Antimicrobials + Antimicrobial resistance

Question 1

what parts of a pathogen do the most effective antibiotics target?

Answer 1

most successful antibiotics hit only three targets or pathways:

◊ The ribosome (which consists of 50S and 30S subunits)
◊ Cell wall synthesis
◊ DNA gyrase or DNA topoisomerase

Question 2

what is the difference between bacteriostatic and bactericidal

Answer 2

bacteriostatic= stops bacteria from reproducing (drugs like these stop the growth and we leave the body to kill it)
e.g. chloramphenicol, tetracyclines, macrolides, trimethoprim, clindamycin

bactericidal= kills the bacteria
e.g. penicillins, cephalosporins, ciprofloxacin, VANCOMYCIN its a type of glycopeptides (used for sepsis), monobactams

n.b. in the clinic most antibacterials are better described as potentially being both bacteriostatic and bactericidal.
Depending on the:
► dose
► duration of exposure
► the state of the invading bacteria

Question 3

antibiotics such as
*beta lactams e.g. penicillins, cephalosporins,carbapenems, monobactams
*vancomycin
*bacitracin
*glycopeptides
what part of the bacteria do these antibiotics target?

Answer 3

antibiotics such as
*beta lactams e.g. penicillins, cephalosporins,carbapenems, monobactams
*vancomycin= inhibits cell wall biosynthesis by targeting the d-Ala-d-Ala terminus of peptidoglycan (PG)
*bacitracin
*glycopeptides

target bacterial cell wall synthesis

Question 4

antibiotics in the class ‘polymyxins’ target which component of the bacteria

Answer 4

polymyxins target the cell membrane of bacterial cells in gram -ve bacteria

Question 5

what do the following antibiotics target on a bacteria:
*sulfonamides
*trimethoprim

Answer 5

these target folate synthesis

Question 6

what do the following antibiotics target on a bacteria:
*quinolones
*Rifampin

Answer 6

these antibiotics target nucleic acid synthesis;
*quinolones (targets DNA gyrase)
*Rifampin(targets RNA polymerase)

Question 7

what do the following antibiotics target on a bacteria:
*macrolides
*clindamycin
*linezolid
*chloramphenicol
*streptogramins

*tetracyclines
*aminoglycosides

Answer 7

all of these target PROTEIN SYNTHESIS IN BACTERIA i.e. it attacks the ribosome

*macrolides
*clindamycin
*linezolid
*chloramphenicol
*streptogramins
=these target 50S subunit

*tetracyclines
*aminoglycosides
=these 2 target the 30S subunit

Question 8

a bacteria synthesises its cell wall made of peptidoglycan with an enzyme called ____. What common antibiotic targets this enzyme?

Answer 8

a bacteria synthesises its cell wall made of peptidoglycan with an enzyme called transpeptidase (it cross links the peptidoglycan cell wall to make it strong)

BETA LACTAMS INTERFERE WITH THIS TRANSPEPTIDASE ENZYME + STOP CELL WALL SYNTHESIS

beta lactams; penicillins, cephalosporins,
carbapenems, monobactams

Question 9

how do glycopeptide antibiotics, such as vancomycin and teicoplanin kill bacterial cell walls?

Answer 9

*heptapeptide antibiotics are effective AGAINST GRAM +VE BACTERIA ONLY;
inhibit cell wall synthesis by forming H-bonds w the D-ala-D-ala cell wall so they bind to PRECURSOR (unlike beta lactams which target ezyme transpeptidase)

Question 10

How do polymyxins antibiotics work?

Answer 10

polymyxins are for gram
-ve bacteria only!
these bind to LPS (lipopolysaccharide); polymyxins do this by competing and displacing cations (Ca2+ and Mg2+) from phosphate– this allows them to bind to lipopolysaccharide (LPS)

Question 11

what is the difference between gram -ve and gram +ve bacteria

Answer 11

major difference between the two groups of bacteria is the thickness of the cell wall and the presence of an outer membrane in Gram negative bacteria only. The bacterial cell wall ranges from 20–80 nm thick for Gram positive and between 1.5–10 nm thick for Gram negative bacteria.

n.b. NEGATIVE GRAM ARE WORSE/harder to kill (NEGATIVE=BAD)

Question 12

How do aminoglycosides (antibiotics) work?
e.g. gentamicin, amikacin, tobramycin, neomycin, and streptomycin

Answer 12

aminoglycosides are bactericidal

they can work on gram +ve and -ve bacteria

they inhibit protein synthesis by binding, with high affinity, to the A-site on the 16S ribosomal RNA of the 30S ribosome

Question 13

• tetracylcines (e.g. doxycycline, minocycline)
  *macrolides (e.g. erythromycin, clarithromycin) and lincosamides (e.g.clindamycin)

these all inhibit protein synthesis by attacking ribosomes; which part do they affect?

