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Antimicrobial therapy PowerPoint Presentation

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Description : Check out this medical presentation on Anaerobic Bacteria, which is titled "Antimicrobial therapy", to know about the bacterial sensitivity to specific antibiotic.

Tags : Anaerobic Bacteria, Antimicrobial therapy, bacterial sensitivity, antibiotic

Published on : Jul 01, 2021 | Views : 1988 | Downloads : 5

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Slide 1-

Antimicrobial therapy Prof Ivo Ivić
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Bacterial sensitivity to specific antibiotic Determinants MIC- minimal inhibitory concentration (inhibit, but does not kill bacteria) disables visible bacterial growth in liquid media (12h) allows growth after inoculation on solid media MBC- minimal bactericidal concentrations kills all bacteria no growth after inoculation on solid media
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Requirements for treatment success (using conventional dosage of antibiotic) to achieve serum antibiotic concentrations above MIC to maintain this concentrations for enough long period after adminstration Time above MIC Amount of antibiotic above MIC The lower the MIC, the better the therapy The greater the AUC, the better the therapy
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Bacterial sensitivity to specific antibiotic – antibiogram Sensitive low MIC values for specific antibiotic conventional dosage = high probability of cure Resistant high MIC values for specific antibiotic therapeutic concentrations not achieveable by conventional or increased dosage
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Bacterial sensitivity to specific antibiotic – antibiogram Intermediate sensitivity MIC values increased (but not high) possibility of treatment failure Increased dosage = sometimes provides therapeutic success Example Str.pneumoniae intermediatedly penicillin sensitive Pneumonia: treatment success with increased dosage Meningitis: tretment failure even with increaed dosage
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Recovery from bacterial infection: relationship between antibiotic and neutrophils Antibiotic: reduces number of bacteria facilitate clearing of bacteria by neutrophils At level of 102-103bacteria/g of tissue Neutrophil clean bacteria without help of antibiotic Usualy, this point is achieved after 5 days of therapy
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Making decision for antibotic therapy
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Presence of bacterial infection? Obtain cultures including blood Observe closely Obtain cultures Patients worsens Determine probable site of infection Begin empiric therapy At day 3 Chek culture and Gram stains Negative, or Colonisation yes no Streamline antibiotic: - narrowest spectrum - fewest drug possible
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Making decision for antibiotic therapy: Checklist Assess the of possibility of bacterial infection Assess site of infection/pahtogen(s) involved Assess antibotic susceptibility of presumed pathogen Check data about previous antibiotic therapy/resistence Check important predisposing host factors After 3 days select drug with the narrowest antibacterial spectrum
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Rational selection of antibiotics Questions to be answered How broad is antibacterial spectrum of choosen antibiotic? Wether the antibiotic(s) is -cidal or -static? What are the antibotics major toxicities? How is the drug metabolised and eliminated? Is there need for dosign adjustment? What is the price of the antibiotic selected?
