CHARACTERISTIC FEATURES OF PRESSURE ULCER INFECTION

Dekubitus je lokalizirano oštećenje kože i/ili priležećeg tkiva uobičajeno iznad koštanih izbočina. Rezultat je pritiska ili pritiska u kombinaciji s posmičnim silama, trenjem i vlagom. S obzirom na dugotrajnost i odgođeno cijeljenje dekubitus je kronična rana. Dekubitus nastaje kao posljedica kombinacije mikroembolije, ishemije i mionekroze. Ti patofi ziološki procesi idealna su podloga za umnožavanje mikroorganizama, dominantno bakterija i razvoj infekcije. Progresija razvoja dekubitusa dinamičan je proces koji prolazi nekoliko faza, a svaka je karakterizirana fi ziološko-anatomskim osobitostima, te mikrobiološkim statusom. Otvorena lezija bez zaštitne pokrovne barijere biva odmah kontaminirana, a ubrzo i kolonizirana fi ziološkom mikrofl orom domaćina, te mikrobima iz okoline. Ako izostanu preventivne mjere rana biva kritično kolonizirana i infi cirana. Karakteristika kronične rane - dekubitusa je da je kolonizirana, a infekcija se razvija ovisno o različitim čimbenicima od 2 % do 80 %. Sposobnost mikroba da uzrokuju infekciju ovisi o brojnim čimbenicima koji uključuju patogena i domaćina. Brojnost i količina virulentnih čimbenika mikroba određuje koefi cijent virulencije o čemu ovisi nadjačavanje imunog sistema domaćina te razvoj infekcije. U razvoju infekcije dekubitusa dominiraju dva bitna čimbenika mikroba, prisustvo adhezina i asocijacija s biofi lmom. Tako je infekcija dekubitusa kao kronične rane karakterizirana polimikrobnom i heterogenom populacijom mikroba, dominacijom fenotipa biofi lma kao primarnog čimbenika virulencije prisutnog u 90 % slučajeva, fenotipskoj hipervarijabilnosti vrsta i rezistencijom ili tolerancijom uzročnika na sve vrste biocida. Najznačajniji virulentni čimbenik je biofilm. To je korporativna zajednica mikroba s jasnom arhitekturom kojom upravljaju quorum sensing molekule. Preko njih se odvija komunikacija između specijesa, mijenja se fenotip i virulencija, te razvija rezistencija na razini genoma. Formiranje biofilma razvija se u nekoliko stadija, a brzina stvaranja mjeri satima. Mikroorganizmi u biofi lmu zaštićeni su od djelovanja imunog sustava domaćina i tolerantni ili rezistentni su na djelovanje antibiotika, antiseptika, stres. Bakterije koje uzrokuju infekciju dekubitusa pripadaju u oportunističke, ali i primarno patogene. Dominacija i kombinacija vrsta ovise o trajanju, lokalizaciji i stupnju dekubitusa. Dominantni uzročnici su Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa, Peptostreptococcus spp. Danas, prevladavaju multiplorezistentne vrste kao što su MRSA, Acinetobacter spp, Pseudomonas spp. Kronična rana kao što je dekubitus idealna je za razvoj infekcije, osobito ako se ne poduzmu ciljani preventivni postupci. Dijagnoza infekcije je kompleksna i temelji se na kombinaciji primarnih i sekundarnih kliničkih simptoma, tkiva u rani, stanju okoline rane, biljezima upale te rezultatima mikrobiološke obrade ciljanih uzoraka - bioptata, koji je zlatni standard. Pri postavljanju dijagnoze infekcije bitno je razlikovati kritičnu kolonizaciju od infekcije dubokog tkiva, a što se temelji na kliničkim kriterijima nazvanim NERDS-STONEES. Učestalost infekcije dekubitusa iznosi 5 % do 80 %, a biofi lm je prisutan u 90%. Razumijevanje epidemiologije dekubitusa i praćenje komplikacija kao što je infekcija, temelj je za razumijevanje kronične rane i napora da se unaprijedi skrb, prevenira razvoj, a kurativni postupci da uključe kombinaciju strategija.Pressure ulcer is a localized injury of the skin and/or adjacent tissue, usually above bone protrusions. It is a result of pressure or pressure combined with shear stress, friction and humidity. With regard to long life and delayed healing, it is a chronic wound. Pressure ulcer appears as a consequence of a combination of micro-embolism, ischemia and myonecrosis. These pathophysiological processes provide an ideal medium for proliferation of microorganisms, predominantly bacteria, and development of infection. Progression in the development of pressure ulcer is a dynamic process manifesting