BRONCHOPNEUMONIA

1. BRONCHOPNEUMONIA

2. Bronchopneumonia • = acute inflammatory process in the area of respiratory bronchioli, alveolar structures and/or lung interstitium • caused by espec. infectious agent • complications: pleuritis, parapneumonic empyema, lung abscess, lung gangrene and sepsis • risk factors: age, CV and respiratory comorbidities, smoking, immunodeficiency • = mortality over 70 yr. to 25%! • Divisionaccording to agent: viral bacterial mycotic parasitic • Divisionofclinicalterms: CAP – community HAP – hospital acquiredpneumonia

3. Clinical signs of disease • = maystartsuddenlywithchills and fever, especiallywhenbacterialetiologic agent • in viraldiseases - developmentisslower, itmayfollowinflammationoftheupperrespiratorytract • temperature in childrenusuallyrelativelyhigh, in elderlysubfebrileto afebrile • cough - firstdry, irritable, and laterwithvariousexpectoration. Attheinflammatoryresponse on thepleura, ismanifestedchestpainlinked to cough and breathing • tachypnoea and dyspnoea, in childrenalarbreathing and cyanosis

5. Therapy of Bronchopneumonia • immediately begin initial empirical anti-infective therapy, with the spectrum of effect covering the most prevailing pathogens, also taking into account individual risk factors • knowledge of the epidemiological situation + resistance of respiratory pathogens to antibiotics in the region • antimicrobial therapy should be directed = necessity to determine etiology and sensitivity of microorganisms to antibiotics /after identification of the pathogen, initial therapy adequately adjusted / + bronchodilators mucolytics expectorances antitussics + rest in bedfluid intakecaloriesintakevitaminintake

6. Etiologic Agents according to Frequency of Occurance • LUNGS respiratory viruses • Str. pneumoniae • H. influenzae • S. aureus • Klebsiella speciei • M. pneumoniae • Str. pyogenes • Chl. psittaci • BRONCHI • respiratory viruses • Str. pneumoniae • H. influenzae • Str. pyogenes • S. aureus • Escherichia coli

7. Antimicrobial Drugs • with targeted mechanism affect the structure or function of microorganism cells, and thus they either kill - bactericidal effect, or inhibit their growth and multiplication - bacteriostaticeffect/immunodeficiency and cachect. patients! / • selective action on the cells of microorganisms:effect on the synthesis of cell wall - bactericideffect on protein and NA synthesis + inhibition of metabolic procedures – bacteriostatic

8. Division of Antimicrob. Substances • chemical – according to similar structure, substance with the same mechanism of action have usually the same AE • baktericid:ß-laktamic ATB, aminoglycosides, bacitracin, isoniazid, metronidazole, quinolones, vancomycin, teicoplanin, rifampin • bacteriostatic:macrolides, tetracyclines, chloramphenicol, sulfonamides, trimetoprim, linkomycin, klindamycin, ethambutol, nitrofurantoin

9. DivisionofAntibioticsAccording to MechanismofAction Drugsaffectingcellwall: Beta-lactamantibacterials: PNC, Cephalosporins, Monobactams, Carbapenems Glycopeptides: teicoplanim, vancomycin Lipopeptides: daptomycin Polymyxins: colistimethatesodium Drugs affecting bacterial DNA: Quinolones, Fluoroquinolones: ciprofloxacin, moxifloxacin, norfloxacin Metronidazole, Tinidazole Nitrofurantoin

10. DivisionofAntibioticsAccording to MechanismofAction Drugs affecting bacterial protein synthesis: Macrolides: azithromycin, clarithromycin, erythromycin, telithromycin Aminoglycosides: gentamycin, netilmycin, streptomycin, tobramycin Tetracyclines: doxycycline, minocycline Chloramphenicol Lincosamides: clindamycin Fusidicacid Oxazolidinones: linezolid Drugs affecting bacterial metabolism: Sulphonamides: sulfadiazine, sulphametoxazole Trimethoprim

