Transcript Foundations in Microbiology

Chapter 12
Drugs, Microbes, Host – The
Elements of Chemotherapy
Principles of Antimicrobial Therapy
The
goal of antimicrobial chemotherapy is deceptively
simple: administer a drug to an infected person that
destroys the infective agent without harming the host’s cells
In
actuality, this goal is rather difficult to achieve, because
many often contradictory factors must be taken into account
The
perfect drug does not exist
Antimicrobial
drugs are produced naturally or chemically
synthesized
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Origins of Antimicrobial Drugs
Nature
is a prolific producer of antimicrobial drugs
Antibiotics are common metabolic products of aerobic
spore-forming bacteria and fungi


bacteria in genera Streptomyces and Bacillus
molds in genera Penicillium and Cephalosporium
By
inhibiting the growth of other microorganisms in the
same habitat (antagonism), antibiotic producers presumably
enjoy less competition for nutrients and space
Now chemists have created new drugs by altering the
structure of naturally occurring antibiotics
There is an active search for metabolic compounds with
antimicrobial effects in species other than bacteria and fungi
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Interactions Between Drug and Microbe
The
goal of antimicrobial drugs is either to disrupt the cell
processes or structures of bacteria, fungi, and protozoa or
to inhibit the virus multiplication cycle
Antimicrobial
drugs should be selectively toxic - drugs
should kill or inhibit microbial growth without simultaneously
damaging host tissues
As
the characteristics of the infectious agent become more
similar to the vertebrate host cell, complete selective toxicity
becomes more difficult to achieve and undesirable side
effects are seen
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Mechanisms of Drug Action
Inhibition
of cell wall synthesis
Disruption
of cell membrane structure or function
Inhibition
of structures and functions of DNA and RNA
Inhibition
of protein synthesis
Blocks
on key metabolic pathways
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The Spectrum of an Antimicrobic Drug
Spectrum
– range of activity of a drug

narrow-spectrum – effective on a small range of microbes
 target a specific cell component that is found only in certain
microbes

medium-spectrum

broad-spectrum – greatest range of activity
 target cell components common to most pathogens
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Antimicrobial Drugs That Affect the
Bacterial Cell Wall
Most
bacterial cell walls contain peptidoglycan
Penicillins
and cephalosporins block
peptidoglycan, causing the cell wall to lyse
Active
synthesis
of
on young, growing cells
Penicillins
do not penetrate the outer membrane and are
less effective against Gram-negative bacteria
Broad
spectrum penicillins and cephalosporins can cross
the cell walls of Gram-negative bacteria
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Antimicrobial Drugs That Disrupt Cell
Membrane Function
A
cell with a damaged membrane dies from disruption in
metabolism or lysis
These
drugs have specificity for a particular microbial
group, based on differences in types of lipids in their cell
membranes
Polymyxins
interact with phospholipids and cause leakage,
particularly in Gram-negative bacteria
Amphotericin
B and nystatin form complexes with sterols on
fungal membranes which causes leakage
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Drugs That Inhibit Nucleic Acid Synthesis
May
block synthesis of nucleotides, inhibit replication, or
stop transcription
Chloroquine
binds and cross-links the double helix;
quinolones inhibit DNA helicases
Antiviral
drugs that are analogs of purines and pyrimidines
insert in viral nucleic acid, preventing replication
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Drugs That Block Protein Synthesis
Ribosomes
of eukaryotes differ in size and structure from
prokaryotes; antimicrobics usually have a selective action
against prokaryotes; can also damage the eukaryotic
mitochondria
Aminoglycosides
(streptomycin, gentamycin) insert on sites
on the 30S subunit and cause misreading of mRNA
Tetracyclines
block attachment of tRNA on the A acceptor
site and stop further synthesis
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Drugs that Affect Metabolic Pathways
Sulfonamides
and trimethoprim block enzymes required for
tetrahydrofolate synthesis needed for DNA and RNA
synthesis
inhibition – drug competes with normal
substrate for enzyme’s active site
Competitive
effect – an additive effect, achieved by multiple
drugs working together, requiring a lower dose of each
Synergistic
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Survey of Major Antimicrobial Drug Groups
Antibacterial
drugs

