ANTIMICROBIAL THERAPY

GOAL OF ANTIMICROBIAL
THERAPY
ADMINISTER A DRUG TO
AN INFECTED PERSON
THAT DESTROYS THE
INFECTIVE AGENT
WITHOUT HARMING THE
HOST’S CELLS
 CHARACTERISTICS OF AN
IDEAL ANTIMICROBIAL DRUG
• Selectively toxic to the microbe
• Microbicidal
• Relatively soluble and functions even
when highly diluted in body fluids
• Remains potent long enough to act and
is not broken down or excreted
prematurely
• Not subject to the development of
resistance
 CHARACTERISTICS OF AN
IDEAL ANTIMICROBIAL DRUG
• Complements or assists the body’s
defenses
• Remains active in tissues or body
fluids
• Readily delivered to the site of
infection
• Not excessive in cost
• Does not disrupt the host’s health
 DEFINITION OF TERMS
• PROPHYLAXIS
– Use of a drug to prevent imminent
infection of a person at risk
• NARROW SPECTRUM
– Antimicrobics effective against a limited
array of microbial types
• BROAD SPECTRUM
– Antimicrobics effective against a wide
variety of microbial types
ANTIMICROBIAL MECHANISM
OF ACTION
ANTIMICROBIAL MECHANISM
OF ACTION
 CELL WALL INHIBITORS
• Act by causing to
produce weak or
incomplete cell
walls that make
the cell osmotically
fragile, thus are –
cidal drugs
 CELL WALL INHIBITORS:
REPRESENTATIVES PENICILLINS
AND CEPHALOSPORINS
• Beta-lactams
• Act by binding and
blocking the enzyme
that cross-links the
sugar molecules of the
peptidoglycan complex
interrupting completion
of the cell wall
PENICILLIN DRUG
PROFILE
DRUG MICROBES AFFECTED
Penicillin V & G Streptococci, Meningococci, Gram
+ and spirochetes
Oxacillin & Staphylococcal Infection
Cloxacillin
Ampicillin & Pen G + enterococci, Listeria, E.
Amoxicillin Coli, H. influenzae
Piperacillin Gram – rods including
Pseudomonas
CEPHALOSPORIN
DRUG PROFILE
• 1st Generation
Cephalosporins
– Cefazolin
– Cephalexin
– Effective against
Streptococci, and
Staphylococci as
well as E coli and
Klebsiella
pneumoniae
CEPHALOSPORIN
DRUG PROFILE
• 2nd Generation
Cephalosporins
– Cefuroxime
– Cefaclor
– Effective for
Bacteroides fragilis
and H influenzae
CEPHALOSPORIN
DRUG PROFILE
• 3rd Generation
Cephalosporins
– Ceftazidime
– Cefoperazone
– Cefotaxime
– With increased gram
negative coverage and
can penetrate the
blood brain barrier
– Active versus: H
influenzae, Neisseria,
Pseudomonas
(ceftazidime)
CEPHALOSPORIN
DRUG PROFILE
• 4th Generation Cephalosporins
– Cefepime
– Combines the gram positive active of 1st
generation cephalosporins and a wider
gram negative coverage compared with
the 3rd generation
 PENICILLIN AND
CEPHALOSPORIN SIDE-EFFECTS
 CELL WALL INHIBITORS:
REPRESENTATIVES
VANCOMYCIN
• Hinders the elongation of
the peptidoglycan
structural complex
• Is one of the “last-resort”
drugs used when
resistance to all possible
drugs against gram-
positive bacteria
• Has no activity versus
gram negative bacteria
• Is not absorbed orally and
is given IV
• ADR: Chills, fever,
phlebitis, oto- and
nephrotoxicity
– RED-MAN SYNDROME
ANTIMICROBIAL MECHANISM
OF ACTION
 PROTEIN SYNTHESIS
INHIBITORS
• Inhibit translation • Inhibitors at 50S
by reacting with Subunit
the ribosome- – Chloramphenicol
mRNA complex – Macrolides
– TARGETS MAY
EITHER BE the 50S • Inhibitors at 30S
or 30S subunits
Subunit
– Aminoglycosides
– Tetracyclines
 AMINOGLYCOSIDES
• Irreversibly binds on
sites on the 30S
subunit and cause
misreading of mRNA
leading to abnormal
proteins
• Are bactericidal and
effective against gram-
negative organisms
• EXAMPLES:
Streptomycin,
gentamycin
• ADR: Oto- and
nephrotoxic
 TETRACYCLINE
• Reversibly binds to the
30S subunit and
distorting it in such a
way that the anticodons
of the charged tRNAs
cannot align properly
with the codons of the
mRNA
• Broad spectrum and
bacteriostatic
• Effective against
Yersinia, Legionella,
Mycoplasma
• ADR: Gastrointestinal
disruption
 CHLORAMPHENICOL
• A broad-spectrum drug that binds to
the 50S subunit of the bacterial
ribosome
• Is bacteriostatic and has good blood-
brain barrier penetration
• Used for typhoid fever, brain
abscesses
• ADR: aplastic anemia
 MACROLIDES
• Act by binding to a receptor site at the
50S subunit preventing movement of
the tRNA from one site to another
• Effective against Mycoplasma,
Corynebacterium, Legionella, B.
pertussis, gram-positive cocci
• Require less frequent dosing
• EXAMPLES: Erythromycin, Azithromycin
and Clarithromycin
• ADR: Gastrointestinal Irritation, Skin
rashes
MACROLIDES
ANTIMICROBIAL MECHANISM
OF ACTION
 DNA SYNTHESIS INHIBITORS:
SULFA DRUGS AND
•
TRIMETHOPRIM
Act by competitive
inhibition, preventing
the normal substrate of
the enzyme to attach to
the enzyme: In Folic Acid
Synthesis
• Act synergistically
• Sulfonamides and
Trimethoprim
• Does not affect humans
• Bacteriostatic
• For UTI against Gram -
infections
 DNA SYNTHESIS INHIBITORS:
QUINOLONES
• Drugs that prevent DNA
unwinding thus preventing
DNA transcription
• Prevents supercoiling
causing bacterial cells to
unwind and burst
• Includes: Ciprofloxacin,
Norfloxacin and Ofloxacin
• Act on both gram-positive
and gram-negative
bacteria
• ADR: Seizures and brain
disturbances; cartilage det.
 DNA SYNTHESIS INHIBITORS:
RIFAMPIN
• Selectively
inactivates the RNA
polymerase
• mRNA synthesis is
prevented
ANTIMICROBIAL MECHANISM
OF ACTION
CELL MEMBRANE DISRUPTORS:
POLYMIXINS
• Damages the cell membranes by
interacting with membrane
phospholipids, distorting the cell
surface, causing leaking of proteins
and other products.
• Effective against gram-negative
bacteria
ANTIFUNGAL
CHEMOTHERAPY
 ANTIFUNGAL DRUGS
• Due to eukaryotic nature of fungi,
treatment of fungal infections
present special problems
– Drugs effective against bacteria are
generally ineffective against fungi
– Antifungals are often toxic to human
cells as well.
MECHANISMS OF ACTION
POLYENES
 POLYENES
• Bind to fungal
membranes
causing loss of
selective
permeability
• Amphotericin B –
the most versatile
and effective of
antifungals but is
nephrotoxic
FLUCYTOSINE
 FLUCYTOSINE
• An analog of cytosine which prevents
attachment of normal cytosine
during DNA and RNA synthesis.
• Used to treat cutaneous mycoses
• When with amphotericin B, can be
used to effectively treat systemic
mycoses
AZOLES
 AZOLES
• Broad-spectrum anti-
fungals that interrupt the
synthesis of sterols which
are components of the
cell membrane
• Includes: Ketoconazole,
Miconazole, Cotrimazole,
for cutaneous mycoses
ANTIVIRAL
CHEMOTHERAPY
ANTIVIRAL CHEMOTHERAPY
INHIBITION OF VIRUS ENTRY
• Fuzeon is a drug
that prevents HIV
infection by
preventing HIV
virus binding
• Amantadine
prevents influenza
virus fusion and
uncoating
INHIBITION OF NUCLEIC ACID
SYNTHESIS
• Acyclovir inactivates
herpesvirus DNA
polymerase
preventing DNA
replication

