In Vitro Synergy of Colistin Combinations against Colistin-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates

Abstract

Colistin resistance, although uncommon, is increasingly being reported among Gram-negative clinical pathogens, and an understanding of its impact on the activity of antimicrobials is now evolving. We evaluated the potential for synergy of colistin plus trimethoprim, trimethoprim-sulfamethoxazole (1/19 ratio), or vancomycin against 12 isolates of Acinetobacter baumannii (n ‫؍‬ 4), Pseudomonas aeruginosa (n ‫؍‬ 4), and Klebsiella pneumoniae (n ‫؍‬ 4). The strains included six multidrug-resistant clinical isolates, K. pneumoniae ATCC 700603, A. baumannii ATCC 19606, P. aeruginosa ATCC 27853, and their colistin-resistant derivatives (KPm1, ABm1, and PAm1, respectively). Antimicrobial susceptibilities were assessed by broth microdilution and population analysis profiles. The potential for synergy of colistin combinations was evaluated using a checkerboard assay, as well as static time-kill experiments at 0.5؋ and 0.25؋ MIC. The MIC ranges of vancomycin, trimethoprim, and trimethoprim-sulfamethoxazole (1/19) were >128, 4 to >128, and 2/38 to >128/2,432 g/ml, respectively. Colistin resistance demonstrated little impact on vancomycin, trimethoprim, or trimethoprim-sulfamethoxazole MIC values. Isolates with subpopulations heterogeneously resistant to colistin were observed to various degrees in all tested isolates. In time-kill assays, all tested combinations were synergistic against KPm1 at 0.25؋ MIC and 0.5؋ MIC and ABm1 and PAm1 at 0.5؋ MIC. In contrast, none of the tested combinations demonstrated synergy against any colistin-susceptible P. aeruginosa isolates and clinical strains of K. pneumoniae isolates. Only colistin plus trimethoprim or trimethoprim-sulfamethoxazole was synergistic and bactericidal at 0.5؋ MIC against K. pneumoniae ATCC 700603. Colistin resistance seems to promote the in vitro activity of unconventional colistin combinations. Additional experiments are warranted to understand the clinical significance of these observations.

In Vitro Activity of Colistin and Trimethoprim/Sulfamethoxazole Against Consortia of Multidrug Resistant Non-Fermenting Gram-Negative Bacilli Isolated from Lower Respiratory Tract

“…The effect of colistin in antibiotic combination is based on its detergent-like property: it interacts with surface LPS A. baumannii 9 (45) 11 (55) and phospholipids, disturbing membrane permeability. Colistin exposure leads to increased permeability to large or hydrophobic compounds such as SXT (8). Synergic effect of colistin and SXT against S. maltophilia was found in 47% of isolates by Giamarellos-Bourboulis et al (13).…”

“…Stenotrophomonas maltophilia isolates were tested in 7 doubling dilutions of colistin and 11 doubling dilutions of SXT, whereas P. aeruginosa and A. baumannii strains were tested in 7 doubling dilutions of SXT and 11 doubling dilutions of colistin. Microbroth plates When synergy was detected by CB, a time-kill assay (TKA) was performed at 1xMIC following a previously published method (8). When MICs were above the therapeutic level, SXT was used at 8 mg/L and colistin at 4 mg/L, which fits the peak serum levels of these agents (9).…”

An Unusual Antibiotic Combination Therapy for Treatment of Colistin Resistant Acinetobacter baumannii: Trimethoprim-Sulfamethoxazole and Colistin Combination

“…Vidaillac ve ark. (28) yaptıkları in vivo çalışmada kolistin dirençli A.baumannii, Pseudomonas aeruginosa ve Klebsiella pneumoniae suşlarında kolistin-SXT kombinasyonunun sinerjik etki gösterdiğini tespit etmiştir. ÇİD Acinetobacter spp.…”

“…Son yıllarda kolistin kullanımının artması ile birlikte kolistin direnci raporlanmaya başlanmıştır. Yapılan çalışmalarda kolistin dirençli A.baumannii suşlarında, bazı antibiyotiklerin kolistin ile kombinasyonunun sinerjistik etkili olduğu gösterilmiştir (6,21,28) . Kombinasyon tedavilerinde karbapenemler gibi bakteri hücre duvarına etki eden antibiyotiklerin yanı sıra, sıklıkla rifampin ve sulbaktam da tercih edilmektedir.…”

Antibiotic Resistance Profiles and Genotypes of <i>Acinetobacter baumannii</i> Isolates and <i>In Vitro</i> Interactions of Various Antibiotics in Combination with Tigecycline and Colistin

“…In a study conducted in 2012, it was emphasized that the use of inappropriate antibiotic combination increases CL resistance. 27 Principe et al 7 for the first time reported that they have noticed the synergy between TGC and CL by TK method in one A. baumannii isolate. In two studies conducted by CB method in TGC-CL combination 28 and in TGC-sulbactam, TGC-CL combinations 29 a synergistic effect was observed.…”