ARTICLE In vitro activity of daptomycin in combination with low-dose colistin against a diverse collection of Gram-negative bacterial pathogens L. Phee & M. Hornsey & D. W. Wareham Received: 25 February 2013 / Accepted: 27 March 2013 / Published online: 23 April 2013 # Springer-Verlag Berlin Heidelberg 2013 Abstract The activity of colistin in combination with daptomycin was assessed using 30 Gram-negative type strains and multidrug-resistant isolates with defined mechanisms of resistance. Daptomycin minimum inhibitory concentrations (MICs) were determined with and without sub-inhibitory con- centrations of colistin. The activity of daptomycin was not affected with respect to Escherichia coli , Klebsiella pneumoniae or Pseudomonas aeruginosa. For colistin- susceptible Acinetobacter baumannii, sensitisation factors ranged from 8 to 128 (median 32), with the daptomycin MIC being reduced to the Clinical and Laboratory Standards Institute (CLSI) enterococci susceptibility breakpoint of 4 μg/ml for the ATCC 19606 type strain. A combination of daptomycin and colistin may be useful for the treatment of A. baumannii but not infections due to other Gram-negative species. Introduction The emergence and spread of antimicrobial resistance amongst bacterial pathogens presents major challenges for the practice of modern medicine. In recent years, the problem has gained increasing attention due to a paucity of new agents available for clinical use, combined with the lack of com- pounds in the later stages of development. The problem is especially acute with respect to the treatment of Gram- negative bacterial infections, where the rise of multidrug- resistant (MDR) and pandrug-resistant organisms threatens to render common infections untreatable [1]. Clinicians are resorting to the use of older agents such as polymyxins, which had previously fallen out of routine use due to concerns over toxicity, or employing unorthodox combinations of licensed drugs in the hope that this might bridge the current develop- mental gap. The potential to exploit the properties of cationic peptide- like molecules, either those already in use as antimicro- bials (polymyxins) or by the construction of novel analogues (e.g. polymyxin nonapeptide, NAB 739, 741 and 7061) [2], has been highlighted by a number of groups [ 3]. Colistin (polymyxin E) retains good in vitro activity against most Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii , including MDR strains [4]. Although colistin is increasingly used as a last-resort treat- ment, there are concerns over its efficacy, toxicity and poten- tial to drive resistance when used as a monotherapy [5]. The antimicrobial activity of colistin is thought to be mediated via an electrostatic interaction with components of bacterial lipo- polysaccharide (lipid A), leading to depolarisation and disrup- tion of the outer membrane, and subsequent cell death via osmotic lysis and the generation of toxic hydroxyl radicals [6]. At high concentrations, colistin is rapidly bactericidal, while its effects on the outer membrane at lower concentrations serve to permeabilise Gram-negative bacteria to com- pounds that are usually excluded. These include hydro- phobic drugs such as rifampicin, macrolides [ 7] and glycopeptides (including, telavancin) [8], compounds that are usually inactive against Gram-negative bacteria alone but show potent synergistic activity when combined with colistin. The results of this study were presented at the 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, California, USA, September 2012. L. Phee : M. Hornsey : D. W. Wareham Antimicrobial Research Group, Centre for Immunology and Infectious Disease, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University London, Blizard Building, 4 Newark Street, Whitechapel, London E1 2AT, UK L. Phee : D. W. Wareham (*) Division of Infection, Barts Health NHS Trust, London E1 2ES, UK e-mail: d.w.wareham@qmul.ac.uk Eur J Clin Microbiol Infect Dis (2013) 32:1291–1294 DOI 10.1007/s10096-013-1875-z