• Nucleoside and Non-

nucleoside RT
inhibitors stop the
action of HIV RT
INHIBITION OF VIRUS
ASSEMBLY/RELEASE
• Protease inhibitors
insert into HIV
protease resulting
in the formation of
a noninfectious
virus
ANTIMICROBIAL
RESISTANCE
HOW RESISTANCE OCCURS
MECHANISMS OF
RESISTANCE
DRUG SUSCEPTIBILITY
TESTING
 FACTORS IN SELECTING THE
PROPER ANTIMICROBIC DRUG
• The Nature of • Though clinical
ORGANISM causing experience may
the INFECTION prompt empiric
treatment, it is
best to identify the
infectious agent
from body
specimens like
blood, stool, urine,
etc.
 FACTORS IN SELECTING THE
PROPER ANTIMICROBIC DRUG
• OVERALL • It is important to
CONDITION of the know the condition
Patient of the patient;
weigh advantages
and disadvantages
of giving the drug,
its benefits and
adverse effects
 FACTORS IN SELECTING THE
PROPER ANTIMICROBIC DRUG
• Determining the • Testing is important for
groups that have shown
DEGREE of patterns of resistance to
SUSCEPTIBILITY of antibiotic therapy like:
the ORGANISM to – Staphylococcus
various DRUGS – Neisseria
– Streptococcus
• More feasible in bacterial
therapy
 TERMS
• Minimum Inhibitory Concentration:
– The smallest concentration of a drug
that visibly inhibits growth of microbes
• THERAPEUTIC INDEX
– The ratio of the dose of the drug that is
toxic to humans as compared to its
minimum inhibitory/effective dose (TI =
Toxic dose / MIC)
 ANTIBIOTIC SUSCEPTIBILITY
TESTING
• Done by exposing a pure
culture of the bacterium
to several drugs and
observing for effects.
• Kirby-Bauer method is a
diffusion test that
measures the zone of
inhibition due to a drug
when given to a pure
culture on agar.
• E-Test: An alternative to
the Kirby-Bauer method,
uses a gradient strip
 TREATMENT FAILURE
• Failure may be due to:
– Inability of the drug to diffuse into the
target body compartment
– A few resistant cells in the culture that
did not appear on sensitivity testing
– An infection caused by more than one
pathogen, some of which are resistant
to the drug