Pharmacology Lecture 28

Front 1

Antimicrobial drugs have the ability to injure or kill an invading microorganism without harming the host

Back 1

selective toxicity

Front 2

Antimicrobial therapies take advantage of these differences that exist between microorganisms and humans

Back 2

biochemical differences

Front 3

These agents are among the most commonly used and misused of all drugs

Back 3

antimicrobial agents

Front 4

These are antibacterial substances produced by various species of microorganisms (bacteria, fungi and actinomycetes) that suppress the growth of other microorganisms

Back 4

antibiotics

Front 5

How are antibiotics different from antimicrobial agents?

Back 5

they differ greatly in physical, chemical and pharmacological properties and MOA

Front 6

These agents inhibit synthesis of bacterial cell walls

Back 6

β-lactams

Front 7

These agents act directly on cell membranes of microorganisms to increase permeability

Back 7

detergents like polymyxin

Front 8

These type of agents disrupt function of 30S or 50S ribosomal subunits to INHIBIT protein synthesis

Back 8

bacteriostatic agents
e.g. tetracyclines

Front 9

These type of agents bind to the 30S ribosomal subunit and ALTER protein synthesis

Back 9

bactericidal agents
e.g. aminoglycosides

Front 10

These agents affect bacterial nucleic acid metabolism which inhibit RNA polymerase or topoisomerases

Back 10

rifamycins

Front 11

These agents inhibit essential enzymes of folate metabolism

Back 11

anti-metabolites

Front 12

Six keys to selection of best Rx

Back 12

1. ID of infecting organism
2. Determining organism's susceptibility to a particular drug
3. Site of infection
4. Patient-specific factors
5. Safety of Rx
6. Cost

Front 13

This type of drugs arrest the growth and replication of bacteria at clinical serum concentrations which limits spread of infection while the immune system attacks

Back 13

bacteriostatic drugs

Front 14

This type of drug kills bacterial at clinical serum concentrations and is used in seriously ill patients

Back 14

bactericidal drugs

Front 15

What 7 factors are patient specific variables in determining rx selection

Back 15

immune function, renal function, liver function, blood flow/perfusion, age, pregnancy and lactation

Front 16

Poor function of this can lead to dangerous accumulation of antimicrobials and cause sever adverse events

Back 16

poor renal function

Front 17

Do antibiotics cross the placenta?

Back 17

YES

Front 18

Agents acting only on a single or limited group of microorganisms
e.g. isoniazid (myobacteria)

Back 18

narrow-spectrum antibiotics

Front 19

Agents effective against gram-positive organisms and a significant number of gram-negative bacteria
e.g. ampicillin

Back 19

extended-spectrum antibiotics

Front 20

Agents affecting a wide variety of microbial species
e.g. tetracycline, chloramphenicol

Back 20

broad-spectrum antibiotics

Front 21

Complications of antibiotic Rx:
Allergic reactions frequently occur to antibiotics and/or their metabolic products. Reactions can range from mild-> anaphylactic shock

Back 21

hypersensitivity reactions

Front 22

Complications of antibiotic rx:
High serum concentrations of certain antibiotics can cause toxicity by directly affecting cellular processes in the host

Back 22

direct toxicity

Front 23

Complications of antibiotic rx:
Drug rx, particularly with broad-spectrum antimicrobials or combo Rx can lead to alterations of normal microbial flora of upper respiratory, intestinal and GI tracts causing overgrowth of opportunistic organisms (esp. fungi or resistant bacteria). Often difficult to treat!

Back 23

super infections

Front 24

This occurs when bacteria are resistant to an antibiotic Rx if the maximal level that can be tolerated by the host does not halt their growth

Back 24

resistance

Front 25

General mechanisms of antibiotic resistance, 3 things

Back 25

1. the drug doesn't reach its target
2. the drug isn't active
3. the drug target is altered

Front 26

What are two genetic alterations that can cause antimicrobial resistance

Back 26

1. spontaneous DNA mutations
2. DNA transfer of drug resistance

Front 27

insertion, deletion or substitution of one or more nucleotides within the genome. resistance mutations allow organisms to proliferate under conditions of drug exposure

Back 27

spontaneous DNA mutations

Front 28

Typically the mutation is transferred to daughter cells this way in spontaneous mutations

Back 28

vertically transferred

Front 29

acquired resistance via DNA transfer from one bacterium strain to another

Back 29

DNA transfer of drug resistance

Front 30

In DNA transfer of drug resistance how is the DNA transferred?

Back 30

horizontally transferred

Front 31

Altered protein expression in drug-resistant organisms can be mediated by what four mechanisms?

Back 31

1. altered drug target expression
2. enzymatic inactivation
3. altered membrane permeability (decreased drug accumulation at site of infection)
4. altered drug pump efflux (decreased drug accumulation at site of infection)

Front 32

A number of antibiotics act by targeting what

Back 32

the bacterial ribosome (because they are structurally distinct from mammalian ribosomes)

Front 33

Bacterial ribosomes are more similar to what type of mammalian ribosome

Back 33

mitochondrial ribosomes

Front 34

Are bacterial ribosomes or mammalian ribosomes smaller?

