Introduction to

Antimicrobial Agents

Dr. Salman
Khan
Chemotherapeutic Agents OR
Anti-microbials
Some Definitions:
Anti-Biotics: These are chemical substances
produced by various species of micro-
organisms ( bacteria, fungi, actenomycetes)
that suppress the growth of other micro-
organisms and may eventually destroy them.(
antibacterials, antivirals, anti-fungals)
Chemotherapeutic Agents OR
Anti-microbials
 Important consideration: Common
usage often extends the term
antibiotics to include synthetic
antibacterial agents, such as
sulfonamides, quinolones, that are not
products of microbes (Goodman & Gillman)
 BUT: we will call them anti-bacterials OR
antimicrobials OR Chemotherapeutic
agents derived from non-living things
OR synthetically produced.
Some Important Definitions:
 Bactericidal: An antimicrobial drug that
can eradicate an infection in the absence of
host defense mechanisms; kills bacteria
 Bacteriostatic: An antimicrobial drug that
inhibits microbial growth but requires host
defense mechanism to eradicate the infection;
does not kill bacteria.
 Beta-lactam antibiotics: drugs with
structures containing a beta-lactam ring;
include penicillins and cephalosporins. The
ring must be intact for antimicrobial action.
 Beta-lactamases: Bacterial enzymes
( penicillinase, cephalosporinase) that
hydrolyze the beta lactam ring of certain
penicillins and cephalosporins.
 Minimal Inhibitory concentration: lowest
concentration of antimicrobial drug capable of
inhibiting growth of an organism in a defined
growth medium. (MIC)
 Penicillin binding Proteins: Bacterial
cytoplasmic membrane proteins that act as
the initial receptors for penicillins and other
beta-lactam antibiotics. (PBPs)
 Peptidoglycan, murein: Chains of
polysaccharides and polypeptides that are
cross linked to form bacterial cell wall.
 Selective toxicity: More toxic to the invader
than to the host; a property of useful
antimicrobials.
 Transpeptidases: bacterial enzymes
involved in the cross-linking of linear
Peptidoglycan chains, the final step in cell wall
synthesis.
Targets for Antimicrobial
∀• Bacterial Cell Wall ∀• Drugs that Bind to the
Synthesis Inhibitors 30S bacterial ribosomal
subunit, leading to cell
death
• Protein Synthesis
Inhibitors: interfere with
30S or 50S bacterial ∀• Agents that interfere

ribosome function with nucleic acid

•Agents that Increase Cell synthesis

Membrane Permeability
∀• Antimetabolites
Bacterial cell wall synthesis Protein synthesis inhibitors: interfere
inhibitors: with 30S or 50S bacterial ribosome
 penicillins
function.
Bacteriostatic
 cephalosporins
chloramphenicol (Chloromycetin)
 cycloserine
tetracyclines
 vancomycin (Vancocin)
erythromycin
 bacitracin
clindamycin

Drugs that bind to the 30S Agents that interfere with nucleic
bacterial ribosomal subunit, acid synthesis:
leading to cell death. rifamycins (rifampin (Rimactane)):

Bactericidal inhibits DNA-dependent RNA

  Aminoglycosides (e.g.gentamicin polymerase
(Garamycin), tobramycin (Nebcin))  quinolones: inhibit gyrase

Antimetabolites Agents that increase cell

 sulfonamides membrane permeability:
polymixins (detergent)
 trimethoprim (generic)
colistimethate (detergent)

nystatin (Mycostatin)(polyene antifungal)

amphotericin B (polyene antifungal)

 Bactericidal agents
Aminoglycosides, bacitracin, beta-lactam
antibiotics, isoniazid, metronidazole,
polymyxins, pyrazinamide, quinolones,
rifampin, vancomycin [Lampris & Maddix
98,p818 and Katzung8th2001p860]
 Bacteriostatic agents
 Chloramphenicol, clindamycin, ethambutol,
macrolides, nitrofurantoin, novobiocin,
oxazolidinones, sulfonamides, tetracyclines,
trimethoprim [Lampris & Maddix 98,p818 and
Katzung8th2001p860]
Spectra of Anti-microbials
The clinical SPECTRUM of organisms is indicated by various
terms. BROAD SPECTRUM includes drugs like the tetracyclines
that have no strong predilection for gram positive or gram
negative organisms and may even act against such organisms
as Rickettsia or even protozoans. Few of the broad spectrum
antimicrobials affect such a wide range of organisms.
NARROW SPECTRUM Drugs, such as penicillin G, are primarily
active against GRAM POSITIVE organisms. Gentamicin is an
example of a drug that is especially used to treat infections by
GRAM NEGATIVE organisms. Some drugs have such a special
clinical niche that they are commonly referred to as a member
of that niche despite the fact that they do have other actions.
The PENICILLINASE resistant penicillins (e.g., methicillin) and
EXTENDED SPECTRUM penicillins (e.g., ticarcillin) are
examples. It is important to note that classifications based on
spectrum do not imply that a drug will be active against all
organisms in the class. Some organisms are notorious for the
unpredictability of their response to an antimicrobial whereas
others are highly predictable.
Combination Therapy
 Combination chemotherapy may be
warranted to:
 Decrease the likelihood of emergence of
resistant mutants.  A single agent will be
effective against sensitive organisms, but not
against those that have developed a mutated
"target" site, which is no longer susceptible or
has diminished susceptibility to the drug. In
this case the single drug will select out the
mutant, resistant strain. This effect is more
likely when the concentration of the
antibacterial agent approximates the MIC
(minimum inhibitory concentration).
 A second agent, which acts by a different
mechanism, may prevent the emergence of
the resistant strain (e.g. impenem +
aminoglycoside for systemic Pseudomonas).
 To take advantage of additive/synergistic
action against some bacteria. Combination of
trimethoprim-sulfamethoxazole (Septran) is
effective against many enteric gram negative
bacteria. And the combination becomes
bactericidal.
 
