antibacterial drugs

1. Antibiotics

2. Plan of lecture:
• Principles of antibiotictherapy.
• Pharmacology of Penicillins, Cephalosporines,
Carbapenems and Monobactams.

3. Antibiotics
Antibiotics and vaccines are among the biggest
medical advances since 1000. (Culver Pictures)

4. Antibiotics ("Anti" – against, "bios" - life)
• Antibiotics - a substance produced by microorganisms, or produced
from vegetable and animal tissues, and their semi-synthetic and
synthetic analogs selectively inhibit the viability of microorganisms
sensitive to them.
Importance of Antibiotics:
• The elimination of the global crisis of infectious diseases (cholera, plague,
dysentery).
• Effective at the dangerous diseases (sepsis, meningitis, peritonitis, pneumonia).
• ≈ 20 million people die each year from infectious diseases.
• 1/3 of all hospital patients are treated with antibiotics.
• Over the past 20 years there were 20 new infectious diseases (Legionnaires'
disease, hairycell leukemia, hemorrhagic fever and others).
• Unconventional use of antibiotics: peptic ulcer, asthma, myocardial infarction,
atherosclerosis.
• In breadth of application group of antibiotics ranked the first place in the world.
• Today, there is no person at least who did not use antibiotics.
• There is no country that doesn’t threat of epidemics and pandemics.

5. Antibiotics could be
• narrow-spectrum and effective only against a
limited variety of pathogens or broad-
spectrum, affecting many different types of
pathogens
• bactericidal if they kill the susceptible bacteria
or bacteriostatic if they inhibit the growth of
bacteria

6. Classification of antibiotics.
I. Β-lactams
1. Penicillins:
 Natural
 Semi-synthetic
 Antistaphylococcal
 Aminopenicillins
 Antipseudomona
 Combined
2. Cephalosporins
3. Carbapenem and
monobactams
II. Glycopeptides
III. Macrolides and
Azalides
IV. Tetracycline
V.Aminoglycosides
VI. Polymyxins
VII. Gramicidin
VII. Cycloserine
IX. Antifungal
X. Lincosamides
XI.Chloramphenicol
XII. Fuzidin

7. A brief history of antibiotics
• 1928 - Scottish microbiologist A. Fleming discovered
penicillin - P. notatum.
• 1940 - British W. Florey and Chain received penicillin E.
• In 1945, Fleming, Florey, Chain received the Nobel Prize for
the discovery of penicillin.
• 1942 - Z. Yermolyeva - Penicillin crustosum.
• 1944 - American Z. Waxman – streptomycin.
• 1960-1980 - cyclosporine, rifampicin, semisynthetic
penicillins, tetracyclines, macrolides, azalides.
• Today ≈ 6 thousand antibiotics. But, 2-3% of them are use
(300 INN ≈ 2000 oficinal names).
• ~ recent year: modifying old drugs, finding new discipline
in antibacterial combats.

8. Requirements for Antibiotic
• high selectivity
• lack of toxicity
• long-term providing of therapeutic concentrations
• lack of rapid resistance development
• availability of suitable dosage forms

9. Classification according SPECTRUM OF ACTION.
• Narrow spectrum (mainly Gr + and Gr-):
• Natural, antistaph. penicillins
• Cephalosporins I generation, monobactams
• Polimyxins, gramicidin C
• Fuzidin
• Antifungal
• Broad-spectrum:
• Semi-synthetic penicillins and cephalosporins II -IV
• Carbapenems, Tetracyclines, Macrolides, Aminoglycosides
• Chloramphenicol

10. Antimicrobial drugs have also been
classified broadly into:
1. bacteriostatic, i.e. those that act primarily
by arresting bacterial multiplication, such as
tetracyclines, chloramphenicol, macrolides,
lincosamides.
2. bacteriocidal, i.e. those which act primarily
by killing bacteria, such as penicillins,
cephalosporins, aminoglycosides, isoniazid
rifampicin, quinolones etc.

12. Classification according MECHANISM OF ACTION
INHIBIT:
the synthesis of
the components
of microbial wall
the function of
the cytoplasmic
membrane
the synthesis of proteines
β- LACTAMS POLIMYXINES MACROLIDES*
AZALIDES
LINCOSAMIDES*
RIFAMYCINS
FUZIDIN
CHLORAM-
PHENICOLES*
GLYCOPEPTIDES GRAMICIDINE TETRACYCLINES*
PHOSPHOMYCINE
CYCLOSERINE
ANTIFUNGAL AMYNOGLY-
COSIDES
Has bactericidal and bacteriostatic* effect