Back 34

bacterial ribosomes are smaller (70S) vs. mammalian (80S)

Front 35

What type of drugs are tetracyclines

Back 35

broad-spectrum, bacteriostatic antibiotics (protein synthesis inhibitors)

Front 36

These drugs are effective against a range of aerobic and anaerobic gram+ and gram- bacteria

Back 36

tetracyclines

Front 37

MOA for this drug:
gram-: enter via passive diffusion through porin channels and energy-dependent transport to inner membrane
gram+: requires energy
Then binds reversibly to the 30S bacterial ribosome, blocking the tRNA binding to A site and inhibits protein translation

Back 37

tetracyclines MOA

Front 38

Because of the high toxicity, this drug is only used in patients with life-threatening infections where no other alternatives exist!

Back 38

Chloramphenicol

Front 39

What four adverse effects are associated with Chloramphenicol?

Back 39

1. hypersensitivity reactions
2. hematological toxicity
3. gray baby syndrome
4. many DDI's

Front 40

MOA of this drug:
inhibits protein synthesis in bacteria and eukaryotic cells, readily penetrates bacterial cells via facilitated difusion, binds reversibly to 50S ribosomal subunit and inhibits mitochondrial protein synthesis in mammalian cells

Back 40

Chloramphenicol MOA

Front 41

Four examples of macrolides

Back 41

azithromycin, clarithromycin, telithromycin, erythromycin

Front 42

These protein synthesis inhibitors are bacteriostatic agents that may be bactericidal for some organisms at high concentrations

Back 42

macrolides and ketolides

Front 43

Erythromycin was the first of this class to be used clinically as an alternative to penicillin in patients who are allergic to β-lactam antibiotics

Back 43

macrolides

Front 44

Typical therapeutic applications for this class of protein synthesis inhibitors include: mycoplasma pneumonia, syphilis, chlamidial infxns, legionellosis, pertussis, sterp, tetanus, diphtheria, campylobacter

Back 44

macrolides

Front 45

MOA for this drug class:
binds reversibly to 50S ribosomal subunits, inhibits translocation step (erythromycin), binds and causes a conformational change that terminates protein synthesis by interfering with transpeptidation and translocation

Back 45

macrolides

Front 46

These two drugs show cross-resistence with erythromycin

Back 46

clarithromycin and azithromycin

Front 47

This drug, a ketolide, can be effective against macrolide-resistant organisms

Back 47

telithromycin

Front 48

1. inability of the organism to take up the antibiotic or the presence of an efflux pump
2. decreased affinity of the 50S ribosomal subunit for the antibiotic due to methylation of an adenine in the 23S bacterial ribosomal RNA
3. presence of a plasmid--associated erythromycin esterase
all are mechanisms of resistance of what class of drugs

Back 48

macrolides

Front 49

What one difference between macrolides and ketolides makes ketolides effective against certain resistance mechanisms macrolides are not?

Back 49

a structural difference in ketolides neutralizes the common resistance mechanism that render macrolides ineffective

Front 50

MOA for this drug:
binds exclusively to the 50S subunit of bacterial ribosomes and suppresses protein synthesis. Binding site is close to erythro and chloram so simultaneous dosing may cause interactions

Back 50

Clindamycin

Front 51

This drug is used primarily to treat infections cause by anaerobic gram+ bacteria such as B. fragilis

Back 51

clindamycin

Front 52

Resistance to clindamycin is mainly often due to

Back 52

altered metabolism

Front 53

This drug was introduced to combat resistant gram+ organisms (vancomycin and methicillin resistant strains) and is generally bacteriostatic

Back 53

linezolid

Front 54

MOA for this drug:
binds on a site on the 50S subunit near the interface with the 30S subunit and inhibits formation of 70S initiation complex

Back 54

linezolid

Front 55

Resistance of this drug occurs due to point mutations in 23S rRNA which leads to decreased binding to target site

Back 55

linezolid

Front 56

This drug is the inhibitor of bacterial cell wall synthesis

Back 56

vancomycin

Front 57

This is a tricyclic glycopeptide effective primarily against gram+ organisms and has become increasingly important in treating multiple drug-resistant organisms

Back 57

vancomycin

Front 58

Adverse effects of this drug include:
hypersensitivity reactions, red man syndrome (toxic effect on mast cells causing histamine release), auditory impairment and nephrotoxicity

Back 58

adverse effects of vancomycin

Front 59

The bacterial cell wall is composed of this polymer

Back 59

peptidoglycan

Front 60

To be maximally effective, inhibitors of this synthesis require actively proliferating microorganisms causing little or no effect on bacteria that aren't growing and dividing

Back 60

inhibitors of cell wall synthesis

Front 61

MOA for this drug:
inhibits synthesis of bacterial cell wall phospholipids and peptidoglycan polymerization via binding to the D-ala-D-ala side chain, which prevents trans-glycosylation step and weakens cell wall. It is bactericial for dividing microorganisms

Back 61

vancomycin

Front 62

Besides vancomycin, what is another inhibitor of bacterial cell wall synthesis?

Back 62

bacitracin

Front 63

This drug is a mixture of polypeptide antibiotics active against a wide variety of gram+ organisms

Back 63

bacitracin

Front 64

This drug is used only in topical application due to serious nephrotoxicity with use
*often combined with neo/polymyxin, opthalmic/derm uses

Back 64

bacitracin

Front 65

MOA of this drug:
binds to and interferes with the dephosphorylation of C55-isoprenyl pyrophosphate, which is a reaction essential for regeneration of lipid carrier required for cyclic synthesis of peptidoglycan

Back 65

bacitracin