Transcript Drugs, microbes and host

Chapter 12
Controlling Microbial Growth in
the Body: Antimicrobial Drugs
Chapter 12
Topics
- Antimicrobial Therapy
- Selective Toxicity
- Survey of Antimicrobial Drug
- Microbial Drug Resistance
- Drug and Host Interaction
Antimicrobial drugs an intro:
• In 1900, 1 in 3 children were expected to die
of an infectious disease before the age of 5.
• The introduction of modern drugs in the
1930’s was a medical revolution, they were
regarded as miracle drugs.
• However in some parts of the world mortality
rates from infectious diseases are as high as
before they were before antimicrobial drugs.
The goal of antimicrobial chemotherapy is
simple: administer a drug to an infected person
that destroys the infective agent without
harming the hosts cells.
The ideal drug should be:
easily administered yet able to reach the
infectious agent anywhere in the body; be
absolutely toxic to the infectious agent while
simultaneously being nontoxic to the host, it
should remain active in the body as long as
needed, yet be safely and easily broken down
and excreted. All while not easily available to
antimicrobial resistance.
Interaction between drug and microbe
• The ideal antimicrobial is:
– Easily administered
– Selectively toxic
– Highly potent
– Stable
– Soluble in the body’s tissues and fluids,
– Does not disrupt the immune system or micro
flora of the host
– Is exempt from drug resistance.
Where did antimicrobials come from?
- Can be naturally occurring or synthetic
- Common metabolic products of aerobic bacteria and fungi
- Normal function is to inhibit growth of other microorganisms
in the same habitat which results in antibiotic producers
having less competition for nutrients and space
- Most come from bacteria in genera Streptomyces
and Bacillus and molds in genera Penicillium and
Cephalosporium
Some Terminology
• Chemotherapeutic drug – any chemical used
in the treatment, relief or prophylaxis of a
disease
• Prophylaxis- use of a drug to prevent imminent
infection of a person at risk
• Antimicrobial chemotherapy – the use of
chemotherapeutic drugs to control infection
• Antimicrobials – all inclusive term for any
antimicrobial drug, regardless of origin
• Antibiotics – substances produced by the natural
metabolic processes of some microorganisms
that can inhibit or destroy other microorganisms
• Semisynthetic drugs – drugs chemically modified
in the lab after being isolated from natural
sources
• Synthetic drugs – the use of chemical reactions
to synthesize antimicrobial compounds in the lab.
• Narrow spectrum (limited spectrum) –
Antimicrobials effective against a limited array
of microbial types. Example: a drug effective
on mainly Gram (+) bacteria.
• Broad spectrum (extended spectrum) –
Antimicrobials effective against a wide variety
of microbial types. Example: a drug effective
against both gram (+) and gram (-) bacteria
Figure 10.8 Spectrum of action for selected antimicrobial agents
Figure 10.9 Zones of inhibition in a diffusion susceptibility (Kirby-Bauer) test
Bacterial lawn
Zone of inhibition
Drug Administration
• The goal: to get an effective amount of drug to
the site of infections before it is broken down
and excreted.
• External therapy
– Local/topical therapy – for skin surface infections
drug is applied directly to infected area.
• Systemic therapy
– Intravenous (IV) administration – introducing the
drug directly into a vein via needle or catheter.
Fastest administration of a high level of drug, but
painful and can result in added infection.
• Intramuscular administration – introduces
drug directly into muscle via injection. Drug
reaches peak level in blood in 15 minutes, but
painful and done by a professional.
• Oral administration (PO – per os) – drug is
swallowed. Absorbed into bloodstream
through GI. Common, simple, painless
administration but slow and inefficient. Only a
fraction of drug reaches bloodstream, and
must be administered often. This leads to
dosage errors and failure to comply.
Elimination of drugs from the body
• Two methods of drug elimination, metabolic
conversion or excretion.
– Metabolic conversion into a different compound
occurs in the liver. This metabolic product is
usually inactive.
– Excretion occurs through the kidneys and into the
urine. A few pass through the liver into bile, and
then into the feces
– Important to know elimination route when dealing
with someone with impaired liver or kidney
function
Mechanism of Drug Action
• Goal of antimicrobial drugs: is to disrupt the
cell processes, or structures of the microbe.
Most interfere with the function of enzymes,
or destroy structures already there.
• Most importantly drugs should be selectively
toxic, they should kill or inhibit microbial cells
without damaging host cells.
Antimicrobial drugs are divided into categories
based on which cell targets they affect:
1. Inhibition of cell wall synthesis.
2. Interference with cell membrane structure or
function.
3. Inhibition of protein synthesis.
4. Inhibition of nucleic acid (DNA or RNA)
structure and function.
