Antibiotics Lecture Notes PDF

Antibiotics  Antibiotics natural byproducts of fungi, actinomycetes and bacteria, or semisynthetic/synthetic derivatives which selectively and in a diluted form kill or inhibit bacterial growth  Beta-lactamic antibiotics Semisynthetic Biosyntheti...

Antibiotics  Antibiotics natural byproducts of fungi, actinomycetes and bacteria, or semisynthetic/synthetic derivatives which selectively and in a diluted form kill or inhibit bacterial growth  Beta-lactamic antibiotics Semisynthetic Biosynthetic penicillins: penicillins: Benzylpenicillin isoxazolyl penicillin (antistaphylococcal benzathine benzylpenicillin antibiotics) (extencilline, retarpen) - oxacillin - cloxacillin procaine benzylpenicillin - flucloxacillin (bicilinele) - dicloxacillin phenoxymethylpenicillin - nafcillin (ospen)  Semisynthetic penicillins Carboxypenicillins: Aminopenicillins: Carbenicillin Carfecillin Carindacillin Ticarcillin ampicillin Ureidopenicillins: Mezlocillin Azlocillin amoxicillin Piperacillin Aminopenicillins: Mecillinam, pivmecillinam, temocillin  First-generation Second-generation cephalosporins cephalosporins Parenteral Parenteral: Cefaclor Cefazolin Cefuroxime Cefamandole Enteral: Cefotetan Cefotiam Cefalexin Cefonicid Cefoxitin Cefadroxil Loracarbef Enteral Cefaclor (ceclor) Cefuroxime axetil  Third-generation Fourth-generation cephalosporins cephalosporins Parenteral Cefepime Ceftriaxone Cefpirome Cefotaxime Ceftazidime Cefoperazone Fifth-generation Cefodizime Cefpodoxime cephalosporins Ceftizoxime Ceftobiprole Ceftaroline Cefsulodin Latamoxef ceftolozane Cefditoren Enteral: Cefixime Ceftibuten Cefpodoxime proxetil  Associations between beta lactam antibiotics Amoxicillin+clavulanic acid Carbapenems Imipenem (tienam) - augmentin, clavomed, amoxiclav, flemoclav Meropenem (meronem) Ampicillin + sulbactam- sultamicillin Biapenem Ertapenem Ticarcillin + clavulanic acid - timentin Faropenem Cefoperazone+sulbactam - sulperazone Doripenem Piperacilină + tazobactam; razupenem Ceftazidime+avibactam – avycaz Monobactami Ceftolozane+tazobactam – zerbaxa Aztreonam Carumonam Meropenem+vaborbactam - vabomere Tigemonam  Aminoglycosides Macrolides generation I: With 14-membered lactone Streptomycin, Neomycin rings: Kanamycin Paromomycin - natural: erythromycin: - semisynthetic: clarithromycin, generation II: roxithromycin, flurithromycin, Gentamicin Tobramycin davercin. Sisomicin With 15-membered lactone generation III: rings (azalides) : azithromycin. Amikacin With 16-membered lactone Netilmicin rings: Isepamicin - natural: spiramycin, josamycin, - semisynthetic: midecamycin rokitamycin Ketolides: telithromycin  Lincosamines Tetracyclines Clindamycin generation I: Lincomycin Tetracycline Amphenicols Oxytetracycline Cloramphenicol Rolitetracycline Cloramphenicol generation II: hemisuccinate Doxycycline Tiamphenicol Metacycline Polimixinele Minocycline - Polymyxin M - Colistin Ansamycins Rifampicin Rifaximin Rifamycin Rifabutin  Glycopeptides polyenes - Vancomycin Ristomycin (antimycotics) - Teicoplanin Nystatin Levorin Lipoglycopeptides: amphotericin b Dalbavancin, oritavancin, griseofulvin telavancin, daptomycin natamycin (gram+ poliresistance) Other antibiotics Glycylcyclines: Cycloserine Capreomycin tigecycline (gram- Fosfomycin Fuzafungine enterobacteriaceae) Bacitracin Mupirocin Gramicidin Macrocyclic macrolides: fuzidic adic fidaxomicin (Cl.dificile)  Antibiotics classification according to mechanism of action I gr. acts on bacterial cell wall (inhibits peptidoglycan synthesis, an essential bacterial cell wall component): ❖beta lactamines (penicillins, cephalosporins, carbapenems, monobactams), ❖glycopeptides; II gr. acts on cytoplasmic membrane(bacteria die as a result of membrane’s osmotic barrier modification and subsequent loss of cytoplasmic constituents:) ⮚ polymyxins; ⮚aminoglycosides III gr. inhibition of protein synthesis or ribosome function by ligation to it’s subunits: ✔30S : tetracycline; ✔50S : chloramphenicol, macrolides, lincosamides; ✔interference between 30S şi 50S subunits: aminoglycosides IV gr. acts on cell nucleus constituents: inhibits the DNA-dependent RNA polymerase and blocks the synthesis of messenger RNA followed by downregulation of protein synthesis by ribosomes: - ansamycins (rifampicin; etc.) Antibiotics mechanism of action Аminoglycozides, tetracyclines, macrolides, chloramphenicol, lincosamides ansamycins Polymyxins, polyenes Penicillins, cephalosporins, glycopeptides  Classification according to mechanism of action I gr - Antibiotics with bactericidal effect - Irreversible intoxication of microbial germs at MIC The bactericidal action can be: Absolute - affects germs during both: latent and multiplication phases: ⮚ polymyxins; ⮚ Aminoglycosides ⮚ ansamycins Degenerative - affects germs only in the multiplication phase: ❖ beta-lactams (penicillins, cephalosporins, carbapenems, monobactams), ❖ glycopeptides; II gr - Antibiotics with bacteriostatic effect - inhibition of germs multiplication with in vivo lysis by the body's defense mechanisms (phagocytosis, etc.): ❑ tetracyclines, ❑ chloramphenicol, ❑ macrolides, ❑ lincosamides.  