Antibacterial chemotherapy

Antibiotic - chemical compound produced from microorganisms or synthetics origin and posed
selective bacteriostatic or bactericidal action on microorganisms.
Bactericidal: an antimicrobial drug that kill bacteria
Bacteriostatic: an antimicrobial drug that does not kill bacteria, but inhibit microbial growth.
Classification of antibiotics according to the chemical structure:
1) Beta-lactamases
7) Glycopeptides
2) Macrolides and azalides
8) Aminoglycosides
3) Lincosamides
9) Fusidic acid derivatives
4) Tetracyclines
10) Ansamycines (rifampicin-derivatives)
5) Chloramphenicol
11) Polyenes
6) Cycle polypeptides
12) Various agents
Mechanism of action:
Categorisation of antibiotics
Target for action against bacteria
Cell wall peptidoglycan synthesis
Cell membrane function
Protein synthesis
DNA synthesis
Biosynthetic pathways - antimetabolites
1) Impairment of bacterial cell wall synthesis (bactericidal action):
-.binding of the drug to specific receptors located in the bacterial cytoplasmic membrane.
-. Inhibition of transpeptidase enzymes that act to cross-link linear peptoglycan chains with
form part the cell wall
- activation of autolytic enzymes that cause lesions in the bacterial cell wall.
Beta-lactamases, glycopeptides, cycloserine
2) Impairment of permeability and/or function of cell. membrane (bactericidal action)
- they interact with phospholipids of the cell membrane and disrupt its structure .
Polymixins and polyenes
3) Inhibition of bacterial protein synthesis
- they bind to the 50S ribosomal subunit (chloramphenicol)
- 30S and 50S-aminoglycosides
- 50S-macrolides
- 30S-tetracyclines
and block the binding of amino acid-charged tRNA to the acceptor site ofthe ribosome-mRNA
complex.
4) Inhibition of bacterial nucleic acid synthesis
- rifampicin inhibits RNA polymerase
- quinolones inhibit DNA gyrase
Principles of antibacterial chemotherapy:
1. to make an exact bacteriological or antigenic diagnosis before treatment.
2. to decide if antibiotic therapy is really necessary
3. to choose the appropriate antibiotic according to antibioticograma
4. to consider patients factors: severity of infection, his diseases
5. to consider the chances of side effects
6. to consider the route of administration, the dose, and the frequency and duration of therapy.
7. to consider the use of adjunctive drugs.

Basis of the selective toxicity of antimicrobial drugs

1. inhibit a reaction vital only to the microbe and not the host, e.g. penicillin inhibits the
crosslinking of microbial peptidoglycan.
2. inhibit a reaction that yields a product vital to both microbe and host However the host
has host. However, an alternative mechanism of obtaining the substance, e.g. sulfa drugs
inhibit folic acid synthesis.
3. undergo biochemical activation to a toxic form in the infected cell, e.g. acyclovir to treat
herpes viral infections.
4 selectively accumulate in the microbe because
4. of a more active cell membrane transport mechanism, e.g. quinine.
5. have a higher affinity for a critical site of action in the microbe, e.g. chloramphenicol
binds to 70s ribosome.

Classification of antibiotics according to the chemical structure

I.
Beta-lactamases:
A. penicillins ( PENAMI)
1) Biosynthetics:
- sodium benzylpenicillin
- bicillin-5
- potassium benzylpenicillin
- phenoxymethylpenicillin
- procain-benzylpenicillin
- benzatin-benzylpenicillin (retarpen or bicillin-1)
2) semisynthetics
a) izoxazolylpenicillins
- methicillin
- dichloxacillin
- oxacillin
- nafcillin
b) aminopenicillins
- ampicillin
- amoxycillin
- pivampicillin
c) carboxypenicillins
- carbenicillin
- carfecillin
- ticarcillin
d) ureidopenicillins
- mezlocillin
- azlocillin
- piperacillin
e) associations between Beta-lactamases and Beta lactamase inhibitors
- augmenthine ( amoxicillin+clavulanic acid)
- tazocine (piperacillin + tazobactam)
B. Cephalosporins:
I generation (enteral administration)
parenteral administration:
- cephalexin
- cefazolin
- cefadroxyl
- cefalopirine
II generation
enteral administration:
parenteral administration:
- cefachlor
- cefuroxime cefamandol
- cefuroxime
- cefoxitine
cefotetan
III generation:
enteral administration
parenteral administration
- cefixime
- cefotaxime
- ceftibuten
- cefoperazone
- ceftriaxone
IV generation:
Parenteral administration:
- cefipime
- cefpirome
C) Carbapenems:
- imipenem meropenem
D) Monobactams: - aztreonam

