handout antimicrobials

8/10/2019 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)

handout antimicrobials

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