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Fotodinamička inaktivacija jedna je od obećavajućih metoda suzbijanja širokog spektra osjetljivih, ali i rezistentnih bakterija koje postaju glavnim javnozdravstvenim problemom današnjice. Svrha ovog rada jest ispitati učinkovitost fotodinamičke inaktivacije u suzbijanju otpornih bakterija u komunalnim otpadnim vodama upotrebom kationskog hidrofilnog porfirina TMPyP3 u kombinaciji sa zračenjem ljubičaste LED lampe intenziteta 40 mW/cm2. Fotodinamički učinak ispitan je određivanjem minimalne efektivne koncentracije (MEK) TMPyP3 i provedbom fotoinaktivacijskog testa. Ispitivanje je izvršeno na rezistentnim sojevima Pseudomonas aeruginosa i Burkholderia cepacia izoliranim iz biofilma unutar bolničkih ustanova te P. aeruginosa, Pseudomonas putida i Vibrio parahaemolyticus izoliranim iz uzorka komunalne otpadne vode. Testiranja su provedena na uzorcima sterilne vode iz slavine, sterilne otpadne vode te sirove otpadne vode. Usporedbom rezultata zaključeno je da učinkovitost TMPyP3 ovisi o karakteristikama ispitivanog soja i mehanizmima rezistencije (MEK za multirezistentni P. aeruginosa u uzorku sterilne otpadne vode je ˃100 μM, a MEK za osjetljivi soj P. aeruginosa pri istim uvjetima je ˃12 μM). Osim toga, fotoinaktivacijskim testom utvrđeno je da je učinkovitost TMPyP3 u inhibiciji multirezistentnog P. aeruginosa u sirovoj otpadnoj vodi smanjena zbog prisustva drugih bakterija (% inhibicije P. aeruginosa u sirovoj otpadnoj vodi ≈ 89% u odnosu na ≈ 92% u sterilnoj otpadnoj vodi) te da se produljenjem vremena zračenja učinkovitost ispitivanog porfirina povećava pri nižim koncentracijama. Photodynamic inactivation is one of the promising methods of combating a wide range of suspectible, but also resistant bacteria that are about to become a major problem in field of public health. The aim of this study was to investigate the effectiveness of photodynamic inactivation on resistant bacteria in municipal wastewater using cationic hydrophilic porphyrin TMPyP3 in combination with purple LED lamp with the intensity of 40 mW/cm2. The photodynamic effect was investigated by determining the miminum effective concentration (MEC) of TMPyP3 and photoinactivation testing. The study was carried out on multiresistant strains Pseudomonas aeruginosa and Burkholderia cepacia isolated from biofilm inside of hospital facilities and P. aeruginosa, Pseudomonas putida and Vibrio parahaemolyticus isolated from municipal wastewater. The tests were done on samples of sterile tap water, sterile wastewater and raw wastewater. By comparing the results, it was concluded that the effectiveness of TMPyP3 depends on the characteristics of tested strains and resistance mechanisms ( MEC for multidrug resistant P. aeruginosa in a sterile wastewater sample is ˃ 100 μM and MEC for suspectible P. aeruginosa under the same conditions is ˃ 12 μM). In addition, the results of photoinactivation test revealed that the efficacy of TMPyP3 in inhibition of multidrug resistant P. aeruginosa in raw wastewater sample was reduced due to the presence of other bacteria (% of inhibition of multiresistant P. aeruginosa in raw wastewater sample is ≈89% in comparison to ≈92% of inhibition in sterile wastewater) and that by prolongation of the irradiation time, the efficiency of the tested porphyrin increases at lower concentrations

Drug resistance, especially bacterial antibiotic resistance, is recognized as a global phenomenon. Potential of endophytic fungi as producers of secondary metabolites with wide spectra of different bioactivities in the field of drug discovery has recently been introduced. The production of these compounds is under the great impact of the variety of factors related to the choice of plant host, climate conditions, nutrition, presence of other microorganisms in the same surrounding, etc. Due to a large number of different indices of endophytic fungi antibacterial activity, critical evaluation with the assistance of data mining analytical methods was performed. The activity towards several pathogen bacteria of endophytes species growing on different