Chemotherapeutics •
&•
antibiotics •
Chemotherapeutics
Chemicals which are used within the body •
tissues to kill or inhibit the growth of
pathogenic organisms
The Spectrum of antimicrobial
Activity
**it is easy to find or develop drugs that •
effective against prokaryotic cells ,& that
do not affect the eukaryotic cells of
humans
**the problem is difficult when the •
pathogen is eukaryotic (fungus,
protozoan, helminthes)
**viral infection more difficult to treat •
The Spectrum of antimicrobial
Activity
Prok.**-differ in cell wall •
-differ in fine structure of their •
ribosome
-details of their metabolism •
Euk.**resemble the human cell •
**the virus is within the human cells •
antibiotics
Antibiotics=are a metabolic products or a
constituent of a microorganism which kills or
inhibit the growth of another microorganism
Nowadays used are semi synthetic (Ampicillin)
synthetic (Sulfa drugs) or
(produced wholly or partly by chemical synthesis)
Low concentrations inhibit the growth of m.o.
7
Characteristics of a good chemotherapeutic
or antibiotic
1-it must kill or inhibit the growth of the pathogenic organism
2-it must cause no damage to the host (it must have
•
selective
•
toxicity)
3-it must cause no allergic reaction
•
4-it must be stable in solid or dissolved state
•
5-it must remain in the desired tissue for the sufficient length of time
(pharmacokinetics)
6- it must kill the pathogenic organism
becomes resistant to the drug
quickly before it mutates and
•
•
Pharmacokinetics have to be desirable •
(absorption, disintegration)
selective toxicity = toxic for the •
pathogenic organism and not toxic for the
host == defined by the therapeutic index
max. tolerated dose (toxic to the host) •
-------------------------------------------------------------- •
min. curative dose (effective therapeutic dose) •
The high the therapeutic index the better the •
antibiotic is
Drug Dosage (per Kg Body Weight)
Therapeutic Index = Toxic Dose/Therapeutic Dose
Small Ratio
(dangerous)
Moderate
Ratio
High Ratio
(safe)
Most
desirable.
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Antibiotics activity
The Spectrum of antimicrobial
Activity
Narrow spectrum = affect only select group
of microorganisms
e.g Penicillin Gaffects
Gram positive bacteria
•
•
Broad spectrum = affect a broad range of •
Gram positive or
Gram
negative bacteria
= affect a more diverse •
range of microbes
•
e.g. Chloramphenicol.
Antibiotics activity
The type of activity
Bactericidal : direct killing of microorganisms •
= kill microorganisms directly •
(Streptomycin) •
Bacteriostatic = inhibit their growth •
= prevent microorganism •
from growth (chloramphenicol) •
#*#* =Host defenses usually destroy
microorganisms by phagocytosis & antibody
production
Combination of •
Mechanisms of Antimicrobial
Action
• Bacteria have their own enzymes for
– Cell wall formation
– Protein synthesis
– DNA replication
– plasma membrane
– Synthesis of essential metabolites
17
Bacterial protein synthesis inhibitors
## initiation of protein synthesis •
## elongation (=interfere with elongation factors) •
Fusidic acid
Bacteriostatic
Gm+ve bacteria only
initiation of protein synthesis inhibitors
Antimicrobial that bind to
the 50S ribosomal subunit
Antimicrobial that bind to the
30S ribosomal subunit
bacteriostatic
Aminoglycosides
Chloramphenicol –
Tetracyclines
broad rang
bacteriostatic
Lincomycin
Clindamycin
Restricted range
Macrolides
Gm+ve bacteria &
Mycoplasma
Erythromycin
broad
spectrum
Tetracyclin,
Minocycline
Doxycycline
Bactericidal
Many gm.-ve
bacteria &some
gm+ve. Bacteria
Streptomycin
Kanamycin
Gentamycin
Neomycin
Tobramycin
Inhibitors of nucleic acid synthesis & function
Inhibitors of RNA
Inhibitors of DNA
(DNA dependent RNA
polymerase)
(DNA gyrase)
Rifampin
Quinolones
Rifamycin
Nalidixic acid
Rifampicin
Ciprofloxacin
Bactericidal
Bactericidal
Wide spectrum
Tuberculosis
Gm+ve bacteria
urinary tract infection
Bacterial cell wall synthesis inhibitors •
Bacterial cell wall synthesis
inhibitors (bactericidal)
penicillins
Bactericidal •
Narrow range •
Effected by Stomach •
acidity=intramuscularly
Susceptible to penicillinase (b •
lactamase) = are enzymes produced by
many bacteria (Staph.) that clave the b
lactam ring
•
Methicillin •
Oxacillin •
Ampicillin & amoxacillin & •
Mezlocillin=broad spectrum
Carbapenems & Monobactam =broad •
• Cephalosporins=gm-ve
• Vancomycin Bacitracin =gm+ve
++ anti mycobacterial agents •
Mycobacterium tuberculosis •
• Antibiotics that interfere with mycolic acid
synthesis or incorporation
– Isoniazid (INH)
– Administerd simultaneously with other
drug (rifampin=rifampicin)
Plasma membrane= phospholipids & •
protein
Polymixin B interfere with phospholipids •
of plasma membrane
Bactericidal •
Gm. – ve bacteria •
Antimetabolite antimicrobials
++ Inhibitors of folic acid synthesis •
(bacteria cannot use pre-formed folic acid, they •
synthesize their own folic acid)
bacteriostatic
antifungal •
Antifungal chemotherapeutics
Fungi are Eukaryotes •
They may be unicellular ( yeast) or •
multicellular (mold).