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Antibacterial spectrum of some antibiotic groups
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antibiotics
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Antibiotic groups: -lactams Aminoglycosides Glycopeptides Macrolides Ketolides Lincosamides Tetracyclines Chloramphaenicol Quinolones Oxazolidines Streptogramins Daptomycin Metrondiaziol Sulfonamides Trimetoprim Colistin
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β-LACTAM ANTIBIOTICS R2 side chain: -pharmacocinetics -methabolism R1 side chain: -anibacterial properties R1 R2
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Cephalosporins Monobactams Carbapenems Clavulanic acid Penicillins
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Antibacterial mechanism of β-lactams Inactivation of cell wall enzymes (PBP-s) Cessation of cell wall sythesis during active cell growth and divison Cell lysis = bactericidal effect antagonised by bacteriostatic agents
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Bacterial resistence mechanisms Destruction of β-lactam ring by β-lactameses penicilinases, cefalosporinases, ESBL, karbapenemases Modification of PBP-s lowered affinity for specific β-lactam antibiotic preserved cell wall syntheis
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Hipersensitivity to β-lactam antibiotics The most common toxicity Immediate or Delayed Anaphylactic (IgE mediated) Urticaria, angioedema Quincke Asthmatic attac Anaphylactic shock Non-anaphylactic Maculopapular rash  
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Hipersenitivity: Penicillins vs Cephaloporins Penicillins 1-10 % allergic reactions 1-7% cross-reactity to cephalosporins Cephalosporins 1- 3% allergic reactions rarely anaphylactic
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A practical approach in case of pencillin allergy Anaphylactic all β-lactams should be avoides or desensitization should be carried out Non-anaphylactic another group of β-lactams is allowed
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Other -lactam adverse reactions Imipenem: siezures in patients with renal dysfunction less frequent with other karbapenems Ceftriaxon: aseptic inflammation of gallbladder drug crystalisation in gallbladder Cephalosporins + aminoglycosides: nephrotoxicity Clostridium difficile diarrhoea
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Penicillins
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Penicillins Natural penicilins Aminopenicilins Penicillaze-resistent pencillins (anti-staphylococcal) Carboxypencillins and ureidopencillins (anti-pseudomonal)
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1.Natural penicilins (PCN) Narrow spectrum S.pygenes, S. viridans, S.pneumoniae, Neisseria meningitidis Anaerobic mouth flora Clostridium perfrigens, C.tetani, Leptosipra Short half-life: dosage 3-6 times/day Renal excretion: dose adjustment with renal funciton Preparations i.v. : PCN G i.m.: prokain PCN G, benzatin PCN G p.o.: PCN V-K
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2. Aminopenicillins (iv, im, po) 2a. Amoxycillin , Ampicillin Moderate spectrum: Gram-positive: Streptococci., Enterococci, Lysteria Gram-negative: E.coli, Salmonella, Haemophilus influenzae (if -lactamase sensitive) Short half life Renal excretion (unchanged)
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2b. Amoxycillin-clavulanate , Ampicilin-sulbactame Broader spectrum with addition of: Meticillin sensitive Staphylococcus aureus (MSSA) -lactamese producing gram-negative bacteria: Moraxella catarrhalis, H.influenzae, Enterobacteriaceae.
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3. Penicillase-resistant penicillins (iv, po) (meticillin sensitivity) Cloxacillin and Dicloxacillin Very narrow spectrum- Indication: MSSA, S.pyogenes (cellulitis) Ineffective against anerobes and enterobacteriaceae Short half-life Hepatal elimination (bile excretion)
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Carboxypenicillins and Ureidopenicillins (iv) (tikarcillin) (piperacilin) Rezisten to -lactamase of gram-negative bacteria: Pseudomonas, other enterobacteriaceae Nowdays market- only with -lactamase inhibitors: Tikarcilin-clavulanate Piperacilin-tazobactam Activity aganist: Gram-negative bactera Anaerobes (+ B.fragilis) MSSA Intrabdominal infections VAP Mixed soft tissue infections
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cephalosporins
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1st generation cephalosporins Activity: Streptoccci, MSSA, oral cavity anaerobes some CA gram negative bacilli (E.coli) Ineffective against MRSA, penicillin-resitant S.pneumoniae H.influenzae Renal excretion Do not pass blood-brain barrier Good for soft tissue infections
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2nd generation cephalosporins Similar to 1st generation, wider gram neg.activity H.influenzae, Neisseria sp, Moraxella catarrhalis Renal excretion Indications Uncomplicated UTI, otitis media Soft tissue infection, pelvic inflammatory disease Oral preparation (cefuroxim-axetil): low serum levels expensive