13. Bacterial cell
Cell wall
Nuclear apparatus
Cytoplasmic membrane
Ribosomes
Violation
of the cell wall
synthesis.
Violation
of cytoplasmic
membranes
permeability.
Violation
of RNA
synthesis
Violation
of protein
synthesis at the
level of
ribosomes.
B-lactams
Glycopeptide
Polymyxins
Gramicidin
Antifungal
Rifampicin
Tetracyclines
Chloramphenicols
Lincosamides
Macrolides
Azalides
Aminoglycosides
Fuzidinum

14. Negative effects of Antibiotics:
1.The emergence of sustainability:
• production of beta-lactamase;
• changes in the permeability of the cytoplasmic membrane;
• changes in the structure of certain portions of ribosomes proteins or
enzymes
2. Superinfection;
3. Dysbiosis;
4. Allergic reactions;
5. Systemic toxicity, nephrotoxicity, hepatotoxicity.
• Penicillins are the least toxic!!!

15. •Antimicrobial therapy and pregnancy
•Azithromycine
•Erythromycine
•Penicillins
•The most of
cefalosporines

16. Conditions for rational use of antibiotics
• Antibiotics should be given according to antibiogram.
• Choose the most active and least toxic antibiotic.
• To determine the optimal antibiotic dose and route of administration
based on the its pharmacokinetic and the concomitant disease. The
concentration of antibiotic in the blood should be 3-4 times bigger in
comparison with minimum inhibitory concentration for the selected
pathogen.
• Apply the first striking dose, followed by supporting.
• To determine the tolerance of antibiotics in patients according to the
basis of medical history.
• To take in account an adverse effects of antibiotics, especially in the
liver and/or kidney failure.
• Early antibiotic treatment till consolidation of therapeutic effect.
• Consideration of cross sensitivity.
• Use a combination of antibiotics in order to expand and strengthen
the action of the antibacterial effect.
• Use of antifungal drugs to prevent dysbiosis.

17. BETA-LACTAM ANTIBIOTICS
(inhibitors of cell wall synthesis)
Their structure contains a beta-lactam
ring.
The major subdivisions are:
(a) penicillins whose official names
usually include or end in “cillin”
(b) cephalosporins which are
recognized by the inclusion
of “cef” or “ceph” in their
official names.
(c) carbapenems (e.g. meropenem,
imipenem)
(d) monobactams (e.g. aztreonam)
(e) beta-lactamase inhibitors (e.g.
clavulanic acid, sulbactam).

18. β-lactams Mechanism of Action
 Action target: cell wall
 on penicillin binding proteins (PBPs)
 Transpeptidases (form cross-links in peptidoglycan)
 Beta-lactam ring attached to 5-membered
thiazolidine ring
 Accessibility of PBPs differ in gram+ and gram- bacteria.
 Amino acyl side chain groups determine spectrum,
adsorption, susceptibility to lactamase.
 Bactericidal inhibitors.

20. Penicillin

21. Classification of penicillins
• 1.Natural penicillins:
• a) Short acting:
• Penicillin-G
• Penicillin-sodium
• Penicillin-potassium
• Penicillin V
• b) Long acting:
• Penicillin G. procaine
• Benzathine penicillin (Bicillin-I)
• Bicillin-3,-5

22. Classification of penicillins
• 2. Semisynthetic penicillins:
• I. Penicillinase resistant
• Oxacillin
• Dicloxacillin
• Cloxacillin
• Methicillin
• II. Broad spectrum penicillins
• Aminopenicillins
• Ampicillin
• Amoxicillin
• Pivampicillin
• Talampicillin

23. Classification of penicillins
• III. Carboxypenicillins
• Carbenicillin
• Ticarcillin
• IV. Ureidopenicillins
• Azlocillin
• Piperacillin
• V. Combined penicillins
• Unazin
• Ampiox (Ampicillin+Oxacillin)
• Augmentin (Amoxycillin+Clavulanic acid)
• Magnapen (Ampicillin+Flucloxacillin)

24. Spectrum of natural penicillins
• Gr+ microorganisms include:
• staphylococci,
• streptococci (pneumoniae, pyogenes and viridans
group),
• bacillus anthracis,
• clostridium perfringens,
• corynebacteria diphtheriae and listeria
monocytogenes

25. Spectrum of natural penicillins (cont.)
• Sensitive Gr- microorganisms include:
• Neisseria gonorrhoeae,
• Neisseria meningitis,
• Leptotrichia buccalis,
• Treponema pallidum,
• Treponema partenue.

26. Pharmacokinetics of natural penicillins
• 1. Acidic instability (exception Penicillin V)
• 2. Extracellular distribution mainly
• 3. Poor penetration through BBB
• 4. Crossing the placenta
• 5. Protein binding 60%
• 6. Small amount metabolizing
• 7. Excretion mainly by tubular secretion. It may be
suppressed by probenecid (uricosuric)

27. Clinical uses of natural penicillins
• Endocarditis
• Pericarditis
• Meningitis
• Pneumonia
• Septicemia caused by streptococcus pyogenes
• Gonorrhea
• Syphillis (congenital and neurosyphillis).

28. Clinical uses of natural penicillins
(cont.)
• Anthrax,
• Actinomycosis (abdominal, cervicofacial or thoracic
disease),
• Botulism,
• Gas gangrene,
• Tetanus,
• Diphtheria (prevention of carrier state),
• Empyema,
• Rheumatic fever,
• Listeriosis.

29. Side effects of natural penicillins
• Penicillin G (benzyl penicillin) is one of the least
toxic antibiotics. It does not cause any direct
toxicity. Only in very high doses, especially injected
IV, it can cause neurotoxic effect and bleeding.
• The hypersensitivity reactions are the major
problem, incidence up to 10%.

30. Semisynthetic penicillins
I. Penicillinase resistant:
• Oxacillin, Dicloxacillin, Cloxacillin, Methicillin
• The advantages of penicillinase resistant
semisynthetic penicillins over natural ones are in
efficacy against penicillinase producing
staphylococci and stability of some of them
(Oxacillin) in acidic medium.
• They are used in treatment of infection caused by
staphylococci resistant to penicillins.

31. Semisynthetic penicillins
• II. BROAD SPECTRUM PENICILLINS
• a) Aminopenicillins
• The aminopenicillins have identical spectrum and
• activity, but amoxicillin is better absorbed orally
• (70–90%).
• They are effective against:
• streptococci, enterococci
• Gram-negative organisms (including H. pylori)
• but have variable activity against staphylococci
• ineffective against P. aeruginosa.
Amoxycillin and Ampicillin

33. •Carboxypenicillins
- Carbenicillin
- Ticarcillin
•Ureidopenicillins
- Azlocillin
- Mezlocillin
- Piperacillin
b) Antipseudomonal penicillins
These drugs retain activity against streptococci and
possess additional effects against Gr-
organisms, including various Enterobacteriaceae
and Pseudomonas.

34. There is cross-allergy between all the various
forms of penicillin, probably due in part to their
common structure, and in part to the degradation
products common to them all.
Partial cross-allergy exists between penicillins
and cephalosporins (a maximum of 10%) which
is of particular concern when the reaction to either
group of antimicrobials has been angioedema or
anaphylactic shock.
Carbapenems and the monobactams
apparently have a much lower risk of cross-reactivity.

35. Adverse effects
 Thrombophlebitis
 Allergic reactions
 Superinfections (diarrhea)
 Seizures (rare)

36. Stevens – Johnson
syndrome
Lyell
syndrome

37. Resistance
 B-lactamase
Types:
 Different substrate specificity
 Penicillinases
 Cephalosporinases
Location:
 Gram+: extracellularly
 Gram-: periplasmic space
 Failure to bind to PBPs
 Cannot penetrate porins (gram-)
 Production of lactamase (penicillinase)
 Lack autolytic enzyme

39. Policy to deal drug resistance
 Ideally, bacteriological management of
clinical infection should involve:
1. Identification of causative organism
2. Sensitivity test
3. Follow-up the drug effect
4. Monitor antibiotic level to avoid toxicity.
 In reality, most patients requiring
antimicrobial therapy are treated empirically.
In serious infections immediate chemotherapy
may be life-saving.

41. CEPHALOSPORINS
 Cephalosporins have 7-aminocephalosporanic
acid nucleus.
 Cephalosporins are produced semisynthetically
from cephalosporin- C obtained from a fungus
Cephalosporium.
 Spectrum – broad
 Mechanism - inhibition of synthesis of bacterial
cell wall.
 Effect - bactericidal

42.  1.FIRST GENERATION
 Cephalosporins of the first generation are highly active against
Gram+ but weaker against Gram- microorganisms.
I.Cefazolin
II.Cefalexin
 2. SECOND GENERATION
 The drugs were developed subsequently to the first generation;
they are more active against Gram-negative microorganisms.
III.Cefuroxim
IV.Cefaklor
5 generations
of CEPHALOSPORINS

43. 5 generations of CEPHALOSPORINS (cont.)
• 3. THIRD GENERATION
• They have enhanced activity against gram-negative bacilli, including
most enteric organisms and Serratia marcescens. Ceftriaxone and
cefatoxime have become agents of choice in the treatment of
meningitis.
• Ceftazidime has activity against Pseudomonas aeruginosa.
• V.Ceftriaxone
• VI.Cefixime
• VII.Cefoperazone
• VIII.Ceftazidime
• IX.Cefatoxime

44. 5 generations of CEPHALOSPORINS (cont.)
• 4. 4-th generation
• These drugs are in many ways similar to cephalosporins of
3rd generation
• X. Cefepim
• XI.Cefpirom
• 5. 5-th generation
• XII.Ceftobiprole
• XIII. Ceftaroline
• Antimicrobial activity: Ceftobiprole has powerful
antipseudomonal effect and is less susceptible to
development of resistance. Ceftaroline does not have an
anti-pseudomonal activity.

