2. Outline
• Introduction/ history of chemotherapy
• Basic terminologies
• General classification of chemotherapeutic agents
• Antiseptics and disinfectants
• Assignments
3. History of chemotherapy
Chemotherapy refers to the use of Chemicals
(drugs) to treat cancer and microbial infections.
Before the discovery of antimicrobial agents,
large number of people always died from
common illnesses.
Now many illnesses are easily treated with
antimicrobials.
However, many antimicrobial drugs are becoming
less useful due to dev’t of resistance.
4. History cont’d
• Ancient Egyptians, the Chinese, and Indians of
central America all used molds to treat infected
wounds. However, they did not understand the
connection of the antibacterial properties of
mold and the treatment of diseases
• ?? S. American Indians Chewed bark of cinchona
tree ----> malarial fever(Plasmodium spp.);
• Wore sandals furry with mould -----> foot
infections
• ~ 1630 Europeans used Quinine (bark of
cinchona) -----> malaria (Plasmodium spp.)
5. History cont’d
• Louis Pasteur Identified bacteria as causative agent of disease towards the
end of the 19th century
• Robert Koch (Germ theory) proposed that since the germs are the ones that
cause diseases, then we need to find out how to stop them.
• In 1877 Pasteur discovered that Soil bacteria injected into animals made
Anthrax harmless.
• In 1888 de Freudenreich Isolated product from bacteria with antibacterial
properties but were toxic and unstable.
• 1910 Paul Ehrlich observed that certain dyes stain bacterial cells and not
animal cells.
He suggested that these could be used to harm bacterial cells but not
human cells.
Thru Systematic search, he discovered a chemical that could be used to cure
syphilis.
• 1928 –Alexander Fleming discovered penicillin, produced by Penicillium
6. History cont’d
• 1935 G. Domagk discovered protocol ( sulphonamide) with a broad
range of antimicrobial activities.
• 1939 Rene Dubos Isolated gramicidin and tyrocidin from Bacillus
brevis; Active against gram positive bacteria
• 1942 The manufacturing process for Penicillin G Procaine was
invented by Howard Florey and Ernst Chain .Penicillin could now be
sold as a drug.
• Fleming, Florey, and Chain shared the 1945 Nobel Prize for
medicine for their work on penicillin.
• In 1943, American microbiologist Selman Waksman made the drug
streptomycin from soil bacteria, the first of a new class of drugs
called aminoglycosides. Streptomycin could treat diseases like
tuberculosis, however, the side effects were often too severe.
• By 1945 Pharmacologists had 5488 derivatives of sulfanilamide
(sulfonamides).
• Since 1950, new classes of antimicrobial agents have been
discovered
9. Basic terminologies
• Chemotherapy- refers to the use of Chemicals (drugs) to
treat cancer and microbial infections.
• Chemotherapeutic agent/ drug – refers to any chemical used
in the treatment, relief and prophylaxis of a disease.
• Prophylaxis- refers to the use of a drug to prevent the
potential for infection of a person at risk.
• Microbial infection – any disease or disorder caused by a
microorganism. Eg bacterial infection, viral, fungal, protozoal
infections etc
• Antimicrobial agent- any chemical substance that can kill or
inhibit growth of micro- organism regardless of its origin.
• Antibiotic - any chemical substance produced by natural
metabolic processes of some microorganisms that can kill or
inhibit the growth of other microorganisms.
• Natural drugs- these are chemical substances from biological
origin that are used to treat infections in their unchanged
form. Eg natural penicillins
10. Terminologies continued
• Semisynthetic drugs- chemical substances from biological origin that are
used to treat infections when modified in the lab after being isolated from
their natural sources
• Synthetic drugs - chemical substances that are used to treat infections
when completely manufactured from the lab.
• Spectrum – refers to the range of microorganisms a given drug can
effectively kill or control. a broad spectrum antibiotic is the one which is
effective against a wide variety of microbial types e.g both gram positive
and gram negative bacteria while a narrow spectrum antibiotic is effective
against a limited array of microbial types e.g gram positive bacteria only or
gram negative bacteria only.
• Bactericidal drug – a drug that kills the bacterium
• Bacteriostatic drug – a drug that inhibits the growth of the bacterium
• Drug Resistance – the decrease in the effectiveness of a drug in treatment
of a given infection as a result of the causative microorganism developing
mechanisms that shield it from the toxic effects of the drug.
• Therapeutic index – the ratio of the lethal dose to the effective dose of a
drug. It is ameasure of the relative toxicity of the drug.
• Selectivity - - ability of a drug to kill harmful microbes without destroying
host cells
15. Antiseptics and disinfectants
An antiseptic is a chemical substance that is capable of destroying
or preventing microorganisms on open surfaces of living tissues
(animate) thus limiting or preventing their harmful effects of
infection. Examples of antiseptics include; iodine, ethanol,
chlorhexidine.
A disinfectant is a chemical substance that is capable killing and
removing microorganisms, including potentially pathogenic ones
from the surfaces of inanimate objects. It does not only bring about
killing of microorganisms, but also reducing them to a level
acceptable for a defined purpose, for example, a level which is
neither harmful to health nor to the quality of perishable goods.
Examples of disinfectant include; formaldehyde, chlorine,
hypochlorite etc
16. Ideal properties of an antiseptic and a
disinfectant
• Should have a broad spectrum activity killing a wide range of
microorganisms.
• Should be selectively toxic to the microorganism but non toxic to the human
cells( large selectivity index)
• Should be highly stable under different physical conditions like PH,
temperature other chemicals.