Classification according to the spectrum of action: I gr. - With a more potent influence on gram-positive flora - Biosynthetic penicillins; - isoxazolyl penicillins; - macrolides; - azalides; - lincosamides; - glycopeptides; - fusidine; - cephalosporins I gen.; Spectrum: Gram+ cocci: staphylococci; streptococci; enterococci; peptostreptococci; peptococci. Gram- cocci: neiseria (gonococi; meningococi), moraxella Gram+ bacilli: bac.antracis; Clostridium perfrigens, Clostridum tetani; Clostridum dificile; Corinebacterium diphtheriae; Listeria monocytogenes; Erysipelotrix; Spirochaetes: treponema palidum; leptospira Sctinomyces : actinomyces israeli Atypical (Mycoplasma, legionella, chlamydia) - macrolides, azalides  II gr. - With a more potent influence on gram-negative flora - polymyxins; aminoglycosides; - amino- and carboxypenicillins; cephalosporins - II gen. Spectrum: Gram- bacilli; E.coli, H.influenzae, Pr.vulgaris şi mirabilis, Salmonella spp., Shighella; Klebsiella pneumoniae, Pseudomonas aeruginosa (pyocyanic infection), , Enterobacter; Serratia, Citrobacter. Acinetobacter, bac. fragilis gram- cocci; gram+ cocci; Aminoglycozides: - Brucella; - Yersinia pestis; - Francisella tularensis; - Micobacterium tuberculosis - Micobacterium avum  II gr. - Broad spectrum tetracyclines; IV gr. - Ultra-broad chloramphenicol; ansamycins. spectrum Spectrum: - ureidopenicillins; - gram+ cocci; - monobacteria; - gram- cocci; - cephalosporins gen.III, IV, - gram+ bacilli; V; - gram- bacilli; - carbapenems; - rickettsia; - combinations of beta- - chlamydia; lactams + beta-lactamase - ureaplasma; inhibitors - vibrions; Spectrum: - mycoplasma; polyresistance agents; - protozoa; nosocomial agents  NATURAL PENICILLINS - Indications A. election: (monotherapy) Streptococcal infections; Erysipelas; community acquired pneumococcal pneumonia; scarlet fever; anthrax, diphtheria, gas gangrene; syphilis, leptospirosis; listeriosis, Lyme disease (borreliosis); actinomycosis. B. in high doses as monotherapy: meningococcal and pneumococcal meningitis; sepsis str.pneumoniae. C. in combination with aminoglycosides: sepsis and endocarditis by susceptible streptococci. D. tetanus prophylaxis in traumatology and infected wounds caused by animal bites. E. rheumatism prophylaxis  Semisynthetic penicillins - indications 1. Oxacillin group. - staphylococcal infections (certain of suspected) resistant to benzylpenicillin; - severe infections with penicillin-resistant staphylococci (sepsis, endocarditis) in combination with aminoglycosides 2. Aminopenicillins - upper and lower respiratory tract infections (acute otitis, sinusitis, exacerbation of chronic bronchitis, community acquired pneumonia); - urinary tract infections (acute cystitis, pyelonephritis); - meningitis with H. influenzae or L. monocytogenes (ampicillin); - endocarditis (ampicillin + streptomycin or gentamicin); - intestinal infections: salmonellosis, shigellosis (ampicillin); - gastric and duodenal ulcer (amoxicillin); - endocarditis prophylaxis.  Semisynthetic penicillins - indications 3. Carboxypenicillins Carbenicillin and ticarcillin in nosocomial infections with Ps.aeruginosa in combination with generation II-III aminoglycosides, fluoroquinolones. Ticarcillin / clavulanate in severe, predominantly nosocomial infections: - lower respiratory tract infections; - severe urinary tract infections; - intra-abdominal infections; - pelvic infections; - skin and soft tissue infections - infections of bones and joints; - sepsis. 4. Ureidopenicillins: Ps.aeruginosa infections (combined with aminoglycosides). Piperacillin / tazobactam in severe, predominantly nosocomial infections: - lower respiratory tract infections; - skin and soft tissue infections, including - diabetic foot; - intra-abdominal infections; - pelvic infections and purulent septic complications after birth; - biliary infections, biliary peritonitis, liver abscess; - urinary tract infections (complicated, caused by a permanent catheter); - infections caused by neutropenia and immunodeficiency conditions.  