plant hosts, deciduous trees as well as herbaceous plants spread worldwide in different climatic zones together with the taxonomy of endophytes was taken into consideration. The principal component analysis was used to explore formed big data set and through finding patterns in data, to point out to a limited number of proper candidates for future pharmaceutical research. The antimicrobial character of Phomopsis species was highlighted and future perspectives in their therapeutic use were projected. Rezistencija na lekove, posebno rezistencija bakterija na delovanje antibiotika, smatra se globalnim problemom. Na polju razvoja novih lekova nedavno su se pojavile endofitne gljive zahvaljujući sposobnosti da proizvedu sekundarne metabolite sa širokim spektrom različitih bioloških aktivnosti. Biosinteza ovih jedinjenja je pod velikim uticajem brojnih faktora koji se vezuju za izbor biljke domaćina, klimatske uslove, ishranu, prisustvo drugih mikroorganizama u istom okruženju itd. Pošto je u literaturi primećen veliki broj različitih indikatora antibakterijske aktivnosti endofitnih gljiva, izvršena je njihova kritička procena korišćenjem analitičkih metoda pretrage podataka. Razmatrana je aktivnost prema nekoliko sojeva patogenih bakterija koje su pokazale endofitne gljive koje rastu na različitim biljkama domaćinima, listopadnom drveću i zeljastim biljkama širom sveta i u različitim klimatskim uslovima, kao i taksonomska rasprostranjenost vrsta endofitnih gljiva. Istraživanje velike grupe podataka je vršeno pomoću analize glavnih komponenata (eng. Principal component analysis) sa ciljem pronalaženja obrazaca u podacima koji bi ukazali na manji broj pravih kandidata za dalji razvoj lekova. Osvetljen je antimikrobni karakter Phomopsis vrsta, a takođe su procenjeni i budući pravci u njegovoj terapijskoj primeni.

Antibiotici su najčešće propisivani lijekovi u kliničkoj praksi. Njihova uporaba posebno je izražena u pedijatrijskim jedinicama intenzivnog liječenja gdje se liječe životno ugrožena djeca. Prilikom primjene lijekova važno je prilagoditi doze lijekova dobi i stanju djeteta te uzeti u obzir razlike koje postoje u odnosu na odrasle (ponajviše u farmakokinetici). U pedijatrijskoj intenzivnoj jedinici se antibiotici najčešće koriste empirijski. Kako uzročnik još nije poznat, koriste se antibiotici širokog spektra. Oni djeluju na više vrsta bakterija: gram pozitivne, gram negativne, aerobne, anaerobne, kako na one patogene, tako i na fiziološku floru. Njihovu uporabu treba maksimalno skratiti te ih što prije zamijeniti antibioticima uskog spektra djelovanja. Zbog neracionalne primjene razvila se rezistencija koja je postala globalni problem u liječenju bakterijskih infekcija. S obzirom na to da ne postoji protokol koji bi optimizirao uporabu antibiotika, započelo je osnivanje bolničkih programa praćenja antimikrobnih lijekova kojima je cilj racionalizirati korištenje antibiotika i smanjiti daljnji razvoj rezistencije., Antibiotics are the most used drugs in clinical practise. Their use is particularly important in pediatric intensive care units where children with life-threatening conditions are treated. When using drugs, it is important to adjust the dose of the medication to the age and condition of the child and to consider the differences that exist in relation to adults (mostly in pharmacokinetics). In the pediatric intensive care unit antibiotics are most frequently used empirically. Since the causative agent is not yet known, broad spectrum antibiotics are used. They act on several types of bacteria: gram positive, gram negative, aerobes, anaerobes, but apart from pathogens, they also act on the physiological flora. Their use should be maximally shortened and replaced as soon as possible with narrow range spectrum antibiotics. Because of irrational use, resistance of bacteria has developed. It has become a global problem in the treatment of bacterial infections. Given that there is no protocol to optimize the use of antibiotics, Antimicrobial Stewardship Programs have been introduced to rationalize the use of antibiotics and reduce further resistance development.

