Abstract
ObjectiveExtreme drug-resistant Pseudomonas aeruginosa (XDR-PA) with decreased susceptibility to polymyxin B (PB) has emerged in Singapore, causing infections in immunocompromised hosts. Combination therapy may be the only viable therapeutic option until new antibiotics become available. The objective of this study is to assess the in vitro activity of various antibiotics against local XDR-PA isolates.MethodsPA isolates from all public hospitals in Singapore were systematically collected between 2006 and 2007. MICs were determined according to CLSI guidelines. All XDR-PA isolates identified were genotyped using a PCR-based method. Time-kill studies (TKS) were performed with approximately 105 CFU/ml at baseline using clinically achievable unbound concentrations of amikacin (A), levofloxacin (L), meropenem (M), rifampicin (R) and PB alone and in combination. Bactericidal activity (primary endpoint) was defined as a ≥3 log10 CFU/ml decrease in the colony count from the initial inoculum at 24 hours.Results22 clinical XDR-PA isolates with PB MIC 2–16 µg/ml were collected. From clonal typing, 5 clonal groups were identified and nine isolates exhibited clonal diversity. In TKS, meropenem plus PB, amikacin plus meropenem, amikacin plus rifampicin, amikacin plus PB exhibited bactericidal activity in 8/22, 3/22, 1/22 and 6/22 isolates at 24 hours respectively. Against the remaining ten isolates where none of the dual-drug combination achieved bactericidal activity against, only the triple-antibiotic combinations of ARP and AMP achieved bactericidal activity against 7/10 and 6/10 isolates respectively.ConclusionBactericidal activity with sustained killing effect of ≥99.9% is critical for eradicating XDR-PA infections, especially in immunocompromised hosts. These findings underscore the difficulty of developing combination therapeutic options against XDR-PA, demonstrating that at least 3 antibiotics are required in combination and that efficacy is strain dependant.
Highlights
Antimicrobial resistance is increasing worldwide and is of particular concern in gram-negative bacilli (GNB) where there is a paucity of new and effective antimicrobial agents [1]
Antibiotic resistance mechanisms in P. aeruginosa include inducible ampC beta-lactamases, efflux pumps (MexAB-OprM), loss of porin channels (OprD) and aminoglycoside-modifying enzymes [5]. These mechanisms are often present simultaneously, thereby conferring extremely-drug resistant (XDR) phenotypes that are defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories [6]
Susceptibility studies Twenty-two XDR-PA isolates were identified from 608 isolates from the urinary tract, blood and respiratory tract
Summary
Antimicrobial resistance is increasing worldwide and is of particular concern in gram-negative bacilli (GNB) where there is a paucity of new and effective antimicrobial agents [1]. Antibiotic resistance mechanisms in P. aeruginosa include inducible ampC beta-lactamases, efflux pumps (MexAB-OprM), loss of porin channels (OprD) and aminoglycoside-modifying enzymes [5]. These mechanisms are often present simultaneously, thereby conferring extremely-drug resistant (XDR) phenotypes that are defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) [6]. Antibiotic-resistant P. aeruginosa is a major concern in Singaporean hospitals. In Singapore, polymyxin B (PB) is often prescribed as a last resort for XDR-P
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