PENICILLIN SIDE EFFECTS Allergic reactions urticaria, erithema (the most frequent, about 60% of all allergic reactions); purpuric rashes, bullous pemphigoid (erupţii buloase?), severe cutaneous skin reactions similar to Stevens-Johnson syndrome (rare); reactions similar to serum sickness , angioneurotic edema, fever, pulmonary eosinophilic infiltration, interstitial nephritis, swollen joints ( rare); şocul anafilactic Reactions caused by the antibacterian action superinfection with penicillin resistant pathogens(Pseudomonas, E.coli, Proteus, B.fragilis) or candidosis; bacteriolysis reaction (worsening, Herkheimer) Dyspeptic symptoms– nausea, vomiting, diarrhea, enteritis, dysbacteriosis. Side effects to parenteral administration: i/m – pain, peripheric nerves damage (paresis, paralysis), aseptic necrosis; in case of endolumbar administration –hyperreflexia, vomiting, muscle rigidity, convulsions; i/v – flebitis and thrombosis. Other side effects Benzylpenicillin in high doses can have irritating action on central nervous system; carboxypenicillins can cause electrolyte disturbances (hypernatremia, hypokalemia), increased transaminases, interstitial nephritis, seizures in case of high doses; anemia, leucopenia (especially in case of semisynthetic drugs). Side effects Skin rash Steven Johnson syndrome Acute bullous dermatitis – Lyell’s syndrome Mucosal candidiasis  “SHEPHERD'S HAT” P O A CEF gen. I G BACTEROIDES CEF gen. II FRAGILIS PIOCIANIC PIOCIANIC CEF gen. III ENTEROCOC ANTIBACTERIAL SPECTRUM OF THE 3rd GEN. OF CEF  Cephalosporins - indications Cefazolin surgical prophylaxis; skin and soft tissues infections; respiratory and urinary tract infections (nowadays is not justified due to the spread of resistant strains); Cephalexin streptococcal tonsillitis and pharyngitis (as an alternative drug); mild and moderate severity outpatient skin and soft tissue infections; IInd generation Cephalosporins Parenteral: outpatient pneumonia requiring hospitalisation; skin and soft tissue outpatient infections; urinary tract infections (moderate and severe pyelonephritis); surgical prophylaxis. Peroral: higher and lower respiratory tract infections (acute otitis media, acute sinusitis, chronic bronchitis flare, outpatient pneumonia); urinary tract infections (pyelonephritis of mild and moderate gravity, pyelonephritis in case of pregnancy and breastfeeding, acute cystitis and pyelonephritis in children). III gen cephalosporins - indications Cefotaxime, ceftriaxone a) outpatient infections (gonorrhea, acute otitis media - ceftriaxone); b) severe outpatient and nosocomial infections: - lower respiratory tract infections; - skin and soft tissue infections; - infections of bones and joints; - intra-abdominal infections; - small pelvic infections; - generalized salmonellosis; - meningitis; - sepsis. Ceftazidime, cefoperazona a) severe outpatient and nosocomial infections of different localization caused by Pseudomonas or Acinetobacter; b) infections due to neutropenia and immunodeficiency. Cefixime, ceftibuten a) urinary tract infections (pyelonephritis- mild and moderate , pyelonephritis in pregnant and lactating women, acute cystitis and pyelonephritis in children); b) the oral stage of step therapy, in various severe outpatient and nosocomial infections with gram-negative bacteria after reaching the stable effect from the use of parenteral preparations; c) upper and lower respiratory tract infections (ceftibuten is not recommended for pneumococcal etiology). Cefoperazona+sulbactam a) severe nosocomial infections mainly caused by germs with poly resistance or mixed infections: - lower respiratory tract infections; - intra-abdominal infections; - small pelvic infections; - complicated urinary tract infections; - sepsis. b) infections due to neutropenia and immunodeficiency.  Cephalosporins - indications IVth –Vth generation - Cefepime, cefpirome a)severe infections, mostly nosocomial, caused by germs with poly-resistance: infections of lower respiratory tract (pneumonia, pulmonary abscess, pleural empyema); intra-abdominal infections; complicated urinary tract infections; skin and soft tissues infections; bone and joint infections; sepsis. b) infections in case of neutropenia and immune deficiency.  CEPHALOSPORINS -ADVERSE REACTIONS Allergic reactions: anaphylactic type; fever,hyperemia,edema; skin rash with pruritus; Stevens-Johnson syndrome (blisters, epithelial desquamation). Hematological deregulations autoimmune hemolytic anemia; hypoprothrombinemia with hemorrhage (cefamandole, cefoperazone, cefotetan, latamoxef). Nephrotoxicity of cephalosporins is low, but may be potentiated in combination with other nephrotoxic preparations (aminoglycosides, polymyxins, furosemide, etc.). Digestive deregulations biliary stasis (pain in the right hypochondrium, in the epigastric region, nausea, vomiting, anorexia - ceftriaxone); pseudomembranous colitis (by superinfection with Clostridium difficile). Dysbacteriosis and superinfection superinfection with gram-positive bacteria (primarily enterococci,staphylococci). Local reactions pain and infiltrates at i/m administration; phlebitis at i/v administration.  