Antibiotics And Antibacterial Drugs 2i4s26

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 Staphylococcі 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 istration 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: А. Penicillins Б. Inhibitors of beta-lactamases and combined drugs, В. Cephalosporins Г. Monobactams Д. Tienamycin (carbapenems). Macrolides, azalides, streptogramins, prystinamycines. Linkozamides. Tetracyclines. Aminoglycosides. Chloramphenicols. Glycopeptides. Cyclic polipeptides (polimixins). Other antibiotics

ANTIBIOTICS Dose-dependent

Time-dependent

Antibacterial effect directly depends on their concentrations in the locus of inflammation (high doses 1-2 times/24h)

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

CH3 CH3 T

L

O

N

C

O OH

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

Mechanism of penicillins action

They form complexes with enzymes - transand carboxypeptidases (P), 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 Antibiotic, way of introduciton

One time dose

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.

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

1 time/week 1 time/2 weeks

Bicillin-3, i.m.

0,6 mln U

1 time/week

Bicillin-5, i.m.

1,5 mln U

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 istration: 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 istration Influence of food on bioavailability Level in sputum Level in urine Appearance of diarrhea

Ampicillin

Amoxycillin

++ + ++/+++ +++

+++ +++ +++ +

40 %

90 %

dicreases in 2 times low high

no influence high very high

frequently

rarely

Indications for istration of amoxicillin Localisation of ifection

Drug of choice

Respiratory tracts

Acute midlle otitis Acute pharingitis Bacterial sinusitit Chronical bronchitis Acute bronchitits Extrahospital pneumonia of light or medium-severe complexity

Kidneys and urinary tracts

Acute pielonephritis Chronical pielonephritis Acute cystitis Acute prostatitis Bacteriouria in children Gonorrhea and pregnant women

Digestive tract Other pathology

Alternative drug

Cholangitis, cholecystitis Typhoid fever Borreliosis

Leptospirosis

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

O

D

N

CH2

C

O

CO

O OH

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

CH3

Classification of cephalosporins Way of introduction

Generation of cephalosporin antibiotics first I

second II

third III

Injection

Cefaloridin Cefadroxil* Cefazolin* Cefalexin* Cephradin*

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

Oral

Cephalexin * Cefadroxil*

Cefuroxime axetyl* Cefaclor *

Cefixime * Ceftibuten *

fourth IV

-

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

Gramnegative bacteria

Stability towards betalactamase Staphylo Gramcocci negative bacteria

І

+++

+/-

++

-

ІІ

++

+

++

+/-

ІІІ

+

+++

+

+

ІV

++

+++

++

++

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 ІІІ 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 І. Natural substances: erythromycin, oleandomycin, spiramycin, jozamycin, midecamycin. ІІ. 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, Legionellа, M. pneumoniae, U. urealyticum etc.)

Pharmacokinetics of macrolides Quiclkly and fully distributed through the tissues (do not 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 (don’t 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 istration 

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 istration

Antacides (Ca+, Mg+ etc.)

Decrease of absorbtion

Iron preparations

Decrease of absorbtion

Rifampicin

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 

І generation: streptomycin, neomycin, monomycin, kanamycin



ІІ generation: gentamycin (garamycin), tobramycin, syzomycin



ІІІ generation: netilmycin (netromycin), amikacin.

Gentamycin

spectrum of action of aminoglycosides

wide 

gram-negative bacteria (escherichia coli, salmonella, klebsiella, especially K. рneumoniae, 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 istration of aminoglycosides   





Ototoxicity Nephrotoxicity Neurotoxicity According to extent of toxicity netilmicin < gentamicin < 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 МRS і MRCNS  Drugs of choice for C. difficile - associated colitis