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Immunology > Antimicrobial Therapies > Flashcards

Antimicrobial Therapies Flashcards

1
Q

What is Prontosil?

A

First example of a sulphonamide antibiotic. Is bacteriostatic and synthetic. often used with trimethoprim for a symbiotic effect.  Used to treat UTIs and RTIs, bacteraemia and prophylaxis for HIV+ individuals. Becoming more commonly used due to resistance to other microbials, despite some host toxicity. Only acts on gram positive bacteria. 

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2
Q

Why might you give a patient multiple different antibiotics?

A

They may act on different stages of bacterial growth and give a symbiotic effect e.g. sulfonamides and trimethoprim act on two different stages of bacterial development.

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3
Q

How do sulfonamides work?

A

Inhibition of other metabolic processes:  Sulfonamides interfere with folic acid synthesis by preventing addition of para-aminobenzoic acid (PABA) into the folic acid molecule through competing for the enzyme dihydropteroate synthetase.

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4
Q

What are beta-lactams?

A

Antibiotics, all of whom contain the beta lactam ring.
Interfere with the synthesis of the peptidoglycan component of the bacterial cell wall. Examples include Penicillin and methicillin. Bind to penicillin-binding proteins (PBP) which catalyse a number of steps in the synthesis of peptidoglycan.

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5
Q

What is an antibiotic and where do the majority come from?

A

An antibiotic is an antimicrobial agent produced by a microorganism that kills or inhibits other microorganisms. Most antibiotics in use today are produced by soil-dwelling fungi (Penicillium and Cephalosporium) or bacteria (Streptomyces and Bacillus). However, antibiotics commonly used today encompass a range of natural, semi-synthetic and synthetic chemicals with antimicrobial activity.

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6
Q

What is an antimicrobial?

A

Chemical that selectively kills or inhibits microbes (bacteria, fungi, viruses).

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7
Q

What is the difference between bactericidal and bacteriostatic?

A

Bactericidal – kills bacteria.

Bacteriostatic – stops bacteria growing.

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8
Q

What is an antiseptic?

A

Chemical that kills or inhibits microbes that is usually used topically to prevent infection.

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9
Q

What is meant by the minimal inhibitory concentration (MIC)?

A

The lowest concentration of antibiotic required to inhibit growth. The breakpoint is a clinically achievable concentration.

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10
Q

How does antibiotic resistance develop?

A

Population contains cells with AB resistance due to mutations/acquired DNA – possibly with a fitness cost e.g. Slow growth.
In absence of selection pressure (e.g. ABs) AB resistant strains have no advantage (and may have a disadvantage). Leads to low prevalence of AB resistant strains in patient population
In presence of selection pressure (e.g. Abs) resistant mutants outcompete. High prevalence of AB resistant strains in patient population.

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11
Q

What were misconceptions about antibiotic resistance initially?

A
  1. Resistance against more than one class of antibiotics at the same time would not occur.
  2. Horizontal gene transfer would not occur.
  3. Resistant organisms would be significantly less ‘fit’
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12
Q

What are the effects of antibiotic resistance?

A
  1. Increased time to effective therapy.
  2. Requirement for additional approaches – e.g. surgery.
  3. Use of expensive therapy (newer drugs).
  4. Use of more toxic drugs e.g. vancomycin.
  5. Use of less effective ‘second choice’ antibiotics.
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13
Q

What are the major Gram Negative AB resistant bacterial pathogens?

A

Pseudomonas aeruginosa
Cystic fibrosis, burn wound infections. Survives on abiotic surfaces.

E. Coli (ESBL) and E. coli, Klebsiella spp (NDM-1)
GI infection, neonatal meningitis, septicaemia, UTI.

Salmonella spp. (MDR)
GI infection , typhoid fever.

Acinetobacter baumannii (MDRAB) 
Opportunistic, wounds, UTI, pneumonia (VAP). Survives on abiotic surfaces.

Neisseria gonorrhoeae
Gonorrhoea.

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14
Q

What are the major Gram Positive AB resistant bacterial pathogens?

A 
Staphylococcus aureus (MRSA, VISA) 
Wound and skin infect. pneumonia, septicaemia, infective endocarditis.

