ANTIBIOTICS

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)

Principles of rational antibiotic therapy

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)

Aminoglycosides Fluoroqinolones Metronidazol Amphotericin B

Beta-lactames Glycopeptides Macrolides Linkozamides

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

Nucleus of penicillin molecule L beta-lactame ring, T thiazoline ring

Mechanism of penicillins action

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

One time dose

0,3-0,6 mln U 1,2 mln U 0,6 mln U

1,5 mln U

1 time/week 1 time/2 weeks 1 time/week 1 time/week

Complications of biosynthetic penicillins

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)

Spectrum of action of aminopecillins (ampicillin, amoxicillin) wide spectrum, destroyed by beta-lactamases

.

Influence on: streptococci, Haemophilus influenzae, causative agent of wooping cough, gonococci, meningococci, proteus, Escherichia coli, salmonella, shigella

Ampicillin

Amoxicillin

Differences between ampicillin and amoxicillin

Parameters
Activity towdards pneumococci H. pylori salmonella shigella Bioavailability after oral administration Influence of food on bioavailability Level in sputum Level in urine Appearance of diarrhea

Ampicillin

Amoxycillin

++ + ++/+++ +++ 40 % dicreases in 2 times low high frequently

+++ +++ +++ + 90 % no influence high very high rarely

Indications for administration of amoxicillin

Localisation of ifection Respiratory tracts Drug of choice Alternative drug

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

Kidneys and urinary tracts

Digestive tract Other pathology

Side effects of semisynthetic penicillins

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

S H2N
L D

CH2

CO

CH3

O
OH

Structure of cephalosporins L beta-lactame ring, D dihydrothiazine ring

Classification of cephalosporins
Way of introduction Injection Generation of cephalosporin antibiotics first I second II third III fourth IV

Cefaloridin Cefadroxil* Cefazolin* Cefalexin* Cephradin*

Cefamandole* Cefotaxime* Cefpirome* Cefoxytyn* Ceftriaxone* Cefepime* Cefuroxime* Cefoperazone* Ceftazidime*

Oral

Cephalexin * Cefadroxil*

Cefuroxime axetyl* Cefaclor *

Cefixime * Ceftibuten *

Cefazolin-sodium (C I)

Cezolin (Cefazolin, C I)

Cefalexin ( C I)

Zinnat (Cefuroxime, C II)

Cefotaxime (C III)

Claphoran (cefotaxime, C III)

Cefobid (Cefoperazone, C III)

Antimicrobial spectrum of cephalosporins

Generation of cephalosporins Active towards
Grampositive bacteria V Gramnegative bacteria

Stability towards betalactamase Staphylo Gramcocci negative bacteria

+++ ++ + ++

+/+ +++ +++

++ ++ + ++

+/+ ++

Complications, caused by cephalosporins

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)

Tienam (imipenem + cylastatin) Meropenem

The widest spectrum of antibacterial action most of aerobe and anaerobe Gram (+) and Gram (-) bacteria, including those which produce beta-lactamase

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)

spectrum of action of maclrolides and azalides

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

Side affects of macrolides

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

Dalacyn C (clindamycini hydrochloridum)

Tetracyclines
1. Natural - biosynthetic: chlortetracycline, oxytetracycline, tetracycline, dimethylchlortetracycline. 2. Semisynthetic: doxycycline (vibramycin), metacycline (rondomycin), minocycline.

Tetracycline

Doxycycline

Vibramycin (doxycycline)

Shemes of tetracyclines administration

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

Antacides (Ca+, Mg+ etc.) Iron preparations Rifampicin

Decrease of absorbtion

Decrease of absorbtion Increase of elimination

Side effects of tetracyclines

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

spectrum of action of aminoglycosides

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

Indications for usage of aminoglycosides

- at the beginning stage of infectious processes of unknown

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,

Complications in administration of aminoglycosides

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

Active towards RS MRCNS Drugs of choice for C. difficile - associated colitis