45. CEPHALOSPORINS
• Type of action: bactericidal = penicillins
• Spectrum: WIDE
• INDICATIONS
• infectious diseases of the respiratory, urinary and biliary
tract, abdominal cavity, skin, bones, joints, heart,
• Gonorrhea, burns, surgical prophylaxis,
• Meningitis and Pseudomonas infection - III -IV generation.
• Side effects: hemorrhage, hemato-, nephro-, neuro-,
hepatotoxicity.
• Contraindications: porphyria, epilepsy, severe liver and
kidney diseases, pregnancy, lactation.

46. Sulperazon - "protected" (Cefoperazone +
Sulbactam)
• Spectrum: wide G+, Gr-, anaerobes
• Resistant to β-lactamases of extended spectrum
(sulperazon and carbapenems)
• Application: for severe community-acquired and
hospital-acquired infective processes: primary and
secondary peritonitis, infected pancreatic necrosis,
sepsis, diabetic foot, phlegmons, nosocomial
pneumonia.

47. Comparison activity of
CEPHALOSPORINS.
Generation
Activity
Gr+ Gr-
1-st
+++ +/-
2-st
++ +
3-st
+ +++
4-st
++ +++

48. Pharmacological "face" of
CEFALOSPORINES
• Similar to penicillin in structure and action.
• Wide spectrum.
• Powerful bactericidal effect.
• Low toxicity.
• Good compatibility with other antibacterial agents.
• Most resistant to staphylococcal β-lactamase.
• Cross allergic to penicillin.
• It penetrates into the tissue fluid, joints, bones.
• Good compatibility with other antibacterials.

49. CARBAPENEMS and MONOBACTAMS
CARBAPENEMS MONOBACTAMS
1. IMIPENEM-CILASTATINE
2. MEROPINEM*
3. AZTREONAM
MECHANISM: inhibit the PBPs (transpeptidase), Imipenem - PBPs-2.
SPECTRUM
ultra-wide: the majority of aerobic
and anaerobic Gr+ and Gr- resistant
bacteria; 80% of strains of
Pseudomonas aeruginosa,
postantibiotic effect (Gr-).
narrow: Gr- aerobes: gono-,
meningococcus, Salmonella, Shigella,
Klebsiella, Proteus and Escherichia
coli, Pseudomonas etc.
INDICATIONS
severe infections of bones and joints,
skin and soft tissue, abdominal,
female genitals, urinary tract
infections, pneumonia, septicemia,
meningitis.
severe infections caused by Gr- flora
resistant to III generation
cephalosporins, aminoglycosides II-III
generation, pseudomonas penicillins.
 - resistant to  -lactamases, * - resistant to renal dehydropeptidase

50. Pharmacological «face» of CARBAPENEMS and
MONOBACTAMS
CARBAPENEMS MONOBACTAMS
 Ultra-wide spectrum,
including strains resistant to
cephalosporins III and IV
generation.
 Potent resistance to β-
lactamase.
 Potent postantibiotical effect.
 Slow development of
resistance.
 Antibiotics of ultradeep
reserve!
 Low toxicity and good
tolerability.
 The narrow spectrum of action
(aerobic Gr-), identical to
cephalosporins III.
 Potent resistance to Gr-
β-lactamase.
 Potent bactetiocidal action.
 Slow development of
resistance.
 No cross-sensitization to
penicillins and cephalosporins.
 The use in newborns.
 Antibiotics of reserve!

51. Side effects of MONOBACTAMS AND CARBAPENEMS
CARBAPENEMS
• CRAMPS,
• WEAKNESS,
• TREMOR,
• ENCEPHALOPATHY,
• HYPOTENSION,
• NAUSEA, VOMITING,
• SUPERINFECTION,
• PSEUDOMEMBRANOUS
COLITIS,
• PHLEBITIS,
• THROMBOCYTOSIS,
• EOSINOPHILIA.
MONOBACTAMS
Allergic reactions:
 URTICARIA,
 PRURITUS,
 ERYTHEMA,
 EOSINOPHILIA,
 ARTHRALGIA,
 VASCULITIS,
 ANGIOEDEMA,
 BRONCHOCONSTRICTION,
 ANAPHYLAXIS.