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Antibiotics Flashcards

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1
Q

What are some types of antimirobial agents?

A

They are defined as antibiotics (naturally occurring), chemotherapeutic agents (synthetic) or semi-synthetic (based on naturally occurring agents but with alterations).

Semi-synthetic drugs can alter pharmacological properties of naturally occurring antibiotics to:
- change the kinetics
- reduce toxicity
- modify antimicrobial spectrum
Furthermore, it can be used to extend a patent and make money for pharmaceutical companies.

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2
Q

How are some antibiotics classified?

A

Antimicrobials can be classified by source (natural/synthetic), by pharmacological class or by their broad mechanisms of action (how they affect bacterial growth - bacteriostatic or bactericidal).

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3
Q

What is the difference between bacteriocidal and bacteriostatic?

A

Bacteriostatic do not kill the bacteria, but instead arrest the reproduction of bacteria.
Bactericidal must cause a 3 log reduction (99.99% lethal).

If the bacteria stop growing in the host, then the host immune system is able to overcome the infection and kill the bacteria without the side effects of bactericidal antibiotics.

Bactericidal must be used in immunocompromised individuals as they have no immune response.

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4
Q

What are some general features of tetracyclines?

A
  • Tetracyclines: Naturally they are eliminated quickly in the body, so by synthetically altering the kinetics of the drug so as to make it more convenient.
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5
Q

What are some general features of beta-lactams?

A
  • Beta-Lactams: many different types of B-Ls. Includes the penicillin group and the cephalosporin group of antibiotics. [know the structure of Penam]
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6
Q

Give a history of the features of penicillins?

A

Many of the beta-lactams are derived from naturally occurring antibiotics but are in fact semi-synthetic.
The original Penicillin was Penicillin G. Has no toxicity unless an individual is allergic. (So okay for pregnancy, infants etc.) However it must be injected because it is acid labile and would be destroyed in the stomach. It is a painful injection (unpleasant for children). The addition of a small group onto the corner of the molecule allowed the penicillin to become acid stable and now it is able to be ingested orally. (Penicillin V)

Penicillin G and V work on Gram positive cocci and rods, however resistance trains of Staph. aureus and Strep. emerged in hospitals where many infections were treated ‘in bulk’. The process of treating with Penicillin was actually selecting for resistance. Methicillin was used for these resistance strains however it was more toxic (could cause renal toxicity) and so they attempted to synthesize a new form that was less toxic. Now, Staph. aureus can become resistant to this and are referred to as Methacillin resistant Staph. aureus (MRSA) - suggesting it is resistance to all beta-lactams.

Ampicillin has a broader spectrum and is active over Gram negative rods as well as that which Penicillin targeted. Amoxycillin is now used, which has a slightly different structure however it bears no clinically significant difference.

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7
Q

What is selective toxicity?

A

Drug that affects the microbe without affecting the host. Some antibiotics that affect the host can be used as anti-cancer drugs as they target the abnormal elements of cancer.

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8
Q

What are some targets of microbial agents?

A

Cell wall: beta lactams, glycopeptides (great target for antibiotics as it targets peptidoglycan synthesis)

Cytoplasmic membrane: polymyxins, polyenes- effective for fungi treatment (not a great target because of the similarity between the bacterial and host cell membrane)

Ribosomes: aminoglycosides, chloramphenicol, tetracyclines, macrolides

Nucleic Acid: rifamycins, quinolones (act on different stages/targets of Nucleic acids ie. transcription, folding etc.)

Folic Acid: suphonamides, trimethoprim (synthetic agents that interrupt with the synthesis of folic acid; we cannot make folic acid naturally but bacteria can so this is a selective targeting mechanism)

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9
Q

What is the general structure of peptidoglycan?

A
  • Made up of two sugars (N-AG and M-AMA) to give layers of sugar that are cross linked by a peptide.
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10
Q

In Staph. Aureus, explain the structure of peptidoglycan?

A
  • Because humans cannot make D amino acids, the alternating D and L in the peptidoglycan causes the rigidity of the cell wall.
  • This molecule is on the outside of the bacteria. The blocks of the peptidoglycan are produced internally in the cell and then transported to the outside one block at a time.
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11
Q

Explain the biosynthesis of peptidoglycan.

A
  • precursors synthesised from intermediated in cytoplasm
  • Becomes immobilised on inner aspect of plasma membrane
  • Synthesis of building block continues
  • When complete, ‘building block’ transported to exterior aspect of membrane
  • Linked to growing peptidoglycan chain

Peptidoglycan is capable of cross linking:

  • Drugs can bind the enzymes that catalyse the cross-linking of peptidoglycan.
  • Enzymes include transpeptidases or penicillin binding proteins and many others. This is because of the many varieties of cell walls.
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12
Q

What is the action of vancomycin?