• Should be toxic to the microorganisms capable of killing even resistant
strains( low lethal dose)
• Sldnt induce allergic reactions to the human tissues
• Should be Cheap to buy, available and easy to use.
• Should not cause irritations to the human eye and skin
• Should be non-corrosive to the skin for convenient usage.
• Should act rapidly bringing its lethal action on all forms of micro-organisms
in a short period of time.
• Does not lead to development of antimicrobial resistant forms.
• Remain active for a long period of time so as to kill microorganisms
17. Check points
All antiseptics are disinfectants!!!!!!!
NO
All disinfectants are antiseptics!!!!!!!!!!
Which one is correct?
18. Assignment
• Instructions:
-to be handed in the next lecture
- should not exceed 2 pages
Questions :
a)Describe the detailed structure of a bacterium
cell.
b) Distinguish between Gram positive and gram
negative bacteria and give examples of each.
c) Outline the different chemical classes of
antibacterial compounds giving two common
examples of each used in your local setting.
19. ANTIBACTERIAL AGENTS
OUTLINE
Review of the bacterial structure and
classification
Review of the various bacteria and their
infections
Classification of antibacterial agents
Discussion of each class (sub classes / examples,
mechanism of action, resistance, side effections
indications & contraindications)
20. Review- bacterial structure
Is an example of Prokaryotic cells (lack a true nucleus ).
The DNA (genetic material) is dispersed within the cytoplasm
(due to the absence of a nuclear membrane)
The DNA is one long chromosome that is highly folded
(nucleoid).
No membrane bound organelles.
Has a cell surface membrane that encloses cytoplasm that
contains enzymes, ribosome, food granules and in same species
additional circular pieces of genetic material(plasmids).
All posses mesosome
Parasitic forms lack chlorophyll
Externally, the cell membrane is enclosed by a cell wall made up
of peptidoglycan
Some have flagella for locomotion
Others have a slimy layer (capsule)
22. Gram positive and gram negative
bacteria
• Both gram-positive and gram-negative bacteria
have a cell wall made up of peptidoglycan and a
phospholipid bilayer with membrane-spanning
proteins.
• However, gram-negative bacteria have a unique
outer membrane, a thinner layer of
peptidoglycan, and a periplasmic space between
the cell wall and the membrane.
• In the outer membrane, gram-negative bacteria
have lipopolysaccharides (LPS), porin channels,
and murein lipoprotein all which are absent in
gram-positive bacteria.
• LPS, blocks antibiotics, dyes, and detergents
protecting the sensitive inner membrane and cell
wall.
• Thus gram-negative cells are more difficult to
destroy eg they are resistant to lysozyme and
penicillin attack.
23. Check point
Put + for gram positive and – for gram negative
on the following bacteria:
S. aureus E. coli Neisseria
Spirochetes pseudomonas Enterococcus
MRSA V. Cholera S. typhi
28. b) Basing on the chemical nature
Class Mechanism of action Examples
β-lactams Inhibit bacteria cell
wall synthesis
Penicillins,
cephalosporins,
bacitracin,
monobactams
Quinolones Inhibit bacterial nucleic
acid synthesis
Nalidixicacid,
ciprofloxacin
Aminoglycosides Inhibit protein
synthesis
gentamicin,
tobramycin, amikacin,
netilmicin, kanamycin,
streptomycin, and
neomycin
sulfonamides Inhibit metabolic
pathway ( folate
metabolism)
trimethoprim and
sulfamethoxazole
Heterocyclic
compounds containing
nitrogen
Disruption of cell
membrane function
Polymyxins
Tetracyclines Inhibit protein
synthesis by binding to
Chlortetracycline
Oxytetracycline
29. Cell wall synthesis inhibitors
1. B- lactams
These prevent the synthesis of bacterial cell wall (peptidoglycan
layer) by interfearing with the cross linkages of the peptides
to the carbohydrate molecules.
This results into weakened cell walls and eventually the
bacterium lyses and hence bactericidal.
Thus , effective only on growing bacteria.
The functional unit is the B- lactam ring that binds to the enzyme
that cross links the NAM subunits. This prevents the growth
of the bacteria.
Examples include: penicillins, cephalosporins, monobactams,
vancomycin, carbapenems, bacitracin
31. Resistance to B- lactams
• The bacteria that are resistant secrete an
enzyme B-lactamase that hydrolyses the B-
lactam ring
32. Penicillins
• The most widely effective and least
toxic drugs known.
• But increased resistance has limited
their use.
• Members of this family differ from one
another in the R substituent attached
to the 6-aminopenicillanic acid
residue.
• The nature of this side chain affects
the antimicrobial spectrum, stability to
stomach acid, cross-hypersensitivity,
and susceptibility to bacterial
degradative enzymes (β-
lactamases).
33. Classification of penicillins
a) Basing on source
1. natural penicillins eg penicillin G and penicillin v
2. Semi- synthetic penicillins eg methicillin,
oxacillin, cloxacillin,ampicillin, amoxicillin etc
3. synthetic penicillin
b) Basing on spectrum
1. narrow spectrum peinicllins eg pen G & pen V
2.Effective against gram + bacteria and some few
non secreting B- lactamases
(penicillinases)
34. 2. Antistaphylococcal Penicillins (eg, Nafcillin, methicillin,
oxacillin)
These penicillins are resistant to staphylococcal -lactamases.
They are active against staphylococci and streptococci but not
against enterococci, anaerobic bacteria, and gram-negative
cocci and rods.