11. Ideal Antibiotic • Wide spectrum • Rapid action • Bactericid • High selectivity, without AE, not causing allergy • Not to occur resistance • High biologiavailability, good penetration to tissues, long biolog. half-life • Low price

12. Choice of Antimicrobial Substance • Ideal antibiotic drug • absorption • distribution • elimination • ADR • price • Which available ATB is close to ideal? • ß-lactams • Macrolides • Quinolones • Tetracyclines • Cotrimoxazol

13. Principles of Antimicrob. Therapy for Respiratory Diseases • racional indication • take into account the nature and severity of infection • take into consideration the clinical condition of the patient • Individual choice of drug • prevent the increase in resistance due to : • incorrect prescription • incorrect dosage • not keeping the optimal length of therapy

14. Choice of the Right Antibiotic • Targeted administration on the basis of identification of causative agent of infection • Consider pharmacokinetic properties • Choosing the most appropriate route of administration and site of administration. At severe infections we begin with parenteral therapy. At limited function of elimination organs we reduce the dose or prolong dosing interval. • Reducing the risk of administration by revealing of predisposing factors such as drug allergy • Determination of the risk groups of patients

15. Problematic of ATB Resistance • = the ability of the bacterial population to survive inhibitory concentration of the given antimicrobial drug, becomes a significant problem nowadays 1. Primary resistance = natural resistance of microbial species, which are outside the range of ATB action /missing are „mechanisms“ (receptors) for the effect of antimicrobial drugs/ absolut resistance + relevant resistance /mikroorganism not sensitive to antibiotic concentrations reachable in human organism, but sensitive to high concentration of antibiotic reached in vitro 2. Secondary resistance occurs during antibiotic therapy, when initially sensitive bacterial population during antibiotic treatment become resistant to them.

16. Resistance to ATB mechanism of resistance: • productions of enzymes, which change structure of antimicrob. substance the way that it looses antimicrobial effect (betalactamases – inactivating some PNC, acetylating enzymes inactivating aminoglycosides) • modification of bacterium so that penetration of the drug is reduced(absence of D2 porin in resistant Pseudomonas aeruginosa – resistance to imipenem) • acquisition of efflux pumps that remove the antibiotic from the cell faster than it can enter (quinolone efflux pumps in Staphylococcus aureus) • structural change in the target molecule for antibiotic (mutated penicillin-binding proteins in enterococci, mutated dihydrofolate reductase not inhibited by trimetoprim) The major mechanisms by which bacteria acquire resistance to antibiotics are: spontaneous mutation, conjugation, transduction and transformation.

17. Possibilities of Slowing Down Resistance Appearance • the right choice of antimicrobial drug • optimal and enough long administration • right dose • in special cases stable combinations /treatment of TBC/

18. Development of Actual Resistance • Penicillin resistant pneumococs (PRP) • Meticillin resistant staphylococs (MRSA) • CA-MRSA (Community-Associated Methicillin-Resistant Staphylococcus Aureus) • Streptococcus pyogenes/macrolides • Quinolone resistant E. coli

19. Agents Causing Pneumonia of Adults lobal: S. pneumoniae, H. influenzae, K. pneumoniae bronchopneumonia: S. pneumoniae, S. aureus, L. pneumophilla atypical: influensa virus, RSV, adenoviruses, HZV, Mycoplasma pneumoniae, Chlamydia pneumoniae

20. Pharmacotherapy of Bronchopneumonia Caused by Streptococcus pneumoniae • Aminopenicillins at high doses • Aminopenicillins protected with inhibitors of betalactamases /ampicillin-sulbactam, amoxicillin-clavulanic acid/ • Cephalosporins III. generation • Fluoroquinolones /levofloxacin, moxifloxacin/ = advantage is higher concentration in the site of action /alveol. fluid, macrophages/ than in plasma!

