Title Klinička ispitivanja pripravaka s bakteriofagima: problemi i rješenja Title (english) Bacteriophage therapy clinical trials: hurdles and solutions Author Marija Magdalena Lukač Mentor Maja Šegvić Klarić (mentor)Committee member Maja Šegvić Klarić (predsjednik povjerenstva)Committee member Anita Hafner (član povjerenstva)Committee member Laura Nižić Nodilo (član povjerenstva)Granter University of Zagreb Defense date and country 2024-09-09, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Abstract Antibiotska rezistencija predstavlja globalni problem koji sve više usmjerava znanstvenu zajednicu prema istraživanju alternativnih metoda za liječenje bakterijskih infekcija. Jedan od potencijalnih pristupa u rješavanju ovog problema jest razvoj i primjena terapijskih sustava baziranih na bakteriofagima. S obzirom na to da je terapijski potencijal bakteriofaga prepoznat već gotovo stoljeće, te da postoje brojni izvještaji i studije koje potvrđuju njihovu učinkovitost u liječenju bakterijskih
... More infekcija, cilj ovog preglednog diplomskog rada bio je istražiti razloge za ograničenu primjenu fagoterapije u kliničkoj praksi. Prema dostupnim podacima, trenutno je u tijeku ili u procesu regrutacije pacijenata ukupno 23 kliničke studije koje istražuju primjenu bakteriofaga. Ove studije provode se u Sjedinjenim Američkim Državama, Kanadi, Francuskoj, Belgiji, Danskoj, Češkoj, Gruziji, Iranu, Uzbekistanu i Kini, a ciljne bakterije uključuju ESKAPE patogene: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa i vrste Enterobacter. Među glavnim izazovima u razvoju terapijskih sustava s bakteriofagima izdvajaju se: 1) farmakokinetička svojstva bakteriofaga, koji zbog svoje kompleksne strukture izazivaju imunološke reakcije i pokazuju varijabilnu stabilnost u različitim fiziološkim uvjetima; 2) ograničena učinkovitost oralne primjene uslijed kiselog pH u želucu, dok je parenteralna primjena, osobito intraperitonealna, učinkovitija jer omogućuje bržu apsorpciju i viši titar bakteriofaga u cirkulaciji; 3) rijetke, ali potencijalne nuspojave koje mogu nastati uslijed oslobađanja endotoksina tijekom bakterijske lize; 4) mogućnost razvoja rezistencije bakterija na bakteriofage kroz mehanizme poput stvaranja biofilma, modifikacije površinskih receptora, inhibicije superinfekcije, restrikcijsko-modifikacijskih sustava, autodestrukcije stanica te CRISPR-Cas sustava adaptivne imunosti. Dodatno, primjena bakteriofaga u terapijske svrhe ograničena je nedostatkom adekvatnih regulatornih okvira u mnogim zemljama, što komplicira međunarodnu suradnju i standardizaciju. Proizvodnja bakteriofaga u skladu sa standardima Dobre proizvođačke prakse (DPP) predstavlja značajan izazov zbog sklonosti ovih virusa evolucijskim promjenama i teškoća u reproducibilnosti proizvodnih procesa. Iako bakteriofagi imaju određena ograničenja, poput mogućnosti razvoja rezistencije i poteškoća s patentiranjem, genetski modificirani bakteriofagi pružaju mogućnosti za poboljšanje njihove učinkovitosti i prevladavanje bakterijske rezistencije. Ipak, njihova primjena suočava se s dodatnim regulatornim izazovima zbog korištenja genetski modificiranih organizama, što dodatno otežava njihovu širu implementaciju u kliničku praksu. Less Abstract (english) Antibiotic resistance represents a global challenge that increasingly directs the scientific community toward the exploration of alternative methods for treating bacterial infections. One potential approach to addressing this issue is the development and application of therapeutic systems based on bacteriophages. Given that the therapeutic potential of bacteriophages has been recognized for nearly a century, and considering the numerous reports and studies confirming their effectiveness in
... More treating bacterial infections, the aim of this review thesis is to investigate the reasons for the limited clinical implementation of phage therapy. According to available data, there are currently 23 clinical trials investigating the application of bacteriophages, either ongoing or in the process of patient recruitment. These studies are being conducted in the United States, Canada, France, Belgium, Denmark, the Czech Republic, Georgia, Iran, Uzbekistan, and China, targeting ESKAPE pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species. The main challenges in the development of bacteriophage-based therapeutic systems include: 1) the pharmacokinetic properties of bacteriophages, which, due to their complex structure, provoke immune responses and exhibit variable stability under different physiological conditions; 2) the limited efficacy of oral administration due to the acidic pH of the stomach, whereas parenteral administration, particularly intraperitoneal, is more effective as it allows for faster absorption and higher bacteriophage titers in circulation; 3) rare but potential side effects that may result from endotoxin release during bacterial lysis; 4) the possibility of bacteria developing resistance to bacteriophages through mechanisms such as biofilm formation, surface receptor modification, superinfection inhibition, restriction-modification systems, cell autodestruction, and the CRISPR-Cas adaptive immunity system. Additionally, the use of bacteriophages in therapeutic applications is constrained by the lack of adequate regulatory frameworks in many countries, complicating international collaboration and standardization. The production of bacteriophages according to Good Manufacturing Practice (GMP) standards presents a significant challenge due to their propensity for evolutionary changes and the difficulties in achieving reproducibility in manufacturing processes. Although bacteriophages have certain limitations, such as the potential for resistance development and patenting issues, genetically modified bacteriophages offer opportunities to enhance their efficacy and overcome bacterial resistance. However, their application faces additional regulatory hurdles due to the use of genetically modified organisms, further complicating their broader implementation in clinical practice. Less Keywords
bakteriofagi
bakterije
rezistencija
klinička ispitivanja
antibiotici
Keywords (english)
bacteriophages
bacteria
resistance
clinical trials
antibiotics
Language croatian URN:NBN urn:nbn:hr:163:202917 Study programme Title: Pharmacy - integrated undergraduate and graduate - university study Type of resource Text File origin Born digital Access conditions Open access Terms of use Created on 2024-10-11 10:21:38