in phases, each of which is characterized by its own physiological-anatomical peculiarities and microbiological status. An open lesion without protective barrier becomes contaminated immediately, and, shortly afterwards, colonized by physiological microfl ora of the host and microbes from the environment. In the absence of preventive measures, the wound becomes critically colonized and infected. The characteristic of chronic wound/pressure ulcer is that it is colonized, and the infection develops depending on various factors in 5% to 80% of cases. The ability of microbes to cause infection depends on a number of factors, which include the pathogen and the host. The number and quantity of virulent factors, microbes, determines the virulence coeffi cient, which is responsible for overcoming the host’s immune system and development of infection. In the development of pressure ulcer infection, two essential microbial factors predominate, i.e. the presence of adhesin and association with biofi lm. Thus, pressure ulcer infection as a chronic wound is characterized by a polymicrobial and heterogeneous population of microbes, domination of biofi lm phenotype as a primary factor of virulence present in 90% of cases, phenotype hypervariability of species, and resistance or tolerance of the etiological agents to all types of biocides. The most significant virulence factor is biofilm. It is a corporative community of microbes with a clear architecture managed by quorum sensing molecules. It is through them that the communication between species takes place, the phenotype and virulence change, and resistance develops at the level of genome. The formation of biofi lm takes place in several stages, and the speed is measured in hours. Microorganisms in the biofi lm are protected from the action of the host’s immune system and, likewise, they are tolerant or resistant to antibiotics, antiseptics, and stress. Bacteria causing pressure ulcer infection are characterized as opportunistic, but also primarily pathogenic. The dominance and combination of species depend on the duration, localization and stage of pressure ulcer. The predominant etiological agents are Staphylococcus aureus, Streptococcus pyogenes, Pseudomonas aeruginosa and Peptostreptococcus spp. Nowadays, multiple-resistant strains predominate, such as MRSA, Acinetobacter spp. and Pseudomonas spp. A chronic wound such as pressure ulcer is ideal for the development of infection, especially if targeted preventive measures are not applied. The diagnosis of infection is complex and is based on the combination of primary and secondary clinical symptoms, tissue in the wound, status of the wound environment, infl ammation markers, and results of microbiological examination of targeted samples – biopsies, which are the gold standard. In reaching the diagnosis of infection, it is crucial to differentiate critical colonization from deep tissue infection, which is based on clinical criteria called NERDS-STONEES. The frequency of pressure ulcer infection is 5% to 80%, and biofi lm is present in 90% of cases. Due knowledge of the epidemiology of pressure ulcer and follow up of complications such as infection make the basis for the understanding of chronic wound, efforts to improve necessary care, prevention of development and application of a combination of treatment strategies

THE ROLE OF ANTISEPTICS AND STRATEGY OF BIOFILM REMOVAL IN CHRONIC WOUND

Kronična rana ne cijeli u očekivanom razdoblju jer je zaostala u upalnoj fazi cijeljenja. Razlog tome je prisutnost nekrotičnog tkiva, velikog broja mikroorganizama - dominantno bakterija koje izlučuju biofi lm - uz ishemiju, hipoksiju i edem. Biofilm je prisutan u 90 % kroničnih i 6 % akutnih rana. Biofilm je korporativna zajednica mikroba adheriranih na površine (rana) kojom upravljaju quorum sensing molekule. Zajednica je okružena s hidratantnim matriksom od ekstracelularnih polimernih sastojaka (slime) koji štite mikrobe od djelovanja antibiotika, antiseptika, obrane makroorganizma i stresa. Primarni uzrok kroniciteta rane je biofi lm, jer uzrokuje