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The problem
drug companies have little interest in financing the testing of their newly discovered antibiotics, because they are more focused on drugs that people require daily for the rest of their lives
superbugs
microorganisms with multiply resistance
MRSA - methicillin/oxacillin-resistant Staphylococcus aureus VISA - vancomycin intermediate resistant Staphylococc VRE - vancomycin-resistant enterococci ESBLs - extended-spectrum beta-lactamases (microorganisms resistant to cephalosporins and monobactams) PRSP - penicillin-resistant Streptococcus pneumoniae
1952 100 % Staphylococcus infections were cured by penicillin 1982 only 10 % infections At nowadays ?........
MRSA causes 19 000 deaths annually in USA (more than VIL)
Presence of substantiated indications for prescription of an antibiotic Choosing of the most effective and the least toxic drug, in time administration Introduction of optimal doses with optimal frequency, taking into consideration complexity of the disease Choosing of the optimal way of introduction Estimation of duration of treatment Control after treatment Monitoring and prophylaxis of negative side effects Decision on expediency of combined antibiotic therapy
ANTIBIOTICS
Beta-lactam antibiotics: . Penicillins . Inhibitors of beta-lactamases and combined drugs, . Cephalosporins . Monobactams . Tienamycin (carbapenems). Macrolides, azalides, streptogramins, prystinamycines. Linkozamides. Tetracyclines. Aminoglycosides. Chloramphenicols. Glycopeptides. Cyclic polipeptides (polimixins). Other antibiotics
ANTIBIOTICS
Dose-dependent Antibacterial effect directly depends on their concentrations in the locus of inflammation (high doses 1-2 times/24h) Time-dependent Effectiveness depends on a period of time, during which concentration in blood overwhelms MIC for a particular causative agent (constant i.v. infusion or 3-6 times/24h)
PENICILLINS
Natural (biosynthetic) penicillins: benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V), novocain salt of benzylpenicillin (benzylpenicillin procain), bicillin-1 (benzatyn benzylpenicillin), bicillin-3, bicillin-5. Semisynthetic penicillins: 1 antistaphylococci penicillinase resistant penicillins izoxazolil-penicillins (oxacillin, dicloxacillin, methicillin); 2 of a spread spectrum aminopenicillins (ampicillin, amoxicillin); 3 antipseudomonade carboxypenicillins (carbenicillin, ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin); 4 combined with inhibitors of beta-lactamases protected penicillins (amoxicillin/clavulanate, ampicillin/sulbactam, ticarcillin/clavulanate, piperacillin/tazobactam).
S H2 N T CH3 CH3 L
O OH
They form complexes with enzymes - transand carboxypeptidases (PCP), which control synthesis of peptidoglycan component of cell-wall of microorganisms
Spectrum of action of biosynthetic penicllins Gram-positive microorganisms Streptococci Bacillus anthracis Causative agents of tetanus, gas gangrene Actinomycets Listeria Gram-negative microorganisms Gonococci Meningococci Moraxella Causative agent of syphilis Leptospiras
schemes on introduction of biosynthetic penicillins Frequency of introduction Benzylpenicillini 0,5-2 mln U (till 10 Every 4-6 hours sodium salt, i.m., mln) (every i.v. 6 hours)
Benzatyn benzylpenicillin (bicillin-1), i.m. Bicillin-3, i.m. Bicillin-5, i.m.
