this slides includes overview of antimicrobial drugs, their classifications, antimicrobial resistance, adverse effects and toxicity, choice of antimicrobial drugs and its uses

1. ANTI MICROBIAL AGENTS
Name: Sanjog Bam

2. INTRODUCTION
• Antimicrobial drugs are the greatest contribution of the
20th century to therapeutics.
• Antimicrobials are designed to kill/inhibit the infecting
organism and to have no/ minimal effects on the recipient.
• The basis of selective microbial toxicity is the action of
drugs on the component of microbes or metabolic process(
folate synthesis), or high affinity for microbes biomolecules
(dihydrofolate reductase).
• Antibiotics: These are substances produced by
microorganisms, which selectively suppress the growth of
or kill other microorganisms at very low concentration.
• Above definition excludes other natural substances which
also inhibit microorganism but are produced by higher
forms(eg: antibodies) or even those produced by microbes
but are needed in high concentrations(ethanol, lactic acid,
hydrogenperoxide)

3. Classification of Antimicrobial drugs
A. On the basis of chemical structure
1. Sulfonamides and related drugs: Sulfadiazine and others and
others, sulfones-Dapsone(DDS), paraaminosalicylic acid
2. Diaminopyrimidines : trimethoprim, pyrimethamines.
3. Quinolones: Nalidixic acids, Norfloxacin, Ciprofloxacin, Gatifloxacin
4. Β-lactam antibiotics: penicillins, cephalosprins,
monobactams,carbapenems
5. Tetracyclines: Oxytetracycline, doxycycline etc
6. Nitrobenzene derivatives: chloramphenicol
7. Aminoglycosides: Streptomycin, gentamicin,neomycin
8. Macrolide antibiotics: erythromycin, clarithromycin, azithromycin
9. Lincosamide antibiotics: lincomycin, clindamycin
10. Glycopeptide antibiotics: vancomycin
11. Oxazolidinone : linezolid
12. Polypeptide antibiotics: polymyxin-B, colistin, bacitracin
13. Nitrofuran derivatives : nitrofurantoin, furazolidone
14. Nitroimidazoles : Metronidazole, tinidazole

4. 15.Nicotinic acid derivates : Isoniazid, pyrazinamide, ethionamide
16. Polyene antibiotics: Nystatin, amphotericin,ethonamide
17. Azole derivatives: miconazole, clotrimazole, ketocanzole, fluconazole
18. others: Rifampin, spectinomycin, sodfusidate, cycloserine, viomycin ,
thioacetazone.
B. Mechanism of action :
1. Inhibits cell wall synthesis: penicillins, cephalsoprins, cycloserine,
vancomycin, Bacitracin
2. Causes leaking from cell membranes: polypeptides, polymyxins, colistin,
bacitracin, polyenes- Amphotericin B,Nystatin Hamycin
3. Inhibits protein synthesis: tetracyclines, chloramphenicol, erythromycin,
clindamycin, linezolid.
4. Cause misreading of mRNA code and affects permeability :
aminoglycosides- streptomycin, gentamicin etc.
5. Inhibiting DNA gyrase: fluoroquinolones, ciprofloxacin and other
6. Interfere with DNA function: rifampin, metronidazole
7. Interfere with DNA synthesis: Acyclovir, Zidovudineol
8. Interfere with intermediary metabolism: sulfonamides, sulfones,
trimethoprim, pyrimethamine

5. C. Type of organism against which primarily active
• Antibacterial : penicillins, aminoglycosides,
erythromycin etc
• Antifungal: griseofulvin, amphotericin B,
ketoconazole etc
• Antiviral : Acyclovir, Amantadine, Zidovudine
• Antiprotozoal : metronidazole, chloroquine,
pyrimethamine, diloxanide
• Anthelmintic : mebendzole, pyrantel,
niclosamide, diethyl carbamazine

6. D. Spectrum of activity
• Narrow spectrum: penicillin G, streptomycin, erythromycin
• Broad spectrum: tetracyclines, chloramphenicol
E. Type of action
Primarily bacteriostatic:
sulfonamides erythromycin linezolid
tetracyclines ethambutol
Cholramphenicol clindamycin
Primarily bactericidal
Penicillins cephalosporins
Aminoglycosides vancomycin
Rifampin nalidixic acid
Isoniazid ciprofloxacin
Metronidazole cotrimoxazole

7. F. antibiotic are obtained from:
Fungi: penicillin, cephalosporin, griseofulvin
Bacteria : Polymxin B, tyrothricin, colistin, Aztreonam, bacitracin
Actinomycetes: aminoglycosides, macrolides, tetracyclines,
polyenes,chloramphenicol
Choice of an antimicrobial agent:
The choice depends on the peculiarities of the patient, the infecting
organism and the drug.
Patient factors:
1. Age : it may affects kinetic of many AMAs. Chloramphenicol’s
conjugation and excretion is inefficient in the newborn; large doses
produces gray baby syndrome.
sulfonamides displaces bilirubin from protein binding sites-can
cause kernicterus in the neonate because their BBB is more
permeable.
T1/2 of aminoglycosides is prolonged in the elderly and they are more
prone to develop VIII nerve toxicity.