permanentnu upalu, odgođeno formiranje granulacijskog tkiva, migraciju epitelnih stanica i rezervoar je mikroba koji uzrokuju infekciju kronične rane. Cilj dobre kliničke prakse jest da omogući cijeljenje kronične rane u očekivanom razdoblju. Za postizanje cilja nužno je reducirati i cjelovito ukloniti biofi lm iz rane i prevenirati njegovu rekonstrukciju. To se postiže primjenom antibiofi lm aktivnih spojeva i postupcima koji će razgraditi quorum sensing molekule, degradirati ekstracelularne polimerne sastojke (EPS) i blokirati prihvaćanje za površine. Suvremena istraživanja ukazala su da primjena antiseptika ima učinak u prevenciji infekcije i potpora je ciljanom liječenju. Činjenica je da su samo neki antiseptici primjenjivi za kronične rane i aktivni na biofi lmove primarnih uzročnika infekcije Staphylococcus spp, Streptococcus spp, Pseudomonas aeruginosa. Učinkoviti antiseptici su oktenidin dihidroklorid, poliheksanidi, povidon jodin i kadeksomer, nanokristalno srebro i manuka-tip meda. Nepokoreni biofi lm je perzistentan problem kroničnih i kroničnih inficiranih rana. Činjenica je da ni jedan pojedinačni terapijski postupak, kao ni pojedini antiseptik, ne mogu cjelovito uništiti biofilm. To je razlog da suvremeni postupci liječenja i skrbi o kroničnoj rani primjenjuju multimodalnu strategiju u obliku kombinacije mehaničko-kemijskih postupaka: debridement, antiseptici, antimikrobne potporne obloge. Debridmanom se otvara terapijski „prozor“ za djelovanje antiseptika i antibiotika tijekom 72 sata što omogućuje uklanjanje biofi lma i aktivno uništavanje sesilnih i planktonskih bakterija. Tim se postupkom onemogućuje i reformacija biofi lma. Postupci se moraju intenzivno ponavljati, antiseptici i potporne obloge izmjenjivati ovisno o stadiju ležišta rane i komorbiditetnim čimbenicima bolesnika. Rezultati kliničkih studija ukazuju da samo takav proaktivan pristup kroničnoj rani omogućuje cijeljenje u očekivanom razdoblju.Chronic wound does not heal within the expected time frame because it remains in the infl ammation phase of healing. The reason for this is the presence of necrotic tissue and a large number of microorganisms, primarily bacteria that secrete the biofi lm, along with ischemia, hypoxia and edema. Biofilm is present in 90% of chronic wounds and 6% of the acute ones. Biofi lm is a corporative association of microbes which adhere to the surface of the wound, guided by quorum sensing molecules. The association is surrounded by a moisturizing matrix of extracellular polymeric substances (slime) which protect the microbes from the impact of antibiotics, antiseptics, macro-organism defense and stress. Biofilm is the primary cause of the wound chronicity because it causes permanent inflammation, delayed granulation tissue formation and migration of epithelium cells, thus providing a reservoir of microbes that lead to infection of the chronic wound. The aim of good clinical practice is to enable healing of a chronic wound within the expected time frame. In order to achieve this aim, it is necessary to reduce and thoroughly remove the biofi lm from the wound and prevent its reappearance. This is achieved by the application of active anti-biofilm compounds and procedures that disintegrate the quorum sensing molecules, degrade the extracellular polymeric substances and block adherence to the surfaces. Recent researches have shown that the application of antiseptics is effective in the prevention of infection and is a support to targeted treatment. However, the fact is that only some antiseptics are applicable to chronic wounds and can have an impact on biofilms of the primary infective agents such as Staphylococcus spp., Streptococcus spp., and Pseudomonas aeruginosa. Effective antiseptics are octenidine dihydrochloride, polyhexanides, povidone and cadexomer iodine, nanocrystal silver and Manukatype honey. Immobile biofi lm is a persistent problem of chronic and chronic infected wounds. In fact, there is no isolated therapeutic procedure or an individual antiseptic that can fully destroy the biofilm. For this reason, modern