BRONCHOPNEUMONIA Bronchopneumonia acute inflammatory process in the area

BRONCHOPNEUMONIA

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%! Division according to agent: viral bacterial mycotic parasitic Division of clinical terms: CAP – community HAP – hospital acquired pneumonia

Clinical signs of disease = may start suddenly with chills and fever, especially when bacterial etiologic agent in viral diseases - development is slower, it may follow inflammation of the upper respiratory tract temperature in children usually relatively high, in elderly subfebrile to afebrile cough - first dry, irritable, and later with various expectoration. At the inflammatory response on the pleura, is manifested chest pain linked to cough and breathing tachypnoea and dyspnoea, in children alar breathing and cyanosis

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 bed fluid intake calories intake vitamin intake

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

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 - bacteriostatic effect/immunodeficiency and cachect. patients! / selective action on the cells of microorganisms: effect on the synthesis of cell wall - bactericid effect on protein and NA synthesis + inhibition of metabolic procedures – bacteriostatic

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

Division of Antibiotics According to Mechanism of Action Drugs affecting cell wall: Beta-lactam antibacterials: PNC, Cephalosporins, Monobactams, Carbapenems Glycopeptides: teicoplanim, vancomycin Lipopeptides: daptomycin Polymyxins: colistimethate sodium Drugs affecting bacterial DNA: Quinolones, Fluoroquinolones: ciprofloxacin, moxifloxacin, norfloxacin Metronidazole, Tinidazole Nitrofurantoin

Division of Antibiotics According to Mechanism of Action Drugs affecting bacterial protein synthesis: Macrolides: azithromycin, clarithromycin, erythromycin, telithromycin Aminoglycosides: gentamycin, netilmycin, streptomycin, tobramycin Tetracyclines: doxycycline, minocycline Chloramphenicol Lincosamides: clindamycin Fusidic acid Oxazolidinones: linezolid Drugs affecting bacterial metabolism: Sulphonamides: sulfadiazine, sulphametoxazole Trimethoprim

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

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

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

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

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.

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 D 2 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.

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/

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

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

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

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

Bacteria: Gram stain

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

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

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%

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 1 g Phenoxymethylpenicillin (Penicillin V) – biosynthet. , acidostable (p. o. ), similar spectrum of activity as PNC G but generally less effective Penamecillin – prolonged effect, á 8 h. Oxacillin, cloxacillin, dicloxacillin, meticillin antistaphylococcal, resistant against betalactamases produced by staphylococci, very narrow spectrum, peroral also perenteral administration, á 4 till 6 h.

PNC with Broader Spectrum - also G- microorg. /E. coli, salmonellas, shigellas, H. influensae/ Aminopenicillins - ampicillin, amoxicillin /=better penetration, higher plasm. conc. / acidostable, aren´t resistant against betalactam. uncomplic. infections of urinary, airway and gallbladder pathways mainly in combination with inhibitors of betalactamases (amoxicillin + clavulanic acid, ampicillin + sulbactam) , peror. also parent. admin. Carboxypenicillins /carbenicillin, tikarcillin/ semisynthet. PNC, also Pseudomonas aeruginosa, Proteus - at syst. infections alone or in combination with aminoglykosides acidolabile – parenter. adm. , tikarcillin in comb. with inh. of betalactamases Ureidopenicillins /azlocillin, mezlocillin, piperacillin/ acidolabile, good penetration to tissues, more intensive on Proteus, Pseudomonas aeruginosa, piperacillin also to some anaerobes, the highest effectivity, reserved to serious infections

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 - 4 th generation successive generations tend to have increased activity against Gbacterias 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)

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

Cephalosporins of 3 rd and 4 th Generation 3 rd 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 4 th generation cefepime, cefpirom intensified effect against staphyloc. , streptococci and pseudomonads severe nosocomial infections

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

Fluoroquinolones chemotherapeutic with high ATB activity baktericid effect – select. inh. of bacterial gyrase activity and 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

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

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

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

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

Macrolides bakteriostatic effect – inhibit proteosynthesis of microorganisms by binding to 50 S 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

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

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

Tetracyclines bakteriostatic, inhibit bacterial protein synthesis by binding reversively to 30 S subunit of ribosome broad-spectrum atb active against many G+ and G- bacterias, infections caused by mykoplasmas, chlamydias, rickettsias resorption at fasting good, not with milk, antacids, Fe 3+, which prevent their resorption good penetration to tissues except to CNS at renal diseases needed dose reduction 2 nd generation: tetracyclin doxycyclin – better pharmacokin. properties /higher bioavailability, longer half-life = administratio 1 -2 times per day/ AE: oft but not severe, GIT, disorders of bones and teeth by calcium chelation = contraindic. at children

Aminoglycosides bakteriostatic, inhibit bacterial protein synthesis by binding irrreversively to 30 S 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

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/ are resistant to all cephalosporis and penicillins, quinolones, aminoglycosides - are resistant also to so called reserve ATB

? New antibiotics Modification of before known molecule: new carbapenems (ertapenem, doripenem) 5 th generation of cephalosporins – anti-MRSA cephalosphorins (ceftobiprole, ceftaronile) 4 th generation of quinolones: fluoroquinolones – respiratory fluoroquinolones (gemifloxacin, moxifloxacin, gatifloxacin) 2 nd generation of glycopeptides: lipoglycopeptides (oritavancin, telavancin, dalbavancin) macrolides – ketolides (telithromycin) tetracyclines – glycylcykline (tigecycline)