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3rd generation cephalosporins Activity Excellent against gram negative bacteria Nessseria sp, H.influenzae, M.catarrhalis Enterobacteriaceae Ceftazidim: the only active against Ps.aeruginosa Excelent against gram positive coccci S.pyogenes, S.viridans, other streptococci S.pneumoniae (including moderately PCN resistant strains) Poor against S.aureus and higly PCN resistant S.pneumoniae
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3rd generation cephalosporins Ceftriaxon- long half life: 1-2 doses/day Others: 3-4 doses/day All cross blood brain barrier Excretion Renal: for most members Ceftriaxone: hepatal (gallbladder crystals!) Indications: CA pneumonia and meningitis UTI and abdominal infections CA: Community Acquired
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PARENTERAL (iv, im) Cefotaxime Ceftriaxone Ceftazidime ORAL Cefexime Cefpodoxime proxetil 3rd generation cephalosporins
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4th generation cephalosporins (cefexime) Resistant to ESBL Wide antibacterial spectrum Similar to 3rd gen.cephalosporins plus: Ps.aeruginosa and MSSA (but not MRSA!) Indicatons Nosocomial infections (iv)
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5th generation cephalosporins (ceftaroline) Antibacterial spectrum Similar to 3.gen.cephalosprins(ceftriaxon) plus: MRSA and VISA (vancomyin intermdately restant SA) Indications CA pneumonia Complicated soft tissue infections
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Carbapenems
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Carbapenems Very wide antibacterial spectrum Gram negative bacteria, including: ESBL producing strains P.aeruginosa (with exception of ertapenem) Gram positive bacteria, including: MSSA (but not MRSA) Anaerobes
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Indications (pending results of the microbiology) Severely ill patients with nosocomial infection Severe mixed infections Carbapenems Imipenem-cilastatin Etrapenem (1dose/day, inactive against P.aeruginosa) Meropenem Doripenem Carbapenems
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aminoglycosides
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Aminoglycosides Derived form Streptomyces bacteria Bactericidal, but inactive low pH medium Post-antibotic effec: Short exposure to antibiotic Prolonged suspension of bacterial growth (despite falling of antibiotic level below MIC) The higer dose, the longer post-antibiotic effect 1 dose/day possible
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Activity Excellent against gram-negative bacteria Sinergy with penicillins for: S.viridans, Enterococcus, P.aeruginosa But not as monotherapy for them Renal excretion Deceased creatinin clearance Dose adjustment Aminoglycosides
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Toxicity Nephrotoxicity (usualy reversible) Ototxycity (usualy ireverible) Avoid aminoglicosides in: Eldery patients Renal disease Patients wit liver disase Dehidration and hypotension Combination with cephalosporins, vankomycin, clindamycin, fursemid Monitoring of serum levels is reccommended Aminoglycosides
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Aminoglycosides (iv, im) Gentamicin Amikacin Netilmicin Tobramicin (topical th- eye infections) Streptomycin (tularemia, plague, tb)
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glycopeptides Vancomycin Teicoplanin
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Glycopeptides Inhibt cell wall sythesis (peptidoglycan)- bactericial Long half life, postantibiotic effect 1-2 dose/day Do not cross blood-brain barrier Activity Gram positive cocci SA, S.pneumoniae, Enterococcus, etc. Renal excretion Deceased creatinin clearance Dose adjustment
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MR staphylococci (MRSA and koagulasa neg.) PCN highly resistant S.peumoniae Enterocci in patients with PNC allergy Clostridum difficile diarrhoea iresponsive to metronidazol (oral therapy) Limited therapeutic indications Glycopeptides
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Macrolides and Ketolides
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Macrolides and Ketolides Macrocyclic lactone ring- basic component Macrolides Erytromicin (natural antibotic) Azitromycin (iv, po) Claritromycin (po) Ketolides Telithromycin (po) Mode of action: Inhibition of protein sythesis One site of action Two sites of action Activ against macrolide resistant bacteria
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Toxicity (rare, safe groups) Macrolides Gastrointestinal nausea, vomiting, cramps, diarrhoea most often erithromycin Prologed QT-interval Ketolides Disturbed accomodation blured vison Severe hepatitis very rare Macrolides and Ketolides Both metabolised by cytochrome P450 Increase levels of: Short acting benzodiazepines Ritoanvir Tacrolimus, ect.
