Handout Antimicrobials
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Transcript of Handout Antimicrobials
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Antimicrobial Drugs
I. Terminology of chemotherapy
II. Where antimicrobial drugs come from
III. How antimicrobials work
IV. Drug resistance
V. Interactions between drugs and hosts
VI. Selecting the right antimicrobial drug
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I. TermsWhen a drug is used to control an infection, the
practice is termed antimicrobial chemotherapyAntimicrobial drugs: a class of compounds which
inhibit or kill microorganisms.
Antibiotics-- _____________ antimicrobial drugs.
Synthetics-- ______________ antimicrobials.
Antibiotics which have been chemically modified are
called_________________.
Broad spectrumagents --
Narrow spectrumagents --
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How do they work?
The main trick if one were to design an antibiotic: findsomething the target pathogen has or does (e.g. a structure or
pathway) which the host cell doesnt. For example, most bacteria
have peptidoglycan while eukaryotes dont so a compound which
destroys it or inhibits its production (like penicillin) shouldnt
affect eukaryotes.
Toxicity to the host is a major concern
Therapeutic Index-- ratio of a drugs_________ _________ to
its minimum __________________ dose. For example:
16 g/ml effective dose
= ____
20 g/ml toxic dose
2 g/ml
= ___
20 g/mlversus
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How do they work (cont.)?
Four main approaches:
1) Inhibition of ________ _______ formation--
e.g. penicillin and cephalosporin
2) Inhibition of ________ ________ synthesis--
e.g. sulfonamides
3) Inhibition of ___________ synthesis-- e.g.
tetracycline4) Inhibition of cell ______________ function
(less common) e.g. polymixin
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Cellular targets of antimicrobial drugs
PenicillinsCephalosporinsVancomycinBacitracin
Novobiocin
Nalidixic acidRifampin
ErythromycinChloramphenicol
TetracyclinesAminoglycosides(Streptomycin,Kanamycin,Gentamicin)
Polymyxins
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Inhibition of cell wall synthesis
Penicillin family
(Beta-lactams)
Penicillin
Amoxicillin
Ampicillin
Carbenicillin
etc.
Varies (and can bemodified)
-_______
ring
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Inhibition of cell wall synthesis (cont.)
Cephalosporins
First isolated from Cephalosporium acremonium
Similar to ___________ because also has -lactam ring:
NHR
O
COOH
RN
S(Also can be O)
Most have
root cef inname
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Nucleic acid synthesis inhibitors
Chloroquine
Trimethoprim
Sulfanilamides (sulfa drugs)Are metabolic ______________of PABA (para-
aminobenzoic acid), necessary for the synthesis of
folic acid. Folic acid is then required for the
synthesis of ___________ and ______________.
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Sulfanilamide
SulfanilamidePABA
Folic acid
Sulfa competes with PABA for the active siteon the enzyme which converts PABA to
dihydrofolic acid, a precursor of folic acid
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Protein synthesis inhibitors
Tetracyclines-- Semisynthetic drug derived from a natural
antibiotic made by Streptomyces. _______________-
binding, bacteriostatic, broad spectrum.
Erythromycin-- Ribosome-binding antibiotic derived from
Streptomyces erythraeus. Also bacterio_________ . In
antibiotic class known as _________________
Aminoglycosides(e.g. streptomycin, kanamycin,
gentimycin, neomycin). Also derived from
Streptomyces, also ribosome-binding but
bacteri_________.
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Structure and derivatives of tetracycline
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Two New Classes of Antibiotics
1) Fosfomycin-- phosphoric acid usedprimarily against _____________________
due to enteric bacteria (E. coli, etc.)
2) Synercid(dalfopristin/quinupristin) and
Zyvox(linezolid)-- narrow spectrum drugs
used primarily against _________________pathogens such as Staphylococcus,
Enterococcus, and Streptococcus.
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Antimicrobial Drugs
I. Terminology of chemotherapy
II. Where antimicrobial drugs come from
III. How antimicrobials work
IV. Drug resistance
V. Interactions between drugs and hosts
VI. Selecting the right antimicrobial drug
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Drug resistance mechanisms
1) Enzyme _____________-- e.g. -lactamases
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Enzyme inactivation (cont.)
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The arms race: -lactamase inhibitors
These are not antimicrobial themselves but are prescribed inconjunction with -lactam antibiotics to increase their
effectiveness. They tend to be expensive.
