Heteroresistance to Colistin in Multidrug-Resistant Acinetobacter baumannii

Abstract

Multidrug-resistant Acinetobacter baumannii has emerged as a significant clinical problem worldwide and colistin is being used increasingly as "salvage" therapy. MICs of colistin against A. baumannii indicate its significant activity. However, resistance to colistin in A. baumannii has been reported recently. Clonotypes of 16 clinical A. baumannii isolates and ATCC 19606 were determined by pulsed-field gel electrophoresis (PFGE), and colistin MICs were measured. The time-kill kinetics of colistin against A. baumannii ATCC 19606 and clinical isolate 6 were investigated, and population analysis profiles (PAPs) were conducted. Resistance development was investigated by serial passaging with or without exposure to colistin. Five different PFGE banding patterns were found in the clinical isolates. MICs of colistin against all isolates were within 0.25 to 2 g/ml. Colistin showed early concentration-dependent killing, but bacterial regrowth was observed at 24 h. PAPs revealed that heteroresistance to colistin occurred in 15 of the 16 clinical isolates. Subpopulations (<0.1% from inocula of 10 8 to 10 9 CFU/ml) of ATCC 19606, and most clinical isolates grew in the presence of colistin 3 to 10 g/ml. Four successive passages of ATCC 19606 in broth containing colistin (up to 200 g/ml) substantially increased the proportion of the resistant subpopulations able to grow in the presence of colistin at 10 g/ml from 0.000023 to 100%; even after 16 passages in colistin-free broth, the proportion only decreased to 2.1%. This represents the first demonstration of heterogeneous colistin-resistant A. baumannii in "colistinsusceptible" clinical isolates. Our findings give a strong warning that colistin-resistant A. baumannii may be observed more frequently due to potential suboptimal dosage regimens recommended in the product information of some products of colistin methanesulfonate.

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

“…Several investigators have reported heteroresistance to colistin in A. baumannii, which has been supposed to cause the emergence of colistin resistance by exposure to colistin [68][69][70]. Heteroresistance is generally defined as a case in which subpopulations of antibiotic-susceptible bacteria show resistance to certain antibiotics [71].…”

Indications of carbapenem resistance evolution through heteroresistance as an intermediate stage in Acinetobacter baumannii after carbapenem administration

“…Heteroresistance, which may be defined as a phenotypic manifestation of resistance within a genetically homogeneous strain 10 , has only rarely been described in Gram-negative bacteria [6][7][8][9] . Although authors are not certain about the clinical impact of this resistance phenotype in Gramnegative rods, our report suggests that heteroresistance may adversely affect the outcome of patients, since the A. baumannii isolate was recovered from the blood of a patient receiving meropenem therapy.…”

New Theoretical Background for Tuberculosis Treatment

“…However, pulmonary infections do not always respond well to such systemic therapy, due to insufficient drug diffusion into pulmonary tissue and lume [8]. Bacteria that have persisted over treatment may develop resistance, but higher drug doses to compensate for poor diffusion may lead to systemic toxicity.…”