ANTIMICROBIAL

CHEMOTHERAPY
OLORO JOSEPH
BSc. MSc. Pharmacology

OBJECTIVES
At the end of this lecture @ student
should be able to;
List the classes of antibiotics, and
describe their mechanisms of action,
therapeutic uses, and adverse
effects.
Outline mechanism of development of
bacterial drug resistance
Describe the factors in choosing
appropriate antibiotic agents

Classification
Antimicrobials
Antibacterial
Antifungal
Antiviral

Antiparasitic
Antiprotozoal
Anthelmintic
Anticancer (Cytotoxic)
Disinfectants, Antiseptics, Sterilants
Immunomodulators

Basis for Classification of Antibiotics

Chemical Structure e.g.
beta-lactams
aminoglycosides
tetracyclines
Specific Targets on the organism
cell wall synthesis inhibitors
protein synthesis inhibitors
Nucleic acid (DNA & RNA) synthesis
inhibitors

Bacterial Targets for Antibiotics

Beta-lactam
antibiotics
1.
2.
3.
4.

Penicillins
Cephalosporins
Carbapenems
Monobactams

Classification of
Penicillins
The prototype
Penicillin G
Acid resistant
Penicillin V
Penicillinase resistant
Methicillin,
Oxacillin
Extended Spectrum
Amoxicillin,
Ampicillin
Antipseudomonas
Azlocillin,
Piperacillin
Combinations
(Penicillin + -lactamase
inhibitor)
Augmentin, Amoxy-Clav

Penicillins

Names end with cillin

Mechanism of action of penicillins

Inhibit bacterial cell wall synthesis

Bind to penicillin binding proteins (PBPs)
Inhibit transpeptidases (form cross-links in
peptidoglycan)
Cross-linking is reduced

Bactericidal inhibitors

Amino acyl side chain groups determine spectrum,

kinetics, susceptibility to lactamase

Characteristics of the
-Lactam Ring

Binds to and
inhibits
transpeptidase
Substrate for lactamases
An unstable
structure
Acid labile
Breakdown
products are
Immunogenic

Bacterial Cell Walls

Gram (+)

Gram (-)

Teichoic
acid

Crosslinks

From: Goodman and Gilman, 9th ed.

Transpeptidase Inhibition

R
C
O

CH3

O
N
C

C
CH

COOH

(D-alanyl-D-alanine-peptidoglycan

Pharmacokinetics of
penicillins

Absorption: can be oral

Stability in acid condition:
PenG (no)
Amoxacillin (yes)
Pen V (yes)
Nafcillin (yes)
Ampicillin (yes)
Piperacillin (no)

Distribution: to most body sites; not in

CSF unless inflamed meninges
Excretion: rapid eliminated by renal
tubulra secretion

SPECTRUM OF PENICILLINS

Natural Penicillins

Penicillin G
Benzathine PN G
Procaine PN G
Penicillin V

Streptococcus
Neisseria meningitidis
Spirochetes

Penicillinase-resistant

Methicillin
Oxacillin
Nafcillin
Cloxacillin
Dicloxacillin

Staphylococcus aureus

Aminopenicillins

Ampicillin
Amoxicillin

Heamophilus influenzae
Proteus mirabilis
E. coli
Neisseria

Carboxypenicillins

Carbenicillin
Ticarcillin

Pseudomonas
Enterobacter
Proteus

Ureidopenicillins

Piperacillin
Azlocillin
Mezlocillin

Pseudomonas
Enterobacter
Klebsiella

Clinical Uses of Penicillins

Pen G (Pen V): natural

Nafcillin: penicillinase-resistant

Staphylococci epidemic; bacteremia, septicemia

Ampicillin, Amoxycillin:

Common streptococci (S. pneumoniae; S. pyrogenes); URTI,

pneumonia meningitis, prophylaxis of rheumatic fever

Gram- spectrum: E. coli; H. influenzae;Salmonella, shigella

pharyngitis, otitis media, UTI, gastroenteritis

Peperacillin:

Expanded spectrum/antipsuedomonal, enteric bacilli;

Systemic infection in hospitalized patients (gram-, P
aeruginoma)

Combinations with -lactamase

inhibitors:
URTI, pneumonias, meningitis, bactermia

Adverse Reactions to Penicillins

Hypersensitivity

5% of population
Anaphylactic shock (0.05%)
Serum sickness type (rare)
Skin rashes

Superinfection
Esp. the broad spectrum penicillins e.g.
ampicillin

Convulsions at high dosage

Due to GABA receptor blockade

The Antigenic Determinant for

Hypersensitivity

Penicilloic acid and

products of alkaline hydrolysis
bound to host protein

Resistance to
Penicillin

Failure to bind to PBPs

Cannot penetrate porins (gram-)
Production of lactamase (penicillinase)

B-lactamase
Types:

Different substrate specificity

Penicillinases
cephalosporinases

Metallo--Lactamase

Location:

Gram+: extracellularly
Gram-: periplasmic space
Serine--Lactamase

RESISTANCE TO
PENICILLIN

NH

CH3
CH3

+H20

NH

CH3
CH3

HN
COOH
COOH
O OH
Hydrolysis of
-lactam bond PENICILLOIC ACID
-LACTAM
RING

-LACTAMASE

INHIBITORS OF CELL WALL

SYNTHESIS
PENICILLINS
CEPHALOSPORINS
OTHER -LACTAM ANTIBIOTICS
Monobactams
Beta-lactamase inhibitors
Carbapenems

NON-BETA LACTAM CELL WALL SYNTHESIS

INHIBITORS
Vancomycin
Bacitracindermatological agent
Cycloserine anti TB drug

Bacterial Targets for

Antibiotics

Cephalosporins
Nucleus: 7-aminocephalosporinic
acid.
Bactericidal
Same mechanism of action as
penicillin.

