SYSTEMS PHARMACOLOGY
Chemotherapy of Infection: Part I
Dr Dhaya Perumal
London Metropolitan University
Dept. Health & Human Sciences
Tower Building: Room T13-10
Telephone: 020 7133 4195
d.perumal@londonmet.ac.uk
1
Pathogenic (Infectious)
Organisms

Are those organisms that cause diseases in
human beings/ animals

Types of pathogenic organisms:
1. Microbes
Bacteria, fungi and viruses
2. Parasites
Protozoa and helminthes (worms)
2
Chemotherapeutic agents

Are naturally occurring or chemically
synthesized substances intended to be
toxic for the pathogenic organisms but
innocuous to the host

Aim- To treat acute, severe, persistent
or progressive infectious disease
3
Factors contributing to
microbial threats to health
1.
2.
3.
4.
5.
6.
7.
Microbial adaptation and change
Human susceptibility to infection
Climate and weather
Changing ecosystem
Human demographics and behaviour
Economic development and land use
International travel and commerce
4
Factors contributing to microbial
threats to health (Contd.)
8.
9.
10.
11.
12.
13.
Technology and Industry
Breakdown of Public Health Measures
Poverty and Social Inequality
War and famine
Lack of Political will
Intent to harm (e.g. weapons of mass
destruction)
5
Classic Definition: Antibiotic


(from Greek, anti – against, bios – life)
A natural substance, or derivative of a
natural substance, which when taken in
small doses will either kill or prevent the
growth of a microorganism, but will not
seriously harm the person taking it
6
Antibiotic-producing
microorganisms
Penicillium and Cephalosporium
Beta-lactam antibiotics: penicillin and cephalosporin


Actinomycetes, Streptomyces species
Tetracyclines
Aminoglycosides
Macrolides
Chloramphenicol
Bacillus species
Polypeptide antibiotics: polymyxin and bacitracin

7
Definition (Modified):
Antibiotics/Antibacterials/Antimicrobials

Any chemical compound used to kill or
inhibit the growth of infectious organisms,
particularly bacteria and fungi

All antibiotics share the property of
selective toxicity: they are more toxic to an
invading microorganism than to the
animal/human host
8
Choice of suitable drug
Two considerations:
1. Patient - history of allergy
- renal/hepatic function
- susceptibilty to infection
- ability to tolerate by mouth
- severity of illness
- ethnic origin
- age
- other medication
- pregnancy, breast-feeding, OC use

9
Choice of suitable drug contd.
2. Known or likely causative organism
- antibacterial sensitivity
Final choice depends on microbiological,
pharmacological and toxicological properties
10
Rational approach to
selecting drug



Example: to treat UTI in a pregnant patient who
has nausea. The organism found to be resistant to
ampicillin but
- sensitive to nitrofurantoin (can cause nausea)
- gentamycin (only by injection and avoided in
pregnancy)
- tetracycline (dental discolouration)
- trimethoprim (teratogenic) and
- cefalexin
Safest in pregnancy is penicillins and cephalosporins
Therefore cefalexin indicated for this patient
11
Spectrum of Activity
A. Broad spectrum of activity
An antimicrobial drug that is effective against
a large variety of microorganisms
ADVANTAGES:
A high degree of efficacy against an
unidentified pathogen
DISADVANTAGES:
A high likelihood of the drug also destroying
the friendly/helpful bacteria making up an
individual’s normal microbial flora
12
Spectrum of Activity (Contd.)
B. Narrow spectrum of activity
An antimicrobial drug that is effective
against only a relatively small subset of
bacteria
13
Effects of Antimicrobials
A. Bactericidal (kill)
Interaction results in an irreversible
disruption or binding  cell death
B. Bacteriostatic (inhibit growth)
Interaction effect involves lower affinity
binding and is reversible when the
antibacterial is removed from the
environment
14
DIAGNOSTIC STAINING
TECHNIQUE
Crystal
violet
Iodine
Gram – Positive Bacteria : BLUE
Gram – Negative Bacteria : RED
Alcohol
wash
Safranin
15
16
DIAGNOSTIC STAINING
TECHNIQUE (Contd.)
Ziehl-Neelsen Stain (Acid-fast bacteria)
1.
2.
3.
Bacteria + Carbofuchsin (bring to boil 3 times)
HCl + Alcohol (1-2 min)
Alkaline methylene blue (3 min)
RESULT:
- Acid-fast bacilli: RED
- Other bacteria: BLUE
17
Spectrum of Antibacterials
Gram Negative Bacteria
2. Acid fast Bacteria
1.
Aerobic – requires oxygen
 Anaerobic – does not require oxygen