Answer 13

these antibiotic groups are all are bacteriostatic

*tetracylines bind to 30S prevent tRNA interacting with the mRNA-ribosome complex

*macrolides + lincosamides bind to 50S prevent translocation of polypeptide chain along ribosome

Question 14

quinolones/fluroquinolones (e.g. ciprofloxacin, levofloxacin) are antibiotics which inhibit _____

Answer 14

quinolones/fluroquinolones are antibiotics which inhibit nucleic acid synthesis

• broad spectrum- bactericidal SYNTHETIC ANTIMICROBIALS

*inhibit DNA synthesis + promote DNA cleavage by binding to:
-topoisomerase II (DNA gyrase)
* topoisomerase IV (DNA topoisomerase)

Question 15

what is the action of Rifampicin antibiotic

Answer 15

Rifampicin= antimicrobial inhibitor of prokaryotic transcription initiation
* treats diverse mycobacterial infections and gram-positive bacterial infections

mechanism:
*Only binds to bacterial DNA dependent RNA polymerase

*Inhibits RNA polymerase in bacterial cells (especially Gram-positive)

*It is lipophilic and good candidate for treating TB meningitis as it an cross the blood-brain barrier

*Used in combination with other drugs to treat Mycobacterium tuberculosis and some staphylococcal infections

Question 16

what do sulphonamides such as co-trimoxazole, trimethoprim, sulfamethoxazole target in bacteria?

Answer 16

sulphonamides are folic acid inhibitors

• bacteria make their own folic acid, PABA (p aminobenzoic acid) is a PRECURSOR to making this folic acid

*sulphonamides mimic structure of PABA

*sulphonamides are competitive inhibitors of the enzymes that synthesise the folic acid in bacteria (DETAILS: inhibit enzyme dihydropteroate synthase)

• broad-spectrum bacteriostatic drugs against both Gram-positive and Gram-negative

Question 17

what do the following terms mean in ‘antibiotic terms’;
* susceptible
*intermediate
* resistant

Answer 17

Susceptible: A bacterial strain inhibited in-vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic success

Intermediate: A bacterial strain inhibited in-vitro by a concentration of an antimicrobial agent that is associated with uncertain therapeutic effect.

Resistant: A bacterial strain inhibited in-vitro by a concentration of an antimicrobial agent that is associated with a high likelihood of therapeutic failure

Question 18

what is an MIC breakpoint?

Answer 18

minimal inhibitory concentration (MIC)= the lowest concentration of an antibiotic which prevents visible growth of a bacterium.

The BREAKPOINT concentration is used to interpret results of in-vitro susceptibility testing and report the organism as S, I or R

Breakpoints are set by national committees and include
○ Microbiological data from MIC distrubutions
○ Dose effect relationships - PK/PD from animal and human studies
○ Clinical data relating outcomes to MIC values

(They are contentious and often change…..)

Question 19

Pharmacodynamic indices are important to understand when measuring antibiotic effectivity; name some of the ratios used + for which antibiotic group

Answer 19

In-vivo only the free fraction of the drug can contribute to antimicrobial activity
Three patterns of activity can be observed:

Concentration-dependent killing with prolonged antibiotic effect (PAE)
* Cmax / MIC ratio most important
* Characteristic of aminoglycoside, some fluoroquinolones

Time-dependent killing with minimal PAE
* T> MIC is most important parameter
* Characteristic of β-lactams

Time-dependent killing with prolonged PAE
* AUC24 / MIC ratio most important
Characteristic of glycopeptides, tetracyclines and macrolides

Question 20

beta-lactamases are enzymes that hydrolyse antibiotics and inhibit their function = these are produced by resistant bacteria

in the example of amoxicillin, what do we mix it with to make co-amoxiclav which is resistant to strains of S.aureus, E.coli and H.influenzae

Answer 20

There are 2 beta-lactamase inhibitors often given with penicillins to prevent these enzymes that can inhibit the effectivity of antibiotics such a beta-lactams, aminoglycosides and macrolides..

• CLAVULANIC ACID
• TAZOBACTAM

e.g. Co-amoxyclav= amoxicillin + clavulanic acid

Question 21

explain the role MDR efflux pumps play in antibiotic resistance

Answer 21

These MDR EFFLUX PUMPS are what bacteria take their nutrients up in; basically when the bacteria takes up the antibiotic it can learn to hijack the antibiotic and decrease its take up of it=== which means these receptors on the bacteria are called MDR efflux pumps – dangerous resistance as the genes for the MDR efflux pumps integrated into plasmids can transfer between bacteria and give rise to highly antibiotic resistant bacteria

Question 22

what type of antibiotic is erythromycin and how does it work

Answer 22

erythromycin is a macrolide antibiotic

macrolides inhibit bacterial protein synthesis by binding to the 50S subunit of a ribosome preventing translocation

Question 23

how does a resistance gene move between bacteria?

Answer 23

how a resistance gene moves between bacteria:
the cells come in contact, a porcess called conjugation and the plasmids move from one to another, taking the resistance gene with them and making the new bacterial cell drug resistant as well

Question 24

what group of antibiotics does vancomycin belong to?

Answer 24

Vancomycin is in a class of medications calledglycopeptide antibiotics (aka heptapeptide). It works by killling bacteria in the intestines. Vancomycin will not kill bacteria or treat infections in any other part of the body when taken by mouth

GLYCOPEPTIDE ANTIBIOTICS are affective against Gram-positive bacteria only

they work by inhibiting bacterial cell wall synthesis by forming hydrogen bonds with D-ala-D-ala senquence that the bacteria use to synthesise their peptidoglycan cell wall

Question 25

Group the following antibiotics/antimicrobials based on whether they target gram +ve bacteria, gram -ve bacteria or both

Answer 25

gram +ve bacteria only=
*beta lactams (however some recent broad spectrum lactams can work on both)
*glycopeptides/heptapeptides
*Rifampin

gram -ve bacteria only=
* polymyxins

both gram +ve and gram -ve=
*aminoglycosides
*macrolides
*tetracyclines
*quinolones
*sulphonamides