Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin

Müller, Laura; Murgia, Xabier; Siebenbürger, Lorenz; Börger, Carsten; Schwarzkopf, Konrad; Sewald, Katherina; Häußler, Susanne; Braun, Armin; Lehr, Claus‐Michael; Hittinger, Marius; Wronski, Sabine

doi:10.1093/jac/dky241

Cited by 41 publications

(34 citation statements)

References 47 publications

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“…This explanation may, however, not apply to our study because TGN is supplemented by glucose, which upregulates the expression of the extracellular polysaccharide-related gene pslA, required for biofilm formation (24). Second, the addition of frozen mucus from patients with CF to preformed biofilms was shown to decrease the activity of tobramycin, which was related to a reduced transport of this polycationic drug in the biofilm (25) due to its strong ionic interactions with components of the biofilm matrix and/or mucus (26). Likewise, colistin strongly binds to mucin in vitro, which considerably decreases its activity (27).…”

Section: Discussionmentioning

confidence: 77%

Activity of Antibiotics against Pseudomonas aeruginosa in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture Medium

Iglesias

Bambeke

2020

Antimicrob Agents Chemother

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Pseudomonas aeruginosa is a major cause of respiratory biofilm-related infections in patients with cystic fibrosis. We developed an in vitro pharmacodynamic model to study the activity of antipseudomonal antibiotics against PAO1 biofilms grown in artificial sputum medium with agar [ASM(+)] versus that against biofilms grown in Trypticase soy broth supplemented with glucose and NaCl (TGN). We measured bacterial counts, metabolic activity (fluorescein diacetate [FDA] hydrolysis), and biomass (crystal violet absorbance). Biofilms grew slower in ASM(+) than in TGN but reached the same CFU counts and metabolic activity in both media and a slightly higher biomass after 48 h in ASM(+) than in TGN. The concentration-response curves of the antibiotics after 24 h of incubation with mature biofilms showed maximal effects ranging from a 3 (ciprofloxacin)- to a 1.5 (ceftazidime, meropenem)-log10-CFU decrease, with tobramycin and colistin showing intermediate values. These maximal reductions in the numbers of CFU were similar in both media for ciprofloxacin and β-lactams but lower in ASM(+) than in TGN for tobramycin and colistin; they were reached at concentrations lower than the human maximum concentration in plasma for ciprofloxacin and β-lactams only. The reductions in metabolic activity and in biomass were low in both media. Small-colony variants were selected by tobramycin in ASM(+) and by ciprofloxacin in both media. The model was then successfully applied to 4 isolates from patients with cystic fibrosis. These biofilms showed CFU counts similar to those of PAO1 biofilms in ASM(+) but a higher biomass than PAO1 biofilms in ASM(+) and moderate differences in their susceptibility to antibiotics from that of PAO1 biofilms grown in this medium. This model proved useful to establish the pharmacodynamic profile of drugs against P. aeruginosa biofilms in the context of cystic fibrosis.

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Section: Discussionmentioning

confidence: 77%

Activity of Antibiotics against Pseudomonas aeruginosa in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture Medium

Iglesias

Bambeke

2020

Antimicrob Agents Chemother

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“…Inhaled colistin has been increasingly used since late 1980s, especially for the treatment of individuals with CF, health care-associated pneumonia, and ventilator-associated pneumonia [15,25,26,27]. Very high colistin concentrations (up to 1137 µg/mL) have been reported in the epithelial lining fluid (ELF) of critically ill patients, after aerosol delivery of 2 million IU (MIU) of colistin methanesulfonate [19,20].…”

Section: Discussionmentioning

confidence: 99%

In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia

et al. 2019

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Stenotrophomonas maltophilia is an emerging global opportunistic pathogen, responsible for a wide range of human infections, including respiratory tract infections. Intrinsic multidrug resistance and propensity to form biofilms make S. maltophilia infections recalcitrant to treatment. Colistin is among the second-line options in case of difficult-to-treat S. maltophilia infections, with the advantage of being also administrable by nebulization. We investigated the potential synergism of colistin in combination with N-acetylcysteine (NAC) (a mucolytic agent with antioxidant and anti-inflammatory properties) against S. maltophilia grown in planktonic phase and biofilm. Eighteen S. maltophilia clinical isolates (comprising three isolates from cystic fibrosis (CF) and two trimethoprim-sulfamethoxazole (SXT)-resistant strains) were included. Checkerboard assays showed a synergism of colistin/NAC combinations against the strains with colistin Minimum Inhibitory Concentration (MIC) >2 µg/mL (n = 13), suggesting that NAC could antagonize the mechanisms involved in colistin resistance. Nonetheless, time–kill assays revealed that NAC might potentiate colistin activity also in case of lower colistin MICs. A dose-dependent potentiation of colistin activity by NAC was also clearly observed against S. maltophilia biofilms, also at sub-MIC concentrations. Colistin/NAC combinations, at concentrations likely achievable by topical administration, might represent a valid option for the treatment of S. maltophilia respiratory infections and should be examined further.

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“…Similarly, mucins in the lung and oral cavity, from where bacteria migrate to the lower respiratory tract, 2 inhibit biofilm formation and downregulate toxins and other virulence factors of pathogenic taxa, such as Pseudomonas aeruginosa , preventing their outgrowth and dominance and thereby promoting community diversity 76‐78 . These protective effects may be subverted, as P aeruginosa can utilize MUC1 for adherence 79 and reside in the mucus to evade exposure to antibiotics, particularly with mucus hypersecretion such as in cystic fibrosis 80,81 …”

Section: Microbiome‐mucous Membrane Interactionsmentioning

confidence: 99%

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

Alemao

Budden

Gomez

et al. 2020

Allergy

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The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a “poor” diet or protection against disease with a “healthy” diet. In addition, many mucosa‐associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host‐microbiome and inter‐microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.

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Human airway mucus alters susceptibility of Pseudomonas aeruginosa biofilms to tobramycin, but not colistin

Abstract: These findings underline the important role of mucus in the efficacy of anti-infective drugs.

Cited by 41 publications

References 47 publications

Activity of Antibiotics against Pseudomonas aeruginosa in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture Medium

Activity of Antibiotics against Pseudomonas aeruginosa in an In Vitro Model of Biofilms in the Context of Cystic Fibrosis: Influence of the Culture Medium

In Vitro Synergism of Colistin and N-acetylcysteine against Stenotrophomonas maltophilia

Impact of diet and the bacterial microbiome on the mucous barrier and immune disorders

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