21. http://www.microbiologynutsandbolts.co.uk/antibiotics.html

22. Bacteria: Gram stain

25. http://www.microbiologynutsandbolts.co.uk/antibiotics.html

26. Betalactamic Antibiotics - in structure betalactamic circle • bactericid • inhibit synthesis of cell wall of mikroorganisms in the last phase of its consolidation with peptidoglycan • hydrophil • low direct toxicity • low occurance of AE • spectrum of effect depends on substance • here belong PNC cephalosporins monobactams carbapenems

27. Penicillins • absorption of peroral PNC after p.o. administration better from empty stomach • G-penicillin, meticillin, carboxypenicillin, ureidopenicillin – unstable in acid environment of stomach - administration parenteral • don´t cross intracelullarly, metabolised a little, excreted through kidneys through glom. filtr. and also tubul. secretion, high concentrations reached in urine • minimal AE, also in high doses not toxic, allergy 5-8%

28. PNC with Narrow Spectrum Benzylpenicillin (Penicillin G) – natural PNC, acidolabile, only parenteral administration (i.m., i.v.) mainly aerobic Gram-positive bacteria (streptococci, pneumococci), limited to Gram-negative bacteria (gonococci and meningococci), anaerobic bacteria only effective to microorganisms that don´t produce betalactamases medium serious inf. caused mailnly by betahaemol. streptococci serious infections – high plasmat. concentrations of Na or K salts of crystalic PNC i.v. /renal diseases!/ depot preparations – i.m.- Procain PNC– 2 times per day 1g Phenoxymethylpenicillin (Penicillin V) – biosynthet.,acidostable (p.o.), similar spectrum of activity as PNC G but generally less effective Penamecillin– prolonged effect, á 8h. Oxacillin, cloxacillin, dicloxacillin, meticillin antistaphylococcal, resistant against betalactamases produced by staphylococci, very narrow spectrum, peroral also perenteral administration, á 4 till 6 h.

29. PNC with Broader Spectrum - also G- microorg./E. coli, salmonellas, shigellas, H. influensae/ Aminopenicillins - ampicillin, amoxicillin /=betterpenetration, higherplasm. conc./ acidostable, aren´tresistantagainstbetalactam. uncomplic. infectionsofurinary, airway and gallbladderpathwaysmainly in combinationwithinhibitorsofbetalactamases (amoxicillin + clavulanicacid, ampicillin + sulbactam) , peror. alsoparent. admin. Carboxypenicillins /carbenicillin, tikarcillin/ semisynthet. PNC, alsoPseudomonasaeruginosa, Proteus - atsyst. infectionsalone or in combinationwithaminoglykosides acidolabile – parenter. adm., tikarcillin in comb. withinh. ofbetalactamases Ureidopenicillins /azlocillin, mezlocillin, piperacillin/ acidolabile, goodpenetration to tissues, more intensive on Proteus, Pseudomonasaeruginosa, piperacillinalso to someanaerobes, thehighesteffectivity, reserved to seriousinfections

30. Cephalosporines • similar mechanism of action as PNC • have beta-lactam ring like PNC • wide use, in pediatria and geriatria • good efficacy and low toxicity • good penetration to tissues • excretion through kidneys by glom. filtr., tub. secretion • according to pharmacodynamic – spectrum of efficacy, ability to penetrate to cells, stability against betalactamases - 4th generation • successive generations tend to have increased activity against G-bacterias at the expense of decreased activity against G+bacterias and increased activity to cross blood-brain barrier • succesive generations are more resistant to betalactamases • several drugs are acidolabile and have to be administered by parenteral route • cefuroxime has been formulated as a prodrug for oral use (cefuroxime axetil)

31. Cephalosporins of 1st and 2nd Generation 1st generation cefalotin, cefazolin, cephalexin,cefradil narrow spectrum, against G+/also staphylococci/, G-sticks, airway, urinary and skin infections 2nd generation cefoxitin, cefaclor, cefamandol, cefuroxime expanded spectrum to G-bact., resistant against betalactamases, act against H. influenzae + some anaerobes, less against staphylococci

32. Cephalosporins of 3rd and 4th Generation 3rd generation cefotaxime, ceftazidime, ceftriaxon, empir. treatment of severe life threatening infections targeted treatment of microorg. resist. to PNC and ceph. of lower gen. - parent. adm. - oft aplication infections of airways – p.o. – 1 times per day 4th generation cefepime, cefpirom intensified effect against staphyloc., streptococci and pseudomonads severe nosocomial infections