Classification of
cephalosporins

1st generation
Parenteral

Cephalothin
Cephaloridine
Cefazolin
Cephapirin

Oral
Cephalexin
Cephradine
Cefadroxil

2nd generation
Parenteral

Cefotetan
Cefuroxime
Cefoxitin
Cefamandole
Cefonicid
Ceforanide
Cefmetazole

Oral

Cefuroxime axetil
Cefaclor
Cefprozil
Loracarbef

3rd generation
Parenteral

Ceftazimide
Ceftizoxime
Ceftriaxone
Cefotaxime
Ceoperazone

Oral
Cefixime
Cefpodoxime
Ceftibuten

4th generation
Parenteral
Cefepime
Cefpirome

 MOA
Inhibition of transpeptidase
inhibition of cell wall synthesis.

Spectrum of activity
1st generation- most effective for gram
+ve bacterial infections.
2nd generation- against gram +ve and ve
bacterial infections except enterococci, P.
aeruginosa. They cross the BBB in absence
of inflammation.
3rd generation- active against +ve
bacteria and anaerobes
4th generation- RTI, multi resistant
hospital acquired infections, septicaemia.

ADR
Seizure 1st generation
Rare disulfiram like rxn with alcoholcefamandole, cefmetazole, cefoperazone,
cefamandole, moxalactum
Bleeding- ceftriaxone and cefoperazone.
Nephrotoxicity- cephaloridine
Stool change and diarrhea- cefixime
Pain after I.M injection
Hypersensitivity reaction
Etc

Uses of cephalosporin
Gram ve bacteria; RTI, UTI, soft tissue
infection
Penicillinase producing staph
Mixed aerobic infections
Typhoid
Gonorrhea
Meningitis
Septicaemia
Neutropenic patients
Most surgical prophylaxis- cefazolin

MONOBACTAMS
Example: Aztreonam [az TREE oh nam]
Mechanism:

Inhibits PBP 3; required for cell wall septum formation

Spectrum: narrow; vs gram ve rods

enterobacteria.
No activity vs gm +ves & anerobes

P/K: admin IV, IM [1-2g q8h]

Adverse effects: relatively non toxic,
ocassionally - phlebitis, skin rash

CARBAPENEMS

Imepenem, Meropenem, Ertapenem

Prototype: Imipenem-Cilastatin [IV, 0.25-0.5g q6-8h]

IMIPENEM binds to PBP-2 required for maintenance of rod shape

CILASTATIN is a peptidase inhibitor that blocks renal degradation of
Imipenem

Broadest spectrum (gm +ve cocci, gm ve rods & anerobes) - Important

role in empiric therapy

Spectrum:

hospital-acquired infections
mixed aerobic and anerobic infections
Used with aminoglycosides for pseudomonal infections that are resistant to
other drugs
Highly PCN-resistant pneumococci

Adverse effects

Allergic reactions
Nephrotoxicity (imepenem singly without cilaststin)

Check list
Define the term antibiotic
Describe the mechanism of antibacterial
action of beta-lactam antibiotics
Identify the prototype drugs in each
subclass of PCNs and describe their
antibacterial activity &
clinical uses
Identify the 4 subclasses of Cephalosporins
and describe their antibacterial activities &
clinical

Check List contd

Compare and contrast PCNs and
cephalosporins
Describe the clinical significance of the
following antibiotics:
Beta-lactamase inhibitors
Vancomycin
Imepenem-cilastatin

Describe 3 mechanisms underlying

resistance

MONOBACTAMS
Example: Aztreonam [az TREE oh nam]
Mechanism:

Inhibits PBP 3; required for cell wall septum formation

Spectrum: narrow; vs gram ve rods

enterobacteria.
No activity vs gm +ves & anerobes

P/K: admin IV, IM [1-2g q8h]

Adverse effects: relatively non toxic,
ocassionally - phlebitis, skin rash

AZTREONAM

-lactam ring

PENICILLIN BINDING PROTEINS:

Mechanism of action of Aztreonam

Site of action of Aztreonam

beta-lactamase
inhibitors
Clavulanic acid, sulbactam,
tazobactam
Used in fixed combinations with
certain hydrolysable PCNs e.g.
Ampicillin
amoxicillin
Antibacterial Spectrum: E. coli, Klebsiella spp., H.
influenza, Moraxella catarrhalis, Providencia spp.,
Bacteroides spp, Staphylococcus spp.
Enterobacter, Pseudomonas, Acinetobacter

beta-lactamase
inhibitors

Clavulanic Acid [cla vue LA nick]

Clavulanic acid + Amoxycillin = Clavamox,
Amoxiclav, Augmentin
Biological source
Streptomyces clavuligerus
Spectrum
Gram-positive and Gram-negative bacteria
Mode of action
Suicide inhibitor of beta-lactamases

CARBAPENEMS

Imepenem, Meropenem, Ertapenem

Prototype: Imipenem-Cilastatin [IV, 0.25-0.5g q6-8h]

IMIPENEM binds to PBP-2 required for maintenance of rod shape
CILASTATIN is a peptidase inhibitor that blocks renal
degradation of Imipenem

Broadest spectrum (gm +ve cocci, gm ve rods & anerobes) Important role in empiric therapy

Spectrum:
hospital-acquired infections
mixed aerobic and anerobic infections
Used with aminoglycosides for pseudomonal infections that are
resistant to other drugs
Highly PCN-resistant pneumococci

Adverse effects
Allergic reactions
Nephrotoxicity (imepenem singly without cilaststin)

Penicillin Binding Proteins

Mechanism of action of Imipenem

Site of action of Imipenem

IMIPENEM-CILASTATIN
(Primaxin )

blactam ring

VANCOMYCIN [van koe MYE

sin]
-Tricyclic glycopeptide antibiotic
-Molecular weight: 1450 Da
-Source: Nocardia orientalis

Mechanism of Action of
Vancomycin
Binds to D-ala-D-ala terminal of the
nascent peptidoglycan, inhibiting
transglycosylation, elongation and
cross-linking.

