Editorial
Are antibiotics and surgery sufficient to treat biofilm-associated infections?
¿Son suficientes los antibióticos y la cirugía para tratar las infecciones asociadas a biofilms?
a Infectious Diseases Division, Clínica Universidad de Navarra, Pamplona, Spain
b Department of Clinical Microbiology, Clínica Universidad de Navarra, Pamplona, Spain
c Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
d Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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"tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "641" "paginaFinal" => "642" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Jose Luis Del Pozo, Robin Patel" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Jose Luis" "apellidos" => "Del Pozo" "email" => array:1 [ 0 => "jdelpozo@unav.es" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">¿</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Robin" "apellidos" => "Patel" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Infectious Diseases Division, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Clinical Microbiology, Clínica Universidad de Navarra, Pamplona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Division of Infectious Diseases, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "¿Son suficientes los antibióticos y la cirugía para tratar las infecciones asociadas a biofilms?" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The biofilm phenotype has been recognized relatively recently in medical history but it has rapidly become clear that the development of many, if not the majority of bacterial infections depend upon the formation of biofilms. Moreover, as the adherence of microorganisms to tissues is part of the process of acute infection, the impact of biofilm formation in infection might in fact be underestimated. Medical device-related infections are one of the clearest examples of biofilm-dependent infections. Such infections are most frequently caused by <span class="elsevierStyleItalic">Staphylococcus epidermidis</span>, <span class="elsevierStyleItalic">Staphylococcus aureus</span>, <span class="elsevierStyleItalic">Pseudomonas aeruginosa</span> and Enterobacteriaceae. Biofilm-associated infections contribute to patient morbidity and healthcare costs, as well as to the emergence and dissemination of antibiotic resistance in nosocomial settings.</p><p id="par0010" class="elsevierStylePara elsevierViewall">At the phenotype level, a microbial biofilm can be characterized as a community of surface-adherent cells that exhibits tolerance to many antimicrobial agents and disinfectants that are otherwise active against the cells of the biofilm once dispersed into their planktonic state. Biofilms contain so-called persister cells, which are dormant cells capable of tolerating very high levels of antimicrobial agents.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> These persister cells are not resistant to antimicrobials in the classic sense, but instead appear to escape killing through what is hypothesized to be a transient dormant state. Even if the majority of the bacteria within a biofilm are killed by antimicrobial therapy, persister cells are capable of reestablishing infection after the threat is removed. The mechanism of dormancy of persister cells is not fully understood, but may be due to the expression of toxin–antitoxin systems.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Consequently, global mechanisms of toxin–antitoxin system regulation and persister formation are potential targets for successful elimination of these dormant cells.</p><p id="par0015" class="elsevierStylePara elsevierViewall">No definitive studies have addressed whether there is a systematic difference between the activities of bacteriostatic and bactericidal agents against biofilm-associated infections <span class="elsevierStyleItalic">in vivo</span>. Experimental biofilms formed by staphylococci are highly resistant to antibiotics that target cell wall biosynthesis while remaining susceptible to antibiotics that target RNA synthesis.