CARBAPENEMS Indications - : severe infections, mainly nosocomial, caused by multidrug-resistant and mixed germs: pneumonia, lung abscesses, pleural empyema; urinary tract infections with complications; intra-abdominal infections; small pelvic infections - sepsis; skin and soft tissue infections; bone and joint infections (only imipenem); endocarditis (only imipenem); bacterial infections in patients with neutropenia; meningitis (meropenem only). Adverse reactions: nausea, vomiting, diarrhea, increased liver enzymes (incidence < 5% ), diarrhea; rash (1-1.5%); allergic reactions may be cross-linked with penicillins; In patients with kidney failure, administration of high doses of imipenem may cause seizures (imipenem);  MACROLIDES - indications higher respiratory tract infections (pharyngitis, tonsillitis, acute sinusitis, acute otitis media); lower respiratory tract infections (chronic bronchitis, COPD, outpatient pneumonia, including atypical); diphtheria (especially in case of carriers); whooping cough(pertussis), erythrasma; anthrax, oral cavity infections (periodontitis, periostitis); skin and soft tissues infections; campylobacter gastroenteritis (erythromycin); gastric and duodenal ulcer(clarithromycin); sexually transmitted urinary tract infections (clamidiosis, siphylis limphogranuloma etc.); toxoplasmosis (spiramycin, josamycin, azithromycin); criptosporidiosis (spiramycin, roxithromycin); Lyme disease (azithromycin); listeriosis, actinomicosis; mycobacterial infections (M.avium) in AIDS-infected patients (clarithromycin, azithromycin); Propionibacterium acnes infections (erythromycin, azithromycin); bacterial endocarditis prophylaxis, including stomatology (azithromycin, clarithromycin); whooping cough prophylaxis in case of contact (erythromycin); rheumatism prophylaxis (erythromycin in case of penicillin allergy); healing meningococcal carriers (spiramycin); decontaminations of the intestines before colon surgeries (erythromycin+kanamycin). MACROLIDES – adverse reactions dyspeptic symptoms – epigastralgia, anorexia, nausea, vomiting, diarrhea, meteorism; cases of hepatotoxicity and cholestatic hepatitis have been reported, increased transaminases. rarely – colitis caused by Clostridium difficile. rarely – allergic reactions: skin rashes, Quincke edema.  LINCOSAMIDES Indications streptococcal tonsillitis, pharyngitis; lower respiratory tract infections (aspiration pneumonia, pulmonary abscess, pleural empyema); skin and soft tissue infections, including diabetic foot; bone and joint infections; intra-abdominal infections (peritonitis, abscesses); pelvic infections (endometritis, adnexitis, salpingo-oophoritis, non-gonorrheal abscess of the salpinges and ovaries, pelviocelulită, anaerobic post surgical vaginal infections); toxoplasmosis (clindamycin in association with pyrimethamine); bacterial vaginosis (topically); acneea vulgaris (topically); tropical malaria resistant to chloroquine (clindamycin). Adverse reaction: dyspeptic symptoms (abdominal pain, nausea, vomiting, diarrhea); pseudomembranous colitis; allergic reactions: skin rashes, associated with erythema, pruritus; rarely: neutropenia, thrombocytopenia. Pseudomembranous colitis  AMINOGLYCOZIDES - indications Empirical treatment (most common in associations): severe infections with gram-negative sensitive bacilli; septic arthritis; posttraumatic and postoperative meningitis and osteomyelitis; severe infections with pyocyanic bacillus (with penicillins, cephalosporins, including and patients with fever, leukopenia, reduced resistance); enterococcal infections (with benzylpenicillin, ampicillin, vancomycin); penicillin-resistant staphylococcal infections (with oxacillin and the like); sepsis of unknown etiology; prophylaxis and treatment of abdominal and pelvic infections in combination with antibiotics active against Bac.fragilis; pyelonephritis; nosocomial pneumonia (with a cephalosporin); diabetic foot; treatment and prophylaxis of ophthalmic infections (kanamycin); Streptomycin - tuberculosis, tularemia; brucellosis; plague, enterococcal endocarditis (in combination with penicyclines). decontamination of the intestine in planar interventions on the large intestine (neomycin, kanamycin with erythromycin)  Aminoglycozides – adverse reactions Ototoxicity - cochlear and vestibular lesions. aminoglycosides accumulate in the perilymph of the inner ear, with toxic action on the epithelium of the cochlear and vestibular nerve ; kanamycin and amikacin mainly cause cochlear disorders; streptomycin and gentamicin - vestibular; tobramycin - equally related cochlear and vestibular disorders; Nephrotoxicity - incidence 2-10%. antibiotics reduce glomerular filtration and affect proximal tubular cells due to inhibition of phospholipase required for prostaglandin formation the risk