strategy in the management of chronic wound applies a multimodal approach which combines mechanical-chemical procedures such as debridement, antiseptics, and antimicrobial supportive compresses. Debridement creates a therapeutic ‘window’ for the action of antiseptics and antibiotics in a 72-hour period, which enables removal of the biofi lm and active destruction of the sessile and planktonic bacteria. This approach also prevents de novo formation of the biofilm. The above procedures must be intensively repeated, and antiseptics and supportive compresses changed, depending on the phase of the wound bed and comorbidity factors in the patient. The results of clinical studies show that only such a proactive approach to chronic wound enables achievement of healing within the expected period of time

ANTISEPTICS IN THE PREVENTION OF CHRONIC WOUND INFECTION – FACTS AND MISCONCEPTIONS

Kronične rane posljedica su brojnih komorbiditetnih čimbenika, a dominantni patoiziološki procesi su ishemija, edem i infekcija uz dob, neuropatiju i traumu. Raspadom integriteta kože nastala rana biva kontaminirana, a zatim i kolonizirana primarno iziološkom lorom domaćina, a zatim mikrobima iz okoline. Sve kronične rane su kolonizirane, a infekcija se razvija u 5 %-40 % slučajeva ovisno o vrsti, lokalizaciji, komorbiditetnim čimbenicima, trajanju, skrbi i liječenju. Posljedica patoizioloških procesa u kroničnoj rani je perzistetna kronična upalna faza s odgođenim cijeljenjem, koje može progredirati u lokalnu infekciju, sepsu, multiorgansko zatajenje i smrt. Različite tvari primjenjuju se u liječenju kroničnih rana milenijima, nažalost bez razumijevanja njihovog djelovanja, koje je često puta posve nejasno. Suvremena istraživanja ukazala su na primjenu antiseptika za kronične rane s efektivnim djelovanjem u prevenciji razvoja infekcije, širenja lokalne infekcije i kao potpora ciljanom liječenju. Prosudba o primjeni antiseptika ovisi o klinički deiniranoj infekciji i kvatitativnoj mikrobiološkoj obradi uzorka kronične rane, uz precizno deiniranu i samu kroničnu ranu. Cilj antisepse je da ubije ili inaktivira mikrobe - primarno bakterije u rani, redukcijom broja ili sprječavanjem multiplikacije u što dužem razdoblju. Antiseptici se primjenjuju u proilaktičke svrhe jednokratno, nekoliko puta tijekom jednog dana ili jednokratno u trajanju od 5 do 7 dana (obloge). Antiseptici primijenjeni u terapijske svrhe primjenjuju se višekratno, kroz duže vrijeme, 7 - 10 - 14 dana ili do početka stvaranja granulacija. Primjena antiseptika je ciljani i ograničeni postupak, osobito pri infekciji kronične rane. Infekcija kronične rane karakterizirana je prisustvom velikog broja mikroba >105CfU/g, miješanom mikrobnom lorom, te brojnim virulentnim čimbenicima od kojih je najznačajniji bioilm. Antiseptici su aktivne tvari, različite kemijske strukture koji se razlikuju po sastavu, spektru djelovanja, učinkovitosti, citotoksičnosti, teratogenosti, indukciji rezistencije i aktivnosti na bioilm. Idealan antiseptik ne postoji pa izbor treba biti praktičan i sa što manje nuspojava. Praktičan izbor antiseptika za kroničnu ranu ovisi o indikaciji, očekivanom patogenu ili patogenima, lokalnoj ili sistemskoj toleranciji, izvedivom vremenju ekspozicije, kumulativnom ili remanentnom djelovanju, lokalnoj i sistemskoj sigurnosti. Apsolutna indikacija za primjenu antiseptika je inicirana akutna i kronična rana, kronična kolonizirana rana u imunonekompetentnog i imunokompromitiranog bolesnika, te svi oblici ozljeda, tj. kontaminirane rane. Antiseptici se rabe do časa pojave granulacija. Antiseptici primijenjeni na kronične rane koji su ujedno učinkoviti na bioilm su klorheksidin diglukonat, poliheksanidi, oktenidin dihidroklorid, povidon jodid i nanokristalno srebro. Zdravstveni djelatnici se susreću s manjkom ili nedostatkom jasnih uputa, kako, kada, koliko dugo i koji od antiseptika primijeniti u svakodnevnoj kliničkoj praksi. Pri primjeni antiseptika nužno je jasno deinirati razloge uporabe, ciljeve i trajanje primjene.Chronic wounds are a consequence of numerous comorbidity factors, and