Lecture No- 2

ANTIBIOTICS

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 Introduction
• The science of chemotherapy began with Paul
Ehrlich in 1910: Ehrlich formulated the principle of
selective toxicity and introduced the drug salvarsan
(a trivalent arsenic compound famous as the magic
bullet) that was used successfully for treatment of
trypanosomiasis and later for syphilis.

• Alexander Fleming 1928: Observed that the mold

Penicillium notatum inhibited the growth of
Staphylococcus aureus colonies - unable to purify
the compound.
• Gerhard Domagk 1935: Therapeutic value of
sulfonamides against streptococcus and other
organisms.

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 Introduction
• Penicillin became available in quantities
sufficient for clinical use in 1941.

• After that，streptomycin, chloramphenicol,

and tetracycline were discovered. Since
then, numerous classes of antimicrobial
agents have been identified, and a lot of
drugs are available for use today.

• Antimicrobials are among the most

commonly used drugs.
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 Definitions
• Chemotherapy: The use of drugs to treat a disease
• Antimicrobial drugs: Interfere with the growth of microbes within
a host.
• Antibiotic: Substance produced by a microorganism that kills or
inhibits the growth of another microorganism (of biological origin,
produced by a microbe, inhibits other microbes).
• Selective toxicity: A drug that kills harmful microbes without
damaging the host.
• Therapeutic index: The maximum tolerable dose divided by the
minimum curable dose.

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EXAMPLES OF SELECTIVE ACTION

1. Penicillin on bacterial cell wall (organisms

without cell wall won’t be inhibited eg
Mycoplasma pneumoniae)
2. Sulphonamides prevent bacteria
synthesising folic acid whereas humans
can use preformed folate
3. Generally drugs acting on cell
membranes or protein synthesis are more
toxic to humans

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1) Antimicrobial agents may have a cidal (killing) effect or
a static (inhibitory) effect on a range of microbes.
2) The range of bacteria or other microorganisms that are
affected by a certain antimicrobial agent are expressed as
its Spectrum of action.
3) Antimicrobials effective against wide range of Gram
positive and Gram negative bacteria are said to be Broad
spectrum.
4) Those acting mainly against Gram positive or Gram
negative bacteria are said to have Narrow spectrum
whereas those acting against a single organism are
referred to as Limited spectrum.
5) Types of chemotherapeutic agents:
Antimicrobial chemotherapeutic agents fall into two
categories:
(A) Antibiotics
(B) Synthetic chemotherapeutic agents
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 • There are many ways for classification of
Antibiotics:
1. According to source:
1) Antibiotics produced by bacteria (bacitracin, polymixins and
gramicidins)
2) Antibiotics produced by fungi (penicillins, gentamicin,
cephalosporins and griseofulvin)
3) Antibiotics produced by actinomycetes (chloramphenicol,
streptomycin, erythromycin and vancomycin)
2. According to chemical nature:
1) Peptides
2) Glycopeptides
3) Aminoglycosides
4) β-lactams
5) Macrolides
6) Polyenes
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3. According to spectrum of action:
1) Antibacterial
2) Antimycobacterial
3) Antifungal
4) Antiprotozoal
4. According to mode of action:
1) Cell wall synthesis inhibitors
2) Cell membrane acting inhibitors
3) Inhibit protein synthesis
4) Inhibitors of nucleic acid

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 Desirable features of antimicrobial
chemotherapeutic agents:
1) Selective toxicity
2) Broad spectrum of action
3) Cidal rather than static
4) Good tissue distribution
5) Low plasma protein binding
6) Oral and parenteral dosing forms
7) Lack of interference with other drugs
8) Cheap

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 Mechanisms of
Antimicrobial Action
• Bacteria have their own enzymes for
– Cell wall formation
– Protein synthesis
– DNA replication
– RNA synthesis
– Synthesis of essential metabolites

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 Mechanism of action of clinically
used antimicrobial agents
1) Inhibition of cell wall synthesis
2) Inhibition of plasma membrane
3) Inhibition of protein synthesis
4) Inhibition of nucleic acid synthesis
5) Inhibition of synthesis of important metabolites by
inhibiting enzymes or competition with their
precursors

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Modes of Antimicrobial Action

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 Antibacterial Agents
A. Drugs acting on cell wall
1. Beta-lactam antibiotics: These all contain beta lactam ring
which is square.