Rezistencija bakterija na antibiotike je ozbiljan globalni problem koji je potaknuo razmatranje „ne-antibiotskih“ mogućnosti liječenja i prevencije bakterijskih infekcija tzv. alternative antibioticima. Najpoznatije alternative antibioticima koje se trenutno istražuju su protutijela, probiotici, bakteriofagi, lizini bakteriofaga, antimikrobni peptidi, imunostimulirajući produkti i cjepiva. Bakteriofagi su virusi koji mogu inficirati i lizirati specifičnu bakteriju. Otkriveni su 1915. godine, ali otkrićem antibiotika i zaboravljeni u većem dijelu svijeta. Razvojem rezistencije, vratio se interes za bakteriofage i njihovu ulogu u liječenju rezistentnih bakterijskih infekcija.Cilj ovog istraživanja bio je ispitati stavove i mišljenja liječnika o rezistenciji na antibiotike i alternativama antibioticima, posebice o bakteriofagima. Za potrebe ovog istraživanja korišten je kvantitativni pristup prikupljanja podataka pomoću validiranog upitnika, a ispitanici su bili liječnici Republike Hrvatske, većinom liječnici obiteljske medicine i specijalisti kliničke mikrobiologije.Većina liječnika u Hrvatskoj smatra rezistenciju bakterija na antibiotike vrlo ozbiljnim problemom. Najviše liječnika u Hrvatskoj je upoznato s probioticima, cjepivima i protutijelima kao alternativama antibioticima. Liječnici u Hrvatskoj nisu dovoljno upoznati s terapijom bakteriofagima, ali su izrazili interes za dodatnim informacijama. Liječnici u Hrvatskoj nemaju izražen negativan stav prema bakteriofagima, ali niti pozitivan. Antibiotic resistance is a serious global problem that has encouraged consideration of "non-antibiotic" possibilities for treatment and prevention of bacterial infections, so called alternatives to antibiotics. The most known alternatives to antibiotics, currently being investigated, are antibodies, probiotics, bacteriophages, lysins, antimicrobial peptides, immune stimulation and vaccines. Bacteriophages are viruses that can infect and lyse a specific bacterium. They were discovered in 1915 but soon forgoten, in most of the world, after the antibiotic discovery. Now, beacuse of antibiotic resistance, the interest for bacteriophages and their role in the treatment of resistant bacterial infections has returned. The aim of this study was to examine the physicians' attitudes and opinions regarding antibiotic resistance and alternatives to antibiotics, especially bacteriophages. For the purposes of this study, the quantitative questionnaire was designed and validated, and physicians from Croatia, mostly general medicine practitioners and clinical microbiology specialists were included in the study. Most physicians in Croatia consider antibiotic resistance a very serious problem. Most physicians in Croatia are familiar with probiotics, vaccines and antibodies as antibiotic alternatives. Physicians in Croatia are not sufficiently familiar with bacteriophage therapy but would like to know more about it. Physicians in Croatia do not show a negative, but neither positive, attitude towards bacteriophages.

Cilj istraživanja: Cilj rada je utvrditi učestalost i epidemiološka obilježja infekcija uzrokovanih rezistentnim mikroorganizmima te ispitati moguće čimbenike rizika odgovorne za kolonizaciju i pojavu infekcija tim uzročnicima. Nacrt studije: Presječno istraživanje. Ispitanici i metode: U istraživanje je uključeno 185 ispitanika liječenih u Jedinici intenzivnog liječenja (JIL) Klinike za anesteziologiju, reanimatologiju i intenzivnu medicinu tijekom 2016. i 2017. godine, kod kojih je bila potvrđena kolonizacija ili infekcija rezistentnim bolničkim mikroorganizmima. Demografski i klinički podatci o ispitanicima prikupljeni su iz povijesti bolesti i mikrobiološkog protokola. Rezultati: Prije dolaska u JIL, 49,2 % ispitanika bilo je kolonizirano, a 31,4 % njih inficirano rezistentnim uzročnikom. Najčešće je izoliran multiplorezistentan Acinetobacter baumannii. Kolonizaciju u JIL-u steklo je 60,5 %, a infekciju 59,4 % ispitanika. Osnovna bolest, kirurški zahvat i vrijeme boravka na odjelu pogodovali su kolonizaciji i infekciji prije dolaska u JIL, dok su kritično stanje, umjetni dišni put, strojna ventilacija, kirurške intervencije i vrijeme boravka u JIL-u rizični čimbenici odgovorni za pojavu kolonizacije i infekcije u JIL-u. Nije uočena razlika u pojavnosti infekcija između kirurških i ne-kirurških bolesnika. Zaključak: JIL-ovi nisu jedini rezervoari rezistentnih mikroorganizama. Dio bolesnika s drugih bolničkih odjela koloniziran je ili inficiran već pri dolasku u JIL, a dio stječe infekciju i kolonizaciju u JIL-u. Izolati su pretežito gram-negativne bakterije među kojima je najzastupljeniji Acinetobacter baumannii. Kolonizaciji i infekciji na odjelima i u JIL-u doprinose priroda i težina bolesti, izloženost invazivnim terapijskim