3. Extended-Spectrum Penicillins (Ampicillin,amoxicillin,
amoxiclav and the Antipseudomonal Penicillins)
These drugs are effective against both gram positive and
gram-negative organisms. Like penicillin, however, they are
relatively susceptible to hydrolysis by B -lactamases.
35. Mechanism of action
• The penicillins interfere with the last step of bacterial
cell wall synthesis(transpeptidation or cross-linkage),
resulting in exposure of the osmotically less stable
membrane.
• Cell lysis can then occur, either through osmotic
pressure or through the activation of autolysins.
• Penicillins target various proteins on the bacterial cell
membrane especially the penicillin-binding proteins
(PBPs) are bacterial enzymes that catalyse the
crosslinking of the peptides so as to form the
peptidoglycan layer.
36. Resistance to penicillins
1. Inactivation of antibiotic by B–lactamase
(most common mechanism)
2. Modification of target PBPs thru mutations
eg MRSA which has altered PBP with reduced
affinity
3. Impaired penetration of drug to target PBP
eg gram negative bacteria due to the
impermeable outer layer and in gram
positive absence of porins.
4. Efflux pumps which continously pump out
the antibiotic .
37. Pk of penicillins
• Can be orally or parentally administered
• Varied absorption after oral administartion eg Pen G poorly
absorbed while pen V well absorbed. Absorption depends on
the nature of the R- group.
• Absorption interfeared by food . To be taken 2hrs before or
after meal
• Protein binding varies from drug to drug but insignificant. Well
distributed.
• Doesnot readiy cross the BBB but when the meninges are
greatyly inflammed it crosses
• Mainly excreted by the kidney but also thru bile and breast
milk
• Have ahigh therapeutic index and hence safe
38. Indications (clinical uses)
• Pneumonia
• Meningitis
• UTI
• Typhoid
Side effects
Hypersensitvity like skin rash (cross reactive &
cross sensitive)
Hepatitis
Cuases seizures in patients with impaired renal
function
39. Penicillins and aminoglycosides
(synergism)
• Because penicillins alter the permeability of
bacterial cells, these drugs can facilitate the
entry of other antibiotics (such as
aminoglycosides) that might not ordinarily
gain access to intracellular target sites.
• This can result in enhanced antimicrobial
activity and hence synergism.
40. Group work
1.By visiting the training hospital or
otherwise, outline the different penicillins that
are in clinical practices and their indications.
why are they falling out of favors?
2. classify the different cephalosporins in
clinical practice basing on their generation.
N.B Groups to present in the next lecture theirs
findings.
41. Cephalosporins
• Resemble penicllins in their mode of action
• Differ in the ring attached to the b-lactam ring
Classification: Classified into generations basing on
spectrum of activity
1. First-generation cephalosporins (cefadroxil, cefazolin,
cephalexin, cephalothin, cephapirin, and cephradin)
• very active against gram-positive cocci, such as pneumococci, st
reptococci, and staphylococci.
• Not active against MRSA, E coli, K pneumoniae, P. aerugi
nosa, proteus, enterobacter, Serratia marcescens, citro
bacter, and acinetobacter.
N.B Cefazolin is the only first-generation parenteral
cephalosporin still in general use
42. SECOND-GENERATION CEPHALOSPORINS
Examples include cefaclor,cefamandole, cefonicid,
cefuroxime, cefprozil, loracarbef, and ceforanide and the
structurally related cephamycins cefoxitin, cefmetazole, and
cefotetan, which have activity against anaerobes.
This is a heterogeneous group of drugs with marked individual
differences in activity, pharmacokinetics, and toxicity.
In general, they are active against organisms inhibited by
first-generation drugs, but in addition they have extended
gram-negative coverage.
Cefamandole, cefuroxime, cefonicid, ceforanide, and cefaclor
are active against H influenzae but not against serratia or B
fragilis.
As with first-generation agents, none is active against
enterococci or P. aeruginosa
43. THIRD-GENERATION CEPHALOSPORINS
• cefoperazone, cefotaxime, ceftazidime, ceftizoxime, ceftriaxon
e, cefixime, cefpodoxime proxetil, cefdinir, cefditoren pivoxil, c
eftibuten, and moxalactam.
• have expanded gram-negative coverage.
• some are able to cross the blood-brain barrier.
• active against citrobacter, S marcescens, and providencia
• Also effective against b-lactamase-producing strains of haemop
hilus and neisseria.
• Ceftazidime and cefoperazone are the only two drugs with usef
ul activity against P aeruginosa.
• Not reliably active against enterobacter species, Serratia, provid
encia, and citrobacter.
44. FOURTH-GENERATION CEPHALOSPORINS
• Cefepime is an example of a so-called fourth-generation cep
halosporin.
• It is more resistant to hydrolysis by chromosomal B -lactamas
es (eg, those produced by enterobacter).
• It has good activity against P aeruginosa, Enterobacteriaceae,
S aureus, and S pneumoniae, MRSA, haemophilus and neisser
ia.
• Useful in treatment of enterobacter infections
• It penetrates well into cerebrospinal fluid.
45. GENERAL PK
• May be given orally or parentally but mostly parentall
y due to poor absorption
• Variable absorption after oral admin
• Well distributed to various body fluids
• Metabolism not significant
• Excreted thru glomerular filtration and bile
• Dose adjustement basing on PK and age
Indications (clinical use)
• UTIs
• Systemic infections
46. Adverse effects
• Allergy
• Nephrotoxicity
• Severe pain
• Thrombophlebitis (inflammation of the veins)
contraindications
Alcoholics
Renal dysfunction
Allergic patients
47. Other cell wall synthesis inhibitors
• Vancomycin: hinders peptidoglycan elongation by
Interfere with particular bridges that link NAM
subunits in many Gram-positives.