8. 2. Renal and hepatic function: cautious use and
modification of the dose of an AMA becomes
necessary when organ of its disposal is
defective.
Antimicrobials needing dose reduction/avoidance in renal failure
Reduce dose even in mild
failure
Reduce dose only in
moderate- severe failure
Drugs to be avoided
Aminoglycosides
Amphotericin B
Cephalosporins
Ethambutol
Vancomycin
Flucystosine
Metronidazole
Cotrimoxazole
Carbenicillin
Fluoroquinolones
Clarithromycin
Aztreonam
Meropenem
Imipenem
Cephalothin
Talampicillin
Tetracyclines
Nalidixic acid
Nitrofurantoin

9. Antimicrobial in liver diseases
Drugs to be avoided Dose reduction needed
Erthryomycin estolate
Tetracycline
Pyrazinamide
Nalidixic acid
Talampicin
pefloxacin
Chloramphenicol
Isoniazid
Metronidazole
Clindamycin
Rifampin
3. Local factors: The conditions prevailing at the site of infection greatly affect the
action of AMAs.
a. Presence of pus and secretions decrease the efficacy of most AMAs, especially
sulfonamides and aminoglycosides.
b. Presence of necrotic material or foreign body makes eradication of infection
practically impossible.
c. Hemaotomas foster growth of bacteria; tetracyclines, penicillins and
cephalosporins get bound to the degraded Hb in the hematoma.
d. Lowering of pH at the site of infection reduces activity of macrolide and
aminoglycosides antibiotic.
e. Anaerobic environment in the centre of an abscess impairs bacterial transport
processes which concentrate aminoglycosides in the bacterial cell, rendering them
less susceptible

10. 4. Drug allergy: history of previous exposure to an AMA should
be obtained. If a drug has caused a allergic reaction-it has to be
avoided in that patients. Eg: drug of choice for syphilis in a patient
allergic to penicillin is tetracycline.β-lactams, sulphonamides,
fluoroquionoles and nitrofurantoin frequently causes allergy.
5. Impaired host defense:
 Integrity of host defence plays a crucial role in overcoming an
infection.
 Pyogenic infections occurs readily in neutropenic patients, while if
cell-mediated immunity is impaired (eg: AIDS), infection by low
gardes pathogens and intracelluar oragnism abound.
 In an individual with normal host immunity, a bacteriostatic AMAs
may achieve cure.
 While intensive therapy with cidal drugs is imperative in those with
impaired host defense.
6. Genetic factors: sulfonamides, fluoroquinolones, chloramphenicol
are likely to produce hemolysis in G-6-PD deficent patients.
7. Pregnancy: all AMAs should be contrindicated in pregnancy.

11. Prophylactic use of Antimicrobials
• Preventing the setting in of an infection or suppressing contacted
before it become clinically manifested.
• The difference treating and preventing infections is that treatment
is directed against a specific organism infecting an individual
patient, while prophylaxis is often against all organisms capable of
causing infection.
1. Prophylaxis against specific organisms:
• Rheumatic fever : group A streptococci: long acting penicillin G is the
drug of choice for preventing recurrences.
• Tuberculosis : in children, HIV positive; isoniazid alone or with
rifampin is recommended
• Myobacterium avium complex(MAC): HIV/AIDS patients may be
protected from MAC infection by azithromycin/clarithomycin.
• HIV infection: Health care worker exposed to blood by needle stick
injury: zidovudin+lamivudin±indinavir. Offspring of HIV positive
women can be protected by zidovudine given to pregnant mother
and then to the newborn for six weeks.
• Meningococcal meningities: during an epidemic, especially in
contacts: rifampin/ sulfadiazine/ceftriaxone.
• Recurrent genital herpes simplex: Acyclovir prophylaxis may be given
when four or more recurrences occur in a year.

12. • Malaria : for travellers to endemic areas with high
transmission rate: chloroquine/mefloquine.
• Influenza A2: during an epidemic , especially in contacts;
amantadine.
• Cholera : tetracycline prophylaxis may be given to close
contact of a case.
• Whooping cough: non-immunized child contact during the
incubation period: erythromycin can abort clinical diseases.
• Plague: contacts curing an epidemic : doxycycline.
• Pneumocystics jiroveci pneumonia : Transplant recipients on
immunosuppresants/ leukemia/ AIDS patients may be
protected by cotrimoxazole.

13. 2. Prevention of infection in high risk situations
It may be valid in some situation and controversial in others
a) Dental extraction, tonsillectomy, endoscopies causes damage to
mucosa harboring bacteria resulting bacteremia; patients with
valvular defects, can cause endocarditis: appropriate prophylaxis
with amoxicillin or clindamycin may be given few hours before to
few hours after the manipulation.
b) Catheterization or instrumentation of urinary tract: cotrimoxazole
or norfloxacin .
c) To prevent recurrences of UTI in patients with abnormalities of
the tract: cotrimoxazole or nitrofurantoin may be given on a long
term basis since the organism mostly is E.colli.
d) Immunocompromised patients( receiving corticosteroid or
chemotherapy, neutropenic patients) penicillin/ cephalosporin ±
an aminoglycosides or fluoroquinolones are often used to prevent
respiratory tract infection and septicemia, but incidence of super
infection is high.

