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One of the main drawbacks of most available antimicrobial-coated devices is the burst release of the adsorbed antibiotics in the first few hours, followed by a long-lasting phase of slow release at very low concentrations. This behaviour can be associated with the development of antimicrobial resistance even if in vitro and in vivo studies, focused on minocycline and rifampicin, have seemingly ruled out the risk possibly associated with the prolonged use of MR-coated catheters Munson et al.

The development of an innovative catheter with long-lasting antibiofilm activity depends on the ability of the catheter constitutive polymer to adsorb large amounts of antibiotic molecules and on their long-term release at relatively constant concentrations.


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In this regard, our group has developed properly functionalized polymers that are able to adsorb large amounts of antibiotic by introducing into the polymer side chains acidic or basic groups able to interact with different classes of drugs Donelli et al. The antimicrobial combination for an ideal antibiofilm catheter should also contain an antifungal drug as it is well known that yeasts, particularly Candida spp.

We therefore performed a combined entrapment in functionalized polyurethanes of fluconazole and albumin, as a pore-forming agent, in order to obtain good and controlled release over time of the antifungal drug, thus inhibiting C. Given the well-known decreased antibiotic susceptibility of bacteria growing in the sessile mode, we carried out experiments with S. Gram-positive and gram-negative bacteria communicate with each other using small diffusible signal molecules called autoinducers. The most common classes of signal molecules are oligopeptides in gram-positive bacteria, N -acyl homoserine lactones in gram-negative bacteria and a family of autoinducers known as AI-2 in both gram-negative and gram-positive bacteria.

This communication process among cells, known as quorum sensing QS , plays a significant role in modulating not only the expression of genes associated with the production of specific enzymes, virulence factors and metabolites but also the development of microbial communities as biofilms. In fact, QS is a regulatory mechanism allowing sessile microorganisms to respond to needs that are related to the increasing population density through the expression of specific sets of genes.

For recent reviews on QS, see Costerton et al. Furthermore, it has been demonstrated recently in P. Thus, the use of molecules interfering with QS is a promising strategy to counteract microbial adaptation to the host environment Fig. In fact, QS inhibitors and antagonists represent the most promising therapeutic tools for the treatment of biofilm-based infections. Potent inhibitors of gram-negative QS are the halogenated furanone purified from Delisea pulchra Givskov et al.

Clinical use of antibacterial mesh envelopes in cardiovascular electronic device implantations

Usnic acid, a naturally occurring dibenzofuran derivative, was demonstrated by our group to be able to affect the morphology thickness and roughness of P. Using a rat model, Cirioni et al. When exposed to RIP, biofilm S. Regarding orthopaedic implants, RIP-loaded polymethylmethacrylate beads were implanted in rats and were demonstrated to be able to prevent in vivo methicillin-resistant S. In addition, stent coating with RIP and teicoplanin increases the antibiotic efficacy in preventing ureteral stent-associated staphylococcal infections Cirioni et al.

Considering the occurrence of multispecies biofilms in device-related infections and the increasing antimicrobial resistance of the microorganisms involved, there is a need for continuous updates in the strategies of microbial killing. In fact, we need to be able to counteract microbial communities inhabited by either gram-positive or gram-negative bacteria as well as fungal species. Thus, the treatment of biofilm-based infections must rely on the combined use of drugs with different antimicrobial spectra and modes of action.

In this regard, Raad et al. However, when rifampicin was added to linezolid or vancomycin, an enhancement of their activity in biofilm killing was observed Raad et al. Kim et al. The authors concluded that the use of combinations of agents that have similar antimicrobial behaviours, but that are not too oxidative, i. Other combinations of antibiotics and antifungal drugs exhibiting synergistic activity include: 1 aminoglycosides and fosfomycin against P.

Another way to enhance the activity of antibiotics is their use in combination with QS-interfering molecules or biofilm matrix-degrading substances Fig. In particular, the combination of furanones, as P. Promoting microbial killing within an established biofilm using a combination of an antibiotic and a matrix-dispersing enzyme a or drug-coated magnetic nanoparticles properly targeted to a localized area in which the drug release is planned to occur b. The efficacy of N -acetyl-cysteine in combination with thiamphenicol in sequential therapy of upper respiratory tract infections sustained by bacterial biofilms has also been demonstrated Macchi et al.

More recently, N -acetylcysteine, EDTA, ethanol and recombinant human talactoferrin, in combination with fluconazole, amphotericin B, vancomycin and nafcillin, were used successfully as catheter lock solutions to salvage colonized catheters. In fact, these combinations were able to inhibit monomicrobial and polymicrobial biofilms of S. Presumably because of its activity in rapidly dissolving S. In vitro experiments have shown that the application of an appropriate electric current can enhance the activity of some antimicrobial agents against some bacterial species growing as biofilm Ehrlich et al.

