June issue of IJAA
Read the latest issue of IJAA and the two Editor's Choice articles which are free to read for a limited time:
Infections caused by multidrug-resistant (MDR) Klebsiella pneumoniae are a current challenge for clinicians. Polymyxins (Polymyxin B and colistin) have shown efficacity against these difficult-to-treat bacteria but their use as monotherapy easily lead to acquired resistance, which suggest its use in combination. In this study, authors have tested the clinical effect of the combination of polymyxin B and minocycline, a tetracycline family drug, on MDR K. pneumoniae. They performed a PKPD modelling strategy to quantify the interaction between polymyxin B and minocycline by combining an in vitro static time-kill study and building an in-silico PK/PD model and predicted the clinical potential of the combination using Monte Carlo simulations. This model represents an interesting way to predict clinical efficacy of antibiotics especially old antibiotics (like minocycline and polymyxins) for which PK/PD models are lacking. In case of the studied association, the predicted clinical effects were moderate on the colistin and minocycline resistant K. pneumoniae used in this study and further works are needed to in vivo confirm the effect of the combination.
Antibiotics resistance mechanisms in Pseudomonas aeruginosa are generally complex and involved efflux pumps, regulation of gene transcription and various other gene mutations. Colistin resistance mechanisms are no exception. It always involves the overexpression of the arn operon, encoding for the synthesis of aminoarabinose and its fixation to lipid A (arn operon) but various regulator genes and two component systems act on the expression of the operon. Authors of this work have created recombinant mutant by constitutively activating the arn operon by replacing the promoter of the operon with the promoter of the housekeeping gene rpsA. Then, they studied variations in lipid A synthesis, effect of divalent cations (Ca++ et Mg++) on colistin resistance and fitness cost. Interestingly, no fitness costs were found to be associated with the presence of aminoarabinose on the OM. However, they find that lipid A aminoarabinosylation was not sufficient to confer colistin resistance, suggesting other mechanisms involved in the increase and the stabilization of this resistance. The role of PmrB and other regulator genes already known to activate the expression of the arn operon, could act on other genes to stabilize the effect of this aminoarabinosylation.