14. Problems that arise with use of AMAs
• Toxicity :
a. Local irritancy: this is exerted at the site of
administration.
 Gastric irritation, pain and abscess formation at the
site of i.m injection
 Thrombophlebities of the injected vein
 Practically all AMAs, especially
erythromycin,tetracyclines, certain cephalosporins
and chloramphenicol are irritants.

15. b. Systemic toxicity : almost all AMAs produce dose related and
predictable organ toxicities. Characteristics toxicities are exhibited by
different AMAs.
some have a high therapeutic index- doses upto 100-fold range may be
given without apparent damage to host cell eg: penicillin, some
cephalosporin and erythromycin.
Antimicrobial agents Toxicity
Aminoglycosides 8th cranial nerve and kidney toxicities
Tetracyclines Liver and kidney damage, antianabolic effect
chloramphenicol Bone marrow depression
Antimicrobial agents Toxicity
Polymyxin B Neurological and renal toxicity
Vancomycin Hearing loss, kidney damage
Amphotericin B Kidney, bonemarrow and neurological toxicity
With lower therapeutic index:
With very low therapeutic index:

16. • Hypersensitivity reaction:
– Practically all AMAs are capable of causing hypersensitivity reactions.
– These are unpredictable and unrelated to dose.
– The whole range of reactions from rashes to anaphylactic shock can be
produced.
– The more common involved AMAs are- penicillin, cephalosporins,
sulfonamides, fluoroquinolones.
• Drug resistance:
– It refers to unresponsiveness of a microorganism to an AMA
Natural resistance :
 Some microbes have always been resistant to certain AMAs.
 They lack the metabolic process or the target site which is affected by
the particular drug.
 This is generally a group or species characteristics, eg: gram negative
bacilli are normally unaffected by penicillin, M.tuberculosis is insensitive
to tetracyclines.
 This type of resistance doesnot pose a significant clinical problems.

17. Acquired resistance: It is the development of resistance by an
organism due to the use of an AMA over a period of time.
This can happen with any microbe and is a major
clinical problem.
Development of resistance is dependent on the
microorganism as well as the drug.
Some bacteria are notorious for rapid acquisition of
resistance eg: staphylococci, coliforms, tubercle bacilli
Strep. pyogens and spirochetes have not developed
significant resistance to penicillin despite its wide
spread use for > 50 yrs.
Gonococci quickly developed resistance to
sulfonamides, but only slowly and low grade
resistance to penicillin.

18. Resistance may be developed by mutation or gene transfer
• Mutation :
– It is a stable and heritable genetic change that occurs
spontaneously and randomly among microorganisms.
– It is not induced by AMAs.
– Any sensitive population of a microbes contains a few
mutant cells which require higher concentration of
the AMA for inhibition.
– These are selectively preserved and gets proliferated
when sensitive population gets eliminated by AMAs.
– Thus in time sensitive strain is replaced by the
resistant one.

19. • Gene transfer: genes transfer (infectious
resistance) from one organism to another can
occur by:
Conjugation: common among gm-ve bacilli of same
or another species, frequently occur in colon
Eg:chloramphenicol resistance of typhoid bacilli,
streptomycin resistance of E.colli, penicillin resistance
of Haemophilus and gonococci
Transduction
Eg: many staph. Aureus strains have aqcuired
resisitance by transduction.
Certain instances of penicillin, erythromycin and
chloramphenicol resistance have been found to be
phage mediated.
Transformation : mechanism probably is not clinically
significant except isolated instances of pneumococcal
resistance to penicillin.

21. Resistant organism can broadly be of the following three types.
• Drug tolerant:
– Loss of affinity of the target biomolecule of the microorganism for a
particular AMA.
– Eg: resistant Staph. Aureus and E.colli develop a RNA polymerase that
does not bind rifampin, certain
– Certain penicillin-resistant pneumococcal strains have altered penicillin
binding proteins.
– Trimethoprim-resistance results from plasmid-mediated synthesis of a
dihydrofolate reductase that has low affinity for trimethoprim
• Drug destroying:
– The resistant microbe elaborates an enzyme which inactivates the drug,
– eg: β-lactmases are produced by staphylococci, haemophilus, gonococci
etc which inactivate penicillin.
– chloramphenicol acetyl transferase is acquired by resistant E.coli, H.
influenza and S.typhi
– Some of the aminoglycoside-resistant coliforms have been found to
produce enzymes which adenylate/acetylate/phosphorylate specific
aminoglycosides antibiotics.

22. • Drug impermeable:
Many hydrophilic antibiotics gains access into
bacteria cell through specific channels called porins,
or need specific transport mechanism.
Porins or other transporter almost absent in resistant
strains, eg conc. of some aminoglycosides and
tetracyclines in the resistant gm -ve bacterial strains
found to be much less than the sensitive one.
Likewise, low degree penicillin- resistant gonococci
are less permeable to penicillin-G
Chloroquine-resistants P. falciparum accumulates less
chloroquine.

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