Advantages of combinations
 Some combinations frequently synergistic
trimethoprim plus sulfonamide
 Enterococcal endocarditis with penicillin and
streptomycin
 Cryptococcal meningitis with amphotericin B
plus flucytosine
 Mixed infections
 Decrease development of resistant organisms
as in treatment of tuberculosis with isoniazid
plus pyrazinamide and rifampin
 Serious, life-threatening infections of unknown
origin or in sepsis or meningitis
Disadvantages of combinations

 Interference with action of cidal

antibiotic that depends on rapid growth
by a static antibiotic that inhibits growth
 Increased risk of toxicity to patient
 Increased cost
 Increased risk of development of
resistant organisms in patient or
population by use of antibacterials not
truly needed
Mechanisms for chemotherapeutic
drugs resistance

 Bacterial resistance may occur because the drug

does not reach its target site, drug is inactivated,
or there is some sort of molecular alteration in
the target itself, possibly due to mutation.
 Resistance may occur because enzymes at or near the
cell surface inactivate the antibiotic; the cell membrane
is impermeable to the drug; there is an absence of
aqueous channels (porins) through which the drug will
reach the cell interior; there is a lack of a necessary
transport system to support drug translocation; the
transport mechanism is present but  inoperative due to
anaerobic metabolism; there are target site changes
that results in reduced or absent antibacterial drug
efficacy.
How Bacteria Acquire
Resistance
 Resistance may be acquired by vertical transfer,
i.e. acquired by mutation and then passed to daughter
cell
 Mutations: Specific genetic mutations are the
molecular basis for resistance to streptomycin
(ribosomal mutation), to quinolones (DNA gyrase gene
mutation) and to rifampin (Rimactane) (RNA polymerase
gene mutation)
o The mutation to rifampin is an example of a single-step
mutation: In this case  E. coli or Staph. aureus exposure
to rifampin results in highly resistant strain due to a
point mutation in the RNA polymerase gene such that
the polymerase protein no longer binds rifampin
 More usually, acquired by horizontal transfer of
resistance factors from a donor cell, perhaps of a
different species by transformation which
involves the incorporation of DNA found free
environment into the bacterial genome
o An example of this process is the basis of penicillin
resistance in. pneumococci and Neisseria gonorrhea.
 Penicillin-resistant pneumococci produce different PBPs
(penicillin-binding proteins).  These different PBPs
exhibit relatively low affinity for penicillin compared to
wild type pneumococci.
 These different PBPs arise from integration of foreign
DNA which were most likely from a closely related
streptococcal strain into the PBP gene by a process of
homologous recombination
 Transduction-based resistance occurs when a
bacteriophage which includes bacterial DNA in its
protein coat infects the bacteria. This bacterial DNA may
contain a gene confiring resistance to antibacterial
drugs.
 Examples of this process:
 Staphylococcus aureus strain resistance development to
penicillin may occur by transduction (Some
bacteriophages carry plasmids [extrachromosomal self-
replicating DNA] that code for penicillinase
 Other phages can transfer genes which confer
resistance to tetracycline (Achromycin), erythromycin
estolate (Ilosone), and chloramphenicol
(Chloromycetin).
 Conjugation is another important mechanism for
single and multi-drug resistance development.  In
conjugation direct passage of resistance-
conferring DNA between bacteria proceeds by
way of a bridge
o The genetic material transfer in conjugation
requires two elements: an R-determinant
plasmid which codes for the resistance and a
resistance-transfer factor (RTF) plasmid which
contains the genes necessary for the bacterial
conjugation process.  Occasionally two
plasmids join to form a complete R factor
o Some genes that are responsible for resistance
are located on transposons which can move
from location to location within plasmid and
 Conjugation mediated resistance is particularly
important in gram-negative bacilli.
o Enterococci may contain plasmids that spread
resistance among gram-positive organisms
• Vancomycin (Vancocin) resistance in enterococcal
strains appears to occur as a result of the conjugation
mechanism.
• Conjugation is not a high efficiency mechanism for
resistance development.  Unfortunately, antibiotic use
provides selection pressures which facilitate the
elaboration of resistance bacteria.  Furthermore, enteric
bacteria carrying plasmids for multidrug resistance is
now a worldwide, serious concern.
 Resistance acquired by horizontal transfer can
disseminate rapidly through the bacterial population by
clonal spread as well as by continuing genetic material
Complications Of Anti-biotic therapy
 Adverse Effects
Adverse effects of antimicrobials
may be divided into three broad
categories:
 Allergic

