Colistin Combined With Tigecycline: A Promising Alternative Strategy to Combat Escherichia coli Harboring blaNDM–5 and mcr-1

Abstract

Infections due to carbapenem-resistant NDM-producing Escherichia coli represent a major therapeutic challenge, especially in situations of pre-existing colistin resistance. The aim of this study was to investigate combinatorial pharmacodynamics of colistin and tigecycline against E. coli harboring bla NDM-5 and mcr-1, with possible mechanisms explored as well. Colistin disrupted the bacterial outer-membrane and facilitated tigecycline uptake largely independent of mcr-1 expression, which allowed a potentiation of the tigecycline-colistin combination. A concentration-dependent decrease in colistin MIC and EC 50 was observed with increasing tigecycline levels. Clinically relevant concentrations of colistin and tigecycline combination significantly decreased bacterial density of colistin-resistant E. coli by 3.9 to 6.1-log 10 cfu/mL over 48 h at both inoculums of 10 6 and 10 8 cfu/mL, and were more active than each drug alone (P < 0.01). Importantly, colistin and tigecycline combination therapy was efficacious in the murine thigh infection model at clinically relevant doses, resulting in >2.0log 10 cfu/thigh reduction in bacterial density compared to each monotherapy. These data suggest that the use of colistin and tigecycline combination can provide a therapeutic alternative for infection caused by multidrug-resistant E. coli that harbored both bla NDM-5 and mcr-1.

Clinical Efficacy and Nephrotoxicity of the Loading Dose Colistin for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients

“…Many recent studies have also shed light on the pharmacodynamic (PD) and pharmacokinetic (PK) aspects of colistin. The colistin's PD profile is summarized as concentration dependent [18][19][20], so the ratio of area under the curve to the MIC (AUC/MIC ratio) is the best PK-PD parameter to reflect the effectiveness profile of colistin, particularly if the therapeutic goal is 50 to 65 mg h/L [18,21,22].…”

Current Update on Intrinsic and Acquired Colistin Resistance Mechanisms in Bacteria

“…Another technique tends to be the standard strategy that involves effective colistin administration and the possible use of combination therapies with additional agents to produce synergistic associations. These agents can include antibiotics that are typically restricted for use against Gram-positive bacteria, such as amikacin ( 228 , 229 ), aztreonam ( 229 ), rifampin ( 230 ), azithromycin ( 230 , 231 ), clarithromycin ( 232 ), linezolid ( 230 ), azidothymidine ( 233 ), tigecycline ( 234 ), and derivatives of tryptamine ( 235 ). Natural products can also be used to act as adjuvants, some of which might interact with LPSs, such as pentamidine and meridianine D analogs, to disturb the outer bacterial membrane ( 236 , 237 ).…”

Pharmacodynamic Target Assessment and PK/PD Cutoff Determination for Gamithromycin Against Streptococcus suis in Piglets

“…The plasma membrane permeability of S. suis cells in broth and serum matrices was measured using a 1-N-phenylnaphthylamine (NPN) uptake assay as previously established ( 20 , 21 ). Bacterial cells from a mid-log phase culture were resuspended in PBS to an OD 600nm of 0.5 and inoculated into porcine serum and MHB supplemented with 25%, 50%, and 75% serum.…”