the predominant pathophysiological processes are ischemia, edema and infection, in addition to age, neuropathy and trauma. With breakdown of the skin integrity, the wound becomes contaminated, followed by colonization irst with the physiological lora of the host and, then with microbes from the environment. All chronic wounds are colonized and infection develops in 5%-40% of cases, depending on the type and localization of the wound, comorbidity factors, duration, medical care and treatment. The consequence of the pathophysiological processes in chronic wound is the persistent chronic inlammatory phase with delayed healing, which may progress to local infection, sepsis, multiorgan failure and death. Various substances have been applied in the treatment of chronic wounds for millennia, unfortunately, without due understanding of their effect, which often remains completely un- clear. Modern researches have pointed to the application of antiseptics in chronic wounds to prevent development of infection and spread of local infection, and as support to targeted treatment. The judgment on the application of antiseptics depends on the clinically deined infection, microbiological analysis of the chronic wound sample, and the chronic wound itself. The aim of antisepsis is to kill or inactivate the microbes, primarily bacteria, in the wound by reducing their number, to prevent their multiplication for as long as possible. Antiseptics are applied for prophylactic purposes once-only, several times a day, or once-only for 5-7 days (dressing). Antiseptics are applied for therapeutic purposes repeatedly for a longer period, i.e. 7-10-14 days or until granulations start appearing. The application of antiseptics is a targeted and limited procedure, especially in the infection of a chronic wound. The infection of a chronic wound is characterized by a large number of microbes (>105 CfU/g), mixed microbial lora and numerous virulence factors, the most important of which is the bioilm. Antiseptics are active substances of different chemical structure, which come in a range of composition, spectrum of activity, eficiency, cytotoxicity, teratogenicity, induction of resistance, and activity on the bioilm. As there is no ideal antiseptic, the choice must be practical with minimum side effects. Practical choice of antiseptics for a chronic wound depends on the indication, expected pathogen or pathogens, local or systemic tolerance, available time of exposure, cumulative or residual activity, and local and systemic safety. An absolute indication for the application of antiseptic is infected acute or chronic wound, chronic colonized wound in an immunologically incompetent and immunocompromised patient, and all forms of injuries, i.e. contaminated wounds. Antiseptics are applied until the appearance of granulations. The following antiseptics are applied for chronic wounds, at the same time being effective on the bioilm: chlorhexidine digluconate, polyhexanides, octenidine dihydrochloride, povidone iodine, and nanocrystal silver. Medical personnel are faced with a lack or inadequately clear instructions on how, when, for how long and which antiseptic to apply in daily clinical practice. In the application of antiseptics, it is necessary to clearly deine the reasons for their use, aims and duration of application

RECOGNITION AND TREATMENT OF CHRONIC WOUND INFECTION

Prepoznavanje i liječenje infekcije kronične rane iznimno je kompleksan posao pri kojem je nužan timski rad i svrsishodno postupno rješavanje problema. infekcija kronične rane je najrizičnija komplikacija, jer može dovesti do smrti bolesnika. principi najbolje kliničke prakse obuhvaćaju temeljitu obradu bolesnika s obzirom na endogene bolesti i čimbenike rizika, definiranje mjesta infekcije i karakteristika rane uz kliničke simptome infekcije. temeljem statusa rane indiciraju se dijagnostički postupci i utvrđuje uzročnik i njegova osjetljivost na antibiotike. S obzirom na težinu kliničke slike radi se plan kirurških intervencija, gdje je temeljni postupak debridement ili se primjenjuju potporne