ANTIBIOTICSANTIBIOTICS

Lector prof. Posokhova K.A.Lector prof. Posokhova K.A.

The problemThe 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 superbugs microorganisms with multiply resistancemicroorganisms with multiply resistance

MRSAMRSA - methicillin/oxacillin-resistant methicillin/oxacillin-resistant Staphylococcus aureusStaphylococcus aureus

VISAVISA - - vancomycin intermediate resistant vancomycin intermediate resistant StaphylococcStaphylococcіі

VREVRE - vancomycin-resistant enterococcivancomycin-resistant enterococci ESBLsESBLs - extended-spectrum beta-lactamasesextended-spectrum beta-lactamases

(microorganisms (microorganisms – resistant to cephalosporins and – resistant to cephalosporins and monobactamsmonobactams))

PRSPPRSP - penicillin-resistant Streptococcus pneumoniaepenicillin-resistant Streptococcus pneumoniae

1952 – 100 % StaphylococcusStaphylococcus infections were cured by penicillin

1982 – only 10 % infections At nowadays ?........

MRSA causes 1MRSA causes 19 9 000 deaths000 deaths annually in USAannually in USA ( (more than VILmore than VIL))

Principles of rational antibiotic therapy

Presence of substantiated indications for Presence of substantiated indications for prescription of an antibioticprescription of an antibiotic

Choosing of the most effective and the least toxic Choosing of the most effective and the least toxic drug, indrug, in time administrationtime administration

Introduction of optimal doses with optimal Introduction of optimal doses with optimal frequency, taking into consideration complexity of frequency, taking into consideration complexity of the diseasethe disease

Choosing of the optimal way of introductionChoosing of the optimal way of introduction Estimation of duration Estimation of duration of of treatmenttreatment Control after treatmentControl after treatment Monitoring and prophMonitoring and prophyylalaxixis of negative side effectss of negative side effects Decision on expediency of combined antibiotic Decision on expediency of combined antibiotic

therapytherapy

ANTIBIOTICS Beta-lactam 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)

Aminoglycosides Aminoglycosides

FFluluororoqoqinolonesinolones

MetronidazolMetronidazol

AmphoterAmphoteriicin Bcin B

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)

Beta-lactamesBeta-lactames

GlycopeptidesGlycopeptides

MacrolidesMacrolides

LinkozamidesLinkozamides

PENICILLINS 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).

Nucleus of penicillin moleculeL – beta-lactame ring, T – thiazoline ring

N

TL

S

CO

OH

CH3

CH3

O

H2N

Mechanism of penicillins actionMechanism of penicillins action

They form complexes with enzymes - trans- and carboxypeptidases (PCP), which control synthesis of peptidoglycan – component of cell-wall of microorganisms

Spectrum of action of biosynthetic penicllins

Gram-positive microorganisms

Gram-negative microorganisms

Streptococci

Bacillus anthracis

Causative agents of tetanus, gas gangrene

Actinomycets

Listeria

Gonococci

Meningococci

Moraxella

Causative agent of syphilis

Leptospiras

 

schemes on introduction oschemes on introduction off biosynthetic penicillins biosynthetic penicillins 

Antibiotic, way of introduciton

One time dose Frequency of introduction

Benzylpenicillini sodium salt, i.m., i.v.

0,5-2 mln U (till 10 mln)

Every 4-6 hours (every

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/weekBicillin-5, i.m. 1,5 mln U 1 time/week

Complications of biosynthetic Complications of biosynthetic penicillinspenicillins

Allergic reactionsAllergic reactions (10 (10 %)%) Endotoxic shockEndotoxic shock Disorders of electrolyte balanceDisorders of electrolyte balance Neurotoxic reactionsNeurotoxic reactions ( (in using of big dosesin using of big doses) – ) –

encephalopathyencephalopathy ( (hyperreflexiahyperreflexia, , seizuresseizures, , hallucinationshallucinations, , comacoma))

Daily dose of BPDaily dose of BP during intratecal during intratecal introductionintroduction should not overcomeshould not overcome 10 10 000 000 UU

(5(5 000 000 UU – – for childrenfor children)) Interstitial nephritisInterstitial nephritis

OxacillinOxacillin 

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 Differences between ampicillin and amoxicillin

