Trends of Antimicrobial Resistance and Combination Susceptibility Testing of Multidrug-Resistant Pseudomonas aeruginosa Isolates from Cystic Fibrosis Patients: a 10-Year Update

Abstract

Antimicrobial combination therapy is a time/resource-intensive procedure commonly employed in the treatment of cystic fibrosis (CF) pulmonary exacerbations caused by Pseudomonas aeruginosa Ten years ago, the most promising antimicrobial combinations were proposed, but there has since been the introduction of new β-lactam plus β-lactamase inhibitor antimicrobial combinations. The aims of this study were to (i) compare in vitro activity of these new antimicrobials with other antipseudomonal agents and suggest their most synergistic antimicrobial combinations and (ii) determine antimicrobial resistance rates and study inherent trends of antimicrobials over 10 years. A total of 721 multidrug-resistant P. aeruginosa isolates from 183 patients were collated over the study period. Antimicrobial susceptibility and combination testing were carried out using the Etest method. The results were further assessed using the fractional inhibitory concentration index (FICI) and the susceptible breakpoint index (SBPI). Resistance to almost all antimicrobial agents maintained a similar level during the studied period. Colistin (P < 0.001) and tobramycin (P = 0.001) were the only antimicrobials with significant increasing isolate susceptibility, while an increasing resistance trend was observed for levofloxacin. The most active antimicrobials were colistin, ceftolozane-tazobactam, ceftazidime-avibactam, and gentamicin. All combinations with β-lactam plus β-lactamase inhibitors produced some synergistic results. Ciprofloxacin plus ceftolozane-tazobactam (40%) and amikacin plus ceftazidime (36.7%) were the most synergistic combinations, while colistin combinations gave the best median SBPI (50.11). This study suggests that effective fluoroquinolone stewardship should be employed for CF patients. It also presents in vitro data to support the efficacy of novel combinations for use in the treatment of chronic P. aeruginosa infections.

Keywords: Etest; Pseudomonas aeruginosa; antimicrobial susceptibility testing; cystic fibrosis; synergy testing.

FIG 1

Resistance profile of study isolates to antimicrobial groups. Antimicrobial agents in the aminoglycoside group are amikacin, gentamicin, and tobramycin. Levofloxacin and ciprofloxacin are grouped as fluoroquinolones, while aztreonam, ceftazidime, meropenem, and imipenem are grouped as the β-lactams. Also included in this group are β-lactam combinations, piperacillin-tazobactam, ceftazidime-avibactam, ticarcillin-clavulanate, and ceftolozane-tazobactam.

FIG 2

Pseudomonas aeruginosa MIC susceptibility patterns to tested antimicrobials. Percentage of susceptible isolates are represented by green bars while orange and blue bars represent Intermediate and resistant isolates. Pip/Tazo, piperacillin-tazobactam; Tic/Clav, ticarcillin-clavulanate; Ceft/Tazo, ceftolozane-tazobactam; Cef/Avi, ceftazidime-avibactam.