 Biological

 Toxic
Allergic Reactions to Antimicrobials

 Beta-lactams
 more likely with parenteral than oral
administration
 shift to different family of drugs
Biological Adverse Effects of
Antimicrobials
 More likely
 Broad spectrum drugs
 Alteration of normal flora

 Skin

 Mucous membranes

 Gastrointestinal tract

 Reproductive tract

 Likely pathogens

 yeasts

 Clostridium difficile

 Superinfection / Suprainfection
 Antibiotic Associated Enterocolitis
 ACCESS!!
 ampicillin, tetracyclines, LINCOMYCIN, and
other broad spectrum antibacterials
 spectrum -- broad, effective against anaerobes
 Antibiotic Associated Pseudomembranous
Enterocolitis
 Associated with overgrowth of Clostridium
difficile
Direct Toxic Effects of
Antibacterials

 Life threatening
o Liver failure -- isoniazid
o Respiratory paralysis -- neuromuscular paralysis --
aminoglycosides
 Severe
o Hearing loss (ototoxicity)-- aminoglycosides
o Nephrotoxicosis -- proximal tubular cells --
aminoglycosides
o Nephrotoxicosis -- tubular crystal formation --
Sulfonamides
o Decreased immune function -- many
antibiotics
o Bone / tooth malformation due to binding to
calcium -- tetracyclines
o Antibody production inhibited by --
amphotericin B, cefoxitin, doxycycline,
rifampin, cefotaxime, chloramphenicol,
moxalactam, and trimethoprim-
sulfamethoxazole.
o Microbiocidal activity impaired by -- amikacin,
cephalothin, gentamicin, sulfonamides,
tetracycline, and tobramycin
 Unpleasant
o Mild abdominal discomfort / pain --
erythromycin
o Dizziness -- minocycline
o Mild vomiting
o Loose stools to mild diarrhea
o Tooth discoloration -- tetracyclines
Appropriate and Inappropriate
Uses of Chemotherapy

 Appropriate Use
 Before the organism is identified: either
combination therapy or a single broad
spectrum agent may be used.
 After the organism is identified, a low-toxicity
regimen with a narrow-spectrum drug is
indicated.
 Selection of the drug should be governed by
its selectivity for the most likely involved
bacteria and its toxicity.
 First decide if an antibiotic is indicated since
antibiotics may be toxic.  Inappropriate use
may hinder diagnosis, and can result in
Some Clinical Issues

 Optimal empirical treatment requires knowledge of

the antibiotic sensitivity of the organisms which is
most likely causing the infection.
 Assessment with Gram's stain and other tests must
be used to narrow the list of pathogens.
 In life threatening situations, the selection of a
single narrow-spectrum agent may not be possible
and broad coverage would be indicated until a
definitive identification is possible.
Inappropriate Uses

 Treatment of Untreatable Infections

 The infection is viral.
 Antimicrobial treatment of measles, mumps and 90% of
upper respiratory infections are inappropriate.
 Treatment of fever of unknown origin:
 Antimicrobials are not antipyretic agents.
 Pyrexia of short duration, without localizing signs, is
most likely due to viral infection.
 Three infections may be associated with
prolonged fever:
 tuberculosis
 hidden intra-abdominal abscesses
 infective endocarditis.
 other causes: cancer, metabolic disorders, hepatitis,
 Improper dosage:
 Some drugs, such as the aminoglycosides, are frequently
administered at subtherapeutic dosages because of concern
about toxicity.
 Clinical treatment failure and selection of resistant strains may
result.
 Inappropriate Dependence on Chemotherapy
Alone:
 Some disorders require both chemotherapy and a
surgical procedure, especially if significant amount of
necrotic tissue is present.
 Example : Pneumonia in a patient with empyema
(accumulation of pus) may be effectively manage
following drainage
 Lack of Adequate Bacteriological Information:

 About one-half of antimicrobial therapy is given to

hospitalized patients without support from
microbiological data. [clinical judgment alone];
 Antimicrobial therapy must be individualized, not
administered based on prescribing habit alone