Antimicrobial therapy MUDr. Lenka Č ernohorsk á, Ph.D .

1. Antimicrobial therapyMUDr. Lenka Černohorská, Ph.D. Antibiotics are substances against bacteria Other groups: Antivirotics –against viruses Antituberculotics - against mycobacteria Antiparasitics – against parasites

2. Antibiotics are devided due to mechanism of efficacy into 4 groups: • Inhibition of cell wall synthesis (betalactames, glycopeptides) • Cell membrane destroy (polypeptides) • Inhibition of NA syntesis (quinolons, imidazols) • Inhibition of proteosyntesis (tetracyclines, chloramphenicol, macrolides, lincosamides, aminoglycosides) • Attack against bacterial metabolism (sulfonamids)

3. Betalactames • Bactericidal, only for growing bacteria • Often cause allergy • Penicillins (PNC, oxacillin, ampicillin, piperacillin) • Cefalosporines (1.- 4. generation) • Monobactams (aztreonam) • Carbapenems (imipenem, meropenem)

4. Penicillins • PNC (penicillin) – per os, i.v. use – streptococci, gonococci, treponema • Oxacillin – against staphylococci, not for MRSA strains • Ampicillin – enterococci etc. • Piperacillin – against Pseudomonas

5. Cefalosporines • 1stgeneration: Cefalotin, cefazolin – cheap, for prophylaxis, cost of therapy - 7 €/day • 2ndgeneration: Cefuroxim, cefoxitin - most often used • 3rdgeneration: Cefotaxim, ceftazidim*/**, cefoperazon**, ceftriaxon* • 4th generation:Cefepim** • Higher generation - decrease effect on G+ bacteria, increase effect of G-bacteria, 4th generation – storage antibiotics, rare used * - transmission through cerebrospinal fluid ** - against Pseudomonas

6. Monobactams and carbapenems • Monobactams (aztreonam) – not often used, now big resistance to them • Carbapenems - storage ATB - imipenem, meropenem – used in case of ESBL or AmpC producers, pseudomonades…cost of therapy: 250 €/day, but effective • Increasing resistance of many bacteria!

7. Glycopeptides • Reserved for G+ bacteria • Vancomycin and less toxic, but more expensive teicoplanin Polypeptides • Ototoxic and nefrotoxic • Polymyxin B only local as part of ear drops - Otosporin • Polymyxin E – colistin rare used • Primary resistence: all G+ bacteria, proteus, providencia, morganella, serratia etc. N

8. Aminoglycosides • Bactericidal,ototoxicity and nefrotoxicity • Synergy with betalactames – decrease of toxicity • Preparates: Streptomycin only against tuberculosis, gentamicin,netilmicin, amikacin,neomycin with bacitracin = framykoin (neomycin is too toxic, only for local using)

9. Tetracyklines • Broad spectrum • Don‘t use until 10 years (teeth development) • Less often used Chloramphenicol • Broad spectrum • Good penetration to cerebrospinal fluid, Hematotoxicity

10. Macrolides I. generation: erythromycin, rare used II. generation: roxithromycin III. generation: clarithromycin, azithromycin – good intracellular penetration and longlasting effect, for G+ bacteria Lincosamides • Lincomycin and clindamycin • Reserved for surgery, good effect to G+ bacteria and anaerobes in addition to Clostridium difficile – risc of pseudomembranous enterocolitis

11. „ Quinolones • Bactericidal • Don‘t use until 15 years (growth cartilages) • I. generation (oxolin acid), II. generation (norfloxacin) only for urinary tract infection • III. generation: ofloxacin, ciprofloxacin – also for systemic infection – often used

12. Analogs of folate acid • Sulfametoxazol in combination with trimetoprim form ko-trimoxazol known as BISEPTOL • Bacteriostatic, worse penetrate into tissues • Nitrofurantoin (and nifuratel) • Effectivity on sugar metabolism. Bacteriostatic, broad spectrum • For urinary tract infection. Weighty undesirable effect: GIT disorder etc. Other antibiotics Linezolid (zyvoxid) – against resistant staphylococci

13. Nitroimidazols • For anaerobes, for protozoas (T. vaginalis etc.) • Metronidazol, Ornidazol Antituberculotics • HRZS,HRZE - starting therapy (INH, rifampicin, pyrazinamid, streptomycin, etambutol) + other • HRZ,HRE – sequenced therapy