postupcima i boravak u okruženju s visokom prevalencijom rezistentnih mikroorganizama., Objectives: The aim of this study is to identify the frequency and epidemiological characteristics of infections caused by multidrug-resistant microorganisms and examine possible risk factors responsible for colonisation and infections with these pathogens. Study design: Cross-sectional study. Participants and methods: The study included 185 participants treated in the ICU of the Clinic for Anesthesiology, Resuscitation and Intensive Care during 2016 and 2017, who were colonised or had infection caused by multidrug-resistant hospital microorganisms. The participants’ demographic and clinical data were taken from the medical records and microbiological protocol. Results: Prior to the admission at the ICU, 49.2% of the participants were colonised and 31.4% of them were infected by the resistant pathogen. The most common isolated pathogen was Acinetobacter baumannii. 60.5% of the participants were colonised at the ICU, 59.4% of them had infection prior to the admission at the ICU. Primary disease, surgical treatment and time spent in hospital ward favoured colonisation and infection prior to the admission at the ICU, while critical condition, artificial airway, mechanical ventilation, surgical intervention and time spent on ICU are considered risk factors responsible for colonisation and infection at the ICU. The difference between the incidence of infections between surgical and non-surgical patients was not found. Conclusion: ICUs are not the only reservoirs of resistant pathogens. A part of the patients is colonised or infected at the admission to the ICU, the other part got infected or colonised at the ICU. The isolates are usually Gram-negative bacteria. The most common is Acinetobacter baumanii. Colonisation and infection at hospital wards and ICUs are under the influence of the nature and severity of a disease, exposure to invasive therapeutic procedures and staying in surroundings with high prevalence of resistant microorganisms.

Rezistencija bakterija globalni je javnozdravstveni problem. Zbog pretjeranog i nepravilnog korištenja antibiotika bakterije su s vremenom evoluirale i postale otporne na pojedine od njih. Neke su bakterije postale rezistentne na vrlo velik broj antibiotika. Takve bakterije nazivamo multirezistentnim bakterijama i one predstavljaju ozbiljnu prijetnju javnom zdravlju. Posebno su opasne za bolničke pacijente, u jedinicama intenzivne njege te na kirurškim odjelima, gdje bolesnici imaju vrlo oslabljeni imunosni sustav i podložni su djelovanju tih bakterija. Glavni uzroci širenja rezistencijskih faktora su neracionalno korištenje antibiotika u humanoj medicini, ali i korištenje antibiotika u poljoprivredi, gdje se najveća količina antibiotika koristi upravo u neterapijske svrhe. U ovom radu proveden je upitnik kojim su ispitani stavovi, mišljenja, predodžbe i znanja laika o antibioticima i njihovoj pravilnoj uporabi. Upitnik je proveden na području Republike Hrvatske, a sudjelovalo je 248 nasumično odabranih ispitanika. Ispitanici su pokazali vrlo dobro znanje o primjeni antibiotika te je pokazano da se najveći broj pacijenata ipak pridržava uputa o korištenju antibiotika. Međutim, velik broj ispitanika i dalje je u uvjerenju da antibiotici liječe velik broj bolesti i stanja, stoga i ne čudi činjenica što su u pravilu vrlo adherentni kad su u pitanju antibiotici. Također, upitnikom je ustanovljeno da je i dalje prisutno medicinski neutemeljeno propisivanje antibiotika od strane liječnika. Liječnici, naime, propisuju antibiotike za nebakterijske infekcije, smatrajući da antibiotici mogu biti učinkoviti i u sprječavanju nastanka mogućih komplikacija virusnih infekcija. Nadalje, vidljivo je da liječnici, ali i ljekarnici, rijetko upozoravaju pacijente na moguće nuspojave antibiotika, potičući time i dalje mit o svemogućnosti tih lijekova. Zadaća cjelokupne zajednice, koja uključuje zdravstvene djelatnike, političare, poljoprivrednike i same pacijente, racionalizirati je uporabu antibiotika kroz izradu smjernica, edukaciju liječnika i bolesnika, novčano podupiranje farmaceutske industrije u otkrivanju i razvoju novih antibiotika i alternativnih oblika liječenja (cjepiva, probiotici, lizini faga i sl.) te smanjenje neterapijske uporabe antibiotika u poljoprivredi. Antimicrobial resistance is a global public health issue. Due to excessive and improper use of antibiotics, bacteria have evolved over time and become resistant to some of them. Some bacteria have become resistant to very large number of antibiotics. Such bacteria are called multi-drug resistant bacteria, and they pose a serious threat to public health. They are especially dangerous for inpatients, in intensive care units and on surgical wards, where