A

Action:
Discovered long ago, not really useful until MRSA came along and now it is used to treat it.
It binds to D-ala, D-ala which is found on Staph. aureus peptidoglycan.
It doesn’t act on gram negative bacteria at all because it is so big and so charged.

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13
Q

What are some resistance mechanisms of vancomycin?

A

Resistance mechanisms:
The baceria can change the attachment site from D-ala-D-ala to have a sugar component. This is often found in enterococci.

If Staph. aureus develops resistance in this fashion to vancomycin, then there would be very limited treatments. It did occur- VRSA. They are very rare and appear to have died out on their own due to the energy strain of adding a sugar component.

It can produce another type of resistance. VISA (Vancomycin Intermediate-resistance Staph. aureus) has far more cell wall which affects the binding capacity of the Vancomycin by acting like a sponge to absorb the Vancomycin.

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14
Q

What are the actions of beta-lactams?

A

Action:
Penicillin mimics the D-ala-D-ala bond that causes the transpeptidase enzymes to bind penicillin instead of causing cross-linking. This inactivates the enzyme. Thus penicillin is a suicide inhibitor.
Penicillin is a bactericidal drug because of the mechanisms of the bacteria to constantly monitor cell wall production. Without the cell wall, the hypertonic nature of bacteria causes the influx of water into the cell which swells up and are then killed by osmotic lysis.

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15
Q

What is a resistance mechanism for beta-lactams?

A
  • Beta-lactamase - produced by bacteria to overcome the effects of beta-lactams; can be overcome by types of beta-lactam that inhibits the action of only plasmid inherited beta-lactamase; clavulanic acid. (P. Auruginosa has chromosomal lactamases and cannot be overcome)
  • altered penicillin-binding proteins
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16
Q

What is the action of beta lactamase?

A

The antibacterial spectrum of beta-lactam antibiotics varies greatly because bacteria have different PBPs. The accessibility of the antibiotic to PBPs varies and the susceptibility of antibiotic to beta-lactamase varies.

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17
Q

Name some antibiotics that act on protein synthesis.

A

Recognition: aminoglycosides, tetracyclines
Peptidyl transfer: chloramphenicol
Translocation: macrolides
Isoleucyl-tRNA synthesis: mupirocin
Formation of initiation complex: oxazolidones

18
Q

What are some features of aminoglycosides?

A

Aminoglycosides are typically used topically or orally by GPs, but they are important in hospitals for serious infections.

Streptomycin was the first drug used for TB, but now we have gentamycin and tobramycin (naturally occurring) as well as amikacin (synthetic).

The drugs interfere with recognition by binding where the amino-acyl transfer RNA would bind and destroying the site.

19
Q

What are some mechanisms for modification of aminoglycosides?

A

Modification of Aminoglycosides:
Any one of these will inactivate the aminoglycoside. They are highly charged and are not very soluble in bacterial cell wall. They initially cross in small []s and then when the structure is damaged, it can cross in larger []s.
Adenylation:
Phosphorylation: { all of these lead to a lack of ability to enter the cell}
Acetylation:

20
Q

What is a resistance mechanism against aminoglycosides?

A
  • Enzymes in the bacteria cause modifications to the drug
  • Efflux is another mechanism where the drug is flushed from the bacteria
  • Ribosomal mutations stop it binding ribosomes
21
Q

What are some general resistance mechanisms to antimicrobial agents?

A

Drug inactivation

  • By hydrolysis, e.g. β-lactams
  • By covalent modification, e.g. aminoglycoside, chloramphenicol

Altering the target of drug action

  • Modify target to a less sensitive form, e.g. β-lactam, vancomycin
  • Overproduce target, e.g. vancomycin

Reduce access of drug to target

  • Reduced entry into cell, e.g. aminoglycosides
  • Increase efflux from cell, e.g. aminoglycosides, tetracycline

Failure to activate inactive precursor of drug
- e.g. metronidazole (synthetic pro-drug that is activate by nitro-reductase which is found in anaerobic microbes - easily overcome with microbial resistance), isoniazid (frontline treatment for TB)

22
Q

What are some examples of antibiotic resistance bacteria?

A
  • Methicillin-resistant Staph. aureus (MRSA)
  • Penicillin-resistant pneumococci (PRP)
  • Vancomycin-resistant enterococci (VRE)
  • Vancomycin-intermediate-resistant Staph. aureus (VISA)
  • Carbapenem-resistant Enterobacteriaceae (CRE)
  • Multidrug-resistant Gram-negative rods
  • Hypervirulent Clostridium difficile
  • Multidrug-resistant Mycobacterium tuberculosis (MDR-TB)
  • Extensively drug-resistant M. tuberculosis (XDR-TB)
23
Q

What is the genetic basis for resistance?

