GENERAL ASPECT OF

ANTIMICROBIALS

Dr. Anish Giri

Lecturer
Department of Pharmacology
 INTRODUCTION
• Chemotherapy : Treatment of systemic infections
with specific drugs that selectively suppress the
infecting microorganism without significantly
affecting the host.
• Antibiotics : These are substances produced by
microorganisms, which selectively suppress the
growth of or kill other microorganisms at very low
concentrations.
 OBJECTIVE OF
CHEMOTHERAPY
• To study and to apply the drugs that have highly
selective toxicity to the pathogenic microorganisms
in host body and have no or less toxicity to the host,
so as to prevent and cure infective diseases caused
by pathogens.
 What is the ideal antimicrobial
drug?
• Have highly selective toxicity to the pathogenic
microorganisms in host body
• Have no or less toxicity to the host.
• Low propensity for development of resistance.
• Not induce hypersensitivity in the host.
• Have rapid and extensive tissue distribution
• Be free of interactions with other drugs.
• Be relatively inexpensive
 SOURCES OF ANTIBIOTICS
• Fungi : Penicillin, Griseofulvin, Cephalosporin

• Bacteria : Polymyxin B, Colistin, Aztreonam

Bacitracin

• Actinomycetes : Aminoglycosides, Macrolides,

Tetracyclines, Polyenes, Chloramphenicol
• Empiric antimicrobial therapy is directed
against an anticipated and likely cause of
infectious disease.
• It is used when antimicrobials are given to a
person before the specific bacterium or
fungus causing an infection is known.
• Definitive therapy refers to the antibiotic
therapy given subsequent to receipt of these
results.
 ANTIMICROBIAL SPECTRUM
• The scope that a drug kills or suppresses the growth
of microorganisms.
• Narrow-spectrum: The drugs that only act on one
kind or one strain of bacteria. E.g Isoniazid,
Streptomycin, Erythromycin, Penicillin G
• Broad-spectrum: The drugs that have a wide
antimicrobial scope. E.g tetracycline,
chloramphenicol
 TYPE OF ACTION
• Bacteriostatic : Drugs that inhibits or supress the
growth of microorganisms.
E.G : Sulfonamides Erythromycin, Tetracyclines,
Clindamycin, Chloramphenicol, Linezolid,
Ethambutol
• Bactericidal : Drugs that completely kills the
microorganisms.
E.G : Penicillins, Cephalosporins, Aminoglycosides,
Vancomycin, Polypeptides, Ciprofloxacin, Rifampin
Metronidazole, Isoniazid, Cotrimoxazole,
Pyrazinamide
 MECHANISMS OF
ANTIMICROBIAL AGENTS
• Inhibition of cell wall synthesis
• Inhibition of functions of cellular membrane
• Inhibition of protein synthesis
• Inhibition of nucleic acid synthesis
• Inhibition of folic acid synthesis
• Antiviral agents
• Inhibition of cell wall synthesis
• Penicillins and cephalosporins stop synthesis of cell
wall by binding to penicillin binding protein (PBP)
and then preventing cross linking of peptidoglycan
units.
• Bacitracin and vancomycin also interfere here.
• Excellent selective toxicity
• Polypeptide antibiotics
– Bacitracin
• Topical application
• Against gram-positives
– Vancomycin
• Glycopeptide
• Important antibiotic against resistant S.
aureus
• Antimycobacterium antibiotics (TB, Leprosy)
– Isoniazid (INH)
• Inhibits mycolic acid synthesis

– Ethambutol
• Inhibits incorporation of mycolic acid
 INHIBITION OF PROTEIN
SYNTHESIS
• Due to differences in ribosomes :
• Procaryotic cells have 70S (50S + 30S subunits)
ribosomes.
• Chloramphenicol, Macrolides and Clindamycin bind
to 50S subunit.
• Tetracyclines and Aminoglycosides bind to 30S
subunit.
• Chloramphenicol:
Binds 50S subunit, inhibits peptide bond formation
• Aminoglycosides:
Binds to 30S subunit and prevents formation of
initiation complex. Changes shape of 30S subunit
• Tetracyclines :
Binds to 30S subunit and interferes with tRNA
attachment
• Macrolides :
Binds 50S subunit, prevents translocation
 INHIBITION OF NUCLEIC ACID
SYNTHESIS
• Stop DNA replication
• Example: Quinolones- inhibits DNA gyrase

• Stop RNA synthesis

• Example: Rifampin – binds to the bacterial DNA-
dependent RNA polymerase.
 INHIBITION OF FOLIC ACID
SYNTHESIS
• A drug mimics a normal metabolite and acts as a
competitive inhibitor.
• Enzyme of cell recognizes the drug instead of the
normal metabolite-Pathways tops.
• Example: Sulfonamides and trimethoprim are
similar to PABA
• Inhibits folic acid synthesis by blocking
dihydrofolic acid synthase and reductase
respectively.
Cause leakage from cell membranes:
• Polypeptides—Polymyxins, Colistin, Bacitracin.