increases with the presence of pre-existing kidney damage, old age, combination with other nephrotoxic remedies (vancomycin, cephalosporins, amphotericin B, polymyxin); Neuromuscular block neuromuscular block is caused by inhibition of acetylcholine release from presynaptic terminations and reduction of postsynaptic reactivity; myasthenia gravis, marked hypocalcemia, combination of muscle relaxants increase the risk of blockage. Calcium is the antagonist in this case. CNS – headache, sleepiness, paresthesias, convulsions, muscle fibrillation Allergic reactions skin rash, fever , eosinophilia  TETRACYCLINES – indications infections with chlamydia (trachoma, psittacosis, urethritis, prostatitis, cervicitis); infections caused by Mycoplasma; Lyme disease, recurrent typhoid fever; riketsiosis; bacterial zoonoses (brucellosis, leptospirosis, anthrax, tularemia, plaque); lower respiratory tract infections (exacerbation of chronic bronchitis, community-acquired pneumonia, including atypical); intestinal infections (cholera, yersiniosis); gynecological infections (anexitis, salpingo oophoritis, etc.); acne vulgaris and rosacea; infected wounds from animal bites; ophthalmic infections; sexually transmitted urinary tract infections (syphilis, penicillin allergy); actinomycosis; gastric and duodenal ulcer; prophylaxis of tropical malaria.  TETRACYCLINES – adverse effects digestive tract, can be: phenomenon of gastric and intestinal irritation - pyrosis,, nausea, vomiting, epigastric pain, diarrhea; intestinal dysbacteriosis and enteric infections with Pseudomonas, Proteus, staphylococci, Candida and other tetracycline-resistant bacteria; due to irritation of the oral mucosa - ulcerative stomatitis; may promote vitamin deficiency. Hepatotoxicity (against pre-existing conditions). high doses, hepatic steatosis; cases of liver necrosis The nephrotoxic action is more common for natural tetracyclines: Fanconi syndrome proximal tubulopathy with polyuria, polydipsia, proteinuria and aminoaciduria, glucosuria, acidosis, nausea and vomiting; the combination of tetracyclines with diuretics may lead to nitrogen retention; nitrogen balance, increased non-protein nitrogen in serum and urinary excretion of nitrogen, weight loss occurs - phenomenon attributed to inhibition of protein anabolism; in patients with renal insufficiency toxic phenomenon, including toxic kidney damage with fatty degeneration of tubular cells; in pregnant women hepato-renal failure with jaundice, acidosis, nitrogen retention and shock.  TETRACYCLINES – adverse effects Bones and teeth. ❖ accumulates in calcified tissues, where they form chelates with calcium orthophosphate; ❖ deposition in the bones may inhibit the growth of children, irreversible to long-term treatment with high doses; ❖ deposition in the teeth produces the coloration of the teeth in brown, with the hypoplasia of the tooth enamel. ❖ in infants, the pressure of the cerebrospinal fluid may increase with the bulging of the fountains. For these reasons, tetracyclines are contraindicated in pregnant women and children under 8, even 12 years. http://www.vvm.com/~bond/tetracyclin  TETRACYCLINES – adverse effects ⮚ Photosensitivity. causes photosensitization phenomenon in the sun and ultraviolet rays, especially in blondes; - phototoxic reactions are sometimes accompanied by high fever. ⮚ Vestibular disorders. vestibular disorders accompanied by dizziness, nausea, vomiting ⮚ Local toxic action on tissues. intravenous administration - venous thrombosis; intramuscular injection causes painful local irritant action. ⮚ Other: ⮚ superinfections (candida mycosis, staphylococcal and pseudomembranous enteritis); ⮚ anti anabolic effect; ⮚ leukocytosis, thrombocytopenia (long-term treatment); ⮚ allergic reactions (dermatitis, Quincke's edema, fever, anaphylactoid reactions).  Amphenicols - indications Chloramphenicol should be used as a reserve antibiotic in the treatment of severe infections when less toxic antibacterial preparations are ineffective or contraindicated: brain abscesses caused by Bacteroides fragilis and other sensitive microorganisms; emergency treatment of typhoid fever caused by Salmonella typhi (not beneficial for Salmonella typhi carriers); meningitis caused by H. influenzae, Neisseria meningitidis, Str.pneumoniae; brain abscesses (caused by anaerobic bacteria); laryngotracheitis (in children), pneumonia (in adults) caused by H. influenzae; Other indications: salmonellosis caused by Salmonella paratyphi A; Qu fever caused by Coxiella burnetii; ehrlichiosis caused by Ehrlichia canis; abdominal sepsis (sometimes in combination with amikacin); exanthematous typhus, brucellosis (as an alternative in cases when tetracyclines are contraindicated).  