• Cycloserine: inhibits the formation of the basic pep
tidoglycan subunits. causes serious CNS effects
• Bacitracin
Blocks transportation of NAG and NAM subunits
from cytoplasm to the growing peptidoglycan.
Highly nephrotoxic and given only topically
• Isoniazid and ethambutol
Disrupt mycolic acid formation in mycobacterium
48. • Monobactams are drugs with a monocyclic b-l
actam ring.
• They are relatively resistant to b-lactamases a
nd active against gram-negative rods (includin
g pseudomonas and serratia).
• They have no activity against gram-positive ba
cteria or anaerobes.
• Aztreonam is the only monobactam available i
n the USA
49. BETA-LACTAMASE INHIBITORS (CLAVULANIC ACID,
SULBACTAM,& TAZOBACTAM)
• resemble b -lactam molecules but have very weak antibacter
ial action.
• potent inhibitors of many but not all bacterial b -lactamases a
nd can protect hydrolyzable penicillins from inactivation by th
ese enzymes.
• most active against A –lactamases bacteria, staphylococci, H i
nfluenzae, N gonorrhoeae, salmonella, shigella, E coli, and K p
neumoniae.
• Not active against enterobacter, citrobacter, serratia, and pseu
domonas.
• Can be combined with penicillins like amoxiclav
50. Carbapenems
• Carbapenems are structurally related to b-lactam antibiotics .Ertapenem, im
ipenem, and meropenem are licensed for use in the USA.
• Imipenem has a wide spectrum with good activity against many gram-negat
ive rods, including P aeruginosa, gram-positive organisms, and anaerobes.
• It is resistant to most b-lactamases but not metallo- -lactamases. Enterococc
us faecium, MRSA,Clostridium difficile.
• Imipenem is inactivated by dehydropeptidases in renal tubules, resulting in l
ow urinary concentrations. Consequently, it is administered together with a
n inhibitor of renal dehydropeptidase, cilastatin.
• Meropenem is similar to imipenem but has slightly greater activity against g
ram-negative aerobes and slightly less activity against gram-positives.
• It is not significantly degraded by renal dehydropeptidase and does not requ
ire an inhibitor.
• N.B Common side effects are nausea, vomiting, diarrhea, skin rashes, a
nd reactions at the infusion sites.
52. PROTEIN SYTHESIS INHIBITORS
The process of protein synthesis is as below
Bacterial ribosome has 2 parts:
– 30S binds to mRNA to translate mRNA into amino acids,
which form proteins
– 50S required for peptide elongation
3 phases from mRNA to protein
– Initiation
– Elongation
– Termination
53. MECHANISM OF ACTION
• Bind irreversibly to ribosome
• mRNA cannot bind to Ribosome (30S) to form
amino acid chains (polypeptide) or elongate the
chains to form proteins (50S)
• Absence of these functional proteins Disrupts ma
ny essential bacterial functions leading to cell de
ath.
• Examples: Aminoglycosides, Macrolides/Ketolid
es, Tetracyclines, Lincomycins, Chloramphenicol,
Oxazolidinones
57. Group assignment
For each of the classes of protein synthesis
inhibitors , discuss with examples the
mechanism of actions, mechanism of
resistance, general P.K citing exceptions, side
effects, indications and contraindications.
Each group should organize a 5 min
presentation which will be scored out of 10 in
the next lecture.
58. AMINOGLYCOSIDES
• Structurally consist of hexose sugar units ( stre
ptidine or streptamine) linked to amino acids
by glycosidic bonds
• They are water-soluble, stable in solution, and
more active at alkaline than at acid pH.
• Poorly absorbed after oral adininistration
• Active mainly on gram negative bacteria
• Examples streptomycin, neomycin, kanamycin
, amikacin, gentamicin, tobramycin, sisomicin
, netilmicin,
59. MOA
• Bind irreversibly on the 30s ribosomal sub unit
and prevent initiation of translation or cause
misreading of the MRNA . This results into abs
ence of functional bacterial proteins and henc
e cell death.
• Entry of these drugs is energy depedent and t
hus requires oxygen
60. MOR
1) production of a transferase enzyme that inactivates
the aminoglycoside by adenylylation, acetylation, or
phosphorylation.
(2) There is impaired entry of aminoglycoside into the
cell. Due to mutation or deletion of a porin (proteins)
involved in transport and maintenance of the
electrochemical gradient
(3) Alteration in the binding site on the ribosome due
to mutation.
4) Natural resistance by anaerobes
61. General pk
• Mainly administered parentally ( IM and IV)
• Poorly absorbed after oral administration
• Not Well distributed due to the polar nature
• Do not penetrate the BBB
• Metabolism not significant
• Excreted by the kidney
• Have a narrow therapeutic index and thus require TDM
• Given single dose daily (originally three times a day )
• Dosage adjustments must be made to avoid accumulation
of drug and toxicity in patients with renal insufficiency
N.B. Aminoglycoside toxicity is both time- and concentration-
dependent.
62. Adverse effects
• Ototoxicity
• Nephrotoxicity
Indications
Gram negative infections
UTIs
TB – streptomycin
Severe sepsis, meningitis, infected burns and
wounds and pneumonia- Gentamicin
N.B. usually given with cell wall synthesis
inhibitors
64. Tetracyclines
Dicovered in the 1950’s but encountered great resistance
Classified basing on source and duration of action
65. MOA
• Bind reversibly on the 30s ribosomal sub unit
and prevent initiation of translation or cause
misreading of the MRNA . This results into abs
ence of functional bacterial proteins and thus i
nhibit bacterial growth hence bacteriostatic.
