

Colistin Comparator Odds ratio Odds ratio


Study or Subgroup Events Total Events Total Weight Fixed, 95% CI Fixed, 95% CI
1.2.1 Pseudorandomized
Betrosian 2008 [131] 5 15 4 13 2.5% 1.13 [0.23, 5.54]
Subtotal (95% CI) 15 13 2.5% 1.13 [0.23, 5.54]
Total events 5 4
Heterogeneity: Not applicable
Test for overall effect: Z = 0.14 (p = 0.88)

1.2.2 Matched retrospective design


Durakovic 2011 [133] 3 26 3 26 2.3% 1.00 [0.18, 5.48]
Kallel 2007 [126] 21 60 15 60 8.5% 1.62 [0.73, 3.56]
Subtotal (95% CI) 86 86 10.8% 1.48 [0.73, 3.03]
Total events 24 18
Heterogeneity: Chi2 = 0.25, df = 1 (p = 0.62); I 2 = 0%
Test for overall effect: Z = 1.08 (p = 0.28)

1.2.3 Non-matched prospective


Garnacho-Montero 2003 [124] 13 21 9 14 3.6% 0.90 [0.22, 3.68]
Hachem 2007 [127] 19 31 30 64 6.6% 1.79 [0.75, 4.30]
Reina 2005 [125] 16 66 34 130 15.1% 0.90 [0.46, 1.79]
Paul 2011 [122] 78 200 85 295 36.6% 1.58 [1.08, 2.31]
Subtotal (95% CI) 318 503 61.9% 1.40 [1.03,1.89]
Total events 126 158
Heterogeneity: Chi2 = 2.64, df = 3 (p = 0.45); I 2 = 0%
Test for overall effect: Z = 2.18 (p = 0.03)

1.2.4 Non-matched retrospective


Gounden 2009 [132] 16 32 9 32 3.9% 2.56 [0.91, 7.20]
Kvirko 2011 (polyB) [135] 30 45 25 88 4.9% 5.04 [2.32, 10.93]
Rios 2007 [128] 16 31 14 40 5.2% 1.98 [0.76, 5.16]
Oliveria 2008 (polyB) [130] 63 82 54 85 10.7% 1.90 [0.97, 3.75]
Subtotal (95% CI) 190 245 24.7% 2.65 [1.76, 3.99]
Total events 125 102
Heterogeneity: Chi2 = 3.93, df = 3 (p = 0.27); I 2 = 24%
Test for overall effect: Z = 4.66 (p < 0.00001)

Total (95% CI) 609 847 100.0% 1.71 [1.36, 2.14]


Total events 280 282
Heterogeneity: Chi2 = 13.23, df = 10 (p = 0.21); I 2 = 24%
0.1 0.2 0.5 1 2 5 10
Test for overall effect: Z = 4.66 (p = 0.00001) Favours colistin Favours comparator
Test for subgroup differences: Chi2 = 6.52, df = 3 (p = 0.09); I 2 = 54.0%
FIG. 1. All-cause mortality in studies comparing colistimethate sodium with other antibiotics. d.f., degrees of freedom.

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Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
CMI Yahav et al. Colistin: new lessons on an old antibiotic 23

