ANTIBIOTICSANTIBIOTICS

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

Principles of rational antibiotic therapy

Presence of substantiated indications for prescription of an Presence of substantiated indications for prescription of an antibioticantibiotic

Choosing of the most effective and the least toxic drug, intime Choosing of the most effective and the least toxic drug, intime administrationadministration

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

Choosing of the optimal way of introductionChoosing of the optimal way of introduction Estimation of treatment duration Estimation of treatment duration Control after treatmentControl after treatment

Monitoring and prophilactics of negative side effectsMonitoring and prophilactics of negative side effects Decision on expediency of combinated antibiotic therapyDecision on expediency of combinated antibiotic therapy

ANTIBIOTICS Beta-lactam antibiotics:Beta-lactam antibiotics: А. Penicillins, Б. Inhibitors of beta-lactamases and

combinated 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 source of inflammation (high doses 1-2 times/24h)

Aminoglycosides Aminoglycosides FFluluororoqoqinolonesinolones

MetronidazolMetronidazolAmphoterAmphoteriicin Bcin B

Effectiveness depends on a period of time, during which concentration in blood overwhelms MIC for a particular causative agent(constant infusion or 3-6 times/24h)

Beta-lactamesBeta-lactamesGlycopeptidesGlycopeptides

MacrolidesMacrolidesLinkozamidesLinkozamides

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: 1antistaphylococci penicillinase resistant penicillins – izoxazolil-

penicillins (oxacillin, dicloxacillin, methicillin); 2of a spread spectrum – aminopenicillins (ampicillin,

amoxicillin); 3antipseudomonade – carboxypenicillins (carbenicillin,

ticarcillin); ureidopenicillins (azlocillin, piperacillin, sulbenicillin); 56combined 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

COOH

CH3

CH3

O

H2N

Mechanism 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

StreptococciBacillus anthracis Causative agents of tetanus, gas gangreneActinomycets Listeria

GonococciMeningococci MoraxellaCausative agent of syphilisLeptospiras 

Directing schemes on introduction og biosynthetic penicillins

  Antibiotic, way of introduciton

One time dose Frequency of introduction

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

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

Every 4-6 hours (every6 hours)

Benzatyn benzylpenicillin (bicillin-1), i.m.

0,3-0,6 mln OD1,2 mln OD

1 time/week 1 time/2 weeks

Bicillin-3, i.m. 0,6 mln OD 1 time/weekBicillin-5, i.m. 1,5 mln OD 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 halfsynthetic 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, destructed 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

Ampicillin Amoxycillin

Activity towdards-         pneumococci-         H. pylori-         salmonella-         shigellaBioavailability after oral administrationInfluence of food on bioavailability

Level in sputum

Level in urine

Appearance of diarrhea

+++

++/++++++

40 %

dicreases in 2 timeslowhigh

frequently

 +++++++++

+

90 %

no influencehigh

very high

rarely

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

Respiratory tracts Acute midlle otitisBacterial sinusititAcute bronchititsExtrahospital pneumonia of light or medium-severe complexity

Acute pharingitisChronical bronchitis

Kidneys and urinary tracts

Acute pielonephritisAcute cystitisBacteriouria in children and pregnant women

Chronical pielonephritisAcute prostatitisGonorrhea

Digestive tract Cholangitis, cholecystitisTyphoid fever

Other pathology Borreliosis Leptospirosis

Ampiox (ampicillin+oxacillin)

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, enha(amoxyclav, augmentin, enhattsin)sin)

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 CefaloridinCefadroxil*Cefazolin*Cefalexin*Cephradin*

Cefamandole* Cefoxytyn*Cefuroxime* 

Cefotaxime*Ceftriaxone*Cefoperazone*Ceftazidime*

Cefpirome*Cefepime* 

 

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 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, судоми, coma) 

Cephalosporines Cephalosporines

NNot recommendedot recommended to combine with other nephrotoxic drugs

(aminoglycosides)

ContraindicatedContraindicated to combine with loop diuretics (furocemid,

etacrinic acid) 

MonobactamsMonobactamsAetreonam

Action spectrum - Gram (-) bacteria, including Escherichia colli, Clebsiellas, Proteum, 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 tracts, soft tissues, meningitis and others (often combined with aminoglycosides , clindamycin, metronidazole, vankomycin).

Carbapenems (tienamytsin)Carbapenems (tienamytsin)

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

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

Classificaion of Classificaion of macrolidesmacrolides

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

ІІ. Half-synthetic substances: rozythromycin, clarithromycin, flurythromycin, dyrythromycin, miokamycin, rokitamycin.

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

ErythromycinErythromycin

Macropen (midecamycin)Macropen (midecamycin)

Sumamed (azithromycin)Sumamed (azithromycin)

Action spectrum of maclrolides Action spectrum of maclrolides and azalidesand azalides

staphylo-, strepto-, hono-, anaerobe cocci, enterobacteria

H.influenzae (clarythromycin, azithromycin) intracellular situated microorganisms (stamps

of Helicobacter, Chlamydia, Legionellа, M. pneumoniae, U. urealyticum etc.)

Pharmacokinetics of Pharmacokinetics of macrolidesmacrolides

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

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

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

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

LOR- infections, infections of upper respiratory tracts, hynecological infection, skin and soft tissues infections; ulcer disease; dyphteria; whooping-cough; honorrhea; syphilis; typhoid fever (azithromycin).

Drugs of choice for: mycoplasma, chlamidial, legionela pneumonia

Side affects of microlidesSide affects of microlides 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 Linkomycin ClindamycinClindamycin

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

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

Usage: usually in heavy infections, caused by anaerobe microorganisms

Complicated side affects

Linkomycini Linkomycini hydrochloridumhydrochloridum