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Such a response is consistent with a diminished role for cell wall biosynthesis in the biofilm population and may reflect an ongoing role for transcription in biofilm establishment, maturation, and propagation. In addition to a growth-inhibiting effect, antimicrobial agents are signaling molecules. Exposure of bacteria to a subminimum inhibitory concentration of various classes of antimicrobials with diverse cellular targets globally affects gene expression regulating not only biofilm formation, but also stress response, virulence and motility.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> For example, the beneficial effect of low-dose chemotherapy with the macrolide azithromycin for the treatment of lung infection with <span class="elsevierStyleItalic">P. aeruginosa</span> may be partially due to its inhibition of biofilm formation.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The results of <span class="elsevierStyleItalic">in vitro</span> investigations of biofilm formation in clinical isolates have not been entirely consistent with the findings from <span class="elsevierStyleItalic">in vivo</span> studies. This might be due to the poor correlation between <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> biofilm formation.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> Recommendations for antibiotic therapies for the management of biofilm-associated infections have been driven largely by empiric observations and typically involve the use of surgery and antimicrobial combination regimens over extended periods.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> However, the existing regulatory climate does not provide a clear path toward the design and implementation of clinical trials to evaluate the efficacy of antimicrobials (or potentiators) in biofilm-related infection settings. Besides, there is limited current evidence of the pursuit of this approach in the pharmaceutical industry.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Clearly, we need novel strategies for the management of biofilm-associated diseases. Although <span class="elsevierStyleItalic">in vitro</span> investigation of biofilm formation has made significant progress over the last decade, the <span class="elsevierStyleItalic">in vivo</span> molecular mechanisms underlying biofilm pathogenesis remain poorly understood.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> To increase the activity of new treatment strategies against bacterial and fungal infections, factors that lead to biofilm growth inhibition, biofilm disruption, or biofilm eradication are being sought. These factors could include enzymes, sodium salts, metal nanoparticles, new antimicrobials, cation chelators, chitosan derivatives, plant extracts, <span class="elsevierStyleItalic">etc.</span>, which influence biofilm structure <span class="elsevierStyleItalic">via</span> various mechanisms and with different efficiencies. Many potential antibiofilm agents are under development, but at this point most are experimental, have not undergone clinical trials, and lack comprehensive pharmacodynamics analysis. In this journal issue, Leite et al.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> present the results of a study designed to determine the susceptibility of <span class="elsevierStyleItalic">S. epidermidis</span> biofilm cells to linezolid in combination with a non-antimicrobial drug (<span class="elsevierStyleItalic">N</span>-acetylcysteine), wherein each of which has different modes of action. Leite et al. show that the combination linezolid plus <span class="elsevierStyleItalic">N</span>-acetylcysteine has a synergistic effect, resulting in a 5-log reduction in the number of biofilm viable cells. This combination could be a potential candidate to combat <span class="elsevierStyleItalic">S. epidermidis</span> biofilm infections. Previous studies have shown that <span class="elsevierStyleItalic">N</span>-acetylcysteine decreases biofilm formation by a variety of bacteria including <span class="elsevierStyleItalic">Escherichia coli</span>, <span class="elsevierStyleItalic">S. epidermidis</span>, and <span class="elsevierStyleItalic">P. aeruginosa</span>. <span class="elsevierStyleItalic">N</span>-acetylcysteine inhibits bacterial adherence and reduce the production of extracellular polysaccharide matrix, while promoting the disruption of mature biofilms and reducing sessile cell viability. Antibiofilm therapies have a high potential of working synergistically with traditional antimicrobial agents and certain agents may exhibit increased efficacy if used in combination with a second antibiofilm that targets a different biofilm component. It is possible that certain antimicrobial agents may exhibit increased efficacy if used in combination with <span class="elsevierStyleItalic">N</span>-acetylcysteine.