A 
The genetic basis of resistance can be intrinsic or extrinsic (via mutation or horizontal gene transfer)
(Intrinsic: Pseudomonas A. has intrinsic resistance towards most early class beta lactams; Enterococci are intrinsically resistant to sulphanomides because they do not synthesize folic acid in a similar way that those drugs don't affect humans because we do not synthesize folic acid.)
24
Q

Explain transformation.

A
  • In transformation, the cell is lysed and the fragments of DNA are taken up by competent bacterium which incorporate that DNA into their genome. Many bacteria aren’t naturally competent and must be activated in a lab setting if they are to take up the DNA.
  • Bacteria are also anxious about taking up DNA; have an ‘immune system’ that is made up of DNA methylation and restriction enzymes(ECHO R1; SOW 3A) - this allows the bacteria to only take in DNA which is related in some way to the innate genetic material of that bacteria.
  • higher numbers tend to be less virulent because the more virulent forms are found/discovered earlier and thus given the early letter/number categorization.
  • The most resistant of bacteria are within our body because they are often exposed to antibiotics. These bacteria can transfer resistance to other more dangerous types of bacteria. For example Staph. Epidermidis is highly resistant and it can transfer resistance to pathogenic bacterial infecting agents (ie. pneumococci)
25
Q

Explain Phage-mediated transduction.

A
  • mediated by bacteria-specific viruses. Many bacterial viruses have a head and a tail; are almost always dsDNA viruses. Their tails have enzymes that can break down peptidoglycan and allow them to penetrate the bacteria.
  • After integration, it can either reproduces happily along with the bacteria (lysogenic cycle- temperate-phage) or it can enter the lytic cycle where it produces many copies of the virus and destroys that bacteria (lysis from within) making it a virulent- phage. This generally happens when the phage senses that there is something wrong with the bacteria.
  • ie. Diphtheria toxin and cholera toxin are phage induced. The non-toxic bacteria undergoes lysogenic transformation and alters the genotype and therefore phenotype of the bacteria.
  • Shiga toxin is what makes E.coli (ON57) pathogenic. It is encoded by a phage. Infection can often give you diarrhoea and many people mistakenly treat with antibiotics. This results in increased production by the bacteria of phage induced toxins which worsens the symptoms of the infection.
  • Resistance by transduction occurs when many phages are produced and the very occasional abnormal phage. The DNA pf this phage, many not induce replication but the DNA an be taken up by the host bacteria. This process happens far more frequently than transformation and so the rare occasion becomes more likely.
  • Phage typing can be used to identify bacteria because only certain types of phage are taken up by a given bacterial type.
26
Q

Explain plasmid-mediated conjugation.

A
  • Plasmids are independent genetic elements. Cytoplasmic bridges are formed by a mechanisms which is not fully understood. This process requires direct contact. The plasmid is replicated as it crosses the bridge. The plasmid is the element that encourages the formation of the bridge.
  • Conjugation can occur between entirely unrelated bacteria unlike the other two mechanisms which require some relation between the donor and the recipient.
    This means that specific resistance of a gut bacterium can be transferred to completely unrelated pathogens.
  • These plasmids have incorporated resistance genes over generations that has led to an overall plasmid that has multi-resistance. This may mean that it has resistance to many types of antibiotics with genetic components that code for proteins/ enzymes such as beta lactamase etc.
  • Multi- resistance plasmids mean that a bacteria can go from completely susceptible to fully resistance in one conjugative genetic step.
  • Antibiotics are also the most powerful selective element of resistant types of bacteria. It is the simplest form of Darwinian evolution.
27
Q

What are some considerations when considering the type of antibiotic treatment to deliver?

A
  • Clinical Diagnosis - know what you are treating?
  • Microbiological Diagnosis - generally involves a susceptibility result from lab results.
  • In vitro Susceptibility (S, R or I)
  • Host Factors - immunocompromised, pregnant, allergic, cannot take oral drugs, etc.
  • Properties of the antibiotics - site of action, can it cross the BBB etc.
28
Q

Explain some processes associated with antimicrobial susceptibility testing.

A

Antimicrobial susceptibility is performed in order to determine any resistance that may be present. Because of acquired resistance, this can be very variable.

  • It is done through:
    • dilution methods
    • diffusion methods (not being replaced, so not as common)
29
Q

What is the MIC?

A

Determination of the MIC:
Minimum Inhibitory Concentration = gold standard

This example is streptomycin and it determines the minimum [ ] required to inhibit the growth of the microbes

Disc Susceptibility Test:
This is an example of a diffusion test.