VANCOMYCIN general
characteristics

Bactericidal

Narrow Spectrum vs gram +ve resistant organisms

Gram (+) cocci, Staph. & Strep., Enterococcus,
Clostridium sp.

Adverse reactions
Chills, fever, phlebitis
Ototoxicity & nephrotoxicity
Red neck/man syndrome diffuse flushing on rapid I.V

Clinical Uses (admn slow IV) 30mg/kg/d in 2-3 divided

doses
Methicillin-resistant Staphylococcus (MRSA)[sepsis,
endocarditis]

Check list
Define the term antibiotic
Describe the mechanism of antibacterial
action of beta-lactam antibiotics
Identify the prototype drugs in each
subclass of PCNs and describe their
antibacterial activity &
clinical uses
Identify the 4 subclasses of Cephalosporins
and describe their antibacterial activities &
clinical

Check List contd

Compare and contrast PCNs and
cephalosporins
Describe the clinical significance of the
following antibiotics:
Beta-lactamase inhibitors
Vancomycin
Imepenem-cilastatin

Describe 3 mechanisms underlying

resistance

Inhibitors of
Protein
Synthesis

MECHANISM OF ACTION
Target site: bacterial ribosome
The bacterial ribosome is smaller
(70S) than the mammalian ribosome
(80S)
It is composed of the 30S and 50S
subunits

Protein Synthesis InhibitorsSites of action

Review of Initiation of Protein

Synthesis
1 3
2 GTP

30S
1
2
3 GTP
Initiation Factors

f-met-tRNA
mRNA

Spectinomycin
3

GDP + Pi
P A

70S
Initiation
Complex

50S

Aminoglycosides

1
2 GTP

30S
Initiation
Complex

Protein Synthesis

Properties of Protein Synthesis

Inhibitors

Mostly bacteriostatic; few

bactericidal
Selectivity due to differences in
prokaryotic and eukaryotic ribosomes
Some toxicity - eukaryotic 70S
ribosomes

Antimicrobials that inhibit the 30S

Ribosomal Subunit

Aminoglycosides
(bactericidal)
streptomycin, kanamycin, gentamicin,
tobramycin, amikacin, netilmicin, neomycin

Mode of action
irreversibly bind to the 30S initiation
complex (30S-mRNA-tRNA)
misreading of mRNA incorporation of
incorrect amino acids into the peptide
non-functional protein

Aminoglycosides contd
Spectrum of Activity Mainly gram -ve
aerobic bacteria; Not effective against
anaerobes (oxygen required for uptake of
antibiotic)
Resistance Common
Synergy - Synergize with beta-lactam
antibiotics, which increase the permeability
of the aminoglycosides.

AminoglycosidesPharmacokinetics
Administration

Parenteral (I.V, I.M) except neomycin( po in hepatic

coma or topically)
Highly polar, polycationic: poorly absorbed from GIT

Distribution

Low conc. in CSF, even when meninges are inflamed

High conc. in renal cortex, and endolymph & perilymph
of the inner ear
High conc. In fetal plasma & amniotic fluid

Metabolism

Not metabolised in the host

Rapidly excreted into urine by glomerular filtration

Special P/k properties

Once-daily dosing preferred
Concentration dependent killing
Post-antibiotic effect
Therapeutic drug-monitoring
Dosage adjustment in renal insufficiency

PREPARATIONS
Gentamicin: 10, 40mg/ml vials (IM, IV)
Streptomycin: 400mg/ml (IM)
Kanamycin:

500mg caps po;

500, 1000mg/ml (IM, IV); 75 mg/ml (peadiatric)

Paromomycin: 250mg caps.

Neomycin: 500mg tabs; 125mg/ml
solution

Adverse effects
Ototoxicity (vestibular & cochlear) fetal
deafness in utero
Enhanced by loop diuretics

Nephrotoxicity
Neuromuscular paralysis
Due to reduced Ach release from prejunctional
n. endings [Rx with Neostigmine or Ca
glugonate]

Therapeutic applications
Streptomycin Tb, plague, tularemia
(lymphoid dx)
Streptomycin + penicillin streptococcal
viridans endocarditis
Aminoglycoside + ampicillin E.Coli
pneumonia
Aminoglycoside + cephalosporin or
antistaphylococcal penicillin Klebsiella,
pseudomonas

Resistance Mechanisms

Altered target site -30S ribosome

Production of drug inactivating enzymes
esp. transferases
Impaired drug entry

Antimicrobials that Bind to the 30S

Ribosomal Subunit contd

Spectinomycin
(bacteriostatic)
Classification: Aminocyclitol
Mode of action - interferes with m-RNA
interaction with the 30S ribosome.
Spectrum of activity - Used in the treatment of
penicillin-resistant Neisseria gonorrhoeae [backup
drug]
as single IM dose

Resistance - Rare in Neisseria gonorrhoeae

Ttracyclines [tet ra SYE kleen]