indicating a significantly higher mortality rate with colistimet- with imipenem against A. baumannii, [83–85], P. aeruginosa
hate sodium. The largest study, contributing the highest [27], and low-inoculum Enterobacter cloacae [86], and with
weight in this comparison, was a prospective cohort study doripenem against A. baumannii, P. aeruginosa, E. coli, and
comparing colistimethate sodium (mostly monotherapy) with K. pneumoniae [87–89]. Imipenem–colistin synergy was
carbapenems or ampicillin–sulbactam that showed a signifi- reported in 50% of K. pneumoniae strains with the blaVIM-1
cantly higher mortality rate with colistin [81]. The multivari- genotype [82]. An in vitro PK/pharmacodynamic study also
able adjusted ORs for 30-day mortality in this study were demonstrated substantial reductions in regrowth of P. aeru-
1.44 (95% CI 0.91–2.26) overall (N = 495) and 1.99 ginosa with a colistin–doripenem combination and reduction
(95% CI 1.06–3.77) for bacteraemic patients (N = 220). and delay in the emergence of colistin-resistant subpopula-
Unlike in other studies, a large percentage of patients treated tions [89]. In vitro synergy with ceftazidime and rifampin
with colistimethate sodium had infections caused by carbape- against P. aeruginosa and A. baumannii has been suggested
nem-resistant K. pneumoniae, and the difference in mortality [90–93]. Other in vitro studies demonstrated significant syn-
was attributable to this subgroup of patients. Four non- ergy when colistin was combined with a glycopeptide against
matched retrospective studies showed a uniformly higher A. baumannii [94,95]. A small in vitro study suggested synergy
mortality rate with colistimethate sodium (pooled OR 2.65, with minocycline against the same organism [96]. Possible
95% CI 1.76–3.99). The two studies comparing colistimet- mechanisms for synergy with colistin and carbapenems or
hate sodium with inappropriate antibiotic treatment both rifampin are subpopulation synergy and mechanistic synergy
showed a lower mortality rate with colistimethate sodium [27] (Bulitta, PAGE (population approach group in Europe)
(pooled OR 0.51, 95% CI 0.24–1.08). 2010, Abstract 1918). In subpopulation synergy, one drug
In summary, contemporary clinical studies have demon- kills the subpopulations that are resistant to the other drug
strated that treatment with colistimethate sodium is proba- and vice versa. Mechanistic synergy means that, because each
bly better than no treatment at all, on the basis of multiple drug acts on a different cellular pathway, one drug increases
cohort studies showing acceptable outcomes with colistimet- the rate or extent of killing caused by the other drug [27].
hate sodium, and two comparative studies showing nearly Concerns regarding colistin monotherapy that have been
halved mortality with colistimethate sodium as compared previously raised include heteroresistance among Gram-nega-
with ineffective treatment. The comparison with other cov- tive bacterial populations exposed to colistin alone [23]. The
ering antibiotics is hindered by the inherent differences clinical significance of this heteroresistance remains unknown
between patients infected with bacteria susceptible only to [97]. Regrowth with colistin monotherapy was demonstrated
colistin and those infected with less resistant bacteria. The in several in vitro studies [91,98], even at supraclinical doses
clear trend in ORs from the least to the most biased study [26,99]. The amplification of colistin-resistant subpopulations
design (Fig. 1, top to bottom) attests to the effect of patient in heteroresistant strains has been shown to contribute to
differences on results. The comparison is further complicated the regrowth following colistin monotherapy [26,98,100].
by the fact that colistimethate sodium was usually given in Recent PK studies have indicated that the colistin Cmax val-
combination with other antibiotics, and infections are fre- ues typically achieved following administration of colistimet-
quently polymicrobial. A compilation of unadjusted mortality hate sodium at the recommended doses are low [42]. Given
results from all studies shows significantly a higher mortality these data, there is a strong theoretical basis for the use of
rate with colistimethate sodium. We believe that there is a colistin as part of combination antimicrobial therapy to maxi-
survival advantage to b-lactams that is probably smaller than mize antimicrobial activity.
that shown in the unadjusted analysis. Clinical studies have yet to show whether colistimethate
sodium combination therapy offers a clinical advantage. Fala-
gas et al. retrospectively assessed 258 patients treated with
Antibiotic Combinations Including
colistimethate sodium monotherapy or combination therapy
Colistimethate Sodium
[80,101,102]. Only 52.3% (136) of patients had pathogens
susceptible only to colistin. Most patients (86%) were hospi-
Some in vitro studies have indicated synergy between colistin talized in the ICU, and 92.3% of infections were caused by
and carbapenems for colistin-susceptible/carbapenem-resis- A. baumannii or P. aeruginosa. The most common infection
tant Gram-negative bacteria. Synergy definition in these trials was pneumonia (60%), and bacteraemia was present in 13%
was based on standard methodology: a 2 log10 decrease in of patients. In total, infection was cured in 83.3% of patients
CFU/mL between the combination and the most active single who received colistimethate sodium monotherapy (36
agent at the different time-points [82]. Synergy was observed patients) or colistimethate sodium combined with merope-

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Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
24 Clinical Microbiology and Infection, Volume 18 Number 1, January 2012 CMI