antibiotics

synthetic drugs
Antifungal
drugs
Antiprotozoan
Antiviral
drugs
drugs
About
260 different antimicrobial drugs are classified in 20
drug families
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Antibacterial Drugs That Act on the Cell
Wall
Beta-lactam
antimicrobials - all contain a highly reactive 3
carbon, 1 nitrogen ring
Primary
mode of action is to interfere with cell wall synthesis
Greater
than ½ of all antimicrobic drugs are beta-lactams
Penicillins
and cephalosporins most prominent beta-lactams
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Penicillin and Its Relatives
Large
diverse group of compounds
Could
be synthesized in the laboratory
More
economical to obtain natural penicillin through
microbial fermentation and modify it to semi-synthetic forms
Penicillium
All
chrysogenum – major source
consist of 3 parts:

thiazolidine ring

beta-lactam ring

variable side chain dictating microbial activity
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Subgroup and Uses of Penicillins
Penicillins
G and V most important natural forms
Penicillin
is the drug of choice for Gram-positive cocci
(streptococci)
and
some
Gram-negative
bacteria
(meningococci and syphilis spirochete).
penicillins – ampicillin, carbenicillin and
amoxicillin have broader spectra – Gram-negative enteric
rods
Semisynthetic
Penicillinase-resistant
Primary
– methicillin, nafcillin, cloxacillin
problems – allergies and resistant strains of
bacteria
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Cephalosporins
Account
for one-third of all antibiotics administered
Isolated
from Cephalosporium acremonium mold
Synthetically
altered beta-lactam structure
Relatively
broad-spectrum, resistant to most penicillinases,
& cause fewer allergic reactions
Some
are given orally; many must be administered
parenterally.
Generic
names have root – cef, ceph, or kef.
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Cephalosporins
4
generations exist: each group more effective against
Gram-negatives than the one before with improved dosing
schedule and fewer side effects

first generation – cephalothin, cefazolin – most effective against
Gram-positive cocci and few Gram-negative

second generation – cefaclor, cefonacid – more effective against
Gram-negative bacteria

third generation – cephalexin, ceftriaxone – broad-spectrum
activity against enteric bacteria with beta-lactamases

fourth generation – cefepime – widest range; both Gramnegative and Gram-positive
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Additional Beta-lactam Drugs
Carbapenems

imipenem – broad-spectrum drug for infections with aerobic and
anaerobic pathogens; low dose, administered orally with few side
effects
Monobactams

aztreonam –newer narrow-spectrum drug for infections by Gramnegative aerobic bacilli; may be used by people allergic to
penicillin
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Non Beta-lactam Cell Wall Inhibitors
– narrow-spectrum, most effective in treatment
of Staphylococcal infections in cases of penicillin and
methicillin resistance or if patient is allergic to penicillin;
toxic and hard to administer; restricted use
Vancomycin
– narrow-spectrum produced by a strain of
Bacillus subtilis; used topically in ointment
Bacitracin
(INH) – works by interfering with mycolic acid
synthesis; used to treat infections with Mycobacterium
tuberculosis; oral doses in combination with other
antimicrobials such as rifampin, ethambutol
Isoniazid
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Antibiotics That Damage Bacterial Cell
Membranes
Polymyxins
from Bacillus polymyxa are narrow-spectrum
peptide antibiotics with a unique fatty acid component that
contributes to their detergent activity
two polymyxins – B and E have any routine
applications and even these are limited by their toxicity to
the kidney
Only
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Drugs That Act on DNA or RNA
Fluoroquinolones
work by binding to DNA gyrase and a
related enzyme, topoisomerase IV both of which are
essential for replication of the bacterial DNA
Fluoroquinolones
are highly potent and provide broadspectrum effectiveness
Norfloxacin
and ciprofloxacin have been successful in
therapy for urinary tract infections, sexually transmitted
diseases,
gastrointestinal
infections,
osteomyelitis,
respiratory infections and soft tissue infections
Sparfloxacin
and levofloxacin are
pneumonia, bronchitis, and sinusitis
recommended
for
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Drugs That Interfere with Protein Synthesis
– composed of 2 or more amino sugars
and an aminocyclitol (6C) ring; binds ribosomal subunit
Aminoglycosides
Products
of various species of soil actinomycetes in genera
Streptomyces and Micromonospora
Broad-spectrum,
inhibit protein synthesis, especially useful
against aerobic Gram-negative rods and certain grampositive bacteria