18
Sensitivity Test
Antibiotic sensitivity determined by size of inhibition zone
19
Mode of action of antibacterials
20
Bacterial cell wall structure
Gram Negative
Gram positive
21
Mode of action of antibacterials
A.
B.
C.
D.
E.
Inhibition of cell wall synthesis
Disruption of cell membrane function
Inhibition of protein synthesis
Inhibition of nucleic acid synthesis
Action as antimetabolites
22
Major modes of action of drugs
23
A. Inhibition of cell wall synthesis



Most bacteria have peptidoglycan-based cell
walls (mammals do not)
Successful cell wall synthesis by these
bacteria is impossible in the absence of
peptidoglycan synthesis
In the absence of cell wall integrity, most
bacteria are susceptible to osmotic lysis
24
SYNTHESIS OF PEPTIDOGLYCAN
• Bacteria increase their size following binary fission, links in
peptidoglycan break, new peptidoglycan monomers insert
and the peptide cross links must be resealed
1. Bacterial enzymes, autolysins, break the glycosidic bonds between the
peptidoglycan monomers and the peptide cross-bridges that link the rows of
sugars together. 2. In this way, new peptidoglycan monomers can be inserted
and enable bacterial growth.
25
SYNTHESIS OF PEPTIDOGLYCAN
1. Transglycosidase enzymes catalize the formation of glycosidic bonds
between the N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) of
the peptidoglycan momomers and the NAG and NAM of the existing
peptidoglycan 2. Finally, transpeptidase enzymes reform the peptide crosslinks between the rows and layers of peptidoglycan to make the wall strong.
26
Beta-lactam antibiotics:
Penicillins and Cephalosporins


Stereochemically related to D-alanyl-Dalanine, which is a substrate for the last
step in peptidoglycan synthesis
Block the final transpeptidation (crosslinkage of pentapeptide side chains)
27
MECHANISM OF ACTION
 inhibits the formation of peptidoglycan cross links
in bacterial cell wall
 final transpeptidation step in the synthesis of the
peptidoglycan is facilitated by transpeptidases
(known as penicillin-binding proteins, PBPs).
 Transpeptidases – bacterial enzymes that crosslink the peptidoglycan chains to form rigid cell wall
 the beta-lactam moiety binds to transpeptidase,
inhibits formation of peptidoglycan component of
the cell wall, weakening the cell wall when
bacterium multiplies.
 Dividing cells swell osmotically and rupture i.e.
bacteriocidal against dividing cells.
28
Role of Penicillins in Blocking Transpeptidase Enzymes
from Assembling the Peptide Cross-Links in Peptidoglycan
Penicillins (and cephalosporins) bind to the transpeptidase enzymes (also
called penicillin-binding proteins) responsible for resealing the cell wall as new
peptidoglycan monomers are added during bacterial cell growth. This blocks
the transpeptidase enzymes from cross-linking the sugar chains and results in a
weak cell wall and subsequent osmotic lysis of the bacterium
29
Glycopeptides: Vancomycin
 covalently bind to the terminal two D-alanine
residues at the free carboxyl end of the
pentapeptide
 Sterically hinder the elongation of the
peptidoglycan backbone
30
Polypeptide: Bacitracin
Blocks the dephosphorylation of the lipid
carrier
Cycloserine
by competitive inhibition, the drug
prevents the addition of the two
terminal alanines to the initial tripeptide
side-chain on N-acetylmuramic acid
31
B. Disruption of cell membrane function

Damage to cytoplasmic membrane –
Increase permeability by disorganizing the
structure or inhibiting the function of
bacterial membranes
- Polymyxins
- Nystatin
- Amphotericin B
- Imidazoles
32
C. Inhibition of protein synthesis