1- Penicillin
Origin Penicillium notatum - Pen.chrysogenum
Structure 6-amino penicillanic acid ,Two rings
Beta-lactam ring: activity
Thiazolidine ring: allergic reaction

Spectrum and Narrow spectrum of action being highly active against gram
uses positive bacteria and gram negative cocci but less active
against other gram negative bacteria.
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1- Penicillin:
Route of administration By parenteral route only
Mechanism of inhibit peptidoglycan synthesis
action

Mechanism of 1- Production of enzymes that destroy the

bacteria resistance active site b-lactamases called penicillinase
2- alteration of (penicillin binding sites)PBPs sites.

Side effect 1- Instability by gastric acidity

2-Susceptible to inactivation by penicillinases
3-Rapid excretion via kidney
4-Allergic reaction, Anaphylactic shock to susceptible
persons

Examples : Penicillin G (benzyl penicillin)(natural penicillin) has a

short half life.
Long acting preparations : procaine penicillin G ,
benzathine penicillin.

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 ANTIBIOTICS ACTING ON CELL WALL OF
BACTERIA

• Beta lactams:
1.Cephalasporins
• Glycopeptides:
1. Vancomycin
2. Teicoplanin

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 Uses of cephalosporins
1. Cefuroxime: Surgical prophylaxis
2. Cefotaxime/ceftriaxone: Meningitis, nosocomial
infections excluding Pseudomonal.
3. Ceftazidime: Nosocomial infections including
Pseudomonal.

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 Non classical β-lactams
• A. Clavams:
They have not antibacterial agents but inhibit B-
lactamases. They called Suicidal inhibitors, as upon their
hydrolysis, their hydrolytic products have affinity to
react with penicillinases and deactivate them.
Ex1- Clavulanic acid: Natural compound
Ex2- Sulbactam, synthetic S + ampicilln. Unasyn.

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 B. Carbapenems
1. Imipenem, meropenem: have a very broad
spectrum activity against gram-negative
bacteria, anaerobes, streps.
2. Now used to treat gram negative infections due
to so called ESBL producing organisms eg, E.
coli, Klebsiella
3. Ertapenem is a new member of the group but
its not active against Pseudomonas.

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 PENICILLIN IS GENERALLY VERY SAFE
BUT….
1. Allergic reactions not uncommon- rashes
2. Most severe reaction being anaphylaxis
3. A history of anaphylaxis, urticaria or rash
immediately after penicillin indicates risk of
immediate hypersensitivity.
4. Allergy is not dependent on the dose given ie, a
small dose could cause anaphylaxis
5. Very high doses of penicillin can cause
neurotoxicity
6. Never give penicillin intrathecally

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 What antibiotics can be used in
penicillin allergy?
1. Macrolides: Erythromycin,
Clarithromycin (mainly gram negative
cover)
2. Quinolones: Ciprofloxacin, Levofloxacin
(mainly gram positive cover)
3. Glycopeptides (serious infections):
Fusidic acid, rifampicin, clindamycin
(mainly gram positive)

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 B- Inhibitors of Bacterial Protein Synthesis
By inhibition of translation step. Selectivity???
I-Agents act on 30 S ribosomal subunits:
1- Aminoglycosides: (Streptomycin, Gentamicin).
a. Gentamicin, amikacin (tobramycin, streptomycin)
b.Mainly active against gram negative bacteria
c. Mainly used to treat nosocomial infections: pneumonia in ITU,
septicaemia
d. Limiting factors are nephrotoxicity (and ototoxicity) and resistance
e. Also used in combination
2- Tetracycline
II-Agents act on 50 S ribosomal subunits:
1) Chloramphenicol:
2-Macrolides (Erythromycin)
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 C) Agents inhibit Nucleic Acids (DNA)
synthesis:

