Colistin: An Update on the Antibiotic of the 21st Century

Table 1. Antimicrobial activity of colistin against pathogenic bacteria from clinical isolates showing proportion of susceptible and resistant isolates in different studies conducted in countries (starting from recent years).
Bacteria (no. of isolates)	Country	Year	S/R (%)	Interpretative criteria	Ref.
Acinetobacter baumannii (46)	Bolivia	2012	100.0/0.0	CLSI	[179]
A. baumannii (75)	Argentina	2011	100.0/0.0	CLSI	[180]
A. baumannii (66) Pseudomonas aeruginosa (102)	Canada	2011	94.0/6.0 88.2/11.8	CLSI	[181]
Salmonella spp. (37)	India	2011	44.1/45.9	CLSI	[182]
A. baumannii (88)	Iran	2011	97.7/2.3		[183]
A. baumannii (45)	Italy	2011	100.0/0.0	CLSI	[184]
A. baumannii (250)	Kuwait	2011	88.0/12.0		[185]
A. baumannii (16)	Poland	2011	100.0/0.0		[186]
Acinetobacter spp. (4686) Klebsiella spp. (9774) P. aeruginosa (9130)	SENTRY study	2011	98.6/1.4 98.5/1.5 99.6/0.4	CLSI	[187]
P. aeruginosa (448)	Spain	2011	99.4/0.6	EUCAST	[188]
A. baumannii (32)	Taiwan	2011	97.0/3.0	EUCAST	[171]
A. baumannii (100)	Thailand	2011	97.0/3.0		[189]
Klebsiella pneumoniae (52)	Tunisia	2011	87.0/13.0	EUCAST	[190]
K. pneumoniae (10)	Greece	2010	90.0/10.0	CLSI	[191]
K. pneumoniae (116)	Greece	2010	72.4/27.6		[192]
P. aeruginosa (315)	Scotland	2010	84.0/16.0	CLSI	[193]
A. baumannii (780) P. aeruginosa (703)	USA	2010	99.9/0.1 99.8/0.2	CLSI	[194]
K. pneumoniae (88)	Israel	2009	95.5/4.5	CLSI	[195]
A. baumannii (30)	SENTRY study	2009	96.7/3.3	CLSI	[84]
P. aeruginosa + A.baumannii (228)	Spain	2009	60.0/40.0 98.8/1.2	CLSI	[196]
A. baumannii (185)	Taiwan	2009	99.0/1.0		[197]
Acinetobacter spp. (124)	Turkey	2009	72.5/27.5	CLSI	[198]
P. aeruginosa (419)	Canada	2008	96.0/4.0	CLSI	[199]
P. aeruginosa (230)	India	2008	61.7/38.3	CLSI	[200]
A. baumannii (107)	Italy	2008	99.0/1.0	CLSI	[201]
K. pneumoniae (55)	Thailand	2008	92.7/7.3		[202]
A. baumannii + P. aeruginosa (11)	Chile	2007	91.0/9.0		[203]
A. baumannii (55)	Korea	2007	90.9/9.1	CLSI	[204]
A. baumannii (142)	USA	2007	97.9/2.1	CLSI	[205]
A. baumannii (73)	Brazil	2006	97.0/3.0	CLSI	[206]
A. baumannii (18)	Bulgaria	2006	83.3/16.7	CLSI	[207]
K. pneumoniae (98) A. baumannii (100)	Greece	2006	84.7/15.3 97.0/3.0	CLSI	[208]
P. aeruginosa (33) K. pneumoniae (16) Acinetobacter spp. (18)	Singapore	2006	67.0/33.0 94.0/6.0 100/0.0	CLSI	[209]
P. aeruginosa (16)	Australia	2005	50.0/50.0	CLSI	[210]
P. aeruginosa (59)	Scotland	2004	60.0/40.0	CLSI	[211]
P. aeruginosa (417)	UK	2003	96.9/3.1	BSAC	[78]
P. aeruginosa (385)	Germany	2002	41.8/58.2	DIN	[65]
Acinetobacter spp. (60) K. pneumoniae (9) P. aeruginosa (80)	SENTRY study	2001	96.7/3.3 100.0/0.0 100.0/0.0	CLSI	[212]
A. baumannii (85)	Czech Republic	1999	94.1/5.9		[213]

BSAC: British Society of Antimicrobial Chemotherapy guidelines; CLSI: Clinical and Laboratory Standard Institute; DIN: German Deutsches Institut für Normung; EUCAST: European Committee on Antimicrobial Susceptibility Testing; SENTRY: Antimicrobial surveillance program including Asia-Pacific, Europe, Latin America and the USA/Canada; S/R: Proportion of susceptible (S) and resistant (R) isolates.