4 fused rings with a system of conjugated double bonds

Tetracyclines

Mode of action - bacteriostatic

Reversibly bind to the 30S ribosome and inhibit binding
of aminoacyl-t-RNA to the acceptor site on the 70S
ribosome.
Spectrum of activity - Broad spectrum; Useful against
intracellular bacteria
Clinical Uses
Primary: Mycoplasma pneumonia, Chlamydia,
Rickettsia, and Vibrio infections
Secondary: Syphilis, Acne
Selective:
H.pylori regimens (tetracyline)
Meningococcal carrier state (Minocycline)
Malaria prophylaxis & Rx Amebiasis (doxycline)
SIADH secretion (Demeclocycline)

Tetracyclines adverse effects

GIT disturbances
Nausea & diarrhoea; Colitis (prolonged use)
Disturbances in normal flora
Oral & vaginal candidiasis
Bacterial superinfections with S.Aureus & C.
difficile

Bony Structures & teeth

Tooth enamel dysplasia- fetal and in young
children- crown deformation in permanent
teeth

Hepatic dysfunction

Tetracyclines adverse
effects
Renal toxicity Fanconi syndrome
(renal tubular acidosis) older
tetracyclines
Photosensitivity (esp.
demeclocycline)
Vestibular toxicity (dizziness &
vertigo) doxycline & minocycline

Drug Resistance Mechanisms

Resistance
Widespread
Plasmid
mediated
Development
of efflux pumps
Increased
drug
extrusion

Antimicrobials that Bind to the

50S Ribosomal Subunit

PhenolsChloramphenicol [klor am FEN i kole]

Chloramphenicol
(bacteriostatic)
Mode of action - binds to the 50S
ribosome and inhibit peptidyl transferase
activity.
Spectrum of activity Classical Broadspectrum antibiotic
Clinical uses very few due to toxicity;
but quite useful in
Meningitis (pneumococcal, meningococcal, H.
influenzae)
Salmonella typhi (backup)

Chloramphenicol
(bacteriostatic)

P/K: adm. po or parenterally

Extremely lipid soluble
Readily crosses the placental and
BB barriers; large Vd (100L)
CSF conc. ~30-50% (meninges not
inflamed); 80% (inflamed)
Inactivated by hepatic
glucuronosyltransferase

Chloramphenical - Adverse
effects
GIT disturbances
direct irritation & superinfections
Bone marrow depression (inhibition
of RBC maturation)
dose dependent and reversible
Attributed to human
mitochondrial ribosome toxicity

Chloramphenical - Adverse effects

contd
Aplastic anemia
rare idiosyncracy, but generally irreversible
& fatal
Ocurrence- 1: 25,000 patients
Onset: weeks-months after Rx
Check blood count twice weekly

Gray baby syndrome (RBCs, cyanosis,

CVS collapse)
Common in neonates
Deficient in hepatic glucuronosyltransferase

Chloramphenicol Resistance Mechanisms

Resistance common
Plasmid mediated,
conferred by the catgene

Cat gene codes

chloramphenicol
acetyltransferase (CAT)
CAT inactivates the drug

Antimicrobials that Bind to the 50S

Ribosomal Subunit contd

Macrolides (big
structures)-

Large lactone cyclic rings with glycosidic

bonds

Macrolides

(bacteriostatic)

Mode of action
bind to the 50S ribosomal subunit
block translocation of peptidyltRNA from the acceptor to the
donor site

P/kinetics

V. good po bioavailability
Azithromycin
Absorption impeded by food
High levels in phagocytes>
plasma
Long t1/2

Macrolides (activity spectrum

& uses)

Erythromycin [er ith roe MYE sin]:

Source: Streptomyces erythreus

Pneumococci, Mycoplasma pneumoniae, Corynebacterium,
Campylobacter jejuni, Chlamydia trachomatis, Legionella
pneumophila, Bordetella pertussis, T pallidum
Spectrum similar to PCN
Effective alternative in patients allergic to PCNs
Quite cheap

Azithromycin: as above + H.influenzae, Chlamydia &

Niesseria
4-day course (o.d) effective for community acquired
pneumonia
Limitation: expensive

Clarithromycin : as above + M avium (prophylaxis & Rx), H

pylori

Macrolides (adverse effects)

General:

GIT irritation (very common) stimulation of motilin

receptors
Skin rashes
Eosinophilia

Erythromycin & Clarithromycin:

Cholestatic hepatitis increased risk in pregnancy

Inhibition of hepatic CYP450 enzymes (plasma levels
of anticoagulants, digoxin, theophylline, carbamezepine
& cisapride)

Azithromycin:

Does not inhibit CYP450 enzymes

Modified lactone ring to avoid the effects above

Lincosamides
Clindamycin [klin da MYE sin]

Biological source

Streptomyces lincolnensis

Mechanism: similar to macrolides

Bind to the 50S ribosomal subunit

Spectrum and Clinical use (Narrow spectrum)

Severe anaerobic infections esp. Bacteroides spp

Endocarditis (prophylaxis & Rx) in patients allergic to PCN
Pneumocystis Carinii
Toxoplasma gondii

Adverse effects

GIT irritation
Neutropenia
C difficile pseudomembranous colitis

Streptogramins
Example: Quinupristin-dalfopristin
(w: w ratio 30%:70%) [Synercid]

Combination of 2 streptogramins derived

from pristinamycin
Bactericidal/ Synergistic
Antibacterial activity > t1/2s of the 2
compounds (Postantibiotic effects)

Mechanism: similar to macrolides

Bind to the 50S ribosomal subunit and

impair translocation
Admin I.V

Streptogramins

Spectrum and Clinical use (Narrow

spectrum)
PCN-resistant pneumoccoci
Methicillin resistant staphylococcus
(MRSA)
Vancomycin-resistant staphylococcus
(VRSA)
Resistant enterococcus feacium

