Resistance

Though resistance rates against colistin are in general still low, infection due to colistin-resistant Enterobacteriacae is a rising challenge in some countries with high usage of colistin. Resistance to colistin is increasingly reported among KPC producing Klebsiella strains. The correlation of excessive use of colistin (due to the frequent isolation of MDR pathogens in a Greek ICU) with the emergence of colonization with colistin-resistant K. pneumoniae and occurence of various infections with colistin-resistant Gram negative bacteria has been shown in a Greek study. 35% of clinical strains of K. pneumoniae (G. Lamprini et al ECCMID 2011). Similarly, in Italy 36% of carbapenem-resistant K. pneumoniae were also colistin-resistant. The high rate of resistance to colistin that was independently associated with worse outcome in this study (A Capone et al. 2012). Even in countries with low resistance issues like UK resistance to colistin in K. pneumoniae appears to be a slowly emerging problem (R Hill et al. ECCMID 2012, P1191)

The development of resistance during treatment with colistin has been reported in K. pneumoniae and other enterobacteriaceae caused by selective pressure due to excessive and prolonged or inadequate colistin use, usually sub optimal dosage. Breakthrough infections with organisms intrinsically resistant to colistin and development of resistance to colistin in subsequent carbapenem resistant isolates are of concern.

Colistin is the last resort for treatment of multidrug-resistant Acinetobacter baumannii. Resistance to colistin has been reported all over the world with the highest resistance rate in some Asian and European countries (up tp 40%). Rates of heteroresistance (subpopulations within the strain exhibit reduced susceptibility although the overall MIC is not altered) are usually higher than the resistance rate.

The European FP7 funded project AIDA (PRESERVING OLD ANTIBIOTICS FOR THE FUTURE) will study the potential of resistance development during therapy with colistin mono vs colistin combination with meropenem. So far clinical evidence is lacking.

In vitro

In vitro several studies show a regrowth of cultures after a rapid killing phase indicating selection of subpopulations with reduced susceptibility. This process is readily apparent in heteroresistant strains.

Microbiological responses observed in the in vitro PK/PD model against two colistin-heteroresistant strains of Acinetobacter baumannii. simulating the colistin PKs of different dosing regimens (C-H. Tan et al 2007):

Colistin resistance in vitro

Regimen 1 (maximum concentration of drug in plasma [Cmax], 3 μg/ml),
regimen 2 (Cmax, 4.5 μg/ml),
regimen 3 (Cmax, 9 μg/ml),
regimen 4 (continuous maintenance of 4.5 μg/ml).

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