The bacterial ribosome and the animal ribosome
differ structurally
Inhibition of some step in the complex process of
protein synthesis
Attack on specific ribosomes
Tetracyclines
Interferes with the attachment of t-RNA to m-RNAribosome complex preventing the addition of new
amino acids to the growing peptide chain
33
Protein synthesis
34
C. Inhibition of protein synthesis
(Contd)
Chloramphenicol
- Binds to the 50S portion and inhibits formation of peptide
bonds
Macrolides, Fusidic Acid
- Binds to the 50S portion and prevents the translocation of
ribosome along mRNA
Aminoglycosides
- Changes the shape of the 30S portion causing the
misreading of code on mRNA
35
36
D. Inhibition of nucleic acid
synthesis
Quinolones
- Inhibit DNA gyrase activity (DNA gyrase –
topoisomerase II- is essential for DNA
replication and allows supercoils to be relaxed
and reformed)
Rifampicin
- Inhibit RNA synthesis by inhibiting DNAdependent RNA polymerase
37
E. Action as antimetabolites
Inhibit the bacterial enzymes required for the
synthesis of folic acid (tetrahydrofolic acid, THF)
Sulfonamides:
structurally
similar
to
para
aminobenzoic acid (PABA), the substrate for the
first enzyme in the THF pathway
Trimethoprim: structurally similar to dihydrofolate
(DHF) and competitively inhibits the second step
in THF synthesis mediated by the DHF reductase
38
SIDE-EFFECTS

Toxicities: inability of drug to completely
distinguish host physiology from pathogen
physiology

Allergies

Normal flora disruptions
39
Antibiotic Resistance
1. Evasion - The organism may enter or be
present in an antimicrobial-resistant state
such that all members of a population are
destroyed by the antimicrobial except those
that happen to be in the resistant state (e.g.
endospores)
40
Antibiotic Resistance Contd.)
2. organism may become mutated such that
the site of action of the antimicrobial is no
longer affected by it (a mutation affecting
ribosome structure) typically resistant to only
a single type of antibiotic
41
Antibiotic Resistance (Contd.)
3.Extrachromosomal
antibiotic
resistance
(acquired antibiotic resistance)
 Is associated with resistance (R) plasmids
 Does not involve the mutation within a given
bacteria to antibiotic resistance but instead the
acquisition of resistance plasmids from other
bacteria
 Involves an inactivation of the antibiotic or a
prevention of entry rather than a change in the
structure of the antibiotic target
42
The “Super Bug” Issue


MRSA (methicillin-resistant Staphylococcus aureus)
Resistance developed against
- Beta-lactam antibiotics
- Aminoglycosides (Streptomycin)
- Macrolides
- Chloramphenicol
- Sulphonamides (Sulpamethoxazole + Trimethoprim)
- Rifampicin
- Fusidic Acid
- Quinolones

Vancomycin was the last resort against it but
resistance has also developed
43
Limiting Antibiotic Resistance



Should be employed only when necessary (now
often used indiscriminately and to excess)
High concentrations of drug should be maintained
over long periods (i.e. taking all of one’s pills over
prescribed duration of treatment)
Two antibiotics administered simultaneously may
be capable of synergism when necessary
44
Combinations of antimicrobial
agents

Necessary when:
- Treating a life-threatening infection
- Preventing the emergence of resistance
- Treating a mixed infection
- Enhancing antibacterial activity
- Using lower concentrations of a toxic drug
45
Common Uses of Antibiotics
a. Gastro-intestinal system (Invasive salmonellosis,
Typhoid fever, Biliary tract, Peritonitis)
b. Cardiovascular system (Endocarditis)
c. Respiratory system (Chronic bronchitis,
Pneumonia)
d. Central nervous system (Meningitis caused by
Meningococci,
Pneumococci,
Haemophilus
influenzae, Listeria)
e. Urinary tract (Acute pyelonephritis or prostatitis,
Lower urinary tract infection)
46
Common Uses of Antibiotics
(Contd.)
f.
Genital system (Syphilis, Gonorrhoea,
Uncomplicated genital chlamydial infection,
Urethritis or pelvic inflammatory disease)
g. Blood (Septicaemia, Meningococcal septicaemia)
h. Musculoskeletal system (Septic arthritis,
Osteomyelitis)
i. Eye, ear, nose and oropharynx (Conjunctivitis,
Sinusitis, Otitis media, Throat, Dental infection)
j. Skin (Acne, Cellulitis, animal/insect bite)
47
Common antibacterials