streptomycin – bubonic plague, tularemia, TB

gentamicin – less toxic, used against Gram-negative rods

newer – tobramycin and amikacin Gram-negative bacteria
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Tetracycline Antibiotics
Broad-spectrum,
block protein synthesis by binding to
ribosomes
The
first antibiotic in this class was aureomycin
Aureomycin
was used to synthesize terramycin and several
senisynthetic derivatives, commonly known as the
tetracyclines
The
scope of microorganisms inhibited by tetracyclines is
very broad
and minocycline – low cost oral drugs; side
effects are a concern
Doxycycline
Treatment
for STDs, Rocky Mountain spotted fever, Lyme
disease, typhus, acne and protozoa
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Chloramphenicol
Isolated
from Streptomyces venezuelae; no longer derived
from natural source
Potent
broad-spectrum drug with unique nitrobenzene
structure
Blocks
peptide bond formation
Very
toxic, restricted uses, can cause irreversible damage
to bone marrow
Typhoid
fever, brain abscesses, rickettsial and chlamydial
infections
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Macrolides and Related Antibiotics
–large lactone ring with sugars; attaches to
ribosomal 50s subunit
Erythromycin
Broad-spectrum,
fairly low toxicity
Taken
orally for Mycoplasma pneumonia, legionellosis,
Chlamydia, pertussis, diphtheria and as a prophylactic prior
to intestinal surgery
For
penicillin-resistant – gonococci, syphilis, acne
Newer
semi-synthetic
azithromycin
macrolides
–
clarithomycin,
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Related Macrolides
– broad-spectrum, serious
anaerobic infections; adverse reactions
Clindamycin
abdominal
– telitromycin (Ketek), new drug with different ring
structure from Erythromycin; used for infection when
resistant to macrolides
Ketolides
– linezolid (Zyvox); synthetic antimicrobial
that blocks the interaction of mRNA and ribosome
Oxazolidinones

used to treat methicillin resistant Staphylococcus aureus (MRSA)
and vancomycin resistant Enterococcus (VRE)
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Drugs That Block Metabolic Pathways
Most
are synthetic; most important are sulfonamides, or
sulfa drugs - first antimicrobic drugs
Narrow-spectrum;
block the synthesis of folic acid by
bacteria

sulfisoxazole – shigellosis, UTI, protozoan infections

silver sulfadiazine –burns, eye infections

trimethoprim – given in combination with sulfamethoxazole – UTI,
PCP
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Newly Developed Classes of Antibiotics
Formulated
Three
from pre-existing drug classes
new drug types:

fosfomycin trimethamine – a phosporic acid effective as alternate
treatment for UTIs; inhibits cell wall synthesis
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synercid – effective against Staphylococcus and Enterococcus
that cause endocarditis and surgical infections; used when
bacteria is resistant to other drugs; inhibits protein synthesis
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daptomycin – directed mainly against Gram-positive; disrupts
membrane function
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Agents to Treat Fungal Infections
Fungal
cells are eucaryotic; a drug that is toxic to fungal
cells also toxic to human cells
Five antifungal drug groups:
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macrolide polyene
 amphotericin B –mimic lipids, most versatile and effective,
topical and systemic treatments
 nystatin – topical treatment
griseofulvin – stubborn cases of dermatophyte infections,
nephrotoxic
synthetic azoles – broad-spectrum; ketoconazole, clotrimazole,
miconazole
flucytosine – analog of cytosine; cutaneous mycoses or in
combination with amphotericin B for systemic mycoses
echinocandins – damage cell walls; capsofungin
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Antiparasitic Chemotherapy
drugs – quinine, chloroquinine, primaquine,
mefloquine, artemisin
Antimalarial
Antiprotozoan
drugs - metronidazole (Flagyl), quinicrine,
sulfonamides, tetracyclines
Antihelminthic
drugs – immobilize, disintegrate, or inhibit
metabolism

mebendazole, thiabendazole- broad-spectrum – inhibit function of
microtubules, interferes with glucose utilization and disables them
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pyrantel, piperazine- paralyze muscles

niclosamide – destroys scolex
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Antiviral Chemotherapeutic Agents
Selective
toxicity is almost impossible due to obligate
intracellular parasitic nature of viruses
Block penetration into host cell
Block replication, transcription and/or translation of viral
genetic material

nucleotide analogs
 acyclovir – herpesviruses
 ribavirin- a guanine analog – RSV, hemorrhagic fevers
 AZT – thymine analog - HIV
Prevent