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Inhibition and/or reversal of the biofilm phenotype have become the focus of research efforts to develop new prophylactic and therapeutic agents. The biofilm phenotype is an attractive target because inhibition of biofilm formation or dispersal of established biofilms would result in maintenance of cells in or reversion of cells to a planktonic phenotype, which would be amenable to treatment with convention antimicrobial agents, and to the host immune system. However, the complexity of biofilm formation makes it difficult to develop a compound that will affect this process. Dispersal strategies are attractive because they hold the promise of efficacy in established infections and do not need to be administered prophylactically. Because the biofilm matrix is composed of DNA, proteins, and extracellular polysaccharides, recent studies have indicated that the disruption of the biofilm structure could be achieved <span class="elsevierStyleItalic">via</span> the degradation of individual biofilm compounds by various enzymes (<span class="elsevierStyleItalic">e.g.</span>, dispersin B, <span class="elsevierStyleItalic">N</span>-acetylcysteine, proteinase K, deoxyribonuclease). These strategies are therapeutically promising because once a biofilm is successfully dispersed, the resident bacterial cells lose the resistance mechanism inherent to biofilm growth, and their susceptibility to antimicrobial agents and immune defenses is restored.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Another promising antibiofilm strategy is the use of lysostaphin and staphylolysin, microbial endopeptidases capable of breaking the pentaglycine bridge in the staphylococcal cell wall peptidoglycan.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Targeting quorum sensing with farnesol or similar substances is also appealing as a therapeutic approach because inhibition is generally not detrimental to growth, relieving selective pressure to acquire resistance. Antimicrobial peptides are produced by a variety of multicellular organisms as a part of the innate immune response and are important to the host defense against infections. The combination of the ability to kill slow-growing or dormant cells, which predominate in biofilms, low rate of spontaneous resistance, and synergistic activity with certain antibiotics makes antimicrobial peptides attractive candidates for new approaches to biofilm therapy. At this point, they are clinically approved only for topical usage, but significant research effort is being invested to develop non-topical therapeutic uses. Phage therapy which, in the preantibiotic era, was used to treat bacterial infections has recently been shown to be effective in treating biofilm infections.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> In the same way, vaccine development may lead to the generation of vaccines against pathogenic biofilm bacteria.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Finally, medical devices that emit low-energy surface acoustic waves, electrical current, or pulsed ultrasound have been reported to either reduce device colonization or enhance the release and/or effectiveness of locally applied antimicrobials.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In the latter category are the so-called intelligent implants,<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> which are designed to locally release agents when they detect microbial colonization. In addition to such device modifications, new studies have evaluated the effectiveness of new antibiotic or microbicide immersion practices with medical devices to suppress surgical-site infections.</p><p id="par0045" class="elsevierStylePara elsevierViewall">As a conclusion, increased knowledge about the molecular mechanisms of biofilm formation is important for the development and analysis of <span class="elsevierStyleItalic">in vivo</span> biofilm models and to establish innovative treatment strategies for biofilm infections. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 2 | 0 | 2 |