• Polymyxin B
– Topical
– Combined with bacitracin and neomycin in over-
the-counter preparation
 ANTIFUNGAL DRUGS

• Inhibition of Ergosterol Synthesis : Azoles

Ergosterol : important part of fungal cell membrane.

• Inhibit synthesis of -glucan : Echinocandins

-glucan : important part of fungal cell wall

• Binds to ergosterol component of cell membrane :

Polyenes – Amphotericin B
• Inhibition of Nucleic Acids : Flucytocine
Cytosine analog interferes with RNA synthesis

• Inhibition of Microtubules (Mitosis) : Terbinafine

 ANTIVIRAL AGENTS
• Inhibits viral DNA polymerase : Acyclovir,
Ganciclovir etc.
• Nucleoside reverse transcriptase inhibitor :
Zidovudine, Stavudine, Lamivudine etc
• Non-Nucleoside reverse transcriptase inhibitors :
Nevirapine and Efavirenz
• Protease Inhibitors : Indinavir, Ritonavir, Saquinavir
etc.
• Antiprotozoal: Chloroquine, Pyrimethamine,
Metronidazole, Diloxanide

• Anthelmintic: Mebendazole, Pyrantel, Niclosamide,

Diethyl carbamazine
 PROBLEMS WITH
THE USE OF AMA
Toxicity
• Local irritation: at the site of administration.
• Gastric irritation, pain and abscess formation at the
site of i.m. injection, thrombophlebitis of the
injected vein
• Systemic toxicity: Almost all AMAs produce dose
related and predictable organ toxicities.
• Aminoglycosides : Nephrotoxicity
• Chloramphenicol : Bone marrow depression
Hypersensitivity reactions
• Unpredictable and unrelated to dose.
• Rashes to anaphylactic shock
• Commonly involved AMAs —penicillins,
cephalosporins, sulfonamides, fluoroquinolones.
Nutritional deficiencies
• Some of the B complex group of vitamins and vit K
are synthesized by the intestinal flora.
• Prolonged use of antimicrobials which alter this
flora may result in vitamin deficiencies.
Masking of an infection
• A short course of an AMA may be sufficient to treat
one infection but only briefly suppress another one
contacted concurrently.
• Syphilis masked by the use of a single dose of
penicillin which is sufficient to cure gonorrhoea.
 SUPERINFECTION
• This refers to the appearance of a new infection as a
result of antimicrobial therapy
• AMAs causes some alteration in the normal
microbial flora
• Nonpathogenic flora (e.g. Candida) predominate
and invade.
• Associated with : broad/extended-spectrum
• Tetracyclines, chloramphenicol, ampicillin, newer
cephalosporins
• More common in immunocompromised.
• Sites : oropharynx; intestinal, respiratory and
genitourinary tracts
Conditions predisposing to superinfections
• Corticosteroid therapy
• Anticancer drugs
• Acquired immunodeficiency syndrome (AIDS)
• Agranulocytosis
• Diabetes
To minimize superinfections:
• Use specific (narrow-spectrum) AMA whenever
possible.
• Do not use antimicrobials for self-limiting or
untreatable (viral) infections.
• Do not unnecessarily prolong antimicrobial therapy.
 ORGANISMS CAUSING
SUPERINFECTION
• Candida albicans

• Resistant staphylococci

• Clostridium difficile: pseudomembranous

enterocolitis associated with clindamycin,
tetracyclines, aminoglycosides, ampicillin

• Pseudomonas: Urinary tract infection

 RESISTANCE TO
ANTIBACTERIAL AGENTS
• Drug resistance : The phenomenon that
susceptibility of pathogenic microorganisms to
drugs becomes lower or even loses after the
microorganisms contact with drugs many times.