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

Tigecycline (glycylcycline antibiotic) Broad spectrum antibiotic from new group of glycylcyclines, derived from TTC, since the year 2005 Mechanism of action: inhibition of proteosynthesis in bacterias spectrum: G+ and G- including multiresistant methicillin/oxacillin-resistant strains of Staph. aureus penicillin-resistant streptococci vancomycin-resistant enterococci bacterias producing broad spectrum betalactamases anaerobes (group Bacteroides) mycoplasmas, chlamydia rapidly growing mycobacteria

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

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, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing

Linezolid (oxazolidinone) yet the only representative of new group of oxazolidinones broad spectrum of effectiveness including community-acquired and nosocomial G+ pathogens oxacillin-resistant staphylococci (S. aureus, S. epidermidis) vankomycin-resistant enterococci (E. faecalis, E. faecium) penicillin and erythromycin-resistant pneumococci interaction potential of linezolid is low, enzyme complex cytochrome P-450 is not participating in metabolism of linezolid

Linezolid (oxazolidinone) oral form achieves the same pharmacologic parameters as parenteral (serum and tissue concentrations) reaches high concentrations in bones, cerebrospinal liquor and mainly in lung parenchyma therapy of nosocomial pneumonias and severe infections of skin and soft tissues bioavailability is very good, what allows administration also initially in p. o. form or as follow-on treatment - p. o. after initial i. v. therapy

Daptomycin (lipopeptide ATB) representative of lipopeptide antibiotics effective only against G+ microorganisms except enterococci treatment of skin and soft tissue infections potentially also for treatment of catether infections

ANTITUSSIVES cough = reflex. protective mechanism, with witch airways are getting rid of any foreign materiala, and also secretory products complete cough supression is unwanted and unreal but long-lasting cough cand weaken patient and strained breathing muscles are painful, that´s when are indicated antitussives we use only when we know ethiology of cough and when we treat causally given disease! Division: 1. antitussives with central effect and with the structure of opioids (not recommended at patients with bronchial asthma and COPD) 2. antitussives with central effect and peripheral effect with different structure

ANTITUSSIVES OF CODEINE TYPE (CODEINE) = decreases sensitivity of center for cough properties similar to morphine, less effective p. o. administered good absorption from GIT, metabolis. in liver to morphine and norcodeine, excreted by kidneys unchanged or as glucuronide, transfer to breast milk = supress of child´s breathing interactions: + IMAO, thymoleptics, physostigmine, neostigmine - naloxone, nalorphine, pentazocine = increases analgetic effect of analgetics-antipyretics = potentiation of suppressive effect of other CNS drugs = with opioid analgetics – deepening depression of CNS and breathing center

ANTITUSSIVES OF CODEINE TYPE (CODEINE) indication: symptomat. supressing of irritating non-productive cough of known etiology in combination with causal therapy of given disease contraindications: difficult expectoration, mainly at advanced stage of bronchopulmonal disease, hypersensitivity to drug, prohibition of alcohol /strongly increases depressive effect on CNS/! dose: 15 – 30 mg 3 times per day

ANTITUSSIVES OF CODEINE TYPE (PHOLCODINE) = derivate of codeine with bigger efficacy, doesn´t decrease bronchial secretion, isn´t usually cause of dependence, supresses cough reflex inhib. by inhibition of centrum for cough in medulla - therapy of dry irritating cough - increases depressive effect of substances supressing CNS and also alcohol dosage: 10 – 20 mg 3 times per day

ANTITUSSIVES OF CODEINE TYPE Etylmorphine = derivate of morphine similar to codeine, stronger analgetic and antitussic effect at dry irritating cough at acute inflammation of airway system, TBC, spontaneous pneumothorax and before diagnostic procedure long-lasting aplication in pregnancy = abstinent signs at newborn, passes to milk! Dextromethorphan = antitussive drug without analgetic. effect, doesn´t supress breathing center, minimal risk of dependence, minimal AE

ANTITUSSIVES OF NONCOD. TYPE central effect: pentoxyverine /one-third effect of codeine, lower effects, at antitus. doses proven no depressive influence on breathing center/, butamirate /effective antitussic used in pediatria, minimum AE/, clobutinol /contraindicated in pregnancy and at breast feeding/ peripheral effect: benzonatate, dropropizine /strong antitussive with properties similar to butamirate, mild antihistaminic effect, minimal effect on on breathing center/

MUCOLYTICS and EXPECTORANTS = getting rid of viscous mucus from airways Mucolytics and secretolytics – lower viscosity of mucus, resp. increase production of mucus Secretomotorics – are increasing activity of cilliar epithelium /β 2 -sympathomimetics, eteric oils/ CAREFUL AT SIMULTANEOUS ADMINISTRATION OF ANTITUSSIVE AGENTS! BROMHEXINE – increasing proportion of liquid bronchial mucus and reduces its viscosity by reduction of transversal bonds of acid mucopolysaccharides, promotes secretion of mucus, improves cilliar function, pharmaco-therapeutically active is metabolite ambroxol AMBROXOL – mukolytic and secretolytic effects, activation of cilliar epithelium N-ACETYLCYSTEINE - cleaves disulfidic bridges connecting mucopolysacharid fibers in sputum, at difficult expectoration, at chronic bronchitis and mucoviscidosis, also prophylactically ERDOSTEINE – newer, decreases the sputum viscoelastic properties and bacterial adhesion to the cell membrane GUAIFENESIN – helps thin and loosen mucus in the lungs PREPARATIONS OF HERBAL ORIGIN – coltsfoot, thyme, plantain, mint and others, well tolerated with a low incidence of adverse reactions; do not administer in suspicion of bronchial asthma