patients have a weakened immune system and are more likely to be affected by these bacteria. The main cause of spreading resistance factors between bacteria is the irrational use of antibiotics in human medicine, but also the use of antibiotics in agriculture, where the largest amount of antibiotics is used for non-therapeutic purposes. In this thesis is conducted a questionnaire in which are examined the opinions, attitudes, perceptions and knowledge of people about antibiotics and their proper use. The questionnaire was conducted on Croatian territory, and was attended by 248 randomly selected respondents. Respondents showed very good knowledge of antibiotic usage and it has been shown that the majority of patients still comply with the instructions on the use of antibiotics. However, many respondents still believe that antibiotics cure a number of diseases and conditions, it is therefore not surprising that they are very adherent when it comes to antibiotics. Also, the questionnaire showed that there is still present medically unjustified prescribing of antibiotics by doctors. Doctors, in fact, prescribe antibiotics for non-bacterial infections, considering that antibiotics can be effective in preventing the occurrence and possible complications of viral infections. Furthermore, it is clear that doctors, but also pharmacists, rarely warn patients about possible side effects of antibiotics, thereby encouraging the myth of the omnipotence of these drugs. The task of the whole community, which includes health professionals, politicians, farmers and patients themselves, is to rationalize the usage of antibiotics through the development of guidelines, educating doctors and patients, financially supporting the pharmaceutical industry in the discovery and development of new antibiotics and alternative treatments (vaccines, probiotics, lysine phage etc.), and reducing non-therapeutic use of antibiotics in agriculture.

Uvod: U našoj zemlji nema smernica za lečenje bakterijskih infekcija u tercijarnim zdravstvenim ustanovama. Odabir antibakterijskih lekova je empirijski, što nije uvek u skladu sa preporučenom terapijom prema međunarodnim smernicama. Zbog toga su na Klinici za infektivne bolesti Kliničkog centra Vojvodine u januaru 2013. godine usvojeni međunarodni protokoli i primenjivani za lečenje infektivnih bolesti bakterijske etiologije. Cilj istraživanja bio je da se ispita i uporedi efikasnost lečenja pojedinih antibiotskih tretmana za lečenja infektivnih bolesti bakterijske etiologije prema kliničkom iskustvu ordinirajućeg lekara, prema međunarodno prihvaćenim protokolima i prema modifikovanim međunarodnim protokolima na osnovu stanja lokalne rezistencije. Materijal i metode: Ispitivanje je bilo retrospektivno-prospektivno u trajanju od tri godine od 01.01.2012-31.12.2014.godine, sprovedeno je na Klinici za infektivne bolesti Kliničkog centra Vojvodine. U studiju je uključeno 1147 pacijenata sa dijagnozom infektivne bolesti bakterijske etiologije (sepsa, infekcija urinarnog trakta, bakterijski meningitis, infekcije kože i mekih tkiva, bakterijski tonzilofaringitisi, pneumonija, febrilni gastroenteritis i spondilodiscitis). U retrospektivnom delu, tokom 2012. godine ustanovljena je efikasnost lečenja prema kliničkom iskustvu ordinirajućeg lekara, kod 459 pacijenata. U drugom delu ispitivanja koje je bilo prospektivno, tokom 2013. godine, kod 487 pacijenata, ustanovljena je efikasnost lečenja prema međunarodnim protokolima i upoređena sa lečenjem prema kliničkom iskustvu ordinirajućeg lekara. Tokom 2012. i 2013. godine, ustanovljena je struktura uzročnika i rezistencija na antimikrobne lekove, i prema stanju lokalne rezistencija modifikovani su međunarodni protkoli i primenjivani su tokom 2014. godine. U trećem delu ispitivanja koje je bilo prospektivno, tokom 2014. godine, kod 201 pacijenta ustanovljena je efikasnost lečenja prema modifikovanim međunarodnim protokolima i upoređena sa lečenjem prema usvojenim međunarodnim protokolima. Efikasnost lečenja praćena je na osnovu vrednosti telesne temperature i na osnovu laboratorijskih parametara (leukocita, C reaktivnog proteina, fibrinogena, sedimentacije eritrocita i prokalcitonina), prvog i sedmog dana hospitalizacije. Za upoređivanje efikasnosti terapijskih režima napravljen je sistem skorovanja telesne temperature i laboratorijskih parametara. Za statističku obradu podataka korišćen je programski paket Statistical Package for Social Sciences - SPSS 21. Statistički značajnim se smatraju vrednosti nivoa značajnosti p0,05). Lečenje pacijenata sa infekcijom urinarnog trakta, prema modifikovanim međunarodnim protokolima je statistički značajno efikasnije u odnosu na efikasnost lečenja prema usvojenim međunarodnim protokolima (p=0,025) poredeći ukupan skor kliničkih i