33. Rezistance of Pneumococci to Antibiotics • increase of rezistance to pneumococci to natural penicillins, also to cephalosporins, macrolides, doxycycline = drug-resistant Streptococcus pneumoniae • risk factors of occurance: age over 65 years ATB therapy in last 3 months immunodeficiency comorbidities

34. Fluoroquinolones • chemotherapeutic with high ATB activity • baktericid effect – select. inh. of bacterial gyrase activityand so inhibiton of the replication of bacterial DNA • resistance – mutation of DNA gyrase • broad spectrum antibiotics • fluor – increased efficacy, better kinetic properties – use at systemic infections, also serious, serious nosocomial pneumonias, uroinfections, gynecol. infections, GIT infections, infections of airways • good absorption after peror. administration, some also parenter. administration /ciprofloxacin/, possible parenteral. starting therapy, than peroral administration • good penetration to soft tissues, bones and lungs

35. Levofloxacin (fluoroquinolone) • high bioavailability • good penetration to bronchial mucosa and lung parenchyma • at middle serious and serious inf. of airways, complic. uroinfections, inf. of skin and soft tissues • interactions at absorption are occuring at simultaneous administration of iron salts, or antacides containing magnesium and alluminium • „respiratory quinolone“ – effect on G+ causative agents of respiratory infections • AE: nausea, diarrhoea, increases hepatic enzymes

36. Moxifloxacin (fluoroquinolone) • fast perfect absorption after peroral administration, quickly distributed to extravasc. space • at metabolism doesn´t undergo oxidation, that´s why not showing signs of interaction with other substances, which are metab. through cytochrome P-450 • excretion by faeces, less by urine • „respiratory quinolone“ – effect on G+ causative agents of respiratory infections

37. Atypical Bronchopneumonia • disease development and a mild physical symptoms does not correspond to significant signs on X-ray of lungs, but some of them have severe acute development with the possible occurance of serious complications / ARDS / • 30 – 40% of bronchopneumonias • causative agents = intracelular parasits /Mycoplasma pneumonie, Chlamydia pneumoniae, Legionella pneumophila, Coxiella burnetii/ + respiratory viruses • occurance mainly in societies of young people • ATB therapy which penetrates intracelullarly and interferes with proteosynthesis of atypical microorganisms

38. Pharmacotherapy of Atypical Pneumonias • Macrolides /erythromycin, klarithromycin, azithromycin/ • Tetracyclines /doxycycline/ • Fluoroquinolones /antipneumococcal/

39. Macrolides • bakteriostatic effect – inhibit proteosynthesis of microorganisms by binding to 50S subunit of bacterias • broad-spectrum atb with similar spectrum as broad-spectrum PNC (often used to treat patients allergic to PNC) • spectrum mainly G+ bacterias, anaerobic bacterias • also penetration to cells and influence on intracel. pathogens /mycoplasma, chlamydia, legionella, bordetella pertussis/ • good penetration to tissues • metabolis. in liver by cytochr. P-450 interactions: increases plasmat. conc. of theophylline, digoxin, anticoagulants. Interaction with antihistaminics causings severe ventricular arrhytmia

40. Macrolides slower and lower development of resistance • stability in acidic surrounding • longer biologic half-life • high concentration in tissues and serum • 2nd generation /erythromycin+spiramicin/ roxithromycin, azithromycin, clarithromycin = better pharmacokinetics and tollerability/ • little toxic, good tolleration • AE: GIT + liver functions

41. Clarithromycin (macrolide) • semisyntetic • verry good tollerance • biotransformation to antimicrobically more effective 14-OH-clarithromycin • typical, atypical, intracelular and ß-laktamase producing pathogens • 8 times more effective as erythromycin to Chl. pneumoniae and M. pneumoniae • very good at infections caused by Legionella pneumophilla and Moraxella catarrhalis