1.
2.
3.
4.
Beta-lactam Antibiotics
A. Penicillins
Natural penicillins
Penicillinase-resistant penicillin
Amino Penicillin
Antipseudomonal Penicillin
48
1. Natural Penicillins
a.
b.
c.
d.
e.
Penicillin G (Benzyl)
Penicillin G sodium/potassium
Penicillin G procaine
Penicillin G benzathine
Penicillin V (Phenoxymethyl-)
49
2. Penicillinase-Resistant
Penicillins
a.
b.
c.
d.
e.
Cloxacillin
Dicloxacillin
Methicillin
Nafcillin
Oxacillin
Orbenin
Diclocil
Pyopen
50
3. Amino Penicillins (broad
spectrum)
a.
b.
c.
d.
e.
Amoxacillin (Amoxil)
Ampicillin (Penbritin)
Bacampicillin (Penglobe)
Pivmecillinam
Pivampicillin
51
4. Antipseudomonal Penicillins
a.
b.
c.
d.
Carbenicillin indanyl sodium (Geopen)
Mezlocillin
Piperacillin (Pipracil)
Ticarcillin (Timentin)
52
Beta-lactamase
53
Beta-lactamase inhibitors

1. Fixed Combination Only
- Clavulanic Acid
- Tazobactam

2. Free combination possible
- Sulbactam
54
B. Cephalosporins
a. Ist generation
b. 2nd generation -
with Haemophilus influenzae and
Bacteroides fragilis activity
c.
3rd
generation
-
with
Pseudomonas
aeruginosa activity
d. 4th generation
55
a) Ist generation

Parenteral form
- Cephalothin (Keflin)
- Cefazolin (Cefamezin)
- Cefaprin (Lopitrex)

Oral form
- Cefadroxil (Duracef)
- Cephalexin (Keflex, Ceporex)
- Cephradine (Velosef)
56
b). 2nd generation

Parenteral form

Oral form
- Cefmetazole (Cefmetazon)
- Cefonicid (Monocid)
- Cefoperazone (Cefobid)
- Cefoxitin (Mefoxin)
- Cefaclor (Ceclor)
- Cefamandole (Mandol)
- Cefetamet pivoxil (Globocef)
- Cefprozil (Procef)
- Cefuroxime axetil (Zinnat)
- Loracarbef (Lorabid)
57
c). 3rd generation

Parenteral form
- Cefotaxime (Claforan)
- Ceftazidime (Fortum)
- Ceftriaxone (Rocephin)

Oral form
- Cefixime
- Cefpodoxime Proxetil (Banan)
- Ceftibuten (Cedax)
58
d). 4th generation

Parenteral Form - Cefepime (Maxipime)
- Cefpirome (Cefrom)
59
Tetracyclines



Cause dental staining and hypoplasia; Absorption
is affected by milk, iron preparations, antacids
(Ca2+, Mg2+, Fe2+ ions);
Drug of choice for chlamydia, rickettsia, brucella
and spirochaete;
E.g. Tetracyclines - Doxycycline (Vibramycin),
Minocycline
(Minocin),
Oxytetracycline
(Terramycin), Tetracycline (Achromycin)
60
Quinolones
For complicated urinary tract infections (Not
recommended for those aged < 12 years)
a. Nalidixic Acid - Nalidixic Acid (Wintomylon),
Pipemidic Acid (Urotractin)
b. Fluoroquinolones - Ciprofloxacin (Ciproxin),
Levofloxacin (Cravit), Lomefloxacin (Maxaquin),
Moxifloxacin (Avelox), Norfloxacin (Lexinor),
Ofloxacin (Tarivid)
61
Extended spectrum



Pefloxacin (Peflacine)
Sparfloxacin (Zaglam)
Trovafloxacin (Trovan)
62
Macrolides
1.
2.
3.
4.
Azithromycin
Clarithomycin
Roxithromycin
Erythromycin
63
Sulphonamides
3.
Sulfadiazine
Sulfamethoxazole
Sulfisoxazole
4.
Trimethoprim + Sulfamethoxazole
1.
2.
64
Aminoglycosides


1.
2.
3.
4.
5.
6.
Usually in parenteral form
Can cause serious ototoxicity and nephrotoxicity
Amikacin (Amikin)
Gentamicin (Garamycin)
Kanamycin (Kanamycin)
Netilmycin (Netromycin)
Streptomycin
Tobramycin (Nebcin)
65
Chloramphenicol


Reserved for typhoid fever
Causes serious blood disorder
Lincosamides


Clindamycin (Dalacin-C) – Pseudomembranous
colitis (antibiotic associated)
Lincomycin (Lincocin)
66