5. Inhibition of folic acid synthesis.
Inhibition of Cell wall synthesis
• Perfect mode of action since peptidoglycan is
unique to bacteria.
• Active cells are constantly making new
peptidoglycan
– Penicillin and Cephalosporin block the final step of
protein cross links.
– Vancomycin and Cycloserine interfere with
synthesizing the NAG and NAM strands.
Interference of Cell membrane
• Not the best site of action, every cell has some
kind of membrane, so selective toxicity is
reduced.
• Often specificity is for particular types of lipids
within cell membranes.
• Best if used topically
• If used systematically, it comes with serious
side effects, fever chills, vomiting and kidney
failure.
– Polymyxins interact with membrane phospholipids
and distort the cell surface.
– Polyene antifungal antibiotics (Amphotericin B and
Nystatin) form complexes with sterols on fungal
membranes. These complexes form passageways.
• Both of these agents cause seepage of liquids,
proteins, and ions.
Inhibition of Protein Synthesis
• The site of action is at the ribosome-mRNA
complex.
• The selective toxicity is achievable because
of the differences between prokaryotic and
eukaryotic ribosomes
(70S vs 80S respectively, S refers to
Svedberg units).
– Streptomycin and gentamicin cause the
misreading of the mRNA = abnormal proteins.
– Tetracyclines block attachment of tRNA to the A
site, stops protein synthesis.
– Chloramphenicol prevents peptide bond formation.
– Erythromycin prevents movement of the ribosome
along mRNA.
Targeting Nucleic acids
• Both prokaryotic and eukaryotic cells contain
nucleic acids.
• Some enzymes are different enough that we
can have enough selective toxicity to be
effective.
• Rifampin inhibits bacterial RNA polymerase,
the Quinolones inhibit a microbial
topoisomerase.
Inhibiting folic acid synthesis
• Through competitive inhibition Sulfonamides
and trimethoprim inhibit folic acid synthesis.
• Given together they provide a synergistic
effect (an additive effect by using both drugs,
which in turns requires less of each drug).
• Good selective toxicity, because we don’t
manufacture folic acid.
Penicillins
- Antibiotic/synthetic: Antibiotics &
semisynthetics
- Mode of action: Inhibits cell wall
- Spectrum: mostly gram +, some gram –
Penicillins share the same basic structure and
differ in the R group attached.
- All are relatively well tolerated
- Problems include
- allergies
- resistant pathogens
beta lactamase enzymes destroy the
beta lactam ring
Clavulanic acid inhibits these enzymes.
Often added to these drugs.
(Clavamox aka Augmentin)
Figure 10.16 How beta-lactamase (penicillinase) renders penicillin inactive
Lactam ring
Penicillin
-lactamase (penicillinase)
breaks this bond
Inactive penicillin
Cephalosporins
Antibiotic/synthetic: Antibiotics & semisynthetics
Mode of action: Inhibits cell wall
Spectrum: mostly gram +, some gram -
- Closely related to Penicillins but different in its
six carbon ring instead of the 5 carbon ring of
penicillin.
- Very effective with gram +’s and with each
generation (there are 4) become more
effective against gram –’s.
- More resistant against to beta lactamases
- Can still cause some allergic reaction like Penicillins
Vancomycin
Antibiotic/synthetic: Antibiotic
Mode of action: Inhibits cell wall
Spectrum: mostly gram +
Most effective in treating Staph in cases of
resistance (penicillin, methicillin) or in those
allergic to Penicillins.
It is very toxic (kidneys), must be administered
intravenously.
Streptomyces synthesizes many different antibiotics such as
aminoglycosides, tetracycline, chloramphenicol, and erythromycin.
Fig. 12.9 A colony of Streptomyces
Aminoglycosides
Antibiotic/synthetic: Antibiotics & a few
semisynthetics
Mode of action: Inhibits protein synthesis
Spectrum: Gram –
Poor absorption when taken orally so must be
injected and can be very toxic.
Resistance can be developed very easily. Often
given in combination with other drugs.
Streptomycin - oldest but still the drug of
choice for the bubonic plague and considered
a good anti-tuberculosis agent.
Gentamicin - is less toxic and is widely
administered for infections caused by gram –’s
Chloramphenicol
Antibiotic/synthetic: Antibiotic now made
synthetically
Mode of action: Inhibits protein synthesis
Spectrum: gram +, gram -, chlamydiae,
rickettsiae, mycoplasmas
Once thought to be ideal:
Doesn’t cause allergies, penetrates tissues,
effective when taken internally, can be stored
w/out refrigeration and few side effects.