42. Tetracyclines • bakteriostatic, inhibitbacterialproteinsynthesis by bindingreversively to 30S subunitofribosome • broad-spectrumatbactiveagainstmany G+ and G- bacterias, infectionscaused by mykoplasmas, chlamydias, rickettsias • resorptionatfastinggood, notwithmilk, antacids, Fe 3+, whichpreventtheirresorption • goodpenetration to tissuesexceptto CNS • atrenaldiseasesneededdosereduction • 2nd generation: tetracyclin doxycyclin–betterpharmacokin. properties /higherbioavailability, longerhalf-life = administratio 1-2 times per day/ • AE: oftbutnot severe, GIT, disordersofbones and teeth by calciumchelation = contraindic. atchildren

43. Aminoglycosides • bakteriostatic, inhibit bacterial protein synthesis by binding irrreversively to 30S subunit of ribosome • active against many G- bacterias (including Pseudomonas) and some G+ bacterias • inactive against anaerobes • useful in serious G-negative infections, when they have synergistic action with drugs that disrupt cell wall synthesis (PNC) • poorly absorbed from gut and given parenterally • ototoxic, nephrotoxic • gentamycin, netilmicin, streptomycin, tobramycin

44. Super-Resistant Bacterias • superbugs or extensively drug-resistant microorganisms • gramnegative bacterias (Pseudomonas aeruginosa, Klebsiella, Enterobacter a Enterobacteriaceae) • carry genes producing metallo-beta-lactamases /broad-spectrum beta-lactamases containing Zn, which break down also ATB, which were so far to gramnegative bacterias the most effective – carbapenems/ • areresistant to all cephalosporis and penicillins, quinolones, aminoglycosides - are resistant also to so called reserve ATB

45. ? New antibiotics Modificationofbeforeknownmolecule: new carbapenems(ertapenem, doripenem) 5th generationofcephalosporins – anti-MRSAcephalosphorins(ceftobiprole, ceftaronile) 4th generationofquinolones: fluoroquinolones – respiratoryfluoroquinolones(gemifloxacin, moxifloxacin, gatifloxacin) 2nd generationofglycopeptides: lipoglycopeptides(oritavancin, telavancin, dalbavancin) macrolides – ketolides(telithromycin) tetracyclines – glycylcykline(tigecycline)

46. ? New antibiotics New molecules: oxazolidinone(linezolid, tidezolid) lipopeptid(daptomycin)

47. Tigecycline (glycylcycline antibiotic) • Broadspectrumantibioticfrom new groupofglycylcyclines, derivedfrom TTC, sincetheyear 2005 • Mechanismofaction: inhibitionofproteosynthesis in bacterias spectrum: • G+ and G- includingmultiresistant • methicillin/oxacillin-resistantstrainsofStaph.aureus • penicillin-resistantstreptococci • vancomycin-resistantenterococci • bacteriasproducingbroadspectrumbetalactamases • anaerobes (groupBacteroides) • mycoplasmas, chlamydia • rapidlygrowingmycobacteria

48. Tigecycline (glycylcycline antibiotic) • treatment of complicated skin and intra-abdominal infections, which are often caused simultaneously by more bacteria (not rarely by multiresistant strains) • it can be used in the treatment of documented infections, as well as initial empiric therapy, before definitive identification of the pathogen • i.v. application

49. Lipoglycopeptides (oritavancin, telavancin, dalbavancin) • Activity against vancomycin-resistant organisms • Indication for the treatment of acute bacterial • skin and skin structure infections, and telavancin, for hospital- • acquired and ventilator-associated bacterial pneumonia • While telavancin is administered daily, theremarkably long half-lives of oritavancin and dalbavancinallow for infrequent dosing

50. Linezolid (oxazolidinone) • yet the only representative of new group of oxazolidinones • broadspectrumofeffectivenessincluding community-acquired and nosocomial G+ pathogens • oxacillin-resistantstaphylococci (S. aureus, S. epidermidis) • vankomycin-resistantenterococci (E. faecalis, E. faecium) • penicillin and erythromycin-resistantpneumococci • interaction potentialof linezolidislow,enzyme complex cytochrome P-450 is not participating in metabolismoflinezolid