Adverse effects
Arthralgia-myalgia syndrome
Inhibit CYP3A4 ( plasma levels of many

CHECK LIST
For each drug class of protein
synthesis inhibitors:
Explain the mechanism of action
Name the most important examples per
class
Identify their clinical uses
Recall the P/Kinetics peculiar to the
major drugs
List the characteristic adverse effects
Identify the 1 mechanisms of resistance

Antimetabolites
&
Fluoroquinolone
s

Antimetabolites & Nucleic acid

Synthesis Inhibitors

Sulfonamides - Mechanism of action

They inhibit the enzyme dihydrofolate
(dihydropteroate) synthase in the
biosynthetic pathway for folic acid.
-Most bacteria cannot utilize external folic acid, a nutrient
which is essential for growth:
-must synthesize it from para-aminobenzoic acid (PABA).
-sulfonamides are structurally similar to PABA

Antibacterial spectrum:
-grm +ve, grm ve bacteria,
-nocardia spp, some protozoa
-enteric bacteria (e.g. E.coli, Salmonella, shigella,
and enterobacter)

PABA

Sulfanilamide

The different sulfonamides are produced by

attachment of substituents to the amido group
(-SO2-NH-) or the amino group (-NH2) of the
sulfanilamide nucleus ---- varying chemical,
pharmacological& antibacterial properties.
Classification:
Short acting: sulfisoxazole, sulfanilamide
Intermediate: sulfamethoxazole
Long acting:
sulfadoxine

DHF synthetase DHF reductase

PABA

DHFA

THFA

Purines

()

Sulfonamides

DNA

Sulfonamides

Clinical uses:
UTIs [sulfamethoxazole + trimethoprim]
Toxoplasmosis [sulfadiazine + pyrimethamine] + Folinic
acid
Malaria [sulfadoxine + pyrimethamine]---FANSIDAR
Ulcerative colitis [sulfasalazine]
Ocular infections [Topical- sulfacetamide]
Burn infections [Topical silver sulfadiazine]

NB: infrequently used as single agents due to

development of resistance of formerly susceptible

Sulfonamides

Adverse effects
Hypersensitivity reactions [skin rash, exfoliative
dermatitis, Stevens-Johnson syndrome]
GIT upsets [N,V,D]
Haemolysis in patients with G-6-PD deficiency
Nephrotoxicity [crystalluria & hematuria]- in overdose
Hematotoxicity [granulocytopenia, thrombocytopenia, &
aplastic anemia]
kernicterus in neonates (displace bilirubin).

{Multiple adverse effects have also led to their

Sulfonamides
Resistance mechanisms
mutations that lead to:
Overproduction of PABA
Expression of a folic acidsynthesizing enzyme that has low
affinity for sulfonamides
Impaired permeability to the
sulfonamide

Cotrimoxazole
Trimethoprim-sulfamethoxazole
[TMP-SMX]- (Co-trimoxazole)
Septrin, Bactrim etc -- {po,
IV}
Mechanism of action
Sequential blockade of folic acid
synthesis
Antimicrobial synergy -- bactericidal
Reduced side effects with combo.

Sulfonamides/Trimethoprim
Trimethoprim inhibits dihydrofolate
reductase
which converts dihydrofolate to
tetrahydrofolate:

DHF synthetase

PABA

DHF reductase

DHFA
()

Sulfonamides

THFA
()

Trimethoprim

Purines

Cotrimoxazole

Clinical use
UTIs (urethritis, prostatitis, cystitis, etc)
Respiratory, Ear & Sinus infections [ H. influenzae]
Immunocompromised patients e.g. AIDS
Pneumocystis jiroveci pneumonia [PCP] prophylaxis & Rx
mortality, hospitalization, other opportunistic infections,
diarrhoea, malaria, etc.

Nocardiosis
Cholera, Typhoid fever, and Shigellosis [backup drug]

Cotrimoxazole
Adverse effects
Trimethoprim [antifolate effects]
Megaloblastic anemia, leukopenia, &
granulocytopenia
(treated with supplementary Folinic acid
[Leucovorin]

TMP-SMX
Effects associated with both sulfonamides &
trimethoprim
Frequency of adverse effects
In immunocompromised patients
At therapeutic dose (>960 mg bid) , if used for a long

Fluoroquinolones

FLUOROQUINOLONES

Classification generations based

on spectrum of activity
1st (Nalidixic acid, Norfloxacin): UTI pathogens
Urinary antiseptics
2nd (Ciprofloxacin, Orfloxacin):
grm ves,
gonococcus, grm +ves, mycobacteria,
mycoplasma pneumoniae
3rd (Levofloxacin, Gatifloxacin, Sparfloxacin):
activity vs grm +ve cocci, S pneumoniae, &
MRSA
th

FLUOROQUINOLONES

Mechanism of action
Bactericidal
Inhibit topoisomerase II (DNA gyrase) &
topoisomerase IV and prevent, respectively;

(a) relaxation of +vely supercoiled DNA -

required for normal transcription & replication
(b) separation of replicated chromosomal DNA
into respective daughter cells during cell division

Inhibition of DNA Gyrase

FLUOROQUINOLONES

Pharmacokinetics
High oral bioavailability (80-95%)
Oral absorption impaired by divalent cations
(including those in antacids)
Serum concentrations I.V similar to those of
oral administration
Elimination mainly by renal mechanisms
(tubular secretion or glomelurar filtration)

FLUOROQUINOLONES

Clinical uses

Urogenital & GIT infections

[gonococci, E coli, K pneumoniae,
Campylobacter jejuni, Enterobacter, P
aeruginosa, Salmonella, Shigella]

Respiratory tract, Skin & soft tissue

infections
Gonorrhoea [Ciprofloxacin & ofloxacin
single po dose; alt. to cephalosporins]