laboratorijskih parametara. Lečenje pacijenata sa tonzilofaringitisima i infekcijama kože i mekih tkiva prema modifikovanim međunarodnim protokolima podjednako je efikasno u odnosu na lečenje prema usvojenim međunarodnim protokolima (p=0,100) poredeći ukupan skor kliničkih i laboratorijskih parametara. Zaključak: Upoređivanjem dobijenih rezultata, omogućeno je određivanje najoptimalnijeg načina lečenja bolesti bakterijske etiologije, uvažavajući preporuke prema međunarodnim smernicama. Dobijeni rezultati ukazuju na to da je praćenjem lokalne strukture uzročnika i stanja lokalne rezistencije omogućeno određivanje optimalnijeg načina lečenja infekcija urinarnog trakta i infekcije kože i mekih tkiva, uvažavajući međunarodne preporuke i modifikaciju međunarodnih smernica prema stanju rezistencija bakterija na antimikrobne lekove u našoj sredini, Introduction:In our country,there are noguidelines for the treatment of bacterial infections in tertiary health institutions. The choice of antibiotic is empirical and it does not always comply with the recommended treatment according to international guidelines. For this reason, international protocols were adopted at the Clinic for infectious diseases of the Clinical Center of Vojvodinain January 2013. and implemented in therapy of infectious diseases caused by bacteria. The aim of the study was to compare different regimens and to evaluate their effectiveness in therapy of the bacterial infections: one based on the clinical experience of the prescribing physician, another based on international guidelines and the third, modified international protocoladapted to comply with the local antibacterial resistance. Material and methods: Thisretrospective-prospective study was conducted at the Clinic for Infectious Diseases of the Clinical Center of Vojvodina and it covered the period of three years, from 01.01.2012.-31.12.2014. 1,147 patients diagnosed with infectious diseases of bacterial etiology (sepsis, urinary tract infections, bacterial meningitis, skin and soft tissue infections, bacterial tonsillopharyngitis, pneumonia, febrile gastroenteritis and spondylodiscitis) were included in the study. In the first, retrospective part of the study, the efficacy of therapy based on the clinical experience of the prescribing physician was analyzed from medical records of 459 patients treated in 2012. In 2013, during the second, prospective part of the study, the efficacy of treatment according to the international guidelines was evaluated in 487 patients and the results were compared to the data obtained from the patients treated according to the clinical experience of the prescribing physician. The types of organism isolated in 2012/2013 were analyzed as well as their resistance to antimicrobials, the international protocols were subsequently modified according to the state of local resistance and implemented during 2014. In 2014, during the third, prospective part of the study, the efficacy of therapy according to modified international protocols was established in 201 patients, and the results were compared to the ones obtained by therapy according to original international protocols. The efficacy of the treatment was estimated by body temperature measurements and laboratory parameters (leukocytes, C-reactive protein, fibrinogen, erythrocyte sedimentation rate and procalcitonin) on day 1 and day 7 of hospitalization. The scoring system for body temperature and laboratory parameters was designed to compare therapeutic regimes efficiency. For statistical analysis, we used a software package Statistical Package for Social Sciences- SPSS 21. The values of p0.05) was observed in efficiency of treatment options for other studied bacterial infections. In therapy of urinary tract infections, modified international protocols proved to be significantly more efficient than the adopted international protocols (p = 0.025) when the total score of clinical and laboratory parameters was compared. Comparing the total score of clinical and laboratory parameters, both adopted international protocols and modified international protocols proved to be equally efficient (p=0,100) in therapy of bacterial tonsillopharyngitis and skin and soft tissue infections. Conclusion:Comparison of the obtained results made possible to develop the optimal way of treating diseases of bacterial etiology, taking into account recommendations by international guidelines.The results suggest that the monitoring of the local structure of pathogens and their resistance pattern enabled the determination of optimal treatment options for urinary tract infections and skin and soft tissue infections, respecting international recommendations and modifying the international guidelines to match bacterial resistance pattern in our community.