• N.B. entry is by passive diffusion and also by e
nergy dependent pumps
66. MOR
(1) Impaired influx or increased efflux by an activ
e transport protein pump;
(2) Ribosome protection due to production of
proteins that interfere with tetracycline
binding to the ribosome;
(3) Enzymatic inactivation.
N.B.Tet(AE) efflux pump-expressing gram-
negative species are resistant to the older
tetracyclines, doxycycline, and minocycline.
They are susceptible, however, to tigecycline,
which is not a substrate of these pumps.
67. General pk
• Can be administered orally and parentally
• Variable absorption after oral admin
• Absorption reduced by food
• Distributed widely to tissues and body fluids
• Metabolism not significant
• Excreted mainly in urine and bile except doxycyclin
e which excreted in feaces.
N.B. Classified as short-acting (6–8 hrs),
intermediate-acting (12 hrs) long-acting (16–18
hrs). Tigecycline( glycylcycline) has a half-life of 36
hrs.
69. Adverse effects
hypersensitivity,Renal toxicity, local tissue
toxicity, photosensitization, GI distress,
discolors teeth, inhibits bone growth in
children, potentially teratogencic,
hepatotoxicity, vestibular toxicity
Contraindication
Pregnant and lactating mothers
Neonates
70.
71. Chloramphenicol
• Potent broad-spectrum drug with unique
nitrobenzene structure
• Blocks peptide bond formation and protein
synthesis
• Only made synthetically today
• Very toxic, restricted uses, can cause
irreversible damage to bone marrow
• Broad-spectrum(Typhoid fever, brain
abscesses, rickettsial, and chlamydial
infections)
72. MOA
• binds reversibly to the 50S subunit of the bact
erial ribosome and inhibits the peptidyl transf
erase step of protein synthesis hence preventi
ng elongation of the growing polypeptide.
• Chloramphenicol is a bacteriostatic broad-spe
ctrum antibiotic that is active against both aer
obic and anaerobic gram-positive and gram-ne
gative organisms.
73. General pk
• well absorbed after oral administration
• Chloramphenicol succinate used for parenteral administration is
highly watersoluble
• distributed into total body water
• excellent penetration into CSF, ocular and joint fluids
• rapidly excreted in urine, 10% as chloramphenicol; 90% as
glucuronide conjugate
• systemic dosage need not be altered in renal insufficiency but mu
st be reduced markedly in hepatic failure
• Newborns less than a week old and premature infants also clear
Chloramphenicol less well, dosage should be reduced at 25 mg/kg/d
74. Indications
1.Typhoid fever but replaced by fluorinated
quinolones.
2.Bacterial meningitis (H.influenza) + penicillin.
3.Topically in eye infections e.g conjunctivitis.
4.Anerobic infections e.g anerobic brain abscess.
• Generally used as drug of last resort for life-t
hreatening infections
75. Adverse effects of chloramphenicol:
1.GIT upset & super infection.
2.Bone marrow depression (dose independent
or idiosyncrasy)- Rare but lethal side effect is
aplastic anemia
3.Gray baby syndrome in neonates.
4.Optic neuritis.
5.Inhibition of hepatic microsomal enzymes that
metabolize several drugs hence undesirable
drug- drug interaction.
76. Macrolides
• Naturally occurring compounds that are end p
roducts of secondary metabolism.
• Mostly extracted from plants, marine organis
ms, ormicroorganisms
• prototype drug is Erythromycin.
• Other examples include Azithromycin,
Clarithromycin,Josamycin,Midecamycin,
Roxithromycin, Spiramycin.
• Ketolides: Telithromycin
77. MOA
• Bind reversibly to 50s unit of the ribosome blocking t
ranslocation of peptides from A-site to P-site of ribos
ome thus preventing elongation of the growing amin
oacid chain.
RESISTANCE:
• reduced permeability of the cell membrane or active
efflux
• Production of esterases that hydrolyze macrolides
• modification of the ribosomal binding site by chromo
somal mutation
78. Erythromycin:
• prototype
• distributed into total body water
• poor CSF penetration
• food interferes with absorption
• serum half life is app. 1.5 h normally and 5 hours in patients w
ith anuria
• not removed by dialysis
• metabolized in the liver
• traverses the placenta and reaches the fetus
N.B. Erythromycin is destroyed by stomach acid and must be
administered with enteric coating.Stearates and esters are
fairly acid-resistant and somewhat better absorbed.
erythromycin estolate is the best-absorbed oral preparation.
79. INDICATIONS
Erythromycin is a drug of choice in
Corynebacterial infections (diphtheria, coryne
bacterial sepsis, erythrasma);
Respiratory, neonatal, ocular, or genital chlam
ydial infections;
Community-acquired pneumonia.
N.B its spectrum of activity includes
pneumococcus, mycoplasma, and legionella.
80. Adverse Effects:
- GIT dysfunction,
- intrahepatic cholestatic jaundice
N.B. Erythromycin metabolites can inhibit
cytochrome p450 enzymes and thus increase
the serum concentrations of theophylline, oral
anticoagulants, cyclosporine and
methylprednisolone;
81.