nem (162 patients). In the adjusted analyses, combination


Aerosolized Colistimethate Sodium in
therapy did not offer a survival advantage overall or among
Patients without CF
patients with infections susceptible only to colistin . Other,
smaller, observational studies found no significant differences
between colistin monotherapy and combination therapies. A One small retrospective report and one case control–study
retrospective study evaluated eight patients with diabetic claimed success for aerosolized colistimethate sodium, with-
foot caused by MDR P. aeruginosa, and found no difference in out intravenous antibiotics, for the treatment of pneumonia
clinical response and safety between colistin alone and colis- [71,72]. Several small retrospective studies assessed aerosol-
tin–rifampin or colistin–imipenem combinations [103]. Linden ized colistimethate sodium with concomitant intravenous
et al. [104] found no difference in clinical response to either therapy for the treatment of MDR Gram-negative pneumo-
colistin alone or colistin combined with amikacin or an anti- nia. These studies demonstrated clinical success rates
pseudomonal b-lactam in a prospective study evaluating 23 between 57% [75,76] and 87.5% [78] with aerosolized colisti-
ICU patients with serious MDR P. aeruginosa infections. methate sodium (in addition to intravenous colistin). One
In a randomized controlled trial (RCT), 53 CF patients prospective study demonstrated bacteriological and clinical
colonized with colistin-sensitive P. aeruginosa were allocated response of 83.3% with adjunctive aerosolized colistimethate
to either intravenous colistimethate sodium alone or colisti- sodium [77]. Two retrospective comparative studies evalu-
methate sodium combined with an antipseudomonal drug ated aerosolized plus intravenous colistimethate sodium with
during a respiratory exacerbation. All patients showed clini- intravenous colistimethate sodium alone for the treatment of
cal improvement, and mean forced vital capacity increased VAP. These studies demonstrated significantly higher clinical
significantly in the dual-therapy group [105]. Colistin com- cure rates with dual therapy (54.5% vs. 32% [73] and 79.5%
bined with rifampin was reported to be effective in the treat- vs. 60.5% [74]), without a significant difference in overall
ment of A. baumannii pneumonia with/without bacteraemia in mortality. In an open-label RCT comparing colistimethate
ICU patients in two prospective uncontrolled small studies sodium inhalation with placebo in 100 evaluable patients with
[106,107]. Gram-negative VAP in Thailand, there was a significant
The limitations of the available data on the clinical efficacy advantage for colistimethate sodium inhalation in microbio-
of colistin combinations include low numbers of patients, logical outcome but no improvement in clinical outcomes
study design, heterogeneity in the definition of outcomes, [79]. Most patients in this trial were treated intravenously
variability in the dosing regimens, differences in the suscepti- with colistimethate sodium or a carbapenem. At the end of
bility testing methods, lack of PK information for colistimet- follow-up (day 28), 60.9% of patients in the intervention
hate sodium and formed colistin, and the fact that most group had a favourable microbiological outcome, and 51%
studies do not stratify outcome by severity of illness [97]. had a favourable clinical outcome, as compared with 38.2%
Several trials assessing colistimethate sodium combination and 53.1%, respectively, in the control group. There was no
treatment are currently being planned or ongoing. Two significant difference between the study arms in overall mor-
RCTs comparing colistimethate sodium with colistimethate tality, mortality caused by VAP, or adverse events (including
sodium plus imipenem for invasive infections caused by carb- renal impairment).
apenem-resistant Gram-negative bacteria are currently being
planned in the USA, Europe, Israel, and Greece, funded by
Intrathecal/Intraventricular Colistimethate
the National Institutes of Health and the EU 7th framework
Sodium
(Keith Kaye and Johan Mouton, personal communication).
Two other trials are ongoing in Thailand, comparing colisti-
methate sodium alone with colistimethate sodium plus fosfo- A case series reviewing 24 patients with MDR A. baumannii
mycin [108] or colistimethate sodium plus rifampicin [109] CNS infections demonstrated an 83% clinical cure rate with
for infections caused by MDR A. baumannii. intrathecal/intraventricular use of colistimethate sodium, with
In summary, although in vitro data are promising, there is a 17% mortality rate [47]. Early initiation of treatment
no clinical proof of an advantage for colistimethate sodium (within 2 days) was associated with survival as compared
combination therapy. In existing studies, colistin was usually with later-onset treatment. Intrathecal/intraventricular colisti-
given in combination with other antibiotics. In vitro data do methate sodium was used as monotherapy in 11 patients,
not necessarily translate into clinical benefit [110]. Well- with high clinical cure rates (91%). Adverse events included
designed randomized trials targeting relevant patient popula- seizures and chemical ventriculitis in four patients. Long-term
tions are underway. survival and neurological outcomes of these patients were