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Pharmacokinetics Long half life (except eritromycin): 1-2 doses/day Azithomycin: prolonged activity (5 days after cesation) Elimination by bile Azithomycin unchaneged High tissue concentrations of drugs 10-100 times of serum conc. Unsuitable to treat bacteriema/sepsis Do not cross blood brain barrier Macrolides and Ketolides
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Anitbacterial spectrum Vide: Gram-positive and –negative bacteria, Oral anaerobes Intracelluar bacteria Mycoplasma, Ureplasma, Chamidia, Legionella Atypical mycobacteria
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Treatment indications Community aquired pneumonia S.pneumoniae- increasing resistence Atypical penumonia- drugs of choice S.pyogenes increasing resistence reserve for PCN allergy Macrolides and Ketolides
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Treatment indications (contined) Atypical pneumonia Legionnarie disease STD (myoplasma, ureaplasma, chlamida) Atypical mycobacteria Replacement of penicillin in PCN allergy Macrolides and Ketolides
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clindamycin (PO, IV)
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Mechanism Inhibits bacterial protein synthesis the same site of action used by macrolides Excretion: liver  bile  stool Toxycity Diarrhoea reduction of sensitive flora for 14 postherapy days Cl.difficile is invoveded in 50% Clindamycin
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Antibacterial spectrum MSSA, S.pneumonae, S.pyogenes for PNC-allergic patients Anaerobic bacteria rising resistence of B.fragilis !! Clindamycin
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tetracyclines Doxycycline (po) Tigecycline (po, iv)
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Mechanism Inhibition bacterial protein synthesis Excretion: liver  bile  stool Toxycity Photosensitivity- rash Depistion in enemal- teeth discoloration not reccomanded under age of 8 years Beningin intracranial hypertension (headake) Tetracycline
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Antibacterial spectrum Very wide: gram positive and gram negative bacteria Anaerobic bacteria Intracellular bacteria Mycoplsama, Ureaplasma Chlamida Ricketssia Borellia Brucella Tetracycline Other antibotics a better ! primary indication
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Quinolones (or fluoroquinolones) 1.Ciprofloxacin 2.Gatifloxacin 3. Levofloxacin 4. Gemifloxacin 5. Moxifloxacin
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Fluorine addition: = enhanced antibacterial activity Piperazin addition = enhanced gram-negative activity Mechanism: inhibition of bacterial DNA Excretion: Kidneys: ciprofloxacin, levofloxacin, gatifloxacin Liver: gemifloxacin, moxifloxacin Quinolones = two 6-member rings
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Toxicity Tendinitis Articular cartilage damage qunolones are not reccommended in children A-V block (prolonoged QT interval)
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Ciprofloxacin : antibacterial spectrum Gram negative (wide) Primarily for Pseudomonas Other gram negative bacteria as alternative drug for prostatitis (high concentrations) Intracellular bacteria Chlamidia, Mycoplasma, Ureaplasma in case of prostatitis Gram positive (narrow) MSSA- bone infections
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Respiratory quinolones (levo-, gati-, gemi-, moxi-floxacin): antibacterial spectrum Ciprofloxacin spectrum, plus: S.pneumoniae (even PCN resistant) Anaerobic bacteria (gemifloxacin) Indications of respiratory quinolones: CAP (community acquired pneumonia) Mixed infections of soft tissue
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OUTPATIENT ORAL ANTIBOTICS
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Reccommendations When? higly suspected or proven bacterial infection Whom to? mild to moderately ill patients Which antibiotic? accoridng to reccommendations IDSA- Infectious Disease Society of America ESCMID- European Society of Clinical Microbiology and Infectious Disease CDC- Center for Disase prevention and Control (USA) ECDC- European CDC
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For instance ….. Bacterial (streptococcal) pharyngitis first choice: Penicillin VK PCN allergy: Azithromycin Community acquired pneumonia (CAP) first choice: amoxicillin or doxycycline CAP with comorbidity: levo- or moxifloxacin