Parameters

Ampicillin Amoxycillin

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

++

+

++/+++

+++

40 %

dicreases in 2 times

low

high

frequently

 +++

+++

+++

+

90 %

no influence

high

very high

rarely

Indications for administration of amoxicillin Localisation of ifection Drug of choice Alternative drug

Respiratory tracts Acute midlle otitis

Bacterial sinusitit

Acute bronchitits

Extrahospital pneumonia of light or medium-severe complexity

Acute pharingitis

Chronical bronchitis

Kidneys and urinary tracts

Acute pielonephritis

Acute cystitis

Bacteriouria in children and pregnant women

Chronical pielonephritis

Acute prostatitis

Gonorrhea

Digestive tract Cholangitis, cholecystitis

Typhoid fever

Other pathology Borreliosis Leptospirosis

SSide effects of ide effects of semisemisynthetic synthetic penicillinspenicillins

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”) Inhibitor-protected (“screened”, “protected”) penicillinspenicillins

Amoxicillin/clavulanateAmoxicillin/clavulanate (amoxyclav, augmentin)(amoxyclav, augmentin)

AmpicillinAmpicillin/sulbactam/sulbactam (sultamycillin, unasin)(sultamycillin, unasin) TicarcillinTicarcillin/clavulanate/clavulanate

(timentin)(timentin) PiperacillinPiperacillin/tazobactam/tazobactam

Structure of cephalosporinsL – beta-lactame ring, D – dihydrothiazine ring

CH2 O CO CH3

C

O

H2N

O

OH

S

L D

N

Classification of cephalosporinsClassification of cephalosporins

Way of introduction

Generation of cephalosporin antibioticsGeneration of cephalosporin antibiotics

ffirstirst I I secondsecond II II thirdthird III III fourthfourth IV IV

Injection CefaloridinCefaloridin

Cefadroxil*Cefadroxil*

Cefazolin*Cefazolin*

Cefalexin*Cefalexin*

Cephradin*Cephradin*

Cefamandole* Cefamandole* Cefoxytyn*Cefoxytyn*

Cefuroxime*Cefuroxime*

  

Cefotaxime*Cefotaxime*

Ceftriaxone*Ceftriaxone*

Cefoperazone*Cefoperazone*

Ceftazidime*Ceftazidime*

Cefpirome*Cefpirome*

Cefepime*Cefepime*

  

  

Oral Cephalexin *Cephalexin *

Cefadroxil*Cefadroxil*

Cefuroxime Cefuroxime axetyl axetyl* *

Cefaclor *Cefaclor *

Cefixime *Cefixime *

Ceftibuten *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 Stability towards beta-lactamase

Gram-positive bacteria

Gram-negative bacteria

Staphylo cocci

Gram-negative bacteria

ІІ ++++++ +/-+/- ++++ --

ІІІІ ++++ ++ ++++ +/-+/-

ІІІІІІ ++ ++++++ ++ ++

ІІVV ++++ ++++++ ++++ ++++

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 Cephalosporines

NNot recommendedot recommended to combine with other nephrotoxic drugs

(aminoglycosides)

ContraindicatedContraindicated to combine with loop diuretics (furosemid,

etacrinic acid) 

MonobactamsMonobactamsAztreonam

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)Carbapenems (tienamytsin)

Tienam (imipenem + cylastatin) Tienam (imipenem + cylastatin)

MeropenemMeropenem

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

Classificaion ofClassificaion of macrolidesmacrolides

І. Natural substances: erythromycin, І. Natural substances: erythromycin, oleandomycin,oleandomycin, spiramycin, spiramycin, jozamycin, midecamycin.jozamycin, midecamycin.

ІІ. ІІ. SemiSemi-synthetic substances: -synthetic substances: roroxxythromycin, clarithromycin, ythromycin, clarithromycin, flurythromycin, dyrythromycin, flurythromycin, dyrythromycin, miokamycin, rokitamycin.miokamycin, rokitamycin.

IIIIII. Azalides. Azalides (neutrogen atom is (neutrogen atom is introduced in lacton ring): introduced in lacton ring): azithromycin.azithromycin.