Cell wall compose of chitin •
Sterols in plasma membrane = ergosterol •
Antifungals
Macrolide Polyenes
Amphotericin B –mimic lipids, most
versatile & effective, topical & systemic
treatments
Nystatin – topical treatment
Azole •
Synthetic azoles – broad-spectrum; •
ketoconazole, clotrimazole, miconazole
(topical treatment of athlets foot)
Allylamine •
Recently developed antifungal=inhibit •
ergosterols
Antifungal drugs
• Flucytosine – analog of cytosine;
coetaneous mycoses or in combination
with amphotericin B for systemic
mycoses
• **interfere with RNA biosynthesis
44
Antiviral drugs •
Antiviral drugs
Attachment •
Penetration •
Uncoating •
Nucleic acid synthesis (polymerases inhibitors) •
Assembly •
release •
Nucleoside & nucleotide analoges •
(acyclovir, ribavirin, lamavudine) •
Lamavudine ==nucleoside analog=cytidine •
Hepatitis B virus •
Reverse transcriptase inhibitor==HIV •
Antiviral drugs
Acyclovair=Zovirax=acycloguanosine=ACV
Guanosine analogus
**Herpes simplex virus infection
(Genital, oral & eye)
**varicilla zoster virus
(Shingles & Chickenpox in immunocompromised
patients)
###viral thymidine kinase phosphorelate the drug
==this inactivate DNA polymerase
@@activity only inside virally infected cells@@
Ribavirin==guanosin analoge •
stop viral RNA synthesis & mRNA •
===nucleoside inhibitor •
***hepatitis C virus •
***respiratory syncytial virus •
Amantadine ==symmetrel •
***uncoating of influenza virus •
Tamiflue…..neuraminidase •
HIV inhibitors •
Reveres transcriptase enzyme •
inhibitors=retrovirus= nucleoside analoge
Protease inhibitors •
(Indinavir, saquinavir, ritonavir) •
Zidovidine=rv.tr. inhibitor •
Antiviral Drugs
Interferon=protein(cytokines) produced by
virally infected cells, that inhibit spread of
the virus & protect other cells
***by the activation of the cell to produce
certain enzyme
==prevent viral protein
synthesis
==kill virally infected cells
==the same way in which cancer
cells be killed (cancers)
• (Viral hepatitis)
52
Anti protozoa chemotherapeutics•
Protozoa are unicellular Eukaryotic microbes •
Have variety of shapes, •
Lives free or as parasite •
They absorb or ingest organic compounds from •
their environment
Anti malaria •
Malaria is an entirely preventable & •
treatable disease
treatment==rapid & complete •
elimination of the parasite ------chronic
& anemia
prevention== of the spread & emerging •
resistance
Drugs used for malaria prophylaxis can
work in one of three ways:
Kill parasites in the liver
Causal prophylaxis
primaquine ++++
malarone ++
Mosquito
Human
Kill sexual parasites
(gametocytes) in RBCs
Gametocytocidal
prophylaxis
primaquine ++++
Kill asexual parasites in RBCs
Suppressive prophylaxis
chloroquine ++++
malarone ++++
mefloquine ++++
doxycycline ++++
56
Antihelminthic Drugs
Praziquantel
Albendazole
Surgery
57
• Helminths are
macroscopic
multicellular
eukaryotic
organisms:
tapeworms,
roundworms,
pinworms,
hookworms
Clinical uses of antimicrobial
drugs
Clinical uses of antimicrobial
drugs
Inappropriate Antimicrobial Use •
 Prescription not taken correctly
 Antibiotics for viral infections
 Antibiotics sold without medical supervision
 Spread of resistant microbes in hospitals due to lack of
hygiene
Proper selection of antimicrobial agent is based on a
number of factors
**-the identity of the pathogen •
**-potential toxicity to the patient •
**-pharmacokinetics & pharmacodynamics of •
the agent
**-site of infection •
**-rout of administration •
**-drug resistance •
**-possible drug interaction •
**-host factors •
**-cost •
Drug selection should be based on it’s •
activity against infecting pathogen
pathogen may be predictably susceptible •
to a particular drug
Therefore lab. guidance is essential for •
safe prescribing
Culture & sensitivity test •
Susceptibility Tests
(cont’d)
Agar diffusion = disk-diffusion test
 Kirby-Bauer Disk Diffusion Test
Sensitive
Intermediate
resistant
62
Minimal Inhibitory Concentration (MIC)=the lowest
concentration of drug capable of preventing bacterial growth
vs.