• Cross resistance : When the bacteria show resistance

to one drug, they are also resistant to some other
drugs. This phenomenon is called cross drug
resistance.
 TYPES OF RESISTANCE
 Intrinsic or natural resistance : resistance existing
on chromosome. Gram-negative bacilli to basic
penicillins

 Acquired resistance : induced by AMAs

• Resistance acquired by mutation: unusual
• Resistance acquired by R-factors on plasmids :
common
 Genetic alterations leading to drug
resistance
Mutations : It is a heritable genetic change that
occurs spontaneously.
 Called vertical transfer of resistance
 Slowly develops and is usually of lower grade.
e.g. When a single anti-tubercular drug is used
• Resistance to streptomycin (ribosomal mutation), to
quinolones (DNA gyrase gene mutation) and to
rifampin (RNA polymerase gene mutation).
• Mutation and resistance may be:
(i) Single step: A single gene mutation. E.g.
enterococci to streptomycin, E. coli and
Staphylococci to rifampin.
(ii) Multistep: A number of gene modifications are
involved
• Resistance to erythromycin, tetracyclines and
chloramphenicol
• Gene transfer : The resistance causing gene is
passed from one organism to the other.
• Horizontal transfer of resistance.
• Rapid spread of resistance
• High level resistance to several antibiotics
(multidrug resistance)
METHODS OF GENE TRANSFER
• Conjugation : Sexual contact through the formation
of a bridge
• Common among gram-negative bacilli
• Involve transfer of gene carrying the ‘resistance’ or
‘R’ factor
• R factor : contains genes coding for enzymes that
make the cell resistant to antibiotics
• Chloramphenicol resistance of typhoid bacilli
• Streptomycin resistance of E. coli
• Penicillin resistance of Haemophilus and gonococci

• Transduction : It is the transfer of gene carrying

resistance through the bacteriophage.
• Bacteriophage : bacterial DNA in its protein coat
• Staph. aureus resistance to penicillin, erythromycin
and chloramphenicol
 MECHANISMS OF
ANTIBACTERIAL RESISTANCE
• Produce enzymes that destroy the chemical
structure of drugs :
 β-lactamses destroy many penicillins and
cephalosporins
 Aminoglycoside-modifying enzymes
 Chloramphenicol acetyltransferase
• Develop an altered structural target for the drug
 Alteration in penicillin binding protein(PBP) : β-
lactams
 Mutation of dihydrofolate reductase : resistant to
trimothoprim.
• Change cell membrane and cell wall permeability
to the drug
 Presence of an efflux system that pumps out the
drug.
 Gram-negative bacteria show a special membrane
(lipopolysaccharide layer) and decrease
penetrability : prevent tetracyclines into the bacillus.
• Develop an altered metabolic pathway

 Sulfonamide resistance may occur as a result of

mutations that cause over-production of PABA or
cause production of a folic acid-synthesizing
enzyme that has low affinity for sulfonamides.
 PREVENTION OF DRUG
RESISTANCE
• Avoid indiscriminate and inadequate or unduly
prolonged use of AMAs
• Prefer rapidly acting and selective (narrow
spectrum) AMAs whenever possible
• Broad-spectrum drugs should be used only when a
specific one cannot be determined or is not suitable.
• Use combination of AMAs whenever prolonged
therapy is undertaken, e.g. T.B, HIV-AIDS
 CROSS RESISTANCE

• Acquisition of resistance to one AMA conferring

resistance to another AMA, to which the organism
has not been exposed.
• Commonly seen between chemically related drugs,
• Resistance to one sulfonamide means resistance to
all others, and resistance to one tetracycline means
insensitivity to all others.
• Called complete cross resistance.
CHOICE OF AN ANTIMICROBIAL AGENT
• Patient factors
1. Age :
• Chloramphenicol : inefficient Conjugation and
excretion in newborn: gray baby syndrome.
• Sulfonamides : displace bilirubin from protein binding
sites—kernicterus in neonate : permeable BBB
• Aminoglycosides : t½ prolonged in the elderly - VIII
nerve toxicity.
• Tetracyclines : deposit in the developing teeth and bone
—discolour teeth and weaken bone : contraindicated < 6
years
2. Renal and hepatic function : Cautious use and
modification of the dose of an AMA (with low
safety margin)
Antimicrobials needing dose reduction/ avoidance in
renal failure
• Reduce dose even in mild failure : Aminoglycosides
Amphotericin B, Cephalosporins, Ethambutol,
Vancomycin, Flucytosine
• Antimicrobials in liver disease
• Drugs to be avoided : Erythromycin estolate,
Tetracyclines, Pyrazinamide, Nalidixic acid and
Pefloxacin

