In vitro activity of tigecycline against clinical isolates of carbapenem resistant Acinetobacter baumannii complex in Pretoria, South Africa

Abstract Background Rifabutin, an oral drug approved to treat Mycobacterium avium infections, demonstrated potent activity against Acinetobacter baumannii in nutrient-limited medium enabled by rifabutin cellular uptake through the siderophore receptor FhuE. Objectives To determine rifabutin in vitro activity and resistance mechanisms in a large panel of A. baumannii isolates. Methods Two hundred and ninety-three carbapenem-resistant A. baumannii clinical isolates collected from Europe, the USA and Asia during 2017–19 were used for MIC determination. Sequencing/genotyping of fhuE, rpoB and arr-2 genes in isolates with elevated rifabutin MIC combined with genetic engineering and gene expression quantification was used to characterize rifabutin’s mode of action and resistance mechanisms. Results Rifabutin showed excellent activity on the strain panel, with an MIC50/90 of 0.008/1 mg/L, and was superior to all other antibiotics tested, including colistin, tigecycline and cefiderocol (MIC90 of 8 mg/L). Rifabutin remained active on resistant subpopulations, including strains resistant to the siderophore–drug conjugate cefiderocol (MIC90 of 2 mg/L, n = 23). At least two independent resistance mechanisms were required to abolish rifabutin activity, which is in line with the dose-dependent mutational resistance frequency reaching 10−9 at rifabutin concentrations at or above 2 mg/L. Conclusions This study demonstrated the potent activity of rifabutin against carbapenem-resistant A. baumannii. We propose that FhuE-mediated active uptake of rifabutin enables activity against rifampicin-resistant isolates. To achieve clinically meaningful strain coverage and to avoid rapid resistance development, rifabutin concentrations ≥2 mg/L are required, something rifabutin oral formulations cannot deliver.

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Comparative in vitro activity of sitafloxacin against multidrug-resistant and carbapenem-resistant Acinetobacter baumannii clinical isolates in Thailand

Pharmaceutical Sciences Asia ◽

10.29090/psa.2020.01.019.0012 ◽

2020 ◽

Vol 47 (1) ◽

pp. 37-42 ◽

Cited By ~ 1

Author(s):

Taniya Paiboonvong ◽

Vipavee Rodjun ◽

Jantana Houngsaitong ◽

Mullika Chomnawang ◽

Preecha Montakantikul ◽

...

Keyword(s):

Acinetobacter Baumannii ◽

Multidrug Resistant ◽

Vitro Activity ◽

Clinical Isolates ◽

In Vitro Activity ◽

Carbapenem Resistant

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Comparative in vitro activity of sitafloxacin against bacteremic isolates of carbapenem resistant Acinetobacter baumannii complex

Journal of Microbiology Immunology and Infection ◽

10.1016/j.jmii.2014.02.002 ◽

2015 ◽

Vol 48 (5) ◽

pp. 545-551 ◽

Cited By ~ 2

Author(s):

Yu-Shan Huang ◽

Jann-Tay Wang ◽

Wang-Huei Sheng ◽

Yu-Chung Chuang ◽

Shan-Chwen Chang

Keyword(s):

Acinetobacter Baumannii ◽

Vitro Activity ◽

In Vitro Activity ◽

Carbapenem Resistant ◽

Acinetobacter Baumannii Complex

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681. In vitro Activity of the β-Lactamase Inhibitor QPX7728 in Combination with Several β-Lactams Against Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PSA)

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.749 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S310-S311 ◽

Cited By ~ 1

Author(s):

Olga Lomovskaya ◽

Jill Lindley ◽

Debora Rubio-Aparicio ◽

Kirk J Nelson ◽

Mariana Castanheira

Keyword(s):

Resistance Mechanisms ◽

Vitro Activity ◽

Clinical Isolates ◽

In Vitro Activity ◽

Microdilution Method ◽

Carbapenem Resistant ◽

Broth Microdilution Method ◽

Data Representative ◽

Lactamase Inhibitor

Abstract Background QPX7728 (QPX) is a novel broad-spectrum boron-containing inhibitor of serine- and metallo-β-lactamases (MBLs). We evaluated the in vitro activity of QPX combined with several β-lactams against carbapenem-resistant AB (CRAB) and PSA clinical isolates with varying β-lactam resistance mechanisms. Methods A total of 503 CRAB (meropenem [MEM] MIC ≥8 µg/mL) and 762 PSA clinical isolates were tested by the reference broth microdilution method against β-lactams alone and combined with QPX (4 µg/mL and 8 µg/mL). PSA isolates were selected to represent the normal distribution of MEM, ceftazidime–avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance according to 2017 surveillance data (representative panel). Additionally, 262 PSA isolates that were either nonsusceptible (NS) to MEM (MIC, ≥4 µg/mL) or to TOL-TAZ (MIC, ≥8 µg/mL), or resistant (R) to CAZ-AVI (MIC, ≥16 µg/mL) (challenge panel) were also tested. Within this 262 strain challenge set, 56 strains carried MBLs and the majority also had nonfunctional OprD. Results Against CRAB, QPX at 4 and 8 µg/mL increased the potency of all β-lactams tested. MEM-QPX was the most potent combination (table) displaying MIC50/MIC90 at 1/8 and 0.5/4 µg/mL with QPX at fixed 4 and 8 µg/mL, respectively. Susceptibility (S) to MEM was restored in >95% of strains. Against the 500 PSA from the representative panel, S for all QPX combinations was >90%. For the challenge panel, TOL-QPX and piperacillin (PIP)-QPX were the most potent combinations, restoring S in 76–77% of strains. TOL-QPX and MEM-QPX or cefepime (FEP)-QPX restored the MIC values to S rates when applying the CLSI breakpoint for the compound alone (comparison purposes only) in ~90% and ~75% of non-MBL-producing strains, respectively, vs. 60–70% for TOL-TAZ and CAZ-AVI. PIP-QPX reduce the MIC values to S values for PIP-TAZ in ~60% of MBL-producing strains vs. 20–30% and 3–7% for other QPX combinations and non-QPX tested combinations, respectively. Conclusion Combinations of QPX with various β-lactam antibiotics displayed potent activity against CRAB and resistant PSA isolates and warrant further investigation. Disclosures All authors: No reported disclosures.

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