Lipopolysaccharide loss produces partial colistin dependence and collateral sensitivity to azithromycin, rifampicin and vancomycin in Acinetobacter baumannii

Old drug, new findings: colistin resistance and dependence of Acinetobacter baumannii

“…Because vancomycin-dependent isolates lack ligase activity because of muta- After Hawley et al [72], Garcia-Quintanilla et al [81] identified partial colistin dependence by using the E-test assay.…”

“…Genotypic analyses revealed that colistin dependence originated from the corresponding susceptible parental isolates, and no evidence of clonal dissemination of the isolates that developed colistin dependence was found. Colistin-dependent mutants have shown increased susceptibility to several antibiotics, such as carbapenems [72,81,82], which is the feature of LPS-deficient, colistin-resistant isolates [51,52]. Of note, patients with colistin-dependent strains have shown higher 3-and 7-day treatment failure than the patients without colistin-dependent strains [82].…”

Inhibition of LpxC Increases Antibiotic Susceptibility in Acinetobacter baumannii

“…Importantly, in this study, mice that were treated with an LpxC inhibitor were completed protected from A. baumannii infection (7). We recently reported that A. baumannii clinical isolates that acquire resistance to colistin via the loss of LPS due to mutations in the lipid A biosynthesis genes lpxA, lpxC, and lpxD demonstrate increased cell permeability and increased susceptibility to certain antibiotics (10). Based on these findings, we hypothesized that pharmacologic inhibition of LPS biosynthesis in A. baumannii with an LpxC inhibitor may similarly increase antibiotic susceptibility.…”

“…These antibiotics were chosen for checkerboard assays, as mutant strains deficient in LPS biosynthesis were previously shown to have increased susceptibility to vancomycin, rifampin, and azithromycin (10). Fractional inhibitory concentration indices (FICI) were calculated as previously described (14), and results were interpreted as follows: the synergistic effect was defined as a FICI of Յ0.5; partial synergism, as a FICI Ͼ0.5 but Ͻ1; additivity, as a FICI of 1; indifference, as a FICI of Ͼ1 but Յ4; and antagonism, as a FICI of Ͼ4.…”

Interacciones evolutivas como un posible mecanismo de interacción medicamentosa: una aproximación para el control de la resistencia bacteriana

“…Una vez establecida la resistencia a colistín, se observaron aumentos en la susceptibilidad de amikacina (4-16 veces), ceftazidima (4-64 veces), imipenem (4-32 veces), cefepime (0-8 veces) y meropenem (4-64 veces) dada la pérdida del lipopolisacárido. Los cambios más significativos se vieron, con respecto al valor basal, en azitromicina (> 32 veces), rifampicina (> 16 veces) y vancomicina (64-512 veces) 17 . Tugce y cols.…”