1、Antibiotics and chemotherapeuticsdefinitionmechanism of actiontype of actiontoxicity and undesirable actionstypes of antibiotics,rational therapyANTIBIOTICS(ATB)Selectively inhibit or kill microbes in concentrations that are not toxic for macroorganism not like desinfections and antiseptics,ATB can
2、be used inside human body Antibiotics(ATB),antimicrobial(ATM)agents are also chemoterapeutics with antimicrobial activiry that have -source in the nature -been produced artifitially ATB according to their source:Producers can be:1.actitnomycetes-aminoglycosides,tetracyclines,macrolides2.other bacter
3、ia(mostly Bacillus sp.)-bacitracin,polymyxin3.microscopic fungi(penicilium,aspergilum)-penicilnyATB can be derived also form plants-fytoncides -from annimal tissues ecmolins ATB according to the aim group:1.antibacterial,antibiotics in proper sense -mostly used common 2.antimycotics -against molds a
4、nd yeast 3.antiprotozoal -against eucaryotic worms,protozoa 4.antiviral -certain antiviral chemotherapeutics Bakteriostasis-situation when ATB inhibit multiplication,division of bacterial cell -bacteria are not killed Natural dieing of living form of bacteria is not influenced Baktericidia-killing o
5、f bacterial cells by ATB-specific impact is during the first 4 hours of ATB therapy-if during this period 99%of bacterial populations is killed the bactericidia is clinically relevantATB according to the type of action1.Primary bakteristatic -chloramphenikol -tetracyclins -macrolides -sulphonamides
6、-nitrofurans.2.Primary baktericidal -penicilins -cephalosporins -streptomycine -polymyxin,.Penicilins and cephalosporins are acting only on dividing bacteriaAminoglykosides kill also resting,not dividing cellsATB according to the spectrum of action:1.Narrow spectrum of ATBs and chemotherapeutics -al
7、low the targeted therapy of usually 1 bacterial group,species Mycobacterium sp,G+,or only staphylococci:napr.antituberculotics,.antistaphylococcal atbs2.Broad spectrum ATBs and chemotherapeutics active on several species(G+and G-)-aminoglycosides -ampicilin -chloramphenicol -tetracyclins -sulphonami
8、des -Mechanism of action at the level of:1.Synthesis of cell wall 2.Disruption of protoplasmatic membrane3.Inhibition of proteosynthesis4.Interference of nucleic acid metabolism Mechanism of action:1.Inhibition of synthesis of peptidoglycans of cell wall Synthesis is going on in 4 phases:I.synthesis
9、 of monomers,II.condensation,III synthesis of phospholipids in cell wall,IV incorporation of peptidoglycan in the preexisting cell wall structure -I to III:bacitracin,vancomycin,cyckloserinn -IV penicilines,cephalosporinesbeta-lactam ATBs those that have heterocyclic beta lactam ring PNC,cephalospor
10、ins inhibit synthesis of peptidoglycans vancomycin,teicoplanin inhibition of condensation of monomers acyl-D-alanyl-D-Alabacitracin -inhibition of phospholipids synthesis Mechanism of action2.Disruption of protoplasmatic membrane-polymyxin ATBs,-some of polyen antimycotics Polymyxins bind lipid and
11、protein molecules and unables bariere function of plasmatic membrane-polymyxins -phospholipids of cytoplasmatic membrane-amphotericin B synthesis of ergosterol-asoles -synthesis of ergosterolMechanism of ATBs action:3.Inhibition of proteosynthesis -tetracyclins,macrolides,aminoglycosides,.-inhibitio
12、n of the binding of aminoacyl-tRNA on receptors of ribosomes -lack of aminoacids -inhibition of polysomes formation from free ribosomes and mRNA-chloramphenicol-tetracyclins -macrolides -clindamycin -aminoglycosides Mechanism of ATBs action4.Inhibition of nucleic acid metabolismNucleic acids:-chinol
13、ons -DNK-gyrase-rifampicin -RNK-polymerase-nitroimidasoles -Synthesis of folic acid:-sulfonamids -synthesis of folic acid -trimetoprim -reductase of dihydrofolic acidGroups of antibacterial ATBspenicilins -synthesis of peptidoglycan of cell wallcefalosporins -/-carbapenems -/-monobactams -/-inhibiti
14、on of beta-lactamaseaminoglycosids -tetracyclins -synthesis of microbial proteinschloramphenicol -/-macrolids -/-polypeptids -synthesis of cell wall structureslincosamids -proteosynthesisglykopeptids -synthesis of mucopeptids of cell wallAntibacterial chemotherapeuticssulphonamids -synthesis of foli