FLUOROQUINOLONES

Clinical uses contd

Chlamydia [ofloxacin 7-day course]

Atypical pneumonia (Mycoplasma, chlamydia,
legionella spp) [Levofloxacin, Gatifloxacin]
2nd line in Rx of TB & atypical mycobacteria
Prophylactic management of neutropenic
patients
Anthrax (prophylaxis & Rx)

FLUOROQUINOLONES

Adverse effects ---- [gen. well tolerated but watch out

for]
GIT distress (N,V,D)
CNS headache, dizziness, insomnia
Abnormal Liver function tests
Tendinitis & tendon rupture [contraindicated in pregnancy &
children
Hyperglycemia in diabetic patients (esp. Gatifloxacin)
Cardiotoxicity [prolongation of the QTc interval-arrythmias]

CHECKLIST
Describe the mechanism of action and adverse
effects of sulfonamides & trimethoprim.
How clinically useful are the sulfonamides? Discuss.
Write short notes on Cotrimoxazole
Folate reductase inhibitors. Discuss.
Are the fluoroquinolones (FQS), the super
antibiotics?. Discuss. What limits the use of some
FQS?

ANTIFUNGAL
DRUGS

Introduction
Defn: Drugs for treating mycoses
Mycoses
Superficial
Skin (dermatophytes) e.g. tinea corporis, capitis
Mucosa (vaginal, oral candidiasis)

Systemic (e.g. Cryptococcus, Aspergillus)

Fungi are eukaryotic

Structures relevant to therapy
Rigid cell wall : chitins & polysaccharides
Cell membrane: ergosterol
Cytoplasmic & nuclear

Classification
Subclass

Prototypes

Others

1. Drugs for systemic

mycoses
- Polyenes
-Azoles
-Pyrimidine
-Echinocandin

Amphotericin
B
Fluconazole,
Ketoconazole Itraconazole
Flucytosine
Caspofungin

2. Systemic drugs for

superficial infections

Griseofulvin

Terbinafine,
ketoconazole,
fluconazole,
itraconazole

3. Drugs for topical or

Nystatin

Miconazole,

Sites of action
Major sites of action
Alteration of cell
membrane
permeability
Which ones?

Inhibition of
ergosterol
synthesis
Which ones?

Blockade of
nucleic acid
synthesis
Which ones

Disruption of
microtubule
Which ones?

Amphotericin B [am foe TER I sin])

Amphoteric polyene
macrolide
Source:
Streptomyces nodosus

M/A:
binds ergosterol
poresmembrane
permeability
Fungicidal

P/K:
admin IV; not orally absorbed
Does not readily cross the BBB
Excretion: biliary & renal

P/K: amphotericin B

Amphotericin

C/Uses: Severe systemic fungal infections

Candidiasis, cryptococcal meningitis,
blastomycosis, histoplasmosis, coccidiosis,
aspergillosis
Mainly for induction of treatment
Dose 0.5-1mg/kg/d

Adverse/toxic effects:
(a) infusion related: fever, chills, m. spasms,
hypotension
How managed?
Slow IV adm
premedication with antipyretic, antihistamines, glucocorticoids

Amphotericin B
(b) Dose-limiting: cumulative nephrotoxicity;
GFR, renal tubular acidosis; K + & Mg2+ wasting
reduced by
sodium loading
liposomal formulation

( c) Neurotoxicity: seizures
(d) phlebitis at IV site

Precautions:
Monitor renal function;
preferably use ABLC (amphocil & ambiosome lessnephrotoxic complex) formulation
Low Therapeutic Index
Test dose (1mg IV)

Flucytosine [flo SYE toe seen]

(5-FC)
Pyrimidine analog
M/A: converted by fungal
deaminases in fungal cells to the
active substance 5-fluorouracil (5FU)
5-FU inhibits DNA & RNA synthesis

P/K: good p.o bioavailability,

penetrates CSF well
C/Use:
Cryptococcus neoformans
Candidal endocarditis
Synergy with Amphotericin B

Adverse effects:
bone marrow suppression,
GI upsets: Toxic enterocolitis

Mechanism of 5-FC

enters fungal cells

via a permease
Converted to 5FdUMP
A false nucleotide
Inhibits thymidylate
synthase

AZOLE ANTIFUNGALS
Synthetic
Classification: (A) Imidazoles
Ketoconazole
Clotrimazole
Miconazole

(B) Triazoles
Fluconazole
Itraconazole
Voriconazole

Mechanism
Inhibit synthesis of
ergosterol; by blocking
demethylation of lanosterol.

Azole Antifungals
Ketoconazole [kee toe KON a zole]
(100-200mg/d)
Narrow antifungal spectrum
Many adverse effects
Inhibits CYP450 enzymes

Rarely used; but effective vs

chronic mucocutaneius candidiasis
Dermatophytes

Azole Antifungals
Fluconazole [floo KON a zole] (100-800mg/d)
Desirable P/K profile
V.good p.o. bioavailability
High degree of H2O solubility
Good CSF penetration

fewer adverse effects

Least effect on CYP450 enzymes
Better GI tolerance
Wide therapeutic index

Widely used; effective vs

mucocutaneous candidiasis (esophageal, oropharyngeal, vaginal)

candidemia
Cryptococcus neoformans (prophylaxis & treatment)
Coccidioides

Azole Antifungals
Itraconazole [it ra KON a zole] (100-400mg/d);
wider spectrum;

Systemic blastomyces and sporothrix

Subcutaneous chromoblastomycosis
Aspergillus, Cocidioides, Cryptocococcus, histoplasma
Resistant esophageal candidiasis
Dermatophytes (onychomycosis)

Voriconazole;(400mg/d)
newer drug, with much wider spectrum; & drug
choice for
Invasive aspergillosis
Candidemia in AIDS patients

Azole antifungals
Adverse effects
Relatively non-toxic; but cause:
GI upsets- vomiting & diarrhea
Hepatotoxicity in patients with prexisting liver dysfunction

Ketoconazole :
Inhibition of CYP450 enzymes
plasma levels of other drugs, oral hypoglycemics, phenytoin,
warfarin
Impaired synthesis of adrenal & gonadal steroids leading to
gynecomastia, menstrual irregularities, and infertility.