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Antifungal agents
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Antifungal agents Polienes Amphotericin B Azoles Fluconazole Ketoconazole Itraconazole Posaconazle Voriconazole Caspofungin Anidulafungin Micafungin Echinocandins Flucytosine ect….. Others
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Modes of action of antifulgals Polyenes ergosterol binding = disrupted membrane synthesis fungicidal Azoles inhihibition of ergosterol synthesis pathway fugnistatic Echinocandins Blocking of cell wall synthesis (β-glucan) Flucytozine Imapirment of DNA and RNA synthesis
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Amphotericin B Azoles Echinocandins Flucytosine Modes of action of antifulgals 1 2 4 3
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Amphotericin B (AB)
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Toxicity Nephrotoxycity- usualy reversible Reduced by hidration Fever during infusion, reduced by: Slow infusion (few hours) Corticosterid premedication Phlebitis Usually CVC required
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Preparations: All intravenous, but: ABD- amphotericin B deoxycholate Te most nephrotoxic. The cheapest. Lipid-complex AB Less nephrotoxic. More expensive. Liposomal AB Almost non-nephrotoxic. Extremely expensive.
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Antifungal spectrum and indications Systemic infections (but not CNS): most Candida Aspergilus Cryptococcus Histoplasama Blastomyces Coccidiomyces Zygomyces
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azoles
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Toxicity Generaly minimal gastointesnal complaints reversible liver enzymes elevation Ketoconazole reduced libido severe hepatitis Voriconazole transient loss of vision during the first few infusions
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Antifungal spectrum and indications Systemic (including CNS) infections and extensive local infections (iv, po) Posaconazole and Voriconazole the widest spectrum (same as AB) very expensive Flukonazole, Itraconazole Inactive against Apergilus
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antiviral agents (other than anti-HIV agents ) Ribavirin Interferon-α DAA for HCV Aciklovir,valacikovir, famciklovir Ganciklovir Inhibitori neuraminidaze
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RIBAVIRIN Mechanism of action Interference with m-RNA Not clearly understood Toxicitiy Oral- reversible hemolytic anemia Areosol- bronchospasm Pharmacokinetics Excretion by the liver and kidney
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Indications RSV bronchiolitis Lasa hemorrhagic fever (Lasa virus, Arenaviridae) Chronic hepatitis C only combined with interferon-α RIBAVIRIN
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INTERFERON-α (INF-α ) Natural occuring antiviral cytokines Mechanism of action enhances immunological kiling of virus-infected cells poor activity against DNA viruses Pharmacokinetics (sc, im) long half-life: 2-3 doses/week Pegliated form (PegINF-α): 1 dose/week
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Toxicity Fever Irritability, depression, somnolece Bone marrow supression neutropenia, thrombocytopenia INTERFERONS
Slide 87-

Indications Chronic hepatitis C Combined with ribavirin Chronic hepatitis B Kaposi sarcoma (HHV-8) Condyloma acuminatum (HPV)
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Direct acting antivirals (DAA) for HCV-infection
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DAA INHIBITORs of Tableted prepartions
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Interaction between DAA and other drugs through CYP450 Drugs that may reduce concentrations of DAA: Antiretroviral drugs Rifampicin Anticonvulsants etc
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G1 HCV (naive): % of cure PegIFN + Rib 50% 48 w 8-12 w Sofosbuvir + other DAA 95-100% Duration of therapy (week)
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NEURAMINIDAZE INHIBITORS (oseltamivir, zanamivir) Mechanism of action inhibit enzim important for budding: release of influenza virus from infected cell effective within first 48h of disease Toxicity Zanamivir (aerosol)- bronchospasm Oseltamivir (po)- safe
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Indications Complicated influenza A and B with penumonia Influenza in high risk patients Therapy of uncomplicated influenza Prolonged prophylaxis (half doze)