An Infection Model / Anti-microbials And Resistance

Question 1

Outline the infection model.

Answer 1

Question 2

What are the determinants of disease?

Answer 2

Patient Pathogen Practice Place

Question 3

In the context of the infection model what can Patient be broken down into?

Answer 3

Question 4

There are four categories of pathogen. What are they?

Answer 4

Viruses Bacteria (Prokaryotes) Fungi (Eukaryotes) Parasites (Eukaryotes)

Question 5

What can parasites be subdivided into?

Answer 5

Protozoa Helminth (Worm)

Question 6

What can a fungus be subdivided into?

Answer 6

Yeast Mould

Question 7

What are the mechanisms of infection?

Answer 7

Contiguous spread Inoculation Haematogenous Ingestion Inhalation Vector Vertical transmission

Question 8

How does infection occur?

Answer 8

Question 9

How is a patient managed?

Answer 9

First they must be diagnosed. History, Examinations and Investigations are important for this. Then there must be treatment (if required). This can be specific or supportive. Prevention of the spread of infection - both in the hospital and the community - must also be considered.

Question 10

What are specific treatments?

Answer 10

Antimicrobials or surgery - drainage, debridement and dead space removal.

Question 11

What are supportive treatments?

Answer 11

Managing symptoms or restoring physiological function.

Question 12

What is the outcome of infection?

Answer 12

A spectrum between cure and death. Chronic infection and/or disability are possible results

Question 13

What is an antimicrobial? How long have they been prominent in fighting infection?

Answer 13

Something that is active against microbes Mainly the last 100 years - Penicillin, 1928 (used in 1941 for the first time)

Question 14

How are antimicrobials classified?

Answer 14

Antibacterials/Antibiotics Antifungals Antivirals Antiprotozoa

Question 15

How can antibiotics be further classified?

Answer 15

Bacteriocidal or bacteriostatic (can be both) Spectrum - Broad or Narrow? Target site (mechanism of action) Chemical structure

Question 16

What does bacteriocidal mean? What does bacteriostatic mean?

Answer 16

It kills bacteria. It stops bacteria dividing.

Question 17

What are the mechanisms of action of antibiotics? (Hint: There are 4); Give an example of the classes of antibiotics that fall under each mechanism of action?

Answer 17

Cell wall synthesis (Beta-lactams & Glycopeptides) Cell membrane function (Polymixins) - not common Protein synthesis (Tetracyclines, Aminoglycosides & Macrolides) Nucleic acid synthesis (Quinolones, trimethoprim, rifampicin)

Question 18

How do quinolones work, in general what are they used for?

Answer 18

They prevent nucleic acid synthesis through inhibiting DNA gyrase. Broad-spectrum antibiotics, very effective against gram negatives, although there is increasing resistance. An example is ciprofloxacin.

Question 19

What is trimethoprim?

Answer 19

It is a dihydrofolate reductase inhibitor and is primarily used to treat UTIs. Can be combined with sulphamethoxazole to treat pneumocystis carinii pneumonia (PCP) and MRSA.

Question 20

What is rifampicin used to treat?

Answer 20

It is of the rifamycin group. It is a bacteriostatic, typically used to treat mycobacterium infections (e.g. TB, Leprosy). Also used to treat MRSA in conjuction with fusidic acid.

Question 21

How do tetracyclines work? What are they used to treat?

Answer 21

Prevent protein synthesis. Broad-spectrum, specific use in penicillin allergy for gram positive bacteria. Active for atypical pathogens in pneumonia as well against chlamydia and some protozoa. Can be used as a prophylaxis for malaria (doxycycline). Given orally only (not to children <12).

Question 22

What are aminoglycosides?

Answer 22

Effective against gram negative aerobes. Reserved for severe gram negative sepsis. An example is gentamycin which is given IV or IM (not absorbed through gut)

Question 23

What are macrolides?

Answer 23

Predominantly used for mild gram positive infections and the gram negative haeomphilus influenzae. Has a broader range than penicillin - often used as a substitute if patient is penicillin allergic. Examples include erythromycin and clarithromycin.