Cilj istraživanja: Cilj istraživanja je načiniti opsežan pregled dosadašnjih spoznaja i zahtjeva za razvoj i primjenu bakteriofaga kao potencijala za suzbijanje infekcija uzrokovanih rezistentnim bakterijskim sojevima. Hipoteze istraživanja su: 1. Mehanizam djelovanja bakteriofaga razlikuje se od mehanizma djelovanja standardnih antibiotika pa razvoj rezistencije može biti odgođen ili se rezistencija može prevladati. 2. Bakteriofagi predstavljaju potencijal za izbjegavanje trenutne krize nedostatka učinkovitih antibiotika, uslijed povećanog razvoja i širenja bakterijske rezistencije. 3. Optimizacijom i razvojem bakteriofagi mogu poslužiti kao nadopuna terapiji antibioticima. Materijal i metode: Pregledom znanstvene literature su opisane trenutne spoznaje o bakteriofagima, njihov mehanizam biološkog djelovanja i interakcije s bakterijskim stanicama. Osim regulatornih, sagledani su i zahtjevi kakvoće te sigurnosti koje bi bakteriofagi trebali zadovoljiti. Razmatrana je terapijska širina, bakterijska rezistencija na bakteriofage, izazovi pri proizvodnji te mogućnosti modifikacije bakteriofaga. Prikazani su dosadašnji rezultati dobiveni primjenom bakteriofaga u suzbijanju bakterijskog rasta te prednosti i nedostaci u odnosu na trenutno dostupnu antibakterijsku terapiju. Rezultati: Predloženo istraživanje pruža uvid u dosadašnje dostupne rezultate te zahtjeve koje je potrebno zadovoljiti kako bi bakteriofagi bili korišteni kao terapija infekcija uzrokovanih rezistentnim sojevima. Interes za primjenu litičkih faga predstavlja njihova mogućnost samoumnažanja na mjestu infekcije u prisutnosti patogenih bakterija, što je potvrđeno ispitivanjem učinkovitosti in vivo. Potrebno je detaljnije utvrditi farmakološke zahtjeve takve terapije. Za proširenje terapijske širine optimalni bi bili kokteli bakteriofaga. U te svrhe potrebno je genotipski i fenotipski definirati izolate bakteriofaga, kako bi se izbjegao razvoj rezistencije kod ciljanih bakterija. Navedeno je značajno i sa sigurnosnog aspekta, da se izbjegnu neželjeni učinci na ljudsko zdravlje. Optimizacija i proizvodnja bi trebala biti u skladu sa zahtjevima dobre proizvođačke prakse uz kvalitetu ugrađenu u proizvod. Redefiniranje regulatornih zahtjeva i provođenje svih faza kliničkih ispitivanja omogućilo bi dostupnost na tržištu takvih pripravaka a) za suzbijanje bakterijskih infekcija, za koje nema drugog učinkovitog odgovora, ili b) kao nadopuna antibiotičkoj terapiji, obzirom da je utvrđen sinergizam između faga i antibiotika. Zaključak: Bakteriofagi predstavljaju značajan, ali trenutno nedovoljno razvijen potencijal za korištenje u terapijske svrhe za suzbijanje bakterijskih infekcija, koji se može koristiti samostalno ili pak kao potpora antibiotičkoj terapiji. Osim toga, budući da se mogu modificirati metodama genetičkog inženjerstva mogli bi poslužiti i za dostavu cjepiva ili DNA u genskoj terapiji. Smjer razvoja i potencijalnu primjenu bakteriofaga definirat će rezultati budućih multidisciplinarnih istraživanja, što će ovisiti o rezultatima kliničkih ispitivanja te potvrdi učinkovitosti i sigurne primjene kod ljudi prema regulatornim zahtjevima Europske Unije i Sjedinjenih Američkih Država. Objectives: The main aim is to make a comprehensive review of recent studies and requests for the development and application of bacteriophages as a potential to combat infections caused by resistant bacterial strains. Hypotheses are: 1. Mechanism of action of bacteriophages is different from the mechanism of action of standard antibiotics and the development of resistance can be delayed or resistance can be overcomed. 2. Bacteriophages represent the potential for avoiding the current crisis due to the lack of effective antibiotics as a result of increased development and spread of bacterial resistance. 3. By optimization and development bacteriophages can be used as a supplement to antibiotics. Material and methods: A review of scientific literature describes the current knowledge of bacteriophages, their mechanism of biological action and interaction with the bacterial cells. In addition to regulatory, perceived are also requirements about quality and security that bacteriophages should fullfil. The therapeutic range, bacterial resistance to bacteriophages, challenges and opportunities in the production of modified bacteriophages were also concidered. Results which are obtained in use bacteriophages to combat bacterial growth so far and their advantages and disadvantages compared to currently available antibacterial therapy are also shown. Results: The proposed research provides insight into obtained results of scientific research and requirements which have to be met in order to make bacteriophages suitable for the treatment of infections caused by bacterial strains resistant to antibiotics. Interest in the application of lytic phages is based on their ability of selfreplication on the site of the infection and in the presence of pathogenic bacteria, as it was confirmed by examining in vivo efficacy. It is necessary to further define the pharmacological requirements of such therapy. Use of bacteriophage cocktails would represent optimal extension of their therapeutic applications. For this purpose it is necessary to define genotype and phenotype of bacteriophage isolates, in order to avoid the development of resistance in the target bacteria, as well as to avoid adverse effects on human health. Optimization of the production should be in accordance with the requirements of good manufacturing practice and quality built into the product. Redefinition of regulatory requests and pass of all clinical trials phases would allow the availability of such preparations on the market a) for the use in the control of bacterial infections, for which there is no effective response, or b) as a supplement to antibiotic therapy, based on the determined synergism between phages and antibiotics. Conclusion: Bacteriophages are an important, but currently not sufficiently developed potential for use in suppression of bacterial infections, that can be used alone or as support to antibiotic therapy. In addition, since they can be modified by the methods of genetic engineering, it could be possible to use them for delivery of DNA vaccines or gene therapy. Development course and potential for the use of bacteriophages will be defined by the future multidisciplinary research, which will depend on the results of clinical trials and confirmation of the efficacy and safety for use in humans according to the European Union and the United States of America regulatory requirements.

In the past decades most infective microorganisms have shown increasing resistance to standard available antibiotics. In pediatrics, the increase in the rate of development of antibiotic resistance in Streptococcus pneumoniae and Haemophilus influenzae is of great concern, because these bacteria are the major etiologic agents causing serious pediatric infections such as meningitis and septicemia. Antibiotic resistance among Gram-negative bacteria has reached critical level. The rise of carbapenem resistance in Enterobacteriaceae carrying additional resistance genes to multiple antibiotic classes has created a generation of organisms nearly resistant to all available therapy. Inappropriate use of antibiotics, especially for viral respiratory infections, has favoured the development and spread of antibiotic-resistant microorganisms. U poslednjih nekoliko decenija kod većine patogenih mikroorganizama registrovan je razvoj rezistencije na standardne antibiotike. U pedijatrijskoj praksi porast broja rezistentnih sojeva Streptococcus pneumoniae i Haemophilus influenzae je zabrinjavajući, jer su ove bakterije česti uzročnici ozbiljnih infekcija kao što su meningitis i septikemija. Rezistencija gram-negativnih bakterija na antibiotike dostigla je kritičan nivo. Sojevi enterobakterija koji su rezistentni na karbapeneme istovremeno nose gene rezistencije na više različitih grupa antibiotika, što praktično znači da se radi o bakterijama koje su otporne na skoro sve trenutno dostupne antimikrobne lekove. Neopravdana primena antibiotika, naročito u slučajevima virusnih infekcija gornjih respiratornih puteva, jedan je od faktora koji su doprineli razvoju i širenju rezistentnih sojeva mikroorganizama.