ª2011 The Authors


Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
CMI Yahav et al. Colistin: new lessons on an old antibiotic 25

not described. Several case reports evaluating intrathecal/ TABLE 2. Further studies needed to answer unsolved ques-
intraventricular colistimethate sodium for the treatment of tions
MDR P. aeruginosa CNS infections have also shown favour- RCTs assessing intravenous CMS vs. CMS plus carbapenem for the treatment
able results [111–113]. The small number of patients and the of strains susceptible only to colistin
RCTs assessing the addition of CMS to empirical therapy regimens in patients at
possibility of publication bias should be considered when high risk for MDR Gram-negative infections
RCTs assessing the effectiveness of adjunctive nebulized CMS for the treatment
interpreting these results. of nosocomial pneumonia caused by to MDR Gram-negative bacteria
PK studies on CMS and formed colistin and analysis of PK and outcome data
stratified by severity of illness
Studies assessing risk factors for the development of resistance to colistin,
Polymyxin B Haemoperfusion including dosing and combination treatment
Trials comparing CMS with aminoglycosides, for infections such as those caused
by carbapenem-resistant Klebsiella pneumoniae, which are frequently susceptible
only to colistin and an aminoglycoside
RCTs assessing the effect of polymyxin B haemoperfusion in addition to the
Haemoperfusion with polymyxin B bound to polystyrene optimal standard of care among critically ill patients with sepsis
fibres, to exploit the endotoxin-binding capacity of polymyx- CMS, colistimethate sodium; MDR, multidrug-resistant; PK, pharmacokinetic;
ins, is a neglected intervention in the West [114]. This inter- RCT, randomized controlled trial.

vention was suggested and is commonly used in Japan in the


treatment of sepsis. A systematic review of the published
evidence included mostly trials conducted in Japan, and the large benefit of covering empirical antibiotic treatment
showed a significant reduction in all-cause mortality with [122]. Although colistimethate sodium has been given in com-
polymyxin B haemoperfusion in sepsis (risk ratio 0.50; bination with b-lactams in most cohorts to date, it is difficult
95% CI 0.37–0.68) among 354 patients in RCTs [115]. A to recommend combination treatment for bacteria suscepti-
more recent multicentre RCT conducted in Italy, including ble only to colistin , owing to concerns about further resis-
64 patients with severe sepsis or septic shock undergoing tance induction and because in vitro data have not been
emergency surgery for intra-abdominal infection, showed a translated into clinical benefit to date. Colistimethate sodium
similar reduction in all-cause mortality (adjusted hazard inhalation may be added to systemic antibiotic treatment in
ratio 0.36; 95% CI 0.16–0.80) [116]. As expected, haemody- the treatment of VAP, although the clinical benefit of this
namic parameters improved. Although the last RCT was intervention is not proven. Given the lack of other treatment
stopped for benefit at the first interim analysis, there is options, intrathecal or intraventricular colistimethate sodium
probably a place for further RCTs to establish the safety and should be considered for patients with meningitis caused by
effects of polymyxin B haemoperfusion in severe sepsis with carbapenem-resistant Gram-negative bacteria.
contemporary critical care. In Table 2 we summarize the studies that we believe are
needed to further define the place of colistimethate sodium
in clinical practice. The urgent need for such trials is empha-
Implications for Practice and Further
sized by the increased mortality rate with tigecycline, one of
Research
the few other antibiotic options for the treatment of carba-
penem-resistant Enterobacteriaceae, in RCTs [123]. Perhaps
Colistimethate sodium should be given to patients with infec- most importantly, methods to prevent the emergence and
tions caused by Gram-negative bacteria susceptible only to spread of MDR Gram-negative bacteria should be devised
colistin . Colistimethate sodium should not be used to treat and implemented.
infections caused by bacteria susceptible to b-lactams or qui-
nolones; currently available studies point to a higher mortality
Transparency Declaration
rate with colistimethate sodium, especially among bacterae-
mic patients and with infections caused by carbapenem-resis-
tant K. pneumoniae [80,81,117]. It is impossible to comment None to declare.
on the choice between colistimethate sodium and aminogly-
cosides when bacteria are susceptible to both. As for colisti-
Supporting Information
methate sodium, there is not enough evidence on
aminoglycoside monotherapy in sepsis and bacteraemia
[118,119], and observational studies point at inferiority vs. b- Additional Supporting Information may be found in the
lactams [120]. Empirical treatment with colistimethate sodium online version of this article:
should be considered for patients at high risk for infection by Table S1. Definitions of renal failure in clinical studies
carbapenem-resistant bacteria with severe sepsis [121], given evaluating colistin.

ª2011 The Authors


Clinical Microbiology and Infection ª2011 European Society of Clinical Microbiology and Infectious Diseases, CMI, 18, 18–29
26 Clinical Microbiology and Infection, Volume 18 Number 1, January 2012 CMI

Please note: Wiley-Blackwell are not responsible for the at: http://www.eucast.org/clinical_breakpoints (last accessed 1
December 2011).
content or functionality of any supporting materials supplied
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