• Dose reduction needed : Chloramphenicol, Isoniazid

Metronidazole, Rifampin and Clindamycin
3. Local factors:
• Presence of pus and secretions : decrease the
efficacy e.g sulfonamides and aminoglycosides -
Drainage of the abscess
• Presence of necrotic material or foreign body
including catheters, implants and prosthesis
• Haematomas
• Anaerobic environment impairs : concentration of
aminoglycosides
4. Drug allergy : History of previous exposure
 β-lactams, sulfonamides, fluoroquinolones and
nitrofurantoin associated with allergic reactions.
 Drug of choice for syphilis in a patient allergic to
penicillin is tetracycline.
• Impaired host defence : intensive therapy with cidal
drugs
5. Pregnancy : All AMAs should be avoided in the
pregnancy.
 Teratogenic : Aminoglycosides, fluoroquinolones,
cotrimoxazole, chloramphenicol, sulfonamides and
nitrofurantoin.
 Penicillins, many cephalosporins and erythromycin
are considered safe
6. Genetic factors :
• Primaquine, nitrofurantoin, sulfonamides,
chloramphenicol and fluoroquinolones carry the risk
of producing haemolysis in G-6-PD deficient
patient.
 ORGANISM-RELATED
CONSIDERATIONS
• Clinical diagnosis itself directs choice of the AMA :
e.g. syphilis, chancroid, diphtheria, tetanus, plague,
cholera, tuberculosis, leprosy, amoebiasis, herpes
simplex etc.
• A good guess can be made from the clinical features
and experience about the type of organism and
sensitivity pattern : Gram stain
• Choice to be based on bacteriological examination :
AMA should be selected on the basis of culture and
sensitivity testing
• Bacteriological sensitivity testing : Disk-agar
diffusion method
• Minimum inhibitory concentration (MIC) : The
lowest concentration of an antibiotic which prevents
visible growth of a bacterium after 24 hours
incubation.
• Minimum bactericidal concentration (MBC) :
concentration of the antibiotic which kills 99.9% of
the bacteria.
Postantibiotic effect (PAE) :
• After a brief exposure if the organism is placed in
antibiotic-free medium, it starts multiplying again,
but after a lag period which depends on the
antibiotic as well as the organism.

• This lag period in growth resumption is known as

‘postantibiotic effect’
 DRUG FACTORS
• Spectrum of activity:
 For definitive therapy : Narrow-spectrum
 For empirical therapy : Broad-spectrum
• Type of activity : Bactericidal or Bacteriostatic
• Sensitivity of the organism : On the basis of MIC
and consideration of postantibiotic effect
• Relative toxicity: less toxic preferred, e.g. a β-
lactam over an aminoglycoside or erythromycin
over clindamycin
• Route of administration : Many AMAs can be
given orally as well as parenterally
• Given by injection : aminoglycosides, penicillin G,
carbenicillin, many cephalosporins, vancomycin,
etc.
• For less severe infections : oral antibiotic
• For serious infections : e.g. meningitis - parenteral
antibiotic
 COMBINED USE OF
ANTIMICROBIALS
• To achieve synergism : B-lactams +
Aminoglycosides
• To reduce severity or incidence of adverse effects :
Amphotericin B + flucytosine for cryptococcal
meningitis
• To prevent emergence of resistance : Anti-
tubercular therapy
• To broaden the spectrum of antimicrobial action
 PROPHYLACTIC USE OF
ANTIMICROBIALS
• Prophylaxis against specific organisms
 Rheumatic fever: A long acting penicillin G
 Tuberculosis: Isoniazid or Ripampin
 HIV infection: zidovudine + lamivudine ±
indinavir.
 Cholera: tetracycline
 Recurrent genital herpes simplex: Acyclovir
 Malaria: Mefloquine or Doxycycline
• Prevention of infection in high risk situations
 Dental extraction, tonsillectomy, endoscopies :
amoxicillin or clindamycin few hours before to few
hours after the procedure

 Catheterization or instrumentation of urinary tract:

prophylaxis with cotrimoxazole or norfloxacin
• Prophylaxis of surgical site infection
 Cefazolin 1 g i.v. 8 hourly + vancomycin 1 g i.v. 12
hourly.
 Cefoxitin 1 g i.v. 6 hourly/ceftizoxime 1 g i.v. 12
hourly
 FAILURE OF ANTIMICROBIAL
THERAPY
• Improper selection of drug, dose, route or duration
of treatment.
• Treatment too late.
• Failure to take necessary adjuvant measures,
e.g. drainage of abscesses, removal of foreign bodies
control of diabetes
• Poor host defence—leukaemias, neutropenia
• Infecting organism present behind barriers : blood
brain-barrier.
• Trying to treat untreatable (viral) infections or other
causes of fever (malignancy)
• Presence of dormant or altered organisms (the
persisters) which later give rise to a relapse.