Question 24

How do polymixins work? What are they used to treat?

Answer 24

Target the lipopolysaccharide membrane - therefore only effective against gram negative bacteria. Are neuro and nephrotoxic - used as a last resort against multi-drug resistant pseudomonas aeuroginosa.

Question 25

How do beta-lactams work?

Answer 25

Effective in gram positive bacteria. Many bacteria have developed becta-lactam resistance (due to their own production of beta-lactamase) so often given with clavulanic acid. Includes penems (penicillins) and cephalosporins.

Question 26

What are glycopeptides used to treat?

Answer 26

Gram positive cocci and normally only patients who are critically ill (has a narrow therapeutic window due to high toxicity), e.g. MRSA. An example is vancomycin. Ggiven parenterally (e.g. IV) because it is not absorbed in the GI (not effective in systemic infections). Given orally if infection is solely in the gut, e.g. C Diff.

Question 27

How can bacteria be resistant to antibacterials?

Answer 27

1. Production of drug inactivating enzymes - beta-lactamases, aminoglycoside enzymes 2. Altered target - The enzyme, that is the target of the antibacterial, changes in some way to reduce its affinity to the antibacterial, e.g. meticillin resistance, 3. Altered uptake - ↓ permeability (e.g. beta-lactams); ↑ efflux (e.g. tetracyclines)

Question 28

How can bacteria become resistant to antibacterials?

Answer 28

Genetically: 1. Chromosomal gene mutation (mutation conferring bacteria resistance - will survive and replicate - survival of the fittest) 2. Horizontal gene transfer - through conjugation, transduction and transformation

Question 29

What are the mechanisms of horizontal gene transfer? Give a brief overview of each.

Answer 29

Conjugation - transfer of genetic material via plasmids between bacteria through direct cell-to-cell contact Transduction - transfer of genetic material between bacteria via a virus or (bacterio)phage Transformation - introducing DNA or RNA to bacteria, which is subseqeuently taken up and expressed

Question 30

How can you measure antibiotic activity?

Answer 30

Disc testing (colonise bacteria in a petri-dish, putting several discs, evenly-spaced, with different antibiotics on them in the petri-dish… etc.) Minimum inhibitory concentration (testing the bacteria with different concentrations of antibiotic - e.g. 0.05, 0.1, 0.2, 0.4 mg/L etc. and observing the lowest effective concentration)

Question 31

What is penicillin effective against? How about amoxicillin?

Answer 31

Gram positive streptococci. Also has some activity against gram negative bacteria.

Question 32

What class of drug is flucoxacillin? What is it used to treat?

Answer 32

A narrow spectrum (predominantly gram positive) penicillin, resistant to beta-lactamase. Effective against staphs and streps. Used to treat soft tissue infections (e.g. cellulitis - although will not cover strep pyogenes - use penicillin as well) as well as URTIs. Also used to treat endocarditis, meningitis, osteomyelitis etc. Can be given orally.

Question 33

What combinations can be used to inhibit beta-lactamases?

Answer 33

Co-amoxiclav - amoxicillin + clavulanic acid Effective against streps, staphs, anaerobes and a few gram negative bacteria, Piperacillin/tazobactam - Same but effective against more gram negatives including Pseudomonas aeruginosa

Question 34

What class of drugs are cephalosporins? What are they effective against?

Answer 34

They are beta lactams effective against some gram positive and negative (more so in recent generations) bacteria. Association with C. Diff.

Question 35

What class of drug is ceftriaxone? What can it be used to treat?

Answer 35

It is a cephalosporin - a type of beta lactam. Ceftriaxone has good activity in the CSF - it is often given in cases of meningitis caused by strep pneumoniae, neisseria meningitidis, haemophilus influenzae amongst others.

Question 36

What class of drugs are carbapenem? What are they effective against?

Answer 36

They are very broad spectrum (including anaerobes). Active against most gram negatives. An example is meropenem. