Carbapenem resistance, mainly among Gram-negative pathogens, is an ongoing public-health problem of global dimensions. This type of antimicrobial resistance, especially when mediated by transferable carbapenemase-encoding genes, is spreading rapidly causing serious outbreaks and dramatically limiting treatment options. In this article, important key points related to carbapenem resistance are reviewed and future perspectives are discussed.

Mutations in crrAB genes encoding a two-component regulator involved in modifications of lipopolysaccharide were searched for among a collection of colistin-resistant Klebsiella pneumoniae isolates. Four isolates, respectively, producing carbapen-emases NDM-1, OXA-181, or KPC-2 showed mutated CrrB proteins compared with those in wild-type strains. Complementation assays with a wild-type CrrB protein restored the susceptibility to colistin in all cases, confirming the involvement of the identified substitutions in the resistance phenotype.

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF). In a retrospective, real-world study across seven Greek hospitals, we evaluated the effectiveness and safety of nintedanib in routine clinical practice. Patients diagnosed with IPF, as per guideline criteria or multidisciplinary diagnosis, received nintedanib between January 2013 and January 2018.We evaluated 244 patients: mean±sd age 71.8±7.5 years, 79.1% male, 45.1% current smokers and 33.1% ex-smokers at treatment initiation. At baseline, predicted forced vital capacity (FVC) was 73.3±20.7% and predicted diffusing capacity of the lungs for carbon monoxide (DLCO) was 42.6±16.7%. On average, patients spent 23.6±15.0 months on nintedanib. At 3 years, 78 patients had died, equating to a 3-year survival rate of 59.4% (unaffected by treatment discontinuation or dose reduction). FVC% pred and DLCO% pred were largely stable at 3 years, with no significant difference from baseline (FVC 73.3±20.7% pred versus 78±20.1% pred, p=0.074; DLCO 42.6±16.7% pred versus 40.4±18.1% pred, p=0.334). Of the 244 patients, 55.7% reported an adverse event. Gastrointestinal events were the most common (173 (77.2%) out of 224 total events) and 45.0% of patients experienced diarrhoea. Only 32 (13.1%) patients had to permanently discontinue nintedanib due to an adverse event.This real-world study shows a 3-year survival rate of 59.4% and a low discontinuation rate due to adverse events. Our experience is consistent with previous findings in clinical trials of nintedanib in IPF.

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative nosocomial pathogens commonly carry one carbapenemase gene conferring resistance to carbapenems and other beta-lactam antibiotics. However, increasing reports show that double-carbapenemase-producing (DCP) and even multi-carbapenemase-producing (MCP) bacteria are emerging in some parts of the world, diminishing further, in some cases, the already limited treatment options. In the present review, the up-to-date reports of DCP and MCP isolates are summarized and concerns regarding their emergence are discussed.

tion of additional mechanisms or is a consequence of mutational events under selective pressure. 2. Intrinsic resistance of Pseudomonas aeruginosa P. aeruginosa shows inherent resistance to antimicrobial agents through a variety of mechanisms: (1) decreased permeability of the outer membrane, (2) efflux systems which actively pump antibiotics out of the cell, and (3) production of antibiotic-inactivating enzymes [6]. 2.1. Outer membrane permeability The outer membrane of Gram-negative bacteria is a barrier which prevents large hydrophilic molecules to pass through it. Aminoglycosides and colistin interact with lipopolysaccharides changing the permeability of the membrane in order to pass whereas beta-lactams and quinolones need to diffuse through certain porin channels. Bacteria produce two major classes of porins: general; which allow almost any hydrophilic molecule to pass [7] and specific; which have binding sites for certain molecules, allowing them to be oriented and pass in the most energy-efficient way [8]. Most bacteria posses lots of general porins and relatively few specific ones. However, the exact opposite occurs for P. aeruginosa that expresses mainly specific porins [7]. 2.2. Efflux systems P. aeruginosa expresses several efflux pumps that expel drugs together with other substances out of the bacterial cell. These pumps consist of three proteins: (1) a protein transporter of the cytoplasmatic membrane that uses energy in the form of proton motive force, (2) a periplasmic connective protein, and (3) an outer membrane porin [5]. Most antibiotics-except polymyxins-are pumped out [9,10] by these efflux systems (Table 1) therefore their first two components are named multidrug efflux (Mex) along with a letter (e.g. MexA and MexB). The outer membrane porin is called Opr along with a letter (e.g. OprM) [11]. 2.3. Antibiotic-inactivating enzymes P. aeruginosa belongs to the SPICE group of bacteria (Serratia spp., P. aeruginosa, Indole positive Proteus, Citrobacter spp., Enterobacter spp.). These microorganisms share a common characteristic: the ability to produce chromosomal-encoded and inducible AmpC beta-lactamases. These are cephalosporinases that hydrolyze most beta-lactams and are not inhibited by the beta lactamase inhibitors. Another endogenous beta-lactamase produced by P. aeruginosa is the class D oxacillinase PoxB [12,13]. This enzyme however has only been found in laboratory mutants and is not clinically significant.