Voriconazole
Class D drug in terms of pregnancy risk

SUMMARY OF AZOLE ANTIFUNGALS

Nystatin [nye STAT in]

Polyene macrolide
antibiotic
M/A: punches
holes in
ergosterol
P/K:
only used topically;
not absorbed from the
GI tract
Too toxic for IV use

C/Use:
Superficial: oral,
esophageal, gastric &
vaginal candidiasis,

TOPICAL AZOLES
Examples:
Miconazole, Clotrimazole

M/A:
inhibit biosynthesis of the
ergosterol

C/Use: topical fungal

infections
Tinea versicolor, capitis, corporis
mucocutaneous candidiasis
Oral thrush
Candida vaginitis

dermatophytes

1-[(2-chlorophenyl)di(phenyl)methyl]imida
zole

Griseofulvin [gri see oh FUL VIN]

Isolated from a Penicillium spp. in 1939
M/A:
inhibits fungal mitosis by disrupting spindle
formation
Binds avidly to keratin in the sratum
corneum of skin, hair & nails

C/use: (1g/d)
dermatopytes of skin, hair &nails
Trichophyton, microsporum, epidermophyton

Adverse effects:

headache, mental confusion

GI upsets
Photosensitivity
Bone marrow suppression

7-chloro-4,6dimethoxycouma
ran-3-one-2spiro-1- (2methoxy-6methylcyclohex2-en-4-one)

Terbinafine (Lamisil)
an allylamine
highly lipophilic ; tends to
accumulate in skin, nails, and
fatty
M/A:
inhibits ergosterol biosynthesis
via inhibition of squalene epoxidase.

C/Use: (250m/d)
dermatophyton, onychomycosis

Adverse effects:(few),; GI upsets

(E)-N,6,6-trimethyl-N Newer drugs related:
(naphthalen-1 Naftifine
Amorolfine

ylmethyl)hept-2-en-4-yn-1amine

ECHINOCANDINS
New class of antifungal
agents;
Caspofungin (70mg IV stat;
then 50md o.d
Micafungin
Anidulafungin

Large cyclic peptides linked

to a long chain fatty acid
M/A:
Inhibit synthesis of (1-3)

Echinocandins
Spectrum:
Candida
Aspergillosis
NOT effective vs cryptococcus

Adverse effects;
Extremely well tolerated
Minor GI upsets
Elevated liver enzymes
Flushing

Ketoconazole contd
Ketoconazole has
multiple drug
interactions
Why?
Identify drugs whose
metabolism is inhibited
by ketoconazole
What is the significance
of
such interactions?

Study Questions
1) With reference to the structure of a
typical fungal cell, determine the
mechanisms of action of the major
classes of antimycotic drugs
For each class, mention examples, their
therapeutic use, and common side effects

2) Describe the pharmacokinetics and

toxicities of Amphotericin B
3)Describe the pharmacokinetics,
toxicities, and drug interactions of the
azoles

ANTIMYCOBACTERIAL
DRUGS

Pathogenesis
Mycobacteria
M tuberculosis (TB)
M leprae
M avium-intracellulare

Therapeutic considerations
Recall/ Review the pathogenesis
Protracted drug treatment
Drug toxicities
Patient compliance

Development of drug resistance

Drugs for TB
Sub-Class

Prototype

Other significant
agents
Ethionamide,
pyrazinamide
Rifabutin

Pyridines

Isoniazid

Rifamycins
Diamines
Aminoglycosid
es
Others

Rifampicin
Ethambutol
Streptomyci Amikacin
n
Ciprofloxacin,
Ofloxacin,
aminosalicylic acid,
capreomycin,

ISONIAZID - (Eye Soe NYEazid)

Chemical nature
Iso-Nicotinic acid
Hydrazide (INH)
Structural analog of
pyridoxine (nicotinamide),
Vit. B6

M/A: Inhibits
synthesis of lipid
membrane & mycolic acid
in the cell wall
Nucleic acid & glycolysis

ISONIAZID
P/K: well absorbed p.o,
Diffuses readily into most fluids, cells and tissues

Effective vs both extracellular & intracellular

organisms
(penetrates into macrophages)

Metabolised in the liver by acetylation or

hydrolysis
Patients may be fast or slow acetylators
(What is the pharmacological significance?)

Acetylation of Isoniazid
A bimodal distribution
of fast and slow
acetylators exists
Acetylation is
genetically regulated
Fast acetylator trait is
autosomally dominant

Any relevance to drug toxicity?

ISONIAZID

Excreted via urine; urinary

excretion of Vit B6
C/Uses ( adult dose 300mg/d)
Prophylaxis of TB (alone)- (in which
cases??)
Active TB (in combo)
Adverse effects
Hepatotoxicity
Neurotoxicity -- peripheral neuritis
(alleviated by pyridoxine (50 100mg/day po)
(INH Injures Nerves and

Interaction of INH with phenytoin

INH inhibits
metabolism of
phenytoin
What are the
consequences?
How would you
manage an epileptic
patient, who has
developed pulmonary
TB, and has been
receiving phenytoin?

