ANTIBIOTICS

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ANTIBIOTICS
Lector prof. Posokhova K.A.
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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

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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)
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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

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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

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ANTIBIOTICS
Dose-dependent Time-dependent
Antibacterial effect directly depends on their concentrations in the locus of inflammation (high doses 1-2 times/24h) Aminoglycosides Fluoroqinolones Metronidazol Amphotericin 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-lactames Glycopeptides Macrolides Linkozamides
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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).

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S
H2N
CH3
CH3
T
L
O
N
C
O
OH
Nucleus of penicillin molecule L beta-lactame
ring, T thiazoline ring
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Mechanism of penicillins action
They form complexes with enzymes - trans- and
carboxypeptidases (PCP), which control synthesis
of peptidoglycan component of cell-wall of
microorganisms
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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  
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schemes on introduction of 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/week
Bicillin-5, i.m. 1,5 mln U 1 time/week
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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

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Oxacillin   Antistaphylococci penicillinase-resis
tant semisynthetic penicillin, acid stable
  Administration intramuscular, intravenously,
oraly 3-6-8 g/24 hours (4-6 times of injections)
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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
.
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Ampicillin
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Amoxicillin
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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
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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
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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)

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Inhibitors of beta-lactamases 
Clavulanic acid Sulbactam
Tazobactam  
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Unasyn (ampicillin/sulbactam)
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Inhibitor-protected (screened, protected)
penicillins Amoxicillin/clavulanate
(amoxyclav, augmentin) Ampicillin/sulbacta
m (sultamycillin, unasin)
Ticarcillin/clavulanate (timentin)
Piperacillin/tazobactam
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S
H2N
L D
CH2 O CO CH3
N
O
O
C
OH
Structure of cephalosporins L beta-lactame
ring, D dihydrothiazine ring
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Classification of cephalosporins
Way of introduction Generation of cephalosporin antibiotics Generation of cephalosporin antibiotics Generation of cephalosporin antibiotics Generation of cephalosporin antibiotics
Way of introduction first I second II third III fourth IV
Injection Cefaloridin Cefadroxil Cefazolin Cefalexin Cephradin Cefamandole Cefoxytyn Cefuroxime   Cefotaxime Ceftriaxone Cefoperazone Ceftazidime Cefpirome Cefepime    
Oral Cephalexin Cefadroxil Cefuroxime axetyl Cefaclor Cefixime Ceftibuten -
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Cefazolin-sodium (C I)
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Cezolin (Cefazolin, C I)
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Cefalexin ( C I)
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Zinnat (Cefuroxime, C II)
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Cefotaxime (C III)
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Claphoran (cefotaxime, C III)
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Cefobid (Cefoperazone, C III)
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Antimicrobial spectrum of cephalosporins
Generation of cephalosporins Active towards Active towards Stability towards beta-lactamase Stability towards beta-lactamase
Gram-positive bacteria Gram-negative bacteria Staphylo cocci Gram-negative bacteria
? /- -
?? /-
???
?V
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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) 

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Cephalosporines Not recommended to combine
with other nephrotoxic drugs (aminoglycosides) Co
ntraindicated to combine with loop diuretics
(furosemid, etacrinic acid)  
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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).
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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
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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.

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Erythromycin
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Macropen (midecamycin)
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Sumamed (azithromycin)
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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.)

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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 12-20 times, they
  get accumulated in source of inflammation -
  macrolides paradoxis

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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

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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

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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

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Linkomycini hydrochloridum
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Dalacyn C (clindamycini hydrochloridum)
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Tetracyclines

• 1. Natural - biosynthetic chlortetracycline,
  oxytetracycline, tetracycline, dimethylchlortetrac
  ycline.
• 2. Semisynthetic
• doxycycline (vibramycin), metacycline
  (rondomycin), minocycline.

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Tetracycline
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Doxycycline
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Vibramycin (doxycycline)
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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

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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
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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

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Photosensitization - tetracyclines
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tetracyclines
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AMINOGLYCOSIDES

• ? generation streptomycin, neomycin, monomycin,
  kanamycin
• ?? generation gentamycin (garamycin),
  tobramycin, syzomycin
• ??? generation netilmycin (netromycin),
  amikacin.

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Gentamycin
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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

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Indications for usage of aminoglycosides

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

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• Concentration of aminoglycosides in blood should
  not overcome
• Amikacin, kanamycin
• 35-40 mkg/ml
• Gentamicin, tobramycin
• 10-12 mkg/ml

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Complications in administration of aminoglycosides

• Ototoxicity
• Nephrotoxicity
• Neurotoxicity
• According to extent of toxicity
• netilmicin lt gentamicin lttobramycin lt amikacin lt
  neomycin lt streptomycin lt monomycin lt kanamycin
• Leuko-, thrombocytopenia, hemmorhages, hemolisis
• Allergic reactions

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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

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Glycopeptide antibiotics

• Vankomycin, Teikoplanin
• Active towards ?RS ? MRCNS
• Drugs of choice for
• C. difficile - associated colitis