15、c acidsulphonamids -/-+diaminopyrimidins nitrofurans -inhibtion of glycid metabolismchinolons -synthesis of nucleic acids nitroimidasoles synthesis of nucleic acids anaerob bacteria Penicilins -primary bactericidal G PNC-G+-streptococci,pneumococci,corynebacteria,listeriae,staphylococci not producin
16、g beta lactamaseantistaphylococcal PNC resistent to betalactamase produce by staphylococci -meticilin,oxacilinbroad spectrum PNC -G rods,not nonfermenters,not proteus,not enterococci-ampicilinantipseudomonad PNC against pseudomonas,proteus indol+-carbapenemsacylureidoPNC -G+,G-,pseudomonas Cephalosp
17、orins -semisynthetic -bactericidal -high concentration in urine and CSF1st generation-G+G-enterobacteriae,urinary tract infection2nd generation-G-rods G-cocci3rd generation-G-4th generation-enterococci,staphylococci,pseudomonas Other betalactamsmonobactams:bactericidal G-enterobacteriaceae,serratia,
18、pseudomonaskarbapenems:baktericidal G+G-very broad spectrumChloramphenicol:bacteriostatic G+G-Tetracyclines:bakteriostatic,in higher concentration bactericidal G+G-treponema,leptospira,mycoplasma,chlamydia Macrolides:bacteriostatic,mid broad spectrum,G+Aminoglycosides:baktericidal broad spectrum,G+G
19、-Polypeptids:baktericidal G-rods(exc.proteus)Linkomycin,clindamicin-G+cocciVancomycin G+(staphylococci,enterococci)Antituberculotics:bakteriostatic toxic only for TBC rifampicin INH,ETM,PYR,PASChemotherapeuticssulfonamids:bacteriostatic G+G-,chlamydia,mycoplasma,nocardia,toxoplasma,cotrimoxazol:comb
20、ination of trimetoprim+sulfametoxasol(both bacteriostatic,but in combination the effect is clinically baktericidal)G+G-chinolons baktericidal 1.gen.nalidixin acid G-,uroinfections 2.gen.Fluorochinolons,G+,G-3.gen.Di.-Tri.-fluorated chinolons Undesirable effectarising when normal general doses and re
21、comended concentrations of ATBs are applied Toxic effectarising when high doses and elevated plasmatic concentration are reached,or are cause by higher reactivity of organisation or unfunctional elimination waysUndesirable effectsAlergy usually after sensibilisation caused by very small dose and giv
22、en in not natural way -frequent in PNC -look for them in history -polymorphic exanthema,eosinoflia,edema,conjunctivitis photodermatoses,anaphylactic shock.-dangerouse formes in parenteral application of ATB -can arise as early or late,whenever during therapy or after it ended -reaction could be caus
23、ed by other molecules(adjuvants,conservations)Undesirable effectsbiological -are connected with the influence of natural bacterial flora of skin or mucous membranes -frequent in broadspectrum ATBs(ampicilin,tetracykln)-clinically like dyspepsia,diarhoeae,hypovitaminosis K,subsequent disorders of hem
24、ostasis -overgrowth of candida or resistent bacteria staphylococci,pseudomonas these complications are problem for therapy pseudomembran colitis Toxic effectshematotoxic -gancyclovir,chloramphenicolnefrotoxic -amfotericin Bhepatotoxic -rifampicin,ketokonasolneurotoxic -nitrofurantoin,gentamycin,izon
25、iazid,streptomycin Resistence of bacteria to the effect of ATB ot chemotherapeutics-natural microbes are out of spectrum of ATB(bacteria without cell wall to PNC)-primary not sensitivity of a part of bacterial population,that is normally in spectrun of ATB efficiency and without any influence of pre
26、liminary therapy with that ATB-secundary not senzitivity of the strain belonging to the spectrum of ATB,that arisis after exposition to the that ATB-mutational related to previous therapy,mutation resistention multiplication of resistent bacteriae-transmissible resistence mediated by plasmids -more
27、frquent in G-transmission of genetic informationTransduction by bacteriophage to another bacterium-cross resistence not sensitivity to several ATB -bidirectionnal(relative ATB)-onedirectionnal(Gent.-Amikacin),Mechanism of resistence1.Production of ensyms:their activity changes the structure of antim