**However in rare cases can cause aplastic
anemia. bone marrow stops producing blood
cells. (fewer than 1 in 30,000)
- Now, only used to treat seriously ill
hospitalized patients
Tetracyclines
Antibiotic/synthetic: Antibiotics & semisynthetics
Mode of action: Inhibits protein synthesis
Spectrum: gram +, gram -, chlamydiae,
rickettsiae, mycoplasmas
Discovered in the 1950’s one of the first to be
categorized broad spectrum.
Well absorbed orally, few allergies occur.
However they do not penetrate the blood/brain
barrier.
Side effects include:
- gastrointestinal pain and diarrhea
- increased sensitivity to sunlight
- can stain developing teeth
Widely used in livestock feed, consequently
resistant strains are plentiful.
Erythromycin
Antibiotic/synthetic: Antibiotic
Mode of action: Inhibits protein synthesis
Spectrum: gram +
- Discovered in 1952, widely used to treat strep
throat and other respiratory infections.
- However resistant S. pyogenes strains have
emerged.
- Easy oral administration, but side effects
include nausea, vomiting, stomach pain.
Quinolones
Antibiotic/synthetic: Synthetics
Mode of action: Inhibits DNA replication
(binds to topoisomerase)
Spectrum: gram +, gram -, mycoplasmas,
mycobacteria
- Relatively new group of drugs, broad spectrum,
easily administered orally, and few side effects
- Drug resistance is not common.
- Ciprofloxacin - used in the Anthrax scare
Antimycobacterial Drugs
Antibiotic/synthetic: Synthetic & semisynthetics
Mode of action: Inhibits protein synthesis
(Rifampin), and inhibits mycolic acids in cell
wall (Isoniazid, Ethambutol)
Spectrum: Mycobacteria
Rifampin
Isoniazid
Ethambutol
Mycobacteria are difficult to treat;
1. Mycolic acid layer nearly impermeable
2. Mycobacteria grow slowly
3. Resistant strains develop readily,
combinations of drugs must be used.
4. Intracellular pathogen
Other types of antimicrobials;
• Antiprotozoan – metronidazole
– Treat giardia
• Antimalarial – Quinine
– malaria
• Antihelminthic – mebendazole
– Tapeworms, roundworms
Antiviral
• Limited drugs available
• Difficult to maintain selective toxicity
• Effective drugs – target viral replication
cycle
– Entry
– Nucleic acid synthesis
– Assembly/release
• Interferon – artificial antiviral drug
Antiviral drug structures and their mode of action.
Table 12.5 Actions of selected antiviral drugs.
Antiviral drug structures and their mode of action.
Table 12.5 Actions of selected antiviral drugs.
Antiviral drug structures and their mode of action.
Table 12.5 Actions of selected antiviral drugs.
Antifungal agents
Antibiotic/synthetic: Antibiotic & synthetics
Mode of action: Inhibits cell membrane, inhibits
protein synth., inhibits cell division.
Spectrum: fungi
- Due to fungi being eukaryotic they pose
specific challenges.
- Selective toxicity focuses on fungal sterols
in the cell membrane
Nystatin – usually topical, Candida albicans.
Imidazoles & Triazoles – can be used topically
or systematically instead of Amphotericin B
(serious side effects).
Griseofulvin – persistant ringworm infections.
Resistance
Natural resistance – the cell may lack the target
the drug attacks, or naturally repel/block the
drug.
Acquired resistance – when strains become drug
resistant due to mutation and genetic
exchange.
1940’s nearly all S. aureus were sensitive to
penicillin, today 90% are resistant.
Mechansims of resistance
Mechanisms of resistance fall
into 3 categories:
1. Acquiring enzymes that
inactivate or destroy the
drug (Beta lactamase)
2. Changing the cellular target
3. Excluding the drug or
removing it once it has
entered (N. gonorrhea)
Selective process that
leads to a change in
genetic frequency
Abuse and misuse of
antibiotics leads to
resistance, and leads to
it more quickly.
How Does Resistance Develop?
1)
Spontaneous mutations in critical chromosomal gene(s)
- mutation is low frequency but occurs because of
huge numbers of bacteria in a population
2)
Acquisition of new genes or sets of genes from another
species
- originates from plasmids containing resistance (R)
factors
- transferred by conjugation, transformation, or
transduction
Natural selection
3)
Ways to slow resistance:
1. Limit non medical use of
antibiotics ie, livestock feed.
2. Stop prescribing antibacterials
for viral infections.
3. Stop selling antibiotics without
prescription.
4. Stop prescribing too often, or
indiscriminately.
5. Use combined therapy (two
drugs at once to ensure
effectiveness.
6. Encourage patient compliance.
Demonstration of how natural selection enables resistant strains
to become dominant.
Fig. 12.15 The events in natural selection for drug resistance