82. PK
• excellent absorption
• low concentration in CSF
• well bone penetration
• excreted mainly via the liver, bile and urine
• half life is 2.5 hours normally and 6 hours in
patients with anuria
• more toxic than erythromycin
83. Indications
• Clindamycin is more clinically used than Lincomyc
in in :
- prophylaxis of endocarditis in patients with
valvular heart disease
- dental procedures
- most important indication is the treatment of
severe anaerobic infection caused by bacteroides
and other anaerobes that often participate in
mixed infections
- + aminoglycoside or cephalosporin used to treat
penetrating wounds of the abdomen and the gut
85. DNA SYNTHESIS INHIBITORS
These are active against a variety of gram-positive and gram-n
egative bacteria.
They block bacterial DNA synthesis by inhibiting bacterial topo
isomerase II (DNA gyrase) and topoisomerase IV.
Inhibition of DNA gyrase prevents the relaxation of positively s
upercoiled DNA that is required for normal transcription .
Inhibition of topoisomerase IV interferes with separation of re
plicated chromosomal DNA into the respective daughter cells
during cell division.
bactericidal
classes : quinolones and fluoroquinolones.
Examples include: nalidixic acid, ciprofloxacin, norfloxacin, g
atifloxacin, levofloxacin, moxifloxacin, gemifloxacin
86. May be classified into generations
1.First generation: nalidixic acid
2.Second generation : ciprofloxacin
3.Third generation : levifloxacin
4.Fourth generation : moxifloxacin
87. Mechanism of resistance
• Mutations in the bacterial chromosomal genes
encoding DNA gyrase or topoisomerase IV
• Active transport of the drug out of the bacter
ia .
N.B . Cross resistance occurs between members
88. pk
• Well absorbed after oral admin
• Oral absorption impaired by divalent cations i
ncluding those in anti-acids
• Distributed widely in body fluids
• Elimination is by the kidney
• Half lives varies ; forexample
3 hrs- norfloxacin and ciprofloxacin
10 hrs. – pefloxacin
> 10 hrs. – sparfloxacin
Long half life : Levofloxacin, moxifloxacin,
sparfloxacin, trovafloxacin
89. Indications
• UTIs
• Typhoid
• Bone, Joint, and Soft Tissue Infections.
• Respiratory tract infections esp those caused by pseudomonas
and entrobacter (cipro)
• Gastrointestinal and Abdominal Infections
• Sexually Transmitted Diseases.
• Prostatiti
• chlamydial urethritis
• cervicitis
• prophylaxis and treatment of anthrax
• prophylaxis of infection in neutropenic patients
90. Adverse effects
• GIT disturbances (N/V/D)
• Skin rash (Steven Johnson syndrome)
• CNS side effects like headache and dizziness
• Photosensitivity Adverse effects & contraindications of Fluoroquinolones:
• Nephrotoxicity.
• Arthropathy in children less than 18 years.
• Inhibit liver microsomal enzymes → dangerous drug interactiona as ↑ lev
el of theophylline & warfarin.
• Others – insomnia, abn liver function test
• Trovafloxacin – associated rarely with acute hepatitis and hepatic failure
• Tendinitis – may rupture
• N.B. The following drugs were removed from the mrket because of their t
oxicity:
temafloxacin (immune hemolytic anemia), trovafloxacin (hepatotoxicity),
grepafloxacin (cardiotoxicity), and clinafloxacin (phototoxicity).
91. DRUG INTERACTION:
• Theophylline – increase metabolism of theoph
ylline – elevated concentration -seizures
CONTRAINDICATIONS:
• Quinolones are contraindicated in pregnancy,
Nursing mothers & patients less than 18 years
(children) as it may lead to arthropathy.
92.
93. Anti metabolites :
Sulphonamides and trimethoprim
Sulfonamides :
• 1st antibiotic to be used in humans (1932)
• Contain sulphur and are mainly synthetic
• Bacteriostatic, interfere with folic acid pathwa
y
• Examples : sulfadiazine,sulfadoxine, sulfaceta
mide,sulfasalazine and
sulfamethoxazole.
94. Classification
• Classified basing on duration if action into ;
1.Short acting (6-9hrs) e.g Sulfacytine ,
Sulfisoxazole , Sulfamethizole
2. Medium acting (10-12hrs) e.g Sulfadiazine,
Sulfamethoxazole, Sulfapyridine
3. Long Acting (greater 24hrs) e.g Sulfadoxine
95. Mechanism of action:
Inhibits growth by reversibly blocking folic acid sy
nthesis
Sulfonamides are structural analogues of PABA ( a
precursor metabolite in the folic acid pathway)
thus they competitively inhibit dihydropteroate s
ynthase (the first enzyme in the folate pathway) l
eading to inhibition of folic acid synthesis
consequently inhibition of DNA & RNA synthesis
N.B. human cells utilize already formed folic acid
COZ do not make folic acid and are not affected
96. Trimethoprim and Pyrimethamine
Trimethoprim selectively inhibits bacterial dihydrofolic acid re
ductase, which converts dihydrofolic acid to tetrahydrofolic aci
d, a step leading to the synthesis of purines and ultimately to
DNA.
Trimethoprim is about 50,000 times less efficient in inhibition
of mammalian dihydrofolic acid reductase.
Pyrimethamine selectively inhibits dihydrofolic acid reductase
of protozoa compared with that of mammalian cells.
Trimethoprim or pyrimethamine is used in combination with a
sulfonamide to block sequential steps in folate synthesis, resul
ting in marked enhancement (synergism) of the activity of bot
h drugs.
N.B. The combination often is bactericidal, compared with the
bacteriostatic activity of a sulfonamide alone.