Examples:
• 1- Rifampicin
• 2- Quinolons
• 3- Metronidazole and Nitrofurantoin
• Ex. nifuroxazide

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D) Antibiotics inhibiting synthesis of essential
metabolites (Competitive inhibitors):
-Para-aminobenzoic acid (PABA) is an essential
metabolite used as substrate for enzymatic
synthesis of folic acid
-Sulfonamides competitively antagonize PABA
&bind to the enzyme instead of PABA, so
stop the formation of folic acid, and stop
growth.
-Humans don’t synthesis folic acid, but obtain
it from food (selectivity).

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 Competitive Inhibitors
Sulfonamides (Sulfa drugs)
Inhibit folic acid synthesis
Broad spectrum

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• E) Antibiotics interfere with cell membrane function:
- Example.
• I- Polymixins
• II- Bacitracin
• III- Antifungal polyenes (nystatin & amphotericin-B)

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 Antimicrobial Resistance

• Relative or complete lack of effect of

antimicrobial against a previously
susceptible microbe .

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 Problems with antibiotic resistance
1. Some bacteria are naturally resistant to particular
antibiotics (Pseudomonas has permeability barrier to
many antibiotics)
2. Some typically susceptible species have minority
populations which are resistant by virtue of
mutational resistance (pneumococcus)
3. Other species acquire resistance via plasmids
(“infectious resistance”) eg Neisseria gonorrhoeae,
many gram negatives

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 Mechanisms of Antibiotic
Resistance
• Enzymatic destruction
of drug
• Prevention of
penetration of drug
• Alteration of antibiotic
or target site
• Rapid ejection of the
drug 28
 What Factors Promote
Antimicrobial Resistance?

• Exposure to sub-optimal levels

of antimicrobial
• Exposure to microbes carrying
resistance genes

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Inappropriate Antimicrobial
Use
• Prescription not taken correctly
• Antibiotics for viral infections
• Antibiotics sold without medical
supervision
• Spread of resistant microbes in
hospitals due to lack of hygiene
• Use of antibiotics in foods 30
 Antibiotics in Foods
• Antibiotics are used in animal feeds
and sprayed on plants to prevent
infection and promote growth
• Multi drug-resistant Salmonella
typhi has been found in 4 states in
18 people who ate beef fed
antibiotics
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 Proposals to Combat
Antimicrobial Resistance

• Speed development of new

antibiotics
• Track resistance data nationwide
• Restrict antimicrobial use
• Direct observed dosing (TB)

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 Proposals to Combat
Antimicrobial Resistance

• Use more narrow spectrum

antibiotics
• Use antimicrobial combination

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Why do we use combination therapy?

1. When treating serious infection

(empirically physician want to cover a
broad spectrum).
2. To prevent the appearance of drug
resistance
3. For synergy
4. For mixed infections
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 The Future of
Chemotherapeutic Agents
• Antimicrobial peptides
–Broad spectrum antibiotics from
plants and animals
• Squalamine (sharks)
• Protegrin (pigs)
• Magainin (frogs)
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 The Future of
Chemotherapeutic Agents

• Antisense agents
–Complementary DNA or peptide
nucleic acids that binds to a
pathogen's virulence gene(s) and
prevents transcription

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 Factors to consider when prescribing an
Antibiotic

1. Any history of allergy and toxicity.

2. Is it appropriate for the spectrum want to cover?
3. What route of admin: oral or i.v.?
4. Any factors affecting absorption?
5. Is it going to reach the site of infection?
6. Any drug interactions?
7. Any serious toxicity e.g: hepatic, renal?
8. Does it need monitoring e.g: aminoglycosides,
vancomycin, streptomycin?

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