Antibiotic, way of introduciton
Allergic reactions (10 %) Endotoxic shock Disorders of electrolyte balance Neurotoxic reactions (in using of big doses) encephalopathy (hyperreflexia, seizures, hallucinations, coma) Daily dose of BP during intratecal introduction should not overcome 10 000 U (5 000 U for children) Interstitial nephritis
Oxacillin
Antistaphylococci penicillinase-resistant semisynthetic penicillin, acid stable Administration: intramuscular, intravenously, oraly 3-6-8 g/24 hours (4-6 times of injections)
Influence on: streptococci, Haemophilus influenzae, causative agent of wooping cough, gonococci, meningococci, proteus, Escherichia coli, salmonella, shigella
Ampicillin
Amoxicillin
Ampicillin
Amoxycillin
Acute midlle otitis Acute pharingitis Bacterial sinusitit Chronical bronchitis Acute bronchitits Extrahospital pneumonia of light or medium-severe complexity Acute pielonephritis Chronical pielonephritis Acute cystitis Acute prostatitis Bacteriouria in children Gonorrhea and pregnant women Cholangitis, cholecystitis Typhoid fever Borreliosis Leptospirosis
Irritation of mucous membrane of digestive tract (diarrhea) Disbacteriosis Superinfection (colonizing of gut with Candida fungi, enterococci, Pseudomonas aeruginosa, clostridia) Pain in injection area, aseptical inflammation, phlebitis Allergic reactions Granulocytopenia (oxacillin) Reduction of platelets agregation (ampicillin) Disorders of liver function Encephalopathy (in introduction of high doses)
Inhibitors of beta-lactamases
Clavulanic acid Sulbactam
Tazobactam
Unasyn (ampicillin/sulbactam)
Inhibitor-protected (screened, protected) penicillins Amoxicillin/clavulanate (amoxyclav, augmentin) Ampicillin/sulbactam (sultamycillin, unasin) Ticarcillin/clavulanate (timentin) Piperacillin/tazobactam
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Classification of cephalosporins
Way of introduction Injection Generation of cephalosporin antibiotics first I second II third III fourth IV
Oral
Cephalexin * Cefadroxil*
Cefixime * Ceftibuten *
Cefazolin-sodium (C I)
Cezolin (Cefazolin, C I)
Cefalexin ( C I)
Cefotaxime (C III)
+++ ++ + ++
++ ++ + ++
+/+ ++
Irritation of mucous membrane of digestive tract, infiltrates after intromuscular introduction , phlebitis after inrtavenous introduction Disbacteriosis, superinfection Allergic reactions, including cross allergy with penicillins Granulocytopenia (in case of treatment during more than 2 weeks) Hemorrhages (inhibition of synthesis of factors of blood coagulation in liver) cephalosporins Nephrotoxicity (accumulation in epithilial cells of kidney canalicules) Encephalopathy (hyperreflexia, seizures, coma)
Cephalosporines
Not recommended to combine with other nephrotoxic drugs (aminoglycosides)
Contraindicated to combine with loop diuretics (furosemid, etacrinic acid)
Monobactams
Aztreonam Action spectrum - Gram (-) bacteria, including Escherichia coli, Clebsiellas, Proteus, Haemophilus influenzae (activity is equal to the activity of cephaloporins of third generation) Ways of introduction: oral (20% are being absorbed), intramuscular, intravenous Clinical uses: sepsis, infection of urinary tract, soft tissues, meningitis and others (often combined with aminoglycosides , clindamycin, metronidazole, vankomycin).
Carbapenems (tienamytsin)
Classificaion of macrolides
. Natural substances: erythromycin, oleandomycin, spiramycin, jozamycin, midecamycin. . Semi-synthetic substances: roxythromycin, clarithromycin, flurythromycin, dyrythromycin, miokamycin, rokitamycin. III. Azalides (neutrogen atom is introduced in lacton ring): azithromycin.
Erythromycin
Macropen (midecamycin)
Sumamed (azithromycin)
staphylo-, strepto-, hono-, anaerobe cocci, enterobacteria H.influenzae (clarythromycin, azithromycin) intracellular situated microorganisms (strains of Helicobacter, Chlamydia, Legionell, M. pneumoniae, U. urealyticum etc.)