98. Mechanism of resistance
Occurs as a result of mutations that:
1. Cause overproduction of PABA
2. Cause production of a folic acid synthesizing
enzyme that has a low affinity for
Sulfonamides
3. Cause a loss of permeability to the
sulfonamides
99. General pk
- 3 major groups:
1. Oral, absorbable
2. Oral, non-absorbable
3. Topical
4. Intravenous Preparation:
Absorbed from stomach and small intestine - distributed widely to tissues and
body fluids (CSF), placenta and fetus
- protein binding 20% to over 90%
- therapeutic concentration – 40-100 ug/ml of blood
- peak blood levels – 2h to 6 h after oral ingestion
- metabolism: glucoronidation or acetylation in liver
- eliminated in urine-mainly by glomerular filtration
100. Oral, Non-absorbable Agents e.g Sulfasalazine
• More effective than soluble sulfonamides or other a
ntimicrobials taken orally in inflammatory bowel dise
ase, ulcerative colitis, enteritis, other inflammatory b
owel disease
• Split by intestinal microflora to yield: Sulfapyridine –
absorbed and may lead to toxic symptoms
N.B. If more than 4 g of sulfasalazine is taken per day
esp. in persons who are slow acetylators 5-
aminosalicylate (5-ASA) – released in colon in high
concentrations & is responsible for anti-
inflammatory effect
101. Indications / clinical uses
1. Urinary tract infection
Sulfisoxazole – 1 gm 4x daily} combined with PHENAZOPYRIDINE
Sulfamethoxazole – 1 g 2-3 x daily } (U.T. anesthetic)
2. Respiratory infections
3. Sinusitis, bronchitis, pneumonia
4. Dysentery
6. Acute Toxoplasmosis
– Sulfadiazine + Pyrimethamine – Synergistic
– Dosage – Sulfadiazine – 1 g 4x daily
– Sulfadiazine + pyrimethamine – 75 mg loading dose ffd by 25 mg OD
– Folinic Acid – administered to minimize bone marrow suppression
7. Eye infection (topical sulfacetamide).
8. Burns (topical silver sulfadiazine).
9. Ulcerative colitis (sulfasalazine).
10. Malaria
- sulfadoxine + pyrimethamine (fansidar) – 2nd line agent in treatment for malaria
102. Adverse effects of sulfonamides
1. Hypersensitivity reactions.
– Cross allergy with the ffg. Carbonic anhydrase inhibitors,
thiazides, furosemide, bumetanide, furosemide, diazoxide,
sulfonylureas, hypoglycemics
2. Urinary tract disturbances: Sulfas may ppt. in urine at neutral
or acid pH -Crystalluria:
Crystalluria & nephrotoxicity due to insoluble metabolite
precipitation and can be avoided by ↑ fluid intake &
alkalinization of urine pH-Crystalluria – treated with sod.
Bicarbonate to alkalinize urine and fluids to maintain
adequate hydration.
103. Adverse effects cont’d
3. Hemopoietic disturbances as granulocytopenia
,thrombocytopenia and hemolytic anemia in patients with
G6PD deficiency - increased risk of kernicterus in newborns
when sulfonamides are taken near the end of pregnancy.
sulfonamides displaces bilirubin from plasma protein → cross
BBB in premature infants→CNS depression.
5. Drug interaction as it ↑ plasma level of oral hypoglycemic &
anticoagulants due to plasma protein displacement.
6. Most common adverse effects: Fever, skin rashes, exfoliative
dermatitis, nausea, vomiting, urticaria, photosensitivity
7. Hematuria
8. Stevens-Johnson Syndrome – uncommon but serious and
potentially fatal type of skin & mucous membrane eruptions
9. Stomatitis
104. Trimethoprim-Sulfamethoxazole
(Co-Trimoxazole)
Combination of sulfamethoxazole (400mg)+ tr
imethoprim(80mg).
Synergistically active antimicrobial agent whic
h blocks two sequential steps in the folate pat
hway in bacteria preventing formation of nucl
eotides: Sulfamethoxazole – competitively in
corporation of PABA into folic acid and Trimet
hoprim inhibits dihydrofolate reductase preve
nting the reduction of dihydrofolate to tetrahy
drofolate
105. Advantages of the combination:
1. Synergestic combination (increases spectrum).
2. More potent.
3. Less and delayed bacterial resistance.
4. Bactericidal & wider spectrum including proteus, salmonella,
shigella, Hemophilus influenza & gonococci.
5. Exhibits selective toxicity for bacteria which must synthesize
their own folic acid.
• Trimethoprim is more potent, more lipid soluble and has a
greater volume of distribution than sulfa drugs
• Penetrates CSF well
• 65-70% of each drug is protein bound
• Eliminated in the urine within 24 h – reduce dose by half if cre
atinine clearance is 15-30 ml/min
106. Therapeutic uses
1.Urinary tract infections,gonococcal urethritis and
prostatitis.
2.Salmonella & shigella infections.
3.Respiratory tract infections due to H. influenza &
pneumococci.
4. Typhoid fever
Adverse effects
• Dermatological effects, GI effects (glossitis, NVD) CNS
disturbances (headache, depression, hallucinations)
Hematologic reactions( aplastic, hemolytic and macr
ocytic anemia, coagulation disorders)Vasculitis, Rena
l impairment or damage.
107. Disrupters of Cell Membranes
Interference with cell membrane integrity
– Few damage cell membrane e.g Polymixn B
– Binds membrane of Gram – cells and alters
permeability Leading to leakage of cellular
contents and and hence cell death.