RIFAMPICIN (Rifampin RIF

am pin)

A Rifamycin antibiotic
produced by Streptomyces
Mediterranei
M/A: inhibits -subunit of
DNA-dependent RNA
polymerase
Bactericidal vs Mtb

P/K: well absorbed when

given p.o, & distributed to
most tissues and cells
CNS
Intracellular (e.g. phagocytic
cells)
Abscesses/ lung cavities

RIFAMPICIN
Clinical Use:
TB (in combo)600mg/d (10mg/kg/d)
Is the only cidal drug active against the 3 pools of TB
bacilli
(a) metabolically extracellular pool
(b) metabolically intracellular pool
(c) necrotic caseous pool

Leprosy

Prophylaxis vs N.meningitidis & H.

influenza
Brucellosis
MRSA

RIFAMPICIN
Adverse effects:
Orange red coloration of body fluids, Hepatotoxic,
Influenza like illness, Nephrotoxic, Renal failure

Metabolism: via MOS,

induces MOS, its own metabolism & of other drugs
Undergoes enterohepatic cycling; excreted in bile
Drug & metabolites (orange colored) are eliminated mainly in
feces

Interactions
strong inducer of CYP450 enzymes (relevance??)

Rifampicin: induction of CYP450

enzymes

What is the
pharmacological
significance of this drug
interaction in the
management of:
Contraception?
Diabetes mellitus?
Hypertension?
Heart failure?
Compare & contrast
Rifampicin to Rifabutin

RIFAMPICINs 4Rs
RNA polymerase inhibitor
Revs up microsomal P450
Red/Orange body fluid
Resistance rapid if used alone

ETHAMBUTOL (e

THAM byootole)

A diamine ; bacteriostatic cpd

M/A: inhibits arabinosyltransferases;
involved in synthesis of
arabinoglycan

2-[2-(1hydroxybutan-2ylamino)ethylamino]butan1-ol
C10H24N2O2

P/K: effective p.o, crosses the BBB

C/use: mtb (in combo)- 12-25mg/kg/d
Adverse effects:
visual disturbance;
optic neuritis
contraindicated in children 12

PYRAZINAMIDE (peer a ZIN a mide)

M/A: not clear, but is converted by
mycobacterial pyrazinamidase to
pyrazinoic acid
Bacteriostatic

P/K: effective po, good CNS

bioavailability
pyrazine-2carboxamide

Taken up my macrophages, very effective

intracellularly in acidic environment

C/Use: mtb (in combo)25mg/kg/d

sterilizing agent

Adverse effects:
C5H5N3
O

polyarthralgia, myalgia
hyperuricemia

Hepatotoxicity

Streptomycin

Aminoglycoside
Penetrates cells poorly; effective vs
extracellular bacilli
Used with other drugs that can access the
intracellular compartment

C/Use: mtb (in combo);--(15mg/kg/d)

Severe forms, disseminated tb, relapse, or
parenteral administration necessary
Tb meningitis
Miliary tb
Potts disease

Second Line (Alternative) anti- TB drugs

E.g: Amikacin, Aminosalicylic acid,

capreomycin, clofazimine, cycloserine,
ethionamide, Quinolones,
clarithromycin
Why 2nd line?:
Less efficacious than 1st line drugs,

When considered:
resistance to 1st line drugs,
failed clinical response to conventional
therapy,

ATYPICAL MYCOBACTERIA
M marinum, M avium intracellulare
(MAC), M ulcerans, M kansasii
Generally opportunistic infections in
immunocompromised patients
MAC most common
Disseminated infection in AIDS patients

Drugs:
Prophylaxis: Azithromycin, Clarithromycin
Treatment : Azithromycin or Clarithromycin
+ Ethambutol + Rifampicin (or Rifabutin)
or Quinolone

DRUGS FOR LEPROSY

Leprosy:
Recall/Review the pathogenesis
Forms of leprosy (learn in medical
nursing)
Class
Prototype
others

Drug examples
Sulfones

Dapsone

Phenazines

Clofazimine

Rifamycins

Rifampicin

Acedapsone

Dapsone [DAP sone]

4-(4aminophenyl)
sulfonylaniline
C12H12N2O2S

M/A: A sulfone, PABA antagonist; inhibits

folate synthesis
P/K:
good p.o. bioavailability, enters
enterohepatic circulation,
metabolized in liver by acetylation
C/Use: (100mg/d)
M leprae (in combo)
PJP (PCP) prophylaxis
Dermatitis herpetiformis
Adverse effects:
Hypersensitivity
Aggranulocytosis
Leprae reactions (erythema

Clofazimine
[Kloe FA zimeen]

M/A: a riminophenazine, binds

to DNA template; inhibits
transcription;
P/K:
good p.o. bioavailability,
highly fat soluble,
stored in RE cells and skin

C/Use: m leprae (in combo)N,5-bis(4chlorophenyl)-3propan-2-yliminophenazin-2-amine

C27H22Cl2N4

(100mg/d)
Multibacillary Leprosy
(Dapsone + Rifampicin +
Clofazimine)

Adverse effects:
red/black skin discoloration
GI upsets

Principles of Therapy

Combination therapy
Delay emergence of resistance
Enhance efficacy
Reduce toxicity

Describe:
Resistance mechanisms of antimycobacterial drugs
E.g. Deletion of katG gene, inhA gene with resistance
to INH, mutation of emb gene; etc
Combination regimens
Ref: UCG (current edition)
Directly observed therapy (DOT) regimens

REFERENCES
Lippincotts illustrated review
pharmacology 4th edition.
B G Katzung 10th edition

THANKS

A Regional University Transcending Boundaries