ErythromycinErythromycin

Macropen (midecamycin)Macropen (midecamycin)

Sumamed (azithromycin)Sumamed (azithromycin)

spectrum spectrum of aof action of maclrolides ction of maclrolides and azalidesand 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 Pharmacokinetics of macrolidesmacrolides

Quiclkly and fully distributed through the tissues (do not pass through HEB)

Correlation Correlation concentration concentration tissues/blood:tissues/blood:Erythromycin – (5-10) : 1Azithromycin – (100-500) : 1Their concentration in phagocyting cells

prevails concentration in blood pasma in 12-20 times, they get accumulated in source of inflammation - macrolides paradoxis

Indications for usage of macrolides and Indications for usage of macrolides and azalidesazalides

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 mSide affects of maacrolidescrolides

Dispeptic disorders, disbacteriosis, superinfectionDispeptic disorders, disbacteriosis, superinfection Cholestasis, cholestatic jaundice (erythromycin)Cholestasis, cholestatic jaundice (erythromycin) Depression of liver microsome enzyme activity Depression of liver microsome enzyme activity

(erythromycin, oleandomycin can not be combined (erythromycin, oleandomycin can not be combined with theophylline, ergot alkaloids, carbamazepine)with theophylline, ergot alkaloids, carbamazepine)

Development of resistance in process of treatmentDevelopment of resistance in process of treatment

Linkosamides Linkosamides

Linkomycin ClindamycinLinkomycin Clindamycin

Action spectrum: Gram positive aerobe cocci, Action spectrum: Gram positive aerobe cocci, grampositive and gramnegatvie anaerobesgrampositive and gramnegatvie anaerobes

Penetrate all the tissues (don’t pass through Penetrate all the tissues (don’t pass through HEB) including intracellurally HEB) including intracellurally

Usage: usually in Usage: usually in heavyheavy infections, caused by infections, caused by anaerobe microorganismsanaerobe microorganisms

A lot ofA lot of side side eeffectsffects

Linkomycini Linkomycini hydrochloridumhydrochloridum

Dalacyn C (clindamycini Dalacyn C (clindamycini hydrochloridum)hydrochloridum)

TetracyclinesTetracyclines

1. 1. Natural - biosynthetic:Natural - biosynthetic: chlortetracycline, oxytetracycline, chlortetracycline, oxytetracycline, tetracycline, tetracycline, dimethylchlortetracycline.dimethylchlortetracycline.

2. 2. SemiSemisyntheticsynthetic::

doxycycline (vibramycin), metacycline doxycycline (vibramycin), metacycline (rondomycin), minocycline.(rondomycin), minocycline.

Tetracycline Tetracycline

DoxycyclineDoxycycline

Vibramycin (doxycycline)Vibramycin (doxycycline)

Shemes of tetracyclines Shemes of tetracyclines administrationadministration

Tetracycline - 0,25-0,5 g 4 times per 24 Tetracycline - 0,25-0,5 g 4 times per 24 hours hours

Methacycline – 0,3-0,6 g 2 times per 24 Methacycline – 0,3-0,6 g 2 times per 24 hourshours

Doxycycline – 0,2 g (first day), 0,1g (next Doxycycline – 0,2 g (first day), 0,1g (next days) 1 time per 24 hoursdays) 1 time per 24 hours

Pharmacokinetics of tetracyclines when combined with Pharmacokinetics of tetracyclines when combined with other drugsother drugs

Drugs Results of combined administration

Antacides (Ca+, Mg+ Antacides (Ca+, Mg+ etc.)etc.)

Iron preparationsIron preparations

Rifampicin Rifampicin

Decrease of absorbtionDecrease of absorbtion

Decrease of absorbtionDecrease of absorbtion

Increase of eliminationIncrease of elimination

Side Side eeffects of tetracyclinesffects of tetracyclines Dispeptic disorders, stomatitis, glositis,esophagitis, Dispeptic disorders, stomatitis, glositis,esophagitis,

pruritus etc). pruritus etc). Disbacteriosis and superinfection with Candida fungi, Disbacteriosis and superinfection with Candida fungi,

proteus, pseudomonadas or staphylococci. proteus, pseudomonadas or staphylococci. Photodermatosis. Photodermatosis. Liver toxicity. Liver toxicity. Absorbtion by bones and teeth of a featus or a child: Absorbtion by bones and teeth of a featus or a child:

hipoplasia of dental enamel, disorder of teeth hipoplasia of dental enamel, disorder of teeth formation, tendency for caries. formation, tendency for caries.