28、icrobial and it causes the loss of efficiencyBeta laktamase extracelularly acting ensyms of microbes,that disrupt beha lactam ring so that ATB of these type loss the efficiency.The similar effect is seen in intracelularly acting acetyltransferzy on chloramphenicol.Classification of betalactamasesCef
29、alosporinase(not inhibited by clavulanic acid)Chromosomally mediated ensyms Ps.aeruginosa,Enterobacter.cloacae Penicilinase,cefalosporinase Inibited by clavulanic acid Mediated by plasmids TEM-typ.,Chromosomally mediated ensyms Klebsiela spp.,staphylococcal ensymss Metaloensyms Ensyms hydrolysing im
30、ipenem,Xantomonas maltophylia Penicilinase(not inhibited by clavulanic acid)Chromosomally mediatedy Ps.cepacia 2.Mutation at the level of intracellular receptor:-changes in structures of PBP-resistence to PNC -metylation of aminoacids on 50 S ribosomes subunits-resistence to erytromycin 3.Inhibition
31、 of penetration of ATB through cell wall:aminoglycosids,tetracyclines 4.Changes in metabolic pathway,in affinity of target ensym 5.Higher elimination of ATB-efflux Mostcommon mechanism of resistence in groups of ATBBeta lactam ATB changes in PBP,decreased permeability,production of ensymsaminoglycos
32、ids,macrolids -decreased binding to target ribosoms decreased permeability of the cell wall inactivating ensyms chloramfenicol decreased binding on ribosomes -permeability -acetyltransferasetetracyclines anavaibility of target ribosomes active effluxChinolons resistence of DNA-gyrase decreased perme
33、ability aktive cell effluxsulfonamides resistence of syntetasetrimetoprim rezistene of reduktase decreased permeabilityEtiological therapy -is ideal -isolation of agens -ATB sensitivity testing -choice of ATB (good acceptance,narrow spectrum)-in chronic disease caused by resistent microbes Empiric t
34、herapy -choice of ATB acc.to expected spectrum of etiological agens -evaluation of clinical state -knowledge of most common ethiological agens Intervention therapy-if the ethiological microbe was not identified -according to algorithm that will identify next therapy if the inicial was not successful
35、l Broadspectrum therapy in life threatning infections -ATB able to cover almost the whole spectrum of possible agenses -combination of several ATB -used in cases of sepses,peritonitis,-imipenem,cefotaxim+piperacilin Combination of ATBs to increase the efficiency increase the spectrum of target bacte
36、ria prevention of bacterial resistenceAditive effect resulting effect of the combination of 2 ATBs equals the addition of 2 effectsIndiferent effect no change of effectAntagonistic effect resulting effect of 2 used ATB is less efficient then use of individual ATB aloneSynergy resulting effect of 2 u
37、sed ATBs is higher then if used of individual ATB aloneATB susceptibility testingkvalitative test-difuse disc testkvantitative-MIC minimal inhibition concentration-MBC minimal bactericidal concentration-E test combination of DDT and MBCOn liquid cultivation media (MIC)or solid media(DDT,E test,MBC)M
38、inimal inhibition concentration(MIC)-the lowest concentration of ATB that inhibits the gorwing and multiplication of bacterium in test medium in vitro.-in testing MIC the standardisation of conditions is crucialresults can be influenced by the size of innoculum,quality of test medium,temperature.Min
39、imal baktericidal concentration(MBC)-lowest concentration of ATB that kills in vitro exposed bacterial population during 24 hours incubation in liquid media and then innoculated on solid media.Aplikation-parenteral -peroral -localDoses -individual -daily -overall Interval of doses -time between indi
40、vidual doses -correction in renal inssuficiency -depends on capacity of the elimination of ATB from the bodyAge old,young,newborneDisease some ATBs do not enter the target place,or do not be active in some places Period of therapy individual(nen complicated gonorrhoeae -7-10 days common infection of respiratory thract -longlasting-absces,granulomas,osteomyelitis tuberculosis,sepsa,endokarditis,borreliosis,chlamydiosis -immunodeficient