Table 2. Summary of polymyxin resistance mechanisms in different pathogenic bacteria.
Mechanism of polymyxin resistance	Bacteria	Ref.
LPS alteration	Escherichia coli, Salmonella, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii	[86,91,94–96,98,104,105,120,213]
Mutations in the pmrA and pmrB genes and two-component signaling proteins	A. baumannii	[86,104,105,120]
Mutations in lpxA, lpxC and lpxD induces loss of the lipid A component of lipopolysaccharide	A. baumannii	[102,103]
Role of OprH, an outer membrane protein altered	P. aeruginosa	[106,111,214]
Changes in negatively charged surface LPS induced by the regulatory loci pmrA and phoP	Enterobacteriaceae	[54]
Resistance by mutation in pmrA and PmrB genes	Salmonella	[119,215]

LPS: Lipopolysaccharide.

Table 3. Results of *in vitro* studies carried out for synergy in combinations of drugs with polymyxins.
Study (year)	Organism (n)	Polymyxin studied	Method	Drug combined	Synergy	Ref.
Liang et al. (2011)	Acinetobacter baumannii (14)	Colistin	Time-kill study	Meropenem Minocycline Rifampicin	100 100 100	[168]
Sheng et al. (2011)	Acinetobacter spp. (17)	Colistin	Time-kill study Checkerboard	Imipenem Imipenem	75–100 42–100	[171]
Wareham et al. (2011)	A. baumannii (6)	Colistin	Time-kill study Checkerboard	Teichoplanin Teichoplanin	100 100	[178]
Souli et al. (2011)	Klebsiella pneumonia (17)	Colistin	Time-kill study	Fosfomycin	11.8	[216]
Gordon et al. (2010)	A. baumannii (39)	Colistin	Etest	Vancomycin	100	[156]
Elemam et al. (2010)	K. pneumonia (12)	PMB	Checkerboard	Rifampicin Doxycycline Tigecycline	100 100 100	[162]
Pankey et al. (2009)	A. baumannii (8)	PMB	Time-kill study Etest	Meropenem Meropenem	100 63	[217]
Principe et al. (2009)	A. baumannii (22)	Colistin	Checkerboard	Tigecycline	8.3	[218]
López et al. (2008)	Pseudomonas aeruginosa (12)	Colistin	Checkerboard	Doxycycline Rifampicin Azithromycin	66.6 16.6 25	[219]
Tan et al. (2007)	A. baumannii (13)	Colistin	Time-kill study	Minocycline	92	[220]
Li et al. (2007)	A. baumannii (8)	Colistin	Checkerboard	Rifampicin	100	[169]
Timurkaynak et al. (2006)	P. aeruginosa (5)	Colistin	Checkerboard	Rifampicin Meropenem Azithromycin	40 0 0	[221]
	A. baumannii (5)	Colistin	Checkerboard	Rifampicin Meropenem Azithromycin	80 60 60
Bolmstrom et al. (2005)	A. baumannii (6)	Colistin	Checkerboard	Rifampicin	100	[170]
Landman et al. (2005)	P. aeruginosa (10)	PMB	Time-kill study	Rifampicin Imipenem Azithromycin	90 80 40	[222]
Tascini et al. (2004)	P. aeruginosa (7)	Colistin	Checkerboard	Rifampicin	14	[223]
Gunderson et al. (2003)	P. aeruginosa (2)	Colistin	Time-kill study	Ceftazidime Ciprofloxacin	100 0	[87]
Hogg et al. (1998)	A. baumannii (13)	Colistin	Checkerboard	Rifampicin	85	[165]

PMB: Polymyxin B.

Sidebar

Key Issues

Colistin was one of the first antibiotics with significant activity against multidrug-resistant (MDR) Gram-negative pathogens, such as Pseudomonas aeruginosa, Acinetobacter baumanniiand Klebsiella pneumoniae.
There are two forms of colistin available in the market: colistin sulfate (tablets or syrup for oral use and powder for topical use) and colistin methanesulfonate (colistimethate sodium [CMS]) for parenteral use.
Although CMS is the form administered parenterally, CMS undergoes conversion in vivoto colistin (formed colistin). Thus, formed colistin is active against MDR bacteria and CMS is an inactive prodrug.
Colistin displaces divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents and bacterial death.
The Clinical and Laboratory Standards Institute has recently revised the colistin interpretative criteria for P. aeruginosaand other non-Enterobacteriaceae, with a MIC ≥8 mg/l recommended as the cutoff to define resistance.
Isolates of Inquilinus, Pandoraeaand Burkholderiaassociated with cystic fibrosis are intrinsically resistant to colistin. Proteusspp., Providenciaspp., Morganella morganiiand Serratia marcescensare also resistant to polymyxin.
The most common mechanisms of resistance to colistin are modifications to lipopolysaccharide.
Nephrotoxicity is by far the most common adverse effect of polymyxins.
Although the use of colistin is considered to be effective, other antibiotics are often used in combination with colistin. Many studies have shown good outcomes for patients treated with colistin alone or in combination with other antimicrobials for pneumonia cases.
Combination therapy with rifampicin and polymixin is one of the most discussed alternatives for the treatment of MDR Gram-negative bacterial infection.
The usefulness of colistin has been clearly documented and we believe that colistin will be the 'last-line' therapeutic drug against MDR Gram-negative pathogens in the 21st century.