| 2024 October | 13 | 12 | 25 |
| 2024 September | 36 | 33 | 69 |
| 2024 August | 18 | 28 | 46 |
| 2024 July | 15 | 15 | 30 |
| 2024 June | 17 | 10 | 27 |
| 2024 May | 16 | 8 | 24 |
| 2024 April | 23 | 9 | 32 |
| 2024 March | 14 | 20 | 34 |
| 2024 February | 14 | 20 | 34 |
| 2024 January | 8 | 19 | 27 |
| 2023 December | 37 | 8 | 45 |
| 2023 November | 18 | 15 | 33 |
| 2023 October | 18 | 10 | 28 |
| 2023 September | 19 | 2 | 21 |
| 2023 August | 11 | 2 | 13 |
| 2023 July | 14 | 4 | 18 |
| 2023 June | 17 | 8 | 25 |
| 2023 May | 42 | 6 | 48 |
| 2023 April | 23 | 0 | 23 |
| 2023 March | 18 | 12 | 30 |
| 2023 February | 21 | 10 | 31 |
| 2023 January | 22 | 10 | 32 |
| 2022 December | 19 | 14 | 33 |
| 2022 November | 47 | 17 | 64 |
| 2022 October | 24 | 15 | 39 |
| 2022 September | 32 | 24 | 56 |
| 2022 August | 28 | 6 | 34 |
| 2022 July | 16 | 10 | 26 |
| 2022 June | 12 | 8 | 20 |
| 2022 May | 42 | 22 | 64 |
| 2022 April | 23 | 12 | 35 |
| 2022 March | 26 | 11 | 37 |
| 2022 February | 29 | 9 | 38 |
| 2022 January | 38 | 9 | 47 |
| 2021 December | 38 | 14 | 52 |
| 2021 November | 21 | 12 | 33 |
| 2021 October | 21 | 18 | 39 |
| 2021 September | 20 | 17 | 37 |
| 2021 August | 17 | 6 | 23 |
| 2021 July | 30 | 11 | 41 |
| 2021 June | 26 | 11 | 37 |
| 2021 May | 13 | 12 | 25 |
| 2021 April | 27 | 14 | 41 |
| 2021 March | 31 | 21 | 52 |
| 2021 February | 24 | 13 | 37 |
| 2021 January | 19 | 18 | 37 |
| 2020 December | 14 | 10 | 24 |
| 2020 November | 14 | 7 | 21 |
| 2020 October | 12 | 4 | 16 |
| 2020 September | 23 | 32 | 55 |
| 2020 August | 14 | 29 | 43 |
| 2020 July | 11 | 16 | 27 |
| 2020 June | 19 | 15 | 34 |
| 2020 May | 27 | 17 | 44 |
| 2020 April | 9 | 15 | 24 |
| 2020 March | 39 | 14 | 53 |
| 2020 February | 24 | 14 | 38 |
| 2020 January | 29 | 11 | 40 |
| 2019 December | 33 | 9 | 42 |
| 2019 November | 29 | 6 | 35 |
| 2019 October | 27 | 10 | 37 |
| 2019 September | 49 | 8 | 57 |
| 2019 August | 34 | 10 | 44 |
| 2019 July | 37 | 15 | 52 |
| 2019 June | 81 | 35 | 116 |
| 2019 May | 175 | 24 | 199 |
| 2019 April | 49 | 19 | 68 |
| 2019 March | 24 | 5 | 29 |
| 2019 February | 30 | 17 | 47 |
| 2019 January | 14 | 5 | 19 |
| 2018 December | 26 | 11 | 37 |
| 2018 November | 32 | 6 | 38 |
| 2018 October | 34 | 12 | 46 |
| 2018 September | 13 | 7 | 20 |
| 2018 August | 10 | 6 | 16 |
| 2018 July | 14 | 2 | 16 |
| 2018 June | 12 | 4 | 16 |
| 2018 May | 11 | 4 | 15 |
| 2018 April | 10 | 3 | 13 |
| 2018 March | 5 | 0 | 5 |
| 2018 February | 5 | 1 | 6 |
| 2018 January | 5 | 0 | 5 |
| 2017 December | 8 | 2 | 10 |
| 2017 November | 13 | 13 | 26 |
| 2017 October | 19 | 3 | 22 |
| 2017 September | 18 | 5 | 23 |
| 2017 August | 23 | 9 | 32 |
| 2017 July | 15 | 5 | 20 |
| 2017 June | 29 | 33 | 62 |
| 2017 May | 28 | 14 | 42 |
| 2017 April | 26 | 5 | 31 |
| 2017 March | 37 | 8 | 45 |
| 2017 February | 38 | 7 | 45 |
| 2017 January | 18 | 2 | 20 |
| 2016 December | 30 | 6 | 36 |
| 2016 November | 37 | 10 | 47 |
| 2016 October | 57 | 5 | 62 |
| 2016 September | 36 | 6 | 42 |
| 2016 August | 22 | 7 | 29 |
| 2016 July | 34 | 3 | 37 |
| 2016 June | 40 | 17 | 57 |
| 2016 May | 27 | 14 | 41 |
| 2016 April | 19 | 30 | 49 |
| 2016 March | 28 | 16 | 44 |
| 2016 February | 30 | 17 | 47 |
| 2016 January | 28 | 21 | 49 |
| 2015 December | 19 | 11 | 30 |
| 2015 November | 25 | 15 | 40 |
| 2015 October | 35 | 18 | 53 |
| 2015 September | 25 | 16 | 41 |
| 2015 August | 36 | 6 | 42 |
| 2015 July | 27 | 4 | 31 |
| 2015 June | 19 | 4 | 23 |
| 2015 May | 15 | 7 | 22 |
| 2015 April | 20 | 12 | 32 |
| 2015 March | 28 | 8 | 36 |
| 2015 February | 23 | 4 | 27 |
| 2015 January | 20 | 6 | 26 |
| 2014 December | 23 | 11 | 34 |
| 2014 November | 20 | 3 | 23 |
| 2014 October | 36 | 13 | 49 |
| 2014 September | 28 | 7 | 35 |
| 2014 August | 31 | 13 | 44 |
| 2014 July | 31 | 7 | 38 |
| 2014 June | 17 | 4 | 21 |
| 2014 May | 24 | 10 | 34 |
| 2014 April | 24 | 7 | 31 |
| 2014 March | 55 | 21 | 76 |
| 2014 February | 52 | 18 | 70 |
| 2014 January | 105 | 44 | 149 |
| 2013 December | 215 | 127 | 342 |
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