14. Antivirotics • Against herpes – acyclovir… • CMV – gancyklovir, foscarnet • Influenza – amantadin, rimantadin, tamiflu • Antiretrovirus therapy – inhibitors of reverse transcriptase (nucleosid+nonucleosid) , inhibitors of protease – in combination Preparates: zidovudin, didanosin …

15. Antimycotics • Fluconazol, itraconazol, ketoconazol etc. – local (vaginal, skin infection) • Amphotericin B – i.v. (in sepsis) Antiparasitics • Against protozoa, helmintes, ectoparasites (moore in parasite capitol) Other preparates • Antimalaric: primachin, chlorochin, meflochin… • Leprosity: dapson

16. Susceptibility testing in vitro • The effect of therapy does not correspond with susceptibility testing in many cases • Quantitative tests (MIC, E-tests) – in relevant patients • Qualitative tests (disc diffusion test) – enough for common cases (susceptible - resistant)

17. Quantitative tests (Microdilution test) MIC is the lowest concentration, which inhibites growth. If MIC is lower than breakpoint, bacteria are susceptible. If MIC is higher, bacteria will be resistant E-tests (quantitative) - Similar to disc diffusion test, but strip is used. An increasing concentration of atb is used. Zone is egg like– simply reading MIC is where borderline of zone cross the scale

18. Resistance of microbes to antibiotics • Primary resistance: all strains of bacteria are resistant. • Secondary resistance: arises unsensitive mutants, by selective antibiotics pressure became dominant * MBC (minimum bactericidal concentracion) isthe lowestconcentration, whichkills bacteria Primary bactericid: atb, where MIC and MBC are almost equal Primary bacteriostatic: atb, where MBC is X-fold higher than MIC - unreal baktericidal effect in human body

19. Resistance factors detection • Special detection methods for resistance factors (for ex. betalactamase). It can be diagnostic strips (chemical detection of specific ensyme) or other tests (ESBL) 1. Betalactamase testing • In neisseria, M. catarrhalis, H. influenzae • destroys betalactams • For therapy we useATB with inhibitors of betalactamase likeclavulanate, sulbactam…

20. Detectionof betalactamase Paper with substrate + moisturingsolution Petri dish with bacteria Touch Colour change (red) Strain produces betalactamase

21. 2. ESBL (extended spectrum betalactamase) E. coli, K. pneumoniae etc. produces ESBL, whichdestroyscheap betalactams. For therapy we useexpensive carbapenems, aminoglycosides (toxicity),problem of ICU, big hospitals ESBL – screening • Inhibitionof growth between discs – owing to a synergism of 2-3 antibiotics such as aztreonam, AMC, ceftriaxon aztreonam Amoxicilin/clavulanate

22. ESBL detection • 4 discs: Cefotaxim (1) and ceftazidim (2), cefotaxim with clavulanate (3) and ceftazidim with clavulanate (4) • Difference between cefalosporines (1,2) and cefalosporineswithclavulanate (3,4) is higher than 5mm Compare 1 with 3 and 2 with 4 3 1 4 2

23. 3. AmpC beta-lactamase K. pneumoniae, M. morganii etc. AmpC destroyscheap betalactams. For therapy we useexpensive carbapenems, aminoglycosides (toxicity) + cefalosporines 4th generation,problem of ICU, big hospitals 1 2 Difference between 1and 2 is higher than 5mm MH alone MH+OXA

24. ESBL andAmpCdetection set (A,B,C,D) Susceptible strain AmpC+ A B A B A cefpodoxime (CPD)B CPD+ESBL inhibitor C CPD+AmpC inhibitor D CPD+both inhibitors C D C D ESBL+,AMPC+ ESBL+ A B A B C D C D Interpretation: compare inhibition zones, if differences are higher than 5 mm

25. Resistance of bacteria is worldwide problem • MRSA – methicillinresistant S.aureus – Therapy: vancomycin, linezolid, quinupristin/dalfopristin (Synercid) • VRE – vancomycinresistant enterococci Therapy: linezolid, rifampicin, combination • VRSA – vancomycinresistant S.aureusTherapy: linezolid, Synercid… • MBL/KPC producers (pseudomonas, enterobacteria) – NDM 1, VIM etc.