metode liječenja, a izbor ovisi o indikacijama i kontraindikacijama. Ciljana metoda liječenja infekcije je sistemska primjena antibiotika uz debridement. značajno je da pri radu s kroničnom inficiranom ranom moramo poštivati principe asepse i antisepse. U kliničkoj praksi postoji raskorak između prihvaćenih kriterija učinkovitog liječenja temeljenog na „evidence base practice“ te objektivnih i subjektivnih problema koji to onemogućuju. tako se prema statističkim podatcima 50 % antibiotika netočno propisuje, izgubi ili propadne, a samo polovica bolesnika se liječi korektno. vrijeme je konsenzusa i prihvaćanja činjenica koje su značajne za liječenje kronične inficirane rane, tj. „medicine temeljene na dokazima“.Recognition and treatment of a chronic wound infection is an extraordinarily complex task that requires team work and purposeful and graduate resolving of the problem. Chronic wound infection is the most risky complication because it may have fatal outcome for the patient. The principles of best clinical practice include thorough examination of the patient with respect to endogenous diseases and risk factors, defining the locality of infection and wound characteristics, along with clinical symptoms of infection. Based on the wound status, diagnostic procedures are initiated and the causative agent and its sensitivity to antibiotics determined. With respect to the seriousness of the clinical picture, a plan of surgical interventions is developed. The main procedure is debridement, followed by supportive treatment methods, the choice depending on the indications and contraindications. The targeted method of treatment is systemic administration of antibiotics along with debridement. It is important to know that on approaching a chronic infected wound, the principles of sepsis and antisepsis should be observed. In clinical practice, there is a discrepancy between the adopted criteria for efficient treatment based on the evidence-based practice and objective and subjective problems that obstruct it. Thus, according to statistical data, 50% of antibiotics are prescribed wrongly or are rendered inefficient for some reason. Only half of the patients are treated correctly. It is high time to reach consensus on this issue and accept the facts relevant for the treatment of chronic infected wound, i.e. evidence-based medicine

The Importance of P-glycoprotein Multidrug Transporter Activity Measurement in Patients with Helicobacter pylori Infection

P-glycoprotein is important in local antibiotic resistance. Aim was to evaluate the role of P-glycoprotein in local antibiotic resistance in patients with antral gastritis during antibiotic therapy to Helicobacter pylori infection. In the group of 53 patients with pathohistologically verified gastritis and microbiologically confirmed H. pylori infection (no signs of antimicrobial resistance) we have determined P-glycoprotein activity in gastric mucosa biopsy specimens, and compared them with the P-glycoprotein activity in 12 control subjects with normal endoscopic findings. The H. pylori positive patients were treated according to Maastricht protocol with short-term 7-day therapy consisting of two antibiotics (amoxicillin and azithromycin/metronidazole and clarithromycin) and a proton pump inhibitor. P-glycoprotein activity was determined in rhodamine dye efflux test and quantified by ratio of the mean fluorescence (RMF) in flow cytometry analysis. H. pylori was successfully eradicated in the first cycle in 20 patients, whereas therapy was continued in 33 patients. The mean pre-treatment RMF values were higher in patients with H. pylori infection then in control subjects (p<0.0046). RMF was also higher in patients with multiple therapeutic failure than in those with successful H. pylori eradication (p<0.0001). RMF increased significantly during the antibiotic therapy (p<0.05). P-glycoprotein might be one of the causes of therapy failure in patients with H. pylori. Our study confirms the importance of quantitative evaluation of P-glycoprotein expression during antibiotic treatment response