Antianabolic action, damage of kidneys (when using Antianabolic action, damage of kidneys (when using tetracyclines with long termed storage, using big tetracyclines with long termed storage, using big doses).doses).

Tetracyclines are forbidden for children under the age of Tetracyclines are forbidden for children under the age of 88/12/12, during pregnancy, liver diseases, kidney , during pregnancy, liver diseases, kidney

insufficiency, miasteniainsufficiency, miastenia

PhotosensitizationPhotosensitization - - tetracyclines tetracyclines

tetracyclinestetracyclines

AMINOGLYCOSIDESAMINOGLYCOSIDES

І generation:І generation: streptomycin, streptomycin, neomycin, monomycin, kanamycinneomycin, monomycin, kanamycin

ІІ generation:ІІ generation: gentam gentamyycin cin (garamycin), tobramycin, syzomycin(garamycin), tobramycin, syzomycin

ІІІ generation:ІІІ generation: netilm netilmyycin cin (netromycin), amikacin. (netromycin), amikacin.

GentamGentamyycincin

spectrum of spectrum of aaction ction of of aminoglycosidesaminoglycosides

widewide 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 aminoglycosidesIndications for usage of aminoglycosides

- at the beginning stage of infectious processes of unknown at the beginning stage of infectious processes of unknown ethiology and severe complexity (combined with beta-ethiology and severe complexity (combined with beta-lactamase); lactamase);

- considerable purulent-inflammatory component of heavy - considerable purulent-inflammatory component of heavy infections (peritonitis, sepsis, mediastinitis, abscesses and infections (peritonitis, sepsis, mediastinitis, abscesses and flegmones of soft tissues);flegmones of soft tissues);

- acute attack of chronical purulent-inflammatory diseases, - acute attack of chronical purulent-inflammatory diseases, including secondary immune defficiency;including secondary immune defficiency;

- early stage of development of secondary bacterial - early stage of development of secondary bacterial meningitis;meningitis;

- bacterial endocarditis;- bacterial endocarditis;- infections of urinary tracts;- infections of urinary tracts;- for prophilaxis of postoperative pustural complications - for prophilaxis of postoperative pustural complications

(combined with beta-lactamase antibiotics, metronidazole (combined with beta-lactamase antibiotics, metronidazole or other antianaerobe drugs);or other antianaerobe drugs);

- skin infections and subcutaneous fat tissue infections, burns.- skin infections and subcutaneous fat tissue infections, burns.

Concentration of aminoglycosides in Concentration of aminoglycosides in blood should not overcome:blood should not overcome:

Amikacin, kanamycin –Amikacin, kanamycin –

35-40 mkg/ml35-40 mkg/mlGentamicin, tobramycin –Gentamicin, tobramycin –

10-12 mkg/ml10-12 mkg/ml

Complications in administration of Complications in administration of aminoglycosidesaminoglycosides

Ototoxicity Ototoxicity Nephrotoxicity Nephrotoxicity NeurotoxicityNeurotoxicity

According to extent of toxicityAccording to extent of toxicitynetilmicin < gentamicin <tobramycin < netilmicin < gentamicin <tobramycin <

amikacin < neomycin < streptomycin < amikacin < neomycin < streptomycin < monomycin < kanamycinmonomycin < kanamycin

Leuko-, thrombocytopenia, hemmorhages, Leuko-, thrombocytopenia, hemmorhages, hemolisishemolisis

Allergic reactionsAllergic reactions

Chloramphenicol – Chloramphenicol – levomycetinlevomycetin

Indications:Indications:

meningitis, typhoid fever, paratyphoid fever, meningitis, typhoid fever, paratyphoid fever, brucellosis, tularemiabrucellosis, tularemia

Side Side eeffects:ffects: Hypochrome and aplastic anemiaHypochrome and aplastic anemia Granulocytopenia, thrombocytopeniaGranulocytopenia, thrombocytopenia «Grey syndrome of a featus»«Grey syndrome of a featus» Disbacteriosis and superinfectionDisbacteriosis and superinfection

Glycopeptide antibioticsGlycopeptide antibiotics

VankomycinVankomycin,, Teikoplanin Teikoplanin

Active towards МActive towards МRSRS і MRCNS і MRCNS Drugs of choice for Drugs of choice for

C. difficile - associated colitisC. difficile - associated colitis