thienam

II.
Macrolides and azalides:
1) Macrolides
2) Azalides:
- erythromycin
- azithromycin (sumamed)
- clarithromycin
- oleandomycin
- roxythromycin
- olethetrin
III. Aminoglycosides:
I generation:
II generation:
III generation:
- streptomycin
- gentamicin
tobramycin
- monomycin
sisomycin
- kanamycin
amikacin
netilmicin
IV Lincosamides : clindomycin, lincomycin
V Tetracyclines:
1. naturals : tetracycline, oxytetracycline, demechlocycline
2. semisynthetics: methacycline, minocycline, doxycycline
VI. Chloramphenicols group
- chloramphenicol
- chloramphenicol succinate
VII. Cycle polypeptides (polymixins):
- polymixin M sulphate
VIII. Glycopeptides:
- vancomycine
- ristomycin
- teicoplanin
IX. Fusidic acid derivatives:
- fusidic acid (fusidine)
X. Ansamycines ( rifampicin derivatives):
- rifampicin
- rifamycin
XI. Polyenes (antifungal drugs)
- amphotericin B
- fluconazole
- nystatin
- ketoconazole
- griseofulvin
- levorine
XII Various groups
1. topical antibiotics: fusafungine, mupirocin
2. anti-tuberculosis drugs: cycloserine,
florimycin,
capreomycin
3. antineoplasics: dactomycin,
rubomycin
olivomycin,
bleomycin
doxorubicin chlorhydrate, carminomycin

Classification of penicillin according to the clinical use:

I. Biosynthetics
A) for parenteral administration acido-non resistant penicillins
a) short duration of action ( 4-6 hours)
- sodium benzylpenicillin
- potassium benzylpenicillin
b) long duration of action
- procain-benzylpenicillin
- benzatin-benzylpenicillin (retarpen or bicillin-1)
- bicillin-5
B) for enteral administration
- phenoxymethylpenicillin
II. semisynthetics
-enteral and parenteral administration (acido-resistant and penicillinase resistant penicillins):
oxacillin, amoxycillin, nafcillin
- broad-spectrum penicillins: ampicillin and amoxycillin
- parenteral administration (acido-nonresistants) with broad-spectrum p.
- carbenicillin, ticarcillin, azlocillin
- enterale administration
- carfecillin, sodium indanyl carbenicillin
Categorisation of antimicrobial agents eg antibacterials
1. Spectrum of activity
Broadspectrum active against a wide range of organisms eg tetracyclines
Narrow spectrum active against small number of species of bacteria eg linozelid
Categorisation of antimicrobial agents
2. Source
synthetic made in the laboratory eg salvarsan, sulpha drugs, linozelid
natural produced by living organisms eg quinine, penicillin
semi-synthetic part naturally produced, part modified chemically in the laboratory to improve
particular properties eg semisynthetic penicillins

Penicillins:
b-lactam antibiotics inhibit cell wall synthesis by interfering with the transpeptidation reaction of
peptidoglycan synthesis.
These antibiotics act as PG precursor analogs that bind to the transpeptidase enzyme.
Transpeptidases are also called penicillin binding proteins (PBPs) since they bind to penicillin,
when it is present, instead of binding to PG precursors and forming the cell wall.
During PG synthesis autolysins have been activated to make cuts to expand the cell wall, but
penicillin inhibits the process of adding in new pieces. The autolysins continue to work, even
though the transpeptidase has been inhibited by penicillin.