N.B. Also bind eukaryotic cells but to lesser
extent
– Limits use to topical application
108. Polymyxins (A, B, C, D, and E)
• Obtained from soil bacterium Bacillus polymyxa
• Usually applied topically, often with bacitracin, to treat
skin infections caused by Pseudomonas
• Internally, can cause numbness in the extremities, serious
kidney damage, and respiratory arrest
Polymyxin B
• Group of basic peptides active against Gram (-), bactericidal
• Treatment of serious enteric infections(Pathogenic E. coli, Shigella,
• Enterobacter, Klebsiella and Pseudomonas , not Proteus)
• Poor tissue distribution
• Attach to and disrupt bacterial cell membrane, bind and inactivate
endotoxin
109. Daptomycin
– Approval by FDA September 2003 for treatment of
complicated skin and soft tissue infections
– Mechanism of action: disruption of plasma
membrane function.
– Bacteriocidal against multidrug-resistant, gram-
positive bacteria, Methicillin-resistant Staphylococcus aureus,
Vancomycin-resistant enterococci, Glycopeptide-intermediate and -
resistant S. aureus, Penicillin-resistant Streptococcus pneumoniae
- Fast bacteriocidal action
- Concentration-dependent killing
- Post antibiotic effect
- Once daily dosing & Excreted mainly by kidneys
110. URINARY ANTISEPTICS
Urinary antiseptics (uroseptics) are agents that
exert antibacterial activity in the urine but have
little or no systemic antibacterial effect. Examples
Nitrofurantoin, Fosfomycin Nitroxoline
UTIs can be divided into two;
1. Lower tract infections
• bladder (cystitis)
• urethra (urethritis))
2. Upper tract infections
• ureters and kidneys (pyelonephritis)
111. Complicated UTI
with factors that
predispose
to ascending
bacterial infection.
Uncomplicated UTI
without
abnormality or
impairment of
urine flow.
112. Antibiotic management of Uncomplicated UTIs
LOWER TRACT
First-line therapy
•Sulphamethoxasole/
Trimetoprim
• Fluoroquinolones
• Urinary antiseptics
Second-line therapy
• Penicillins
• Cephalosporins
• Fluoroquinolones
UPPER TRACT
• Penicillins
• Cephalosporins
• Carbapenems
• Fluoroquinolones
(II-IV generations)
• Aminoglycosides
N.B. Urinary antiseptics
used only in the
treatment of lower
urinary tract infections
113. Nitrofurantoin
Antibacterial Spectrum
• High antibacterial activity
E.coli, Staphylococcus, saprophyticus
• Low antibacterial activity
S. aureus,Streptococcus spp,
Klebsiella .
MOA: inhibits bacterial DNA synthesisS
S.E: Alergical reactions: rash, urticaria.
• Pulmonitis and pulmonary fibrosis
• Haemolysis and haemolytic anaemia
in patients with G-6-PD deficiency.
• Colours urine a dark orange-brown.
• • Antagonism with quinolones.
114. ANTIMYCOBACTERIAL AGENTS
• Tuberculosis (TB) is a chronic infectious disease killing about 2 million peopl
e globally and about 27000 people in Uganda every year (WHO, 2011).
• The situation is escalated by co-infection with HIV among TB patients with 5
0 % of the HIV patients having TB (Copp, 2003).
• TB is caused by Mycobacterium tuberculosis which is a slowly growing and h
ealing bacillus. It mainly affects the respiratory system (pulmonary / infectio
us TB) but also affects other organs (non-infectious TB).
• The bacteria possess a unique cell wall made up of mycolic acid and arabino
galactan responsible for many of the medically challenging physiological cha
racteristics of tuberculosis, including resistance to antibiotics and host defe
nse mechanisms (Copp, 2003).
• It is transmitted from person to person via cough droplets from people wit
h the active respiratory disease (WHO, 2011).
• Management of TB has become a serious problem due to development of
multidrug Resistant TB and extensively drug Resistant TB (Pauli et al., 2005).
115. TREATMENT OF TB
TREATMENT CONCERNS
• Anti-tuberculous drugs
• DOT (Directly observed therapy)
• Multi-drug resistant tuberculosis
• Combination therapy
• Long duration of treatment
FIRST LINE ANTI-TB:
Isoniazid,Rifampicin,Pyrazinamide, Ethambutol.
SECOND-LINE DRUGS: Streptomycin,Capreomycin,
Clarithromycin,Ciprofloxacin and cycloserine.
116. TREATMENT OF TB
Currently susceptible TB is treated with multiple drugs to a
void drug resistance and to increase therapeutic outcome i
n two phases for six months.
An intensive phase during which four drugs are given for t
wo months (rifampicin, isoniazid, pyrazinamide, and etham
butol or streptomycin) FIRST LINE THERAPY.
The continuation phase involves giving two drugs for four
months (isoniazid and rifampicin).
This long period of treatment reduces compliance and adh
erence to treatment (Camacho-corona et al., 2008).
This has promoted the development of multi drug resistant
TB which is expensive to treat (Pauli et al., 2005) and exten
sively drug resistant TB which is virtually untreatable.
117. MDR TB is a form of TB which is resistant to two of the
first line anti TB drugs rifampicin and isoniazid.
XDR TB is a form of TB resistant to all the first line drugs
which are safe, two of the injectable second line drugs
and atleast one fluoroquinolone
MDR-TB is an increasing global problem, with most cases
arising from a mixture of physician error and patient
non-compliance during treatment of susceptible TB
TB Prevention
• Role of immunization -BCG (bacillus Calmette Guerin)
• Improved social conditions- housing /nutrition
• Case detection & treatment
• Contact tracing
• Evidence of infection / disease
• Treatment of infected / diseased contacts
