Narcisa Mesaros

In vivo development of antimicrobial resistance in Pseudomonas aeruginosa strains isolated from the lower respiratory tract of Intensive Care Unit patients with nosocomial pneumonia and receiving antipseudomonal therapy.

Pseudomonas aeruginosa causes severe nosocomial pneumonia in Intensive Care Unit (ICU) patients, with an increased prevalence of multiresistant strains. We examined the impact of the use of antipseudomonal antibiotic(s) on the susceptibility of P. aeruginosa isolated from ICU patients with clinically suspected hospital-acquired pneumonia collected in five teaching hospitals (110 non-duplicate initial isolates; 62 clonal pairs of initial and last isolates during treatment). Minimum inhibitory concentrations (MICs) were determined for amikacin, ciprofloxacin, meropenem, piperacillin/tazobactam (TZP), cefepime and ceftazidime (used in therapy) as well as five reporter antibiotics (aztreonam, colistin, gentamicin, piperacillin and ticarcillin) using Clinical and Laboratory Standards Institute (CLSI) methodology. Susceptibility was assessed according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) and CLSI breakpoints. Resistance rates prior to treatment exceeded 25% for cefepime, ceftazidime, piperacillin, ticarcillin and aztreonam (EUCAST and CLSI) and for gentamicin, TZP and colistin (EUCAST only). The highest rates of cross-resistance were noted for ceftazidime and cefepime and the lowest rate for amikacin. Mean MIC values were systematically higher in isolates from patients previously exposed (1 month) to the corresponding antibiotic. For clonal pairs, a systematic increase in MIC between initial and last isolates (significant for amikacin, cefepime, meropenem and TZP) was noted. There was a significant correlation between the use of antibiotics (adjusted for respective proportional use of each drug) and loss of susceptibility at the population level when using EUCAST breakpoints. The high level of resistance of P. aeruginosa in ICU patients with nosocomial pneumonia as well as its further increase during treatment severely narrows the already limited therapeutic options. Further observational studies and the development of early diagnosis for resistant isolates are warranted.

Pseudomonas aeruginosa : résistance et options thérapeutiques à l’aube du deuxième millénaire☆

Pseudomonas aeruginosa is a major cause of nosocomial infections. Due to its genetic plasticity, it can adapt to a wide variety of environments, causing infections in almost all body sites (with however a predilection for the respiratory tract, especially in cystic fibrosis patients). It also shows a remarkable capacity to resist to antibiotics, either intrinsically (through constitutive expression of β-lactamases and efflux pumps, or low permeability of the outer membrane), or upon exposure to antibiotics through acquisition of resistance genes (coding fo antibiotic-degrading enzymes inactivating or target modifications), overexpression of efflux pumps, decreased expression of porins, or target mutations. Worryingly also, these mechanisms are often present simultaneously, conferring multiresistant phenotypes. Susceptibility testing is therefore crucial in clinical practice. Empiric treatment is usually initiated using a bitherapy, selected based on local epidemiology (β-lactam plus aminoglycoside or fluoroquinolone). However, it should be streamlined as soon as possible, based on susceptibility data and patient’s evolution. Alternative drugs (colistin, e.g.) have proven useful for multiresistant strains. Innovative therapeutic options for the future remain scarce, while attempts to develop vaccines have been so far unsuccessful. Among broad-spectrum antibiotics in development, ceftobiprole, sitafloxacin and doripenem show interesting in vitro activity. The two first molecules, however, are evaluated in the clinics towards Gram-positive only. Pump inhibitors are under study but proved much more difficult to develop than originally anticipated. Therefore, selecting appropriate antibiotics and optimizing their use based on pharmacodynamic concepts remains the only way to cope with pseudomonal infections.