normal maturation of viral particles
protease inhibitors – HIV
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Drugs for Treating Influenza
rimantidine – restricted almost exclusively to
influenza A viral infections; prevent fusion of virus with cell
membrane
Amantadine,
and tamiflu – slightly broader spectrum; blocks
neuraminidase in influenza A and B
Relenza
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Antiherpes Drugs
Many
antiviral agents act as nucleotide analogs and are
incorporated into the growing viral DNA chain; replication
ends

acyclovir – Zovirax

valacyclovir – Valtrex

famiciclovir – Famvir

peniciclovir – Denavir
Oral
and topical treatments for oral and genital herpes,
chickenpox, and shingles
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Drugs for Treating HIV Infections and AIDS
Retrovirus
offers 2 targets for chemotherapy:

interference with viral DNA synthesis from viral RNA using
nucleoside reverse transcriptase inhibitors (nucleotide analogs)

interference with synthesis of DNA using nonnucleoside reverse
transcriptase inhibitors

azidothymidine (AZT) – thymine analog
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Interferons (INF)
Human-based
glycoprotein
fibroblasts and leukocytes
Therapeutic
produced
primarily
by
benefits include:

reduces healing time and some of the complications in certain
infections

prevents or reduces symptoms of cold and papillomavirus (warts)

slows the progress of certain cancers (bone and cervical),
leukemias and lymphomas

treatment of hepatitis C, genital warts, Kaposi’s sarcoma
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The Acquisition of Drug Resistance
Drug
resistance is an adaptive response in which
microorganisms begin to tolerate an amount of drug that
would ordinarily be inhibitory; due to genetic versatility or
variation and adaptability of microbial populations
The
property of drug resistance can be intrinsic or acquired
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Intrinsic Drug Resistance
Intrinsic
drug resistance means that bacteria are resistant to
any antibiotic that they produce. This type of resistance is
limited, however to a small group of organisms and is
generally not a problem with regard to antimicrobial
chemotherapy
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Acquired Drug Resistance
Acquired
resistance:

spontaneous mutations in critical chromosomal genes

acquisition of new genes or sets of genes via transfer from
another species
 originates from resistance (R) factors (plasmids) encoded
with drug resistance, transposons
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Mechanisms of Drug Resistance
Drug
inactivation
penicillinases
by
acquired
enzymatic
activity
-
Decreased
permeability to drug or increased elimination of
drug from cell – acquired or mutation
Change
in drug receptors – mutation or acquisition
Change
in metabolic patterns – mutation of original enzyme
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Natural Selection and Drug Resistance
Large
populations of microbes likely to include drug
resistant cells due to prior mutations or transfer of plasmids
– no growth advantage until exposed to drug
If
exposed, sensitive cells are inhibited or destroyed while
resistance cells will survive and proliferate
population will be resistant – selective pressure natural selection
Eventually
Worldwide
indiscriminate use of antimicrobials has led to
explosion of drug resistant microorganisms
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Interactions Between Drug and Host
Estimate
that 5% of all persons taking antimicrobials will
experience a serious adverse reaction to the drug – side
effects
Major
side effects:

direct damage to tissue due to toxicity of drug

allergic reactions

disruption in the balance of normal flora or microflorasuperinfections possible
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Considerations in Selecting an Antimicrobial
Drug
Identify
the microorganism causing the infection
the microorganism’s susceptibility (sensitivity) to
various drugs in vitro when indicated
Test
The
overall medical condition of the patient
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Identifying the Agent
Identification
of infectious agent should be attempted as
soon as possible
Specimens
should be taken before antimicrobials are
initiated
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Testing for Drug Susceptibility
Essential
for groups of bacteria commonly showing
resistance
Kirby-Bauer
E-test
disk diffusion test
diffusion test
tests – minimum inhibitory concentration (MIC) smallest concentration of drug that visibly inhibits growth
Dilution
profile of drug sensitivity – antibiogram which
guides the choice of a suitable drug
Provide
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The MIC and Therapeutic Index
In
vitro activity of a drug is not always correlated with in vivo
effect

if therapy fails, a different drug, combination of drugs, or different
administration must be considered
Best
to choose a drug with highest level of selectivity but
lowest level toxicity – measured by therapeutic index – the
ratio of the dose of the drug that is toxic to humans as
compared to its minimum effective dose
High
index is desirable
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