Pharmacokinetics of macrolides
Quiclkly and fully distributed through the tissues (do not pass through HEB) Correlation concentration tissues/blood: Erythromycin (5-10) : 1 Azithromycin (100-500) : 1 Their concentration in phagocyting cells prevails concentration in blood pasma in 1220 times, they get accumulated in source of inflammation - macrolides paradoxis
Indications for usage of macrolides and azalides LOR- infections, infections of upper respiratory tracts, gynecological infections, skin and soft tissues infections; ulcer disease; dyphteria; whooping-cough; honorrhea; syphilis; typhoid fever (azithromycin). Drugs of choice for: mycoplasma, chlamidia, legionella pneumonia
Dispeptic disorders, disbacteriosis, superinfection Cholestasis, cholestatic jaundice (erythromycin) Depression of liver microsome enzyme activity (erythromycin, oleandomycin can not be combined with theophylline, ergot alkaloids, carbamazepine) Development of resistance in process of treatment
Linkosamides
Linkomycin
Clindamycin
Action spectrum: Gram positive aerobe cocci, grampositive and gramnegatvie anaerobes Penetrate all the tissues (dont pass through HEB) including intracellurally Usage: usually in heavy infections, caused by anaerobe microorganisms A lot of side effects
Linkomycini hydrochloridum
Tetracyclines
1. Natural - biosynthetic: chlortetracycline, oxytetracycline, tetracycline, dimethylchlortetracycline. 2. Semisynthetic: doxycycline (vibramycin), metacycline (rondomycin), minocycline.
Tetracycline
Doxycycline
Vibramycin (doxycycline)
Tetracycline - 0,25-0,5 g 4 times per 24 hours Methacycline 0,3-0,6 g 2 times per 24 hours Doxycycline 0,2 g (first day), 0,1g (next days) 1 time per 24 hours
Pharmacokinetics of tetracyclines when combined with other drugs Drugs Results of combined administration
Decrease of absorbtion
Dispeptic disorders, stomatitis, glositis,esophagitis, pruritus etc). Disbacteriosis and superinfection with Candida fungi, proteus, pseudomonadas or staphylococci. Photodermatosis. Liver toxicity. Absorbtion by bones and teeth of a featus or a child: hipoplasia of dental enamel, disorder of teeth formation, tendency for caries. Antianabolic action, damage of kidneys (when using tetracyclines with long termed storage, using big doses). Tetracyclines are forbidden for children under the age of 8/12, during pregnancy, liver diseases, kidney insufficiency, miastenia
Photosensitization - tetracyclines
tetracyclines
AMINOGLYCOSIDES
generation: streptomycin, neomycin, monomycin, kanamycin generation: gentamycin (garamycin), tobramycin, syzomycin generation: netilmycin (netromycin), amikacin.
Gentamycin
wide
gram-negative bacteria (escherichia coli, salmonella, klebsiella, especially K. neumoniae, proteus, iersinia, brucella, campilobacteria, helicobacters, serratsia, shigella etc.). some gram-positive microorganisms, including staphylococci which are resistant to other antibiotics
ethiology and severe complexity (combined with betalactamase); - considerable purulent-inflammatory component of heavy infections (peritonitis, sepsis, mediastinitis, abscesses and flegmones of soft tissues); - acute attack of chronical purulent-inflammatory diseases, including secondary immune defficiency; - early stage of development of secondary bacterial meningitis; - bacterial endocarditis; - infections of urinary tracts; - for prophilaxis of postoperative pustural complications (combined with beta-lactamase antibiotics, metronidazole or other antianaerobe drugs); - skin infections and subcutaneous fat tissue infections, burns.
Concentration of aminoglycosides in blood should not overcome: kanamycin 35-40 mkg/ml Gentamicin, tobramycin 10-12 mkg/ml
Amikacin,
Ototoxicity Nephrotoxicity Neurotoxicity According to extent of toxicity netilmicin < gentamicin <tobramycin < amikacin < neomycin < streptomycin < monomycin < kanamycin
Leuko-, thrombocytopenia, hemmorhages, hemolisis Allergic reactions
Chloramphenicol levomycetin
Indications: meningitis, typhoid fever, paratyphoid fever, brucellosis, tularemia
Side effects: Hypochrome and aplastic anemia Granulocytopenia, thrombocytopenia Grey syndrome of a featus Disbacteriosis and superinfection
Glycopeptide antibiotics
Vankomycin, Teikoplanin