Minimal Bactericidal Concentration (MBC)=the
lowest concentration of chemotherapeutic agent that kills bacteria
32 ug/ml
16 ug/ml
8 ug/ml
Sub-culture to agar medium
4 ug/ml
2 ug/ml
1 ug/ml
MIC = 8 ug/ml
MBC = 16 ug/ml
Minimum inhibitory concentration •
(MIC)
is determined when •
**a patient does not respond to treatment •
**thought to be adequate, •
**relapses while being treated •
.**when there is immunosuppression •
Host factors play an important part in proper
selection of antimicrobial drug
**-age •
**-circulating & tissue phagocyte activity •
e.g. hematological malignancy=acute •
leukemia
Bactericidal= amino glycosides •
broad spectrum penicillins •
cephalosporin •
quinolones •
Pharmacological factors
By achieving satisfactory drug concentration at the site
of infection
Standard pharmacokinetics =absorption •
distribution •
metabolism •
excretion •
Oral---- G.I. absorption should be satisfactory •
interaction with food •
vomiting (surgery) •
***Parenteral agent will be required •
•
Site of infection
---lipid solubility of the drug •
Amino glycosides are poorly lipid –soluble •
=penetrate CSF poorly (bacterial meningitis)
Meningeal inflammation also affect drug •
penetration into the tissues
Beta-lactam agents achieve satisfactory •
concentration within CSF but the
inflammation subsides drug concentration
super infection
Normal flora (skin & mucous membrane) •
Microbial overgrowth of resistant pathogen •
Oral & vaginal candidiasis •
Broad spactrum-(ampicillin or tetracycline) •
Pseudo-membranous colitis •
Toxin-producing strain of clostridium •
Following the use of clindamycin •
Managed by oral vancomycin •
surgery •
Proper selection of antimicrobial agent is based on a
number of factors
**-the identity of the pathogen •
**-potential toxicity to the patient •
**-pharmacokinetics & pharmacodynamics of •
the agent
**-site of infection •
**-rout of administration •
**-drug resistance •
**-possible drug interaction •
**-host factors •
**-cost •
Drug resistance
Intrinsic= inherent properties of bac. are •
responsible for preventing antibiotic action
==always chromosomally mediated
0r •
Acquired= occurs when bac. which were •
previously susceptible then become resistance
== occur by mutation in the chromosome or by •
acquisition of genes coding for resistance from
external source (plasmid)
Plasmid mediated resistance has been •
recognized among Gm.-ve bact.== can
code for multiple resistant
##cephalosporins, chloromphinicol, amino
glycosides
==enzymatic inactivation •
hospitals & intensive care units •
Multi-drug resistance
Methicillin resistant Staph.aureus (MRSA) •
=resist to many antibiotics •
Hospitals, intensive care units, burn •
,cardiothoracic units
Glycopeptides , vancomycin •
Mechanisms of Antibiotic
Resistance
Enzymatic destruction of drug
(B lactamase) Drug inactivation – penicillinases
Prevention of penetration of drug
to its target site within the bacteria
(tetracycline resistance) Decreased permeability
to drug or increased elimination of drug from cell
74
Mechanisms of Antibiotic
Resistance
Alteration of drug's target site(a.a
changes in the ribosome) Change in
metabolic patterns
Rapid ejection of the drug
Change in drug receptors
Efflux pump= antibiotic is rapidly extracted from •
the cell by an energy-dependent mechanism
( tetracyclines & macrolides)
++ Inpaired cell wall or cell envelope •
penetration
++ Enzymatic inactivation •
++ Altered binding sites •
++ Efflux pump= antibiotic is rapidly
•
extracted from the cell by an energy-dependent
mechanism( tetracyclines & macrolides)
What Factors Promote Antimicrobial
Resistance?
Exposure to sub-optimal levels of
antimicrobial
Exposure to microbes carrying
resistance genes
79
To lower Antimicrobial Resistance
Development
• Use more narrow spectrum antibiotics
• Use antimicrobial cocktails
Effects of combinations of drugs
• Synergism
Penicillin and streptomycin, Sulfa and trimethoprim
• Antagonism
Penicillin and tetracycline
•
80
Addition
Combination of Drugs
 For antibiotics “A” and “B” used in combination:
81
 Actual killing rate = A + B  Additive
 Actual killing rate > A + B  Synergistic
 Actual killing rate < A + B  Antagonistic
 Typically bacteriostatic agents are antagonistic to
bactericidal agents.
 Bacteriocidal agents can be synergistic (think of the latter
as one antibiotic weakens more bacteria than it kills,
making the not-killed bacteria more susceptible to
additional insult by the second antibiotic).
 Additive means that the two (or more) antibiotics neither
hinder nor help each other’s ability to kill.
 Also relevant to rates of mutation to resistance.
Second term exam. •
Good luck •