Streptococcus pneumoniae
Pneumonia, septicaemia.

Clostridium difficle
Pseudomembranous colitis, antibiotic-associated diarrhoea.

Enterococcus spp (VRE) 
UTI, bacteraemia, infective endocarditis. 
Mycobacterium tuberculosis (MDRTB, XDRTB) 
Tuberculosis
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15
Q

What are aminoglycosides, how do they work, and when are they used?

A

Bactericidal antibiotics such as gentamycin or stretomycin. Target protein synthesis (30S ribosomal subunit), RNA proofreading and cause damage to cell membrane. Some toxicity thus limited use - but resistance to other antibiotics has led to increasing use.

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16
Q

What is rifampicin?

A

A bactericidal AB which targets the RpoB subunit of RNA polymerase. Spontaneous resistance is frequent.
It makes secretions go orange/red which affects compliance.

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17
Q

What is vancomycin?

A

A bactericidal AB which targets lipid II component of cell wall biosynthesis as well as wall crosslinking via D-alanine residues. Toxicity means it has limited use, but resistance to other antibiotics has lead to increasing use e.g against MRSA

18
Q

What is linezolid?

A

A bacteriostatic AB which inhibits the initiation of protein synthesis by binding to the 50S rRNA subunit.
It has a gram-positive spectrum of activity.

19
Q

What is daptomycin?

A

Bactericidal AB which targets the bacterial cell membrane. It has a gram-positive spectrum of activity.
Its toxicity limits its dose.

20
Q

Why don’t antibiotics harm human cells?

A

ABs have selective toxicity. They target different bacterial processes not found in mammals.

21
Q

Which different bacterial processes do ABs target?

A
  1. DNA replication
  2. Cell wall synthesis
  3. Plasma membrane damage
  4. Protein synthesis
     - Transcription
    - Translation
  5. Enzymatic activity/synthesis of metabolites
22
Q

What are the 4 mechanisms of antibiotic resistance?

A
  1. Altered target site
  2. Inactivation of the antibiotic
  3. Altered metabolism
  4. Decreased drug accumulation
23
Q

How do altered target sites arise in resistant bacteria? Provide examples

A

Can arise via acquisition of alternative gene or a gene that encodes a target-modifying enzyme.
Methicillin-resistant Staphylococcus aureus (MRSA) encodes an alternative PBP (PBP2a) with low affinity for beta-lactams.
Streptococcus pneumoniae resistance to erythromycin occurs via the acquisition of the erm gene, which encodes an enzyme that methylates the AB target site in the 50S ribosomal subunit.

24
Q

How do resistant bacteria inactivate antibiotics? Provide examples

A

Enzymatic degradation or alteration, rendering antibiotic ineffective.
Examples include beta-lactamase (bla) and chloramphenicol acetyl-transferase (cat).
ESBL and NDM-1 are examples of broad-spectrum beta-lactamases (can degrade a wide range of beta-lactams, including newest)

25
Q

How does penicillin resistance work?

A

Penicillin is a beta lactam and so beta lactamases break a bond in the beta lactam ring of penicillin, disabling the molecule.

26
Q

How do bacteria alter their metabolism to resist the effects of antibiotics?

A

Increased production of enzyme substrate can out-compete antibiotic inhibitor (e.g. increased production of PABA confers resistance to sulfonamides).
Alternatively, bacteria switch to other metabolic pathways, reducing requirement for PABA.

27
Q

How do resistant bacteria decrease drug accumulation?

A

Reduced penetration of AB into bacterial cell (permeability) and/or increased efflux of AB out of the cell – drug does not reach concentration required to be effective

28
Q

What are macrolides?

A

Antibiotics used to treat Gram-positive and some Gram-negative infections. Targets 50S ribosomal subunit preventing amino-acyl transfer and thus truncation of polypeptides e.g. Erythromycin, azithromycin.

29
Q

What are quinolones?

A

Synthetic, broad spectrum, bactericidal ABs. Target DNA gyrase in Gm-ve and topoisomerase IV in Gm+ve

30
Q

What are the 3 sources of antibiotic resistance genes?