Very recently, Di Poto et al. This strategy, known as photodynamic treatment PDT , was based on the combined action of visible light and a photosensitizer drug that generates cytotoxic reactive oxygen species and free radicals that are bactericidal. Furthermore, PDT of S. A further novel strategy that represents a promising, but still poorly investigated tool for biofilm eradication from device surfaces and surrounding tissues is represented by the use of nanoparticles able to target antimicrobial agents, alone or possibly in combination with QS-interfering agents or enzymes.

In fact, nanoparticles, either polymeric or inorganic, can be properly targeted to a localized area in which the drug release is planned to occur Fig. Our group is now experimenting with the use of magnetic nanoparticles to concentrate antimicrobial agents exclusively in the infected area surrounding the implanted medical device, thus potentiating the activity of the antimicrobial agents against the biofilm.

The use of substances able to destroy the physical integrity of the biofilm matrix is an attractive antibiofilm approach Fig. Chaignon et al. In fact, the heterogeneity of the biofilm matrix suggests that at least two successive treatments, for example Dispersin B, followed by a protease proteinase K or trypsin , may be necessary for the entire degradation of staphylococcal biofilms Chaignon et al. Engineered bacteriophages able to express Dispersin B were also successfully tested against E.

Finally, the use of bacteriophages has been reported recently Fu et al. In fact, even just 15 years later, although great advances have been made from both the scientific and the technological points of view, most of the targets listed by Maki remain unreached, even though an enormous number of papers have been published in the last decade on these critical issues. Producing medical devices that are refractory to microbial colonization and biofilm formation remains an uphill task and it is necessary to establish closer collaborations between scientists working in universities or research institutes and industrial investigators to hasten achievement of the above objectives and find more advanced solutions to prevent medical device-related infections.

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Sign In. Advanced Search. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents. Microbial biofilms: resistant enemies. Do we need novel antibiofilm biomaterials, new synergistically acting antimicrobial compounds or both? Concluding remarks. Prevention and control of biofilm-based medical-device-related infections Iolanda Francolini.

Oxford Academic. Google Scholar. Gianfranco Donelli. Editor: John Costerton.

Biofilms and Implantable Medical Devices

Cite Citation. Permissions Icon Permissions. Abstract Biofilms play a pivotal role in healthcare-associated infections, especially those related to the implant of medical devices, such as intravascular catheters, urinary catheters and orthopaedic implants. Open in new tab Download slide. Prevention of biofilm formation using agents that interfere with QS. Use of heparin-coated central venous lines to prevent catheter-related bloodstream infection. Mixed species biofilms of Candida albicans and Staphylococcus epidermidis. Search ADS.

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Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Absence of amphotericin B-tolerant persister cells in biofilms of some Candida species. Surface heparinization of central venous catheters reduces microbial colonization in vitro and in vivo : results from a prospective, randomized trial. Quorum sensing inhibitory drugs as next generation antimicrobials: worth the effort? Antibacterial activity of antibiotic-soaked polyvinylpyrrolidone-grafted silicon elastomer hydrocephalus shunts. Oxygen limitation contributes to antibiotic tolerance of Pseudomonas aeruginosa in biofilms.

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Susceptibility of staphylococcal biofilms to enzymatic treatments depends on their chemical composition. RNAIII-inhibiting peptide significantly reduces bacterial load and enhances the effect of antibiotics in the treatment of central venous catheter-associated Staphylococcus aureus infections. RNAIII-inhibiting peptide affects biofilm formation in a rat model of staphylococcal ureteral stent infection. Risk of intravascular cardiac device infections in patients with bacteraemia: impact on device removal. Bacterial communications in implant infections: a target for an intelligence war.

Efficacy of antimicrobial-impregnated bladder catheters in reducing catheter-associated bacteriuria: a prospective, randomized, multicenter clinical trial. Comparison of antimicrobial impregnation with tunneling of long-term central venous catheters: a randomized controlled trial. Antimicrobial and antibiofilm efficacy of triclosan and DispersinB combination.

Del Pozo. The electricidal effect: reduction of Staphylococcus and Pseudomonas biofilms by prolonged exposure to low-intensity electrical current. Di Poto. The effect of photodynamic treatment combined with antibiotic action or host defence mechanisms on Staphylococcus aureus biofilms. Efficacy of antiadhesive, antibiotic and antiseptic coatings in preventing catheter-related infections: review.

Towards Securing Implantable Medical Devices