The diameter of the zone of inhibition is an indication of the MIC.

30
Q

How do you Determine the Disk Diameter Breakpoints in a disc susceptibility test?

A

Illustrates the relationship between the MIC and the zone of inhibition diameter.

From the MIC we determine if the bacteria is resistant (R) or susceptible (S) but there is also an intermediate susceptibility (I) that allows for variation between tissues and individuals.

31
Q

What is an E-test Strip?

A

This is patented method that is a diffusion method of directly determining the MIC without graphical indication.

The MIC is directly read off of the results.

It is efficient but also quite expensive.

32
Q

What are some Specific Considerations regarding the Choice of Antimicrobial Agent?

A
  • Antimicrobial spectrum
  • Clinical efficacy
  • Route of administration
  • Route of excretion
  • Pharmacokinetics/pharmacodynamics
  • Availability
  • Cost- Not all drugs cost the same amount; and as such it is a consideration of the choice of drug.
33
Q

What are some elements on the League Table of Prescribing Errors?

A
  1. Prescribing an antimicrobial when one isn’t needed
  2. Prescribing the wrong antimicrobial
  3. Using the correct antimicrobial inappropriately:
    • wrong dose, course, route, patient
34
Q

What are some Considerations in Empirical (“Best Guess”) Antimicrobial Chemotherapy?

A

Quite often treatment is given before susceptibility testing and serotyping etc. are done in order to alleviate symptoms. For this reason, empirical treatment or best guess treatment is used. It follows the following checklist:

- Is treatment with an antimicrobial needed? 
- Is it safe and reasonable to wait before treating? 
- Are diagnostic samples needed? 
- If so, have they been collected? - good to collect before treatment in case treatment doesn't work
- What is the likely aetiological agent? 
- What is its antimicrobial susceptibility? 
- Is there evidence that treatment will benefit the patient?
35
Q

Why might antibiotic combinations be used?

A

Rationale: combinations of antibiotics are used for many reasons

  • As a temporary measure in an ill patient - so that you are making sure that the patient doesn’t die when you aren’t aware of the type of infection.
  • To delay the emergence of resistance - ie. drugs for TB: generally we want to use at least two drugs because they are acid fast drugs and replicate slowly, which means that there is a high chance of mutation so more drugs limits the chances of that TB strain becoming resistant.
  • To treat mixed infections
  • To reduce toxicity- antifungals
  • To achieve a synergistic effect
36
Q

What are some of the effects of antibiotic combination treatments?

A

Indifferent effects can be called an additive effect. It means that there is no advantage/disadvantage to using them together (unless one is toxic- and you can use less of that one drug)

Antagonism occurred in the treatment of meningitis with tetracyclins and penicillin (Penicillin works on growing bacteria so they need to be reproducing, and tetracyclins are bacteriostatic which means that penicillin isn’t working properly.)

Synergistic Relationships include amoxicillin and clavulanic acid. Another example is penicillin and an aminoglycoside.

37
Q

What are the mechanisms of synergy?

A
  • Block sequential steps of a metabolic pathway.
    • For example: Sulphonamides and trimethoprim in the synthesis of folic acid.
  • Inhibit Enzymatic Degradation
  • Enhance Antimicrobial Uptake by Bacterial Cell
    • aminoglycosides get into the cell pooorly and penicillins interfere with cell wall synthesis and make it easier for those drugs to get into the now more permeable cell wall.
38
Q

What are mechanisms of antagonism?

A
  • Inhibition of bactericidal activity by a bacteriostatic agent
    (e. g., tetracycline + penicillin G in meningitis)
  • Induction of enzymatic degradation
    (e. g. ampicillin + piperacillin)
    • ampicillin is not only destroyed by beta lactamase but it also causes more beta lactamase to be produced in more abundance. This is enhanced by piperacillin.
  • Competition for binding to the same target
    (e. g. lincosamide + macrolide?)
    • mechanism is uncertain.
  • Inhibition of target
    (e. g. polyene + imidazole?)
    • polyene (amphoteracin) and imidazole are anti-fungals and the use in combination may be synergistic or antagonistic.
39
Q

What are Jawetz’s Laws of combination?

A
  • Bacteriostatic + bacteriostatic = additive or indifferent
  • Bacteriostatic + bactericidal = antagonistic
  • Bactericidal + bactericidal = synergistic

(This is a rough guide; there are exceptions; but it is a nice simple guide for now and needs to be confirmed by lab tests)

40
Q

What is a method of Assessing Antibiotic Combination in Vitro?

A

The two edge rows give MICs for the two drugs in isolation.

  • Streptomysin: 32
  • Penicillin: 8

Empty wells below the line suggests synergistic combination; above the line suggests antagonism.

Microbiology (21 decks)

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