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Other drug resistance mechanisms
2) Decreased permeability to the drug
Early penicillins could not pass the __________ _____________
of Gram-negatives
3) Altered ______________ for the drug-- altered cell wall
receptors, altered target proteins (e.g. altering 50S ribosomal bindingsite for erythromycin)
4) Changes in metabolic pathways or enzymes-- e.g. alteration
in ________ _________ synthesis
5) Efflux __________-- antibiotics can be pumped out as fast as they
come in.Pseudomonasare particularly famous for this.
_____________________ is pumped out of cells by plasmid-
encoded cytoplasmic membrane proteins
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The emergence of antibiotic resistance
Relationship between antibiotic use and the percentage of bacteria isolated
from diarrheal patients resistant to the antibiotic
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Percentage of reported cases of gonorrhea caused by
antibiotic-resistant strains
9000 cases
59000 cases
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Appearance of antibiotic resistance in several human
pathogens since the beginning of antibiotic therapy
At Rockingham Memorial Hospital, for example, 88% of Staphylococcus aureus
strains isolated in 1999 were resistant to penicillin, ampicillin, and amoxicillin.
Th A R C i S
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The Arms Race Continues: S. aureus
resistance to a brand-new antibiotic
07/20/2001
Associated Press
LONDON In a frustrating development in the battle against drug-
resistant bacteria, scientists report that the first entirely new type
of antibiotic in 35 years has been beaten by the staphsupergerm little more than a year after being introduced.
Researchers at Harvard Medical School describe in theLancet
medical journal this week how an 85-year-old man on dialysis
came down with a staph infection in the lining of his intestines
that was not vulnerable to the new drug, Zyvox [Linezolid]. It isthe first report of staph resistance to the medicine.
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Antimicrobial Susceptibility Profiles of
Selected Aerobes,
Rockingham Memorial Hospital, 1999
Organism
Number of
iso lates
tested
Ampi-
cillin/
Amoxi-
cillin
Augmen-
tin
Cefoxit
in
Ceftazi-
dime
Erythro-
mycin
Genta-
micin
Peni-
cillin
Vanco-
mycin
Staphylococcusaureus 715 12 55 90 12 100
Staphylococcus
epidermid is 81 11 38 65 11 100
Streptococcus
pneumoniae 42 76 52 100Ps eudomonas
aeruginosa 115 0 3 0 92 82
Es cherichi a co l i 118 57 78 99 100 95Klebs ie lla
pneumoniae 62 0 91 95 97 97
Percent Susceptible
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EXPOSURE TO DISINFECTANTS SUCH AS PINE-BASED CLEANERS
MAY CONTRIBUTE TO ANTIBIOTIC RESISTANCE
Repeated exposure to household cleaners containing pine oil may cause bacteria to
develop resistance to some common antibiotics, say researchers from TuftsUniversity School of Medicine in the December 1997 issue of the journal
Antimicrobial Agents and Chemotherapy.
In the study the researchers repeatedly exposed the bacteria Escherichia coli to a
household cleaner containing the disinfectant pine oil or pure pine oil itself in
order to isolate pine-oil resistant strains. The resistant strains were then tested
against a variety of antibiotics. All pine oil-resistant strains were alsomultidrug resistant.
To our knowledge, the selection of chromosomal antibiotic resistance, albeit low
level, by a disinfectant has not previously been reported for gram-negative
bacteria, say the researchers. Whether pine oil in products meant for
household use could lead to a significant problem of antibiotic resistance is notknow. However, it seems possible that additional disinfectants might be
capable of selecting for resistance to antibiotics and vice versa.
(M.Moken, L.M. McMurry and S. Levy. 1997. Selection of multiple-antibiotic-
resistant mutants of Escherichia coli by using the disinfectant pine oil: roles of
the mar and acrAB loci. Antimicrobial Agents and Chemotherapy. 41:2770-
2772.)
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Host/drug reactions (adverse or side effects)
Tissue toxicity-- kidneys, liver, heart, skin, nerves,
teeth and bones_____________ reactions
sensitized on first contact.
often due to reaction to a metabolic byproduct
Disruption of normal flora (mucking with themicrobial ecology of our bodies)
frequent cause of diarrhea
____________________-- secondary infection caused
by destruction of normal microflora.
Example: yeast (Candida albicans) infections caused by
destruction of vaginal lactobacilli with broad-spectrum
antibiotics
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Tube dilution test
Minimum Inhibitory Concentration (MIC)