Amphenicols – adverse effects Hematotoxicity reversible bone marrow depression with anemia, leukopenia and thrombocytopenia. depression of hematopoiesis with pancytopenia - aplastic anemia, leukopenia or agranulocytosis, thrombocytopenia; hemolytic anemia - in the presence of glucose-6-phosphate dehydrogenase deficiency. Digestive deregulations dyspeptic- nausea, vomiting, diarrhea; dysbacteriosis with candidiasis of the mucous membranes (especially of the oral cavity and vagina); pseudomembranous rectocolitis rarely. Neurological deregulations toxic neuropsychic complications due to optic neuritis, polyneuritis, less often - mental confusion, delirium. Gray baby syndrome in newborns clinical symptoms of "gray syndrome": vomiting, anorexia, hypothermia, tachypnea, cyanosis with gray skin, lethargy; Caused by antibacterial action: Bacteriolysis reaction (Herxheimer)  ANSAMYCINS The antibacterial spectrum includes: Mycobacterium - Mycobacterium tuberculosis, atypical mycobacterium (many types), gram-positive cocci – staphylococci (including methicillin-resistant), pneumococci (poly-resistant strains), streptococci, gram-negative cocci – meningococci, gonococci, gram-positive bacilli : Clostridium spp., Bacillus anthracis. Brucella spp., M/O atipice -Chlamydia trachomatis, Legionella pneumophila, Some gram-negative bacteria are less sensitive  ANSAMYCINS - indications pulmonary and extrapulmonary tuberculosis (in combination with other antituberculous drugs); leprosy (in combination with dapsone); staphylococcal infections (endocarditis, osteomyelitis, septic arthritis) in combination with other antibiotics; brucellosis (in combination with doxycycline); pneumonia caused by Legionella (in combination with macrolides); for prophylaxis of meningococcal meningitis (people who have been in contact with patients or for the sterilization of N. meningitidis carriers).  ANSAMYCINS Adverse effects hepatotoxicity - increased transaminases, hyperbilirubinemia; digestive deregulations – nausea, vomiting, diarrhea, anorexia, abdominal pain; allergic reactions – hives(urticaria), Quincke's edema, arthralgias, fever; Neurological deregulations – headache, ataxia, disorientation, confusion; kidney deregulations – interstitial nephritis; reacţii imunologice – thrombocytopenia, hemolytic anemia. GLYCOPEPTIDES - indications ⮚ infections caused by S.aurens OSSA and ORSA; ⮚ staphylococcal infections in β-lactam allergy; ⮚ severe infections caused by Enterococcus spp., B.cereus, F. meningosepticum; ⮚ endocardita infecţioasă, provocată de str.bovis în alergie la β-lactamine; ⮚ infective endocarditis, caused by E. faecalis (in combination with gentamicin); ⮚ meningitis caused by Strp. pneumoniae, resistant to penicillins; Empirical treatment of severe infections caused by staphylococcal etiology: ⮚ infective endocarditis of the tricuspid or prosthetic valve (in combination with gentamicin); ⮚ catheter-associated sepsis, post-traumatic or postoperative meningitis (in combination with generation III cephalosporins or fluoroquinolones); ⮚ peritoneal dialysis peritonitis (PD-associated peritonitis) ⮚ neutropenic fever (inadequacy of initial therapy). ⮚ orally - in pseudomembranous colitis with Cl.difficile; ⮚ surgical site infection prevention in orthopedic and cardiac surgery (by ORSA) ⮚ infective endocarditis prophylaxis for high-risk patients.  GLYCOPEPTIDES Adverse effects: thrombophlebitis (local phlebitis);; allergic reactions (erythema and urticaria, fever, chills, Stevens-johnson syndrome, anaphylactic shock); Ototoxicity and nephrotoxicity; leukopenia, neutropenia (agranulocytosis), anemia, thrombocytopenia, eosinophilia; “Red man syndrome” “Red man syndrome” VANCOMYCIN  Polymyxin - indications Polymyxina M Topical used: otitis externa; corneal ulcers and other superficial eye infections (especially caused by pyocyanic bacillus prophylaxis and treatment of skin infections with sensitive germs; Preventing infections before, during and after surgery – to reduce wound infection aerosol- tracheobronchial infections with gram-negative germs (in the early days); Intrarahidian - in meningitis with pyocyanic bacillus; oral: - colibacillary dyspepsia in infants and children - acute and chronic bacillary dysentery. Polimixina B Parenteral - severe infections with gram-negative sensitive bacilli (resistant to aminoglycosides, fluoroquinolones, cephalosporins, etc.). Colistina Pneumonia caused by Ps.aeruginosa in children with cystic fibrosis Diseases caused by gram-resistant bacilli with multidrug resistance  Polymyxins - side effects extremely toxic, especially in case of systemic administration nephrotoxicity - proteinuria, cylindruria and hematuria, afterwards (in case of a dose increase) -decrease in glomerular filtration rate and increased azotemia. hyponatremia, hypokalemia, hypochloremia. neurotoxicity - perioral paresthesias, vertigo, visual disturbances, vasomotor instability, confusion; skeletal muscle paralysis with respiratory stop caused by motor terminal plate block,; local irritative action, meningeal symptoms acţiune iritantă locală, reacţii meningeale in case of intrathecal administration. rare- allergic reactions  Fusidic acid- indications processes caused by gram-positive pathogens, especially staphylococci, streptococci; osteomyelitis (acute and chronic), septic arthritis, prosthesis infection and osteosynthesis remedies; staphylococcal septicemia; skin and soft tissues infections; pseudomembranous colitis and diarrhea associated with Clostridium difficile; topically, as an ointment (in association with glucocorticoids) in infected dermatoses.  Fusidic acid -adverse reactions incidence 10-20%; digestive system- low or medium intensity; nausea, vomiting, abdominal pain, increased transaminases, cholestasis, jaundice; allergic reactions, eosinophilia; Rarely - thrombocytopenia; i/v. - flebitis, thrombophlebitis  Rezistența antibacteriiilor  MICROBIAL RESISTANCE Natural and aquired; Streptomycin type „or sudden step” - is characterised by mutation after one or two contacts with the antibiotic and does not depend on the dose (is specific for streptomycin, rifampicin, novobiocin, macrolides, fusidic acid); Penicillin type, slowly, "multiple step“ - is characterised by multiple mutation with increase in the dose (is specific for penicillins, cephalosporins, tetracyclines, chloramphenicol, polymyxins, vancomycin); Chromosomal - transfer of genetic material from chromosomes through de novo mutations or down-regulation of genes controlling enzyme synthesis; Extrachromosomal - information about resistance is contained in plasmids-pieces of DNA containing the S factor responsible for resistance. It is transmitted between the same strain of pathogens , but limited between pathogens from different species or genera  MICROBIAL RESISTANCE Mechanisms of antibiotic resistance Mechanisms of occurrence or biochemical? 1.Microorganisms produce enzymes that inactivate the antibiotic: beta-lactamases inactivate penicillins and cephalosporins; acetylases, adenylases, phosphorylases - aminoglycosides; macrolide phosphotransferase-macrolide 2. M / o modifies permeability through transport systems. (glycopeptide); 3. Alteration of the antibiotic site of action at the m / o (macrolides, aminoglycosides, tetracyclines, ansamycins). 4. At m/o, modified metabolic pathways are formed to avoid inhibited antibiotic reactions. 5. M/o produces the modified enzyme capable of performing its own metabolic function, which is little affected by the antibiotic. 6. M/o develops efflux pumps that expel antibiotic from bacterial cell (macrolides, tetracyclines)  Mechanisms of bacterial resistance Conjugation - process of sexual transmition of the genetic material through direct contact through plasma bridges.In this case, resistance appears quickly, polyresistace is possible as well: transformation - transmission of material containing DNA from cells injured by recipients. In this case, whole DNA or fragments can be transmitted; traduction - transmission of genetic material which determines resistance (small fragments of genome) through bacteriophages.  Ways to decrease bacterial resistance synthesis and use of new enzyme-resistant antibiotics (penicillins and IIIrd and IVth generation cephalosporins, semisynthetic aminoglycosides); synthesis of bacterial enzymes inactivating substances , ensuring the antibiotic effect(clavulanic acid, sulbactam etc.); Synthesis of new classes of antibiotics; use of major doses; exclusion of antibiotics use for a certain period (6-12 months); prohibition of local unjustified use of antibiotics.  WHO pathogens with dangerous resistance I gr. –with a very high degree of resistance Acinetobacter baumannii - resistant to carbapenems Pseudomonas aeruginosa – resistant to carbapenems Enterobacteriaceae - resistant to carbapenems, producing wide spectrum beta- lactamases; II gr.- with a high degree of resistance Enterococcus faecium- resistant to vancomycin Staphylococcus aureus – resistant to methicillin, moderately resistant to vancomycin Helicobacter pylori – resistant to clarithromycin Campylobacter spp.