Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium

Abstract

Pseudomonas aeruginosa is a major cause of nosocomial infections. This organism shows a remarkable capacity to resist antibiotics, either intrinsically (because of constitutive expression of beta-lactamases and efflux pumps, combined with low permeability of the outer-membrane) or following acquisition of resistance genes (e.g., genes for beta-lactamases, or enzymes inactivating aminoglycosides or modifying their target), over-expression of efflux pumps, decreased expression of porins, or mutations in quinolone targets. Worryingly, these mechanisms are often present simultaneously, thereby conferring multiresistant phenotypes. Susceptibility testing is therefore crucial in clinical practice. Empirical treatment usually involves combination therapy, selected on the basis of known local epidemiology (usually a beta-lactam plus an aminoglycoside or a fluoroquinolone). However, therapy should be simplified as soon as possible, based on susceptibility data and the patient's clinical evolution. Alternative drugs (e.g., colistin) have proven useful against multiresistant strains, but innovative therapeutic options for the future remain scarce, while attempts to develop vaccines have been unsuccessful to date. Among broad-spectrum antibiotics in development, ceftobiprole, sitafloxacin and doripenem show interesting in-vitro activity, although the first two molecules have been evaluated in clinics only against Gram-positive organisms. Doripenem has received a fast track designation from the US Food and Drug Administration for the treatment of nosocomial pneumonia. Pump inhibitors are undergoing phase I trials in cystic fibrosis patients. Therefore, selecting appropriate antibiotics and optimising their use on the basis of pharmacodynamic concepts currently remains the best way of coping with pseudomonal infections.

The Use of Systemic and Topical Fluoroquinolones

“…20 In adult patients, Pseudomonas resistance to both fluoroquinolones and other antimicrobial agents is problematic. 21 Data on resistance in Escherichia coli isolated from adults with UTIs who were seen in emergency departments in the EMERGEncy ID NET, a network of 11 geographically diverse university-affiliated institutions, suggest a low but stable rate of resistance of approximately 5%, 22 although in specific locations, rates of resistance for outpatients are closer to 10%. 23,24 Similar published data do not exist for children, although in current reports that include outpatient data, stratified by age, rates of fluoroquinolone resistance in E coli in children have been generally well below 3%.…”

Multidrug resistant Pseudomonas aeruginosa infection in children undergoing chemotherapy and hematopoietic stem cell transplantation

“…[1][2][3][4][5] In a European survey of intensive care units, PA was the most frequent bacterial isolate accounting for 29% of the total isolates; 6 furthermore, its multi-resistance also represents an increasing problem. [7][8] The low permeability of its cell wall, together with mutations leading to antibiotic-resistance via overexpression of efflux pumps, decreased expression of porine, or mutations in quinolone targets, 8 make PA a pathogen with high propensity to become multi-resistant to antibiotic therapy. 9 Multi-resistant strains may be responsible for nosocomial outbreaks, especially among populations at risk such as patients with cancer or cystic fibrosis.…”

Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response

“…Pseudomonas pneumonia often results in sepsis and death (2,3) and, as a cause of ventilatorassociated pneumonia, P. aeruginosa has a high mortality compared with other pathogens (3). From a treatment perspective, P. aeruginosa is regarded as a problem pathogen due to its remarkable ability to resist antibiotics (4). Therefore, insight in factors involved in the host defense during P. aeruginosa pneumonia and sepsis could help identify possible new therapeutic targets in this severe infection.…”