Spectrum of action:
Natural Penicillins
Narrow spectrum
Susceptible to inactivation by -lactamase
Penicillin G (Benzylpenicillin)
Gram +/- cocci, Gram + bacilli, spirochetes, anaerobes
Extended spectrum penicillins
Ampicillin, Amoxycillin
active against many Gram-negative bacteria
the amino group in the side-chain improves penetration of the outer membrane the amino group
also
makes it resistant to acid hydrolysis
Indications: meningitis, endocarditis, otitis, pharyngites, bronchitis and other
Side effects: allergy, skin rashes, dermatitis, anemia, leucopenia
Action of -lactam antibiotics
Inhibit final stages of assembly of the peptidoglycan
must penetrate the cell wall and operate on the outer surface of the cell membrane
bind to 'penicillin-binding proteins' in the outer leaf of the cell membrane
enzymes responsible for the final stages of assembly of the peptidoglycan molecule
PBPs use a serine containing molecule to bond covalently with the peptidoglycan chains then
releases it to cross link with another part of the chain
Penicillin binds to the serine but does not release it permanently blocks the active site
The three-dimensional structure of a beta-lactam closely resembles the Dalanyl- D-alanine end of
the peptide in peptidoglycan just before final assembly
Binding of penicillin molecule to PBP prevents synthesis of the final stable peptidoglycan
molecule
Peptidoglycan is essential to the stability of the bacterial cell wall and so the affected cell
disintegrates
Summary of -lactam action
Interferes with last step of bacterial cell wall synthesis, causing cell lysis
Bactericidal
Only effective against rapidly growing organisms that synthesize a peptidoglycan cell wall
Inactive against mycobacteria, fungi, viruses
Penicillins plus -lactamase inhibitors
Clavulanic acid, tazobactam & sulbactam semisynthetic - - lactamase inhibitors
Bind to -lactamase more efficiently than the penicillins
Used in combination with ampicillin, ticarcillin, piperacillin

Cephalosporins:
Spectrum of action:
I generation: Gr + cocci(staphylococci and common streptococci), E. coli and
K pneumoniae, Minimal activity against Gr cocci, enterococci
Indication: treatment of infections caused by these organisms and surgical prophylaxis
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II generation: they have less activity against Gr + organismsthan the Ig. But have an extended Grcoverage
Indications: Infectious caused by Bacterioides fragilis, H. influenzae, Moraxella catarrhalis
III generation: increased activity against Gr organisms: enterobacter, Serratia marcescens,
pseudomonas a.o.
Indications: bacterial meningitis, gonorrhea, otitis media
IV generation: is more resistant to beta-lactamases produced by Gr organisms, including
enterobacter, haemophilus, neisseria
Side effects: allergy, pain at i/m injection, phlebitis, hypoprothrombinemia, severe bleeding.
Macrolides and Azalides:
Macrolide antibiotics: ex. erythromycin, inhibits protein synthesis at the ribosome, used clinically
in place of penicillin in patients allergic to penicillin.
Spectrum of action (narrow spectrum) (G+ cocci, bacillus G+, Listeria, Bordetella pertusis,
Mycoplasma, Treponema palidum, Hlamidia, Cocci GModerate sensibility.
Indication: Chlamidia trachomatis, enterocolitis, campylobacter fetus, diphtheria, Pneumonia with
Mycoplasma.
Side effects: gastrointestinal irritation, skin rashes, eosinophilia, hepatitis ,
arrhythmias
Lincosamides : clindomycin, lincomycin
Spectrum of action: like macrolides
Indications: prophilaxis of endocarditisin valvular disease patients.Pneumocystis carinii,
toxoplasma gondii
Side effects like macrolides
Aminoglycosides
Aminoglycoside antibiotics: ex. streptomycin, inhibit protein synthesis at the ribosome, used
against gram-neg. bacteria, has serious side effects, bacterial resistance readily develops, used as a
last resort when other antibiotics fail.
Spectrum of action:
Very active - Gr- aerobic bacillus: Enterobacter, E.coli, Klebsiela pneumoniae, Proteus mirabilis,
Pseudomonas aeruginosae, Salmonella, Seratia-Shigela
Active- Gr+cocci Mycobacterium tuberculosis (streptomycin and canamycin)
Resistant- anaerobic bacterium.
Indications: serious infections with aerobic G- bacteria (enumerate) ,
meningitis, respiratory infections and others.
Side effects- ototoxicity, nephrotoxicity, neuromuscular blockade, skin reactions
Administration only parenteral , elimination by urine (50/90%)
Monobactam ( aztreonam)
spectrum of action: narrow spectrum: G- agents; klebsiella, pseudomonas, serratia they have no
activity against G+ bacteria or anaerobes.
Administration only i/v, elimination by urine
Carbapenems:
imipenem
meropenem
thienam
spectrum of action: G- rods and anaerobes
administration parenteral. Side effects: gastrointestinal distress, skin rash, CNS toxicity
(convulsions, confusion), rare-hepatotoxicity.
Monbactams & Carbapenems
Aztreonam (a monobactam)
synthetic analogue of an antibiotic isolated from Streptomyces spp
Stable to most betalactamases
Effective against most Gramnegative bacteria
Imipenem (a carbapenem)
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 semisynthetic
Widest activity of any antibiotics, Stable to most betalactamases.