A

Plasmids – extra-chromosomal circular DNA, often multiple copy. Often carry mutliple AB resistance genes – selection for one maintains resistance to all.

Transposons. Integrate into chromosomal DNA. Allow transfer of genes from plasmid to chromosome and vice versa.

Naked DNA. DNA from dead bacteria released into environment.

31
Q

What are the three mechanisms for horizontal spread of AB resistance in bacteria?

A

Transformation (uptake of extracellular DNA), Conjugation (pilus-mediated DNA transfer) and Transduction (phage-mediated DNA transfer).

32
Q

What are the non-genetic mechanisms for resistance/treatment failure?

A
  1. Biofilm
  2. Intracellular location
  3. Slow growth
  4. Spores
  5. Persisters
33
Q

What are the 5 given reasons for treatment failure aside from AB resistance?

A
  1. Inappropriate choice for organism
  2. Poor penetration of AB into target site
  3. Inappropriate dose (half life)
  4. Inappropriate administration (oral vs IV)
  5. Presence of AB resistance within commensal flora e.g. secretion of beta-lactamase
34
Q

How can you measure AB resistance?

A
  1. Swabs are typically streaked out onto diagnostic agar to identify causative organism.
  2. Once identified, the pathogen streaked over a plate and then over-laid with AB-containing test strips or discs.
  3. Other approaches include broth micro-dilution and PCR detection of resistance genes.
35
Q

Why is AB resistance common in hospitals?

A

Large numbers of infected people receiving high doses of antibiotics - strong selective pressure for emergence/maintenance of AB resistance

36
Q

What are the risk factors for Hospital Acquired Infections?

A
  • High number of ill people! (immunosuppression)
  • Crowded wards
  • Presence of pathogens
  • Broken skin – surgical wound/IV catheter
  • Indwelling devices - intubation
  • AB therapy may suppress normal flora
  • Transmission by staff – contact with multiple patients

PINC BIT

37
Q

What are some common pathogens picked up through noscomial infection?

A 
Methicillin-resistant S. aureus (MRSA) 
Vancomycin-insensitive S. aureus (VISA) 
Clostridium difficle 
Vancomycin-resistant enterococci (VRE) 
E. coli (ESBL/NDM-1)  
P. aeruginosa 
Acineterbacter baumannii 
Stenotrophomonas maltophilia
38
Q

What harm can come about when antibiotic therapy impairs commensal flora?

A

In health, commensal organisms can out-compete pathogen with regards to adhesion, metabolism, growth. Pathogen cannot colonise at levels sufficient for infection. After AB therapy => pathogen has no competition which can lead to overgrowth.  When a pathogen then produces toxins which damages the host, it becomes a symptomatic infection, and can spread to other patients

39
Q

How can we prevent the emergence of drug resistant bacteria and nosocomial infections?

A
  1. Prescribing strategies – tighter controls, temporary withdrawal of certain classes. Restriction of ABs for certain serious infections
  2. Reduce use of broad-spectrum antibiotics
  3. Quicker identification of infections caused by resistant strains
  4. Knowledge of local strains/resistance patterns
  5. Modification of existing medications to e.g. Prevent cleavage (beta-lactams) or enhance efficacy. E.g. Methicillin.
  6. Combinations of antibiotic + inhibitor of e.g. Beta-lactamase. E.g. Augmentin.
40
Q

What are fungi?

A

Fungi are eukaryote organisms that digest their food outside of the cell by secreting hydrolytic enzymes which can break down biopolymers to be absorbed for nutrition.

41
Q

What classes of conditions do fungi cause?

A
  1. Allergy – allergic reactions to fungal products e.g. allergic bronchopulmonary aspergillosis (ABPA)
  2. Mycotoxicoses – ingestion of fungi and their toxic products e. g. aflatoxin
  3. Mycoses – superficial, subcutaneous or systemic colonisation, invasion and destruction of human tissue.
42
Q

What are the targets for antifungal therapy?

A
  1. Cell membrane - fungi use principally ergosterol instead of cholestrol
  2. DNA synthesis - some compounds may be selectively activated by fungi, arresting DNA synthesis
  3. Cell wall - fungi have a cell wall

Immunology (9 decks)

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