- resistant to fluoroquinolones Salmonellae - resistant to fluoroquinolones Neisseria gonorrhoeae, - resistant to cephalosporins, fluoroquinolones III gr. – moderate degree of resistance Streptococcus pneumoniae - resistant to penicillin Haemophilus influenzae - resistant to ampicillin Shigella spp. - resistant to fluoroquinolones  Antistaphylococcal antibiotics Staphylococcus aureus sensitive to methicillin: Ist line: oxacillin, dicloxacillin, flucloxacillin, cefazolin Reserve group: Vancomycin, IIIrd-IVth generation cephalosporins, clindamycin, erythromycin resistant to methicillin: Ist line: Vancomycin Reserve group: teicoplanin, fluoroquinolones (levofloxacin, moxifloxacin) rifampicin, linesolide Resitant to vancomycin Linesolide, eperesolide  Antibiotics effective in gram- negative infections Pseudomonas aeruginosa Ist line: antipseudomonas penicillins, cephalosporins III-IV gen. (+aminoglycosides in case of severe infections, ciprofloxacin (urinary tract infections) Reserve group: Aztreonam or imipenem (+aminoglycosides in severe infections), ceftazidime + aminoglycosides, ciprofloxacin +antipseudomonas penicillin or aminoglycoside (severe infections); Haemophilus influenzae Ist line: Ceftriaxone or cefotaxime, cloramfenicol, amoxicillin-clavulanate Reserve group: Doxycycline, cefuroxime axetil, ciprofloxacin, aztreonam, azithromycin  Antibiotics effective in gram- negative infections Enterobacter spp Ist line:.Aminoglycosides, imipenem, extended-spectrum Penicillin, Reserve group:fluoroquinolones, IVth and Vth generation cephalosporins; Proteus mirabilie and vulgaris Ist line: aminoglycosides, IIIrd generation cephalosporins Reserve group: Amoxicillin-clavulanate, aztreonam, imipenem, fluoroquinolones; Serratia Ist line: Imipenem, cefoxitin, cefotetan or cefalosporină gen.III, extended-spectrum penicillin + aminoglycoside Reserve group: ampicillin, cloramfenicol, aztreonam, antipseudomonas penicillin+ beta-lactamase inhibitors  Combination antibiotic therapy Combination criteria: Action spectrum(synergic action against a certain pathogen or extension of the spectrum against various pathogens); Mechanism of action and antibacterial effect; Possible adverse reactions (associations between drugs with similar side effects or major toxic potential are not adequate)  Classification according to mechanism of action I gr - Antibiotics with bactericidal effect - Irreversible intoxication of microbial germs at MIC The bactericidal action can be: Absolute - affects germs during both: latent and multiplication phases: ⮚ polymyxins; ⮚ Aminoglycosides ⮚ ansamycins Degenerative - effects germs only in the multiplication phase: ❖ beta-lactams (penicillins, cephalosporins, carbapenems, monobactams), ❖ glycopeptides; II gr - Antibiotics with bacteriostatic effect - inhibition of germs multiplication with in vivo lysis by the body's defense mechanisms (phagocytosis, etc.): ❑ tetracyclines, ❑ chloramphenicol, ❑ macrolides, ❑ lincosamides.  Indications for combination antibiotic therapy 1. Empiric treatment (the pathogen is not known) - severe infections –initially, until the isolation, identification and establishing sensitivity 2. Polymicrobial infections: - Peritonitis with intestinal perforation; - Endometritis; - Posthysterectomy infections (gram- and anaerobic bacteria); - Patients with neutropenia (caused by cytotoxic anticancerous drugs) – infections with endogenous bacteria (E.coli,Klebsiella, Pr.mirabilis, Ps.aeruginosa, Staph.aureus). 3. Potenciation of the antibacterial effect towards a certain pathogen: - Endocarditis cause by Enterococcus and Str.viridans; - Tuberculosis; - severe infections with Ps.aeruginosa; - Staph. Aureus and Staph. Epidermidis infections 4. Prevention of bacterial resistance: - tuberculosis; - H.pylori infections; - stafilococci infections  Combination antibiotic therapy The most effective and recommended: beta-lactamics + aminoglycosides; Allowed (for spectrum extension): Beta-lactamics + macrolides, lincosamides; Aminoglycosides+fluoroquinolones, co-trimoxazol; Macrolides, lincosamides+fluoroquinolones, co-trimoxazol; Tetracyclines,chloramphenicol + macrolides, lincosamides; Tetracyclines,chloramphenicol +fluoroquinolones, co-trimoxazol; Aminoglycosides + tetracyclines, chloramphenicol; Beta-lactamics + fluoroquinolones; Between beta-lactamics. Antagonistic combinations, not recommended: Beta-lactamics + tetracyclines, chloramphenicol; Prohibited combinations: Aminoglycosides + polymixins; Tetracyclines + chloramphenicol; Macrolides +lincosamides;  ADVERSE REACTIONS of antibiotics 1.INTOLERANCE AT THE ADMINISTRATION SITE (oral, i/m; i/v; intrarahidian; intraperitoneal etc.); 2. TOXIC (nephrotoxicity; hepatotoxicity; ototoxicity; neurotoxicity; medullotoxicity, etc.); 3. ALLERGIC (general; cutaneous-mucous; pulmonary; renal; hematological; anaphylactic shock, etc.); 4. BIOLOGICAL (dysmicrobisms; superinfections); 5. BACTERIOLOGICAL (Herxheimer's phenomenon; endotoxic shock); 6. METABOLIC (dysmetabolism; hypo- and avitaminosis); 7. EMBRYOTOXICITY, TERATOGENICITY, FETOTOXIC; IN NEWBORN AND BABY CHILDREN; 9. INTERFERENCE OF POST-INFECTIOUS IMMUNITY (relapses; reinfections; chronicity); 10. DRUG INTERFERENCES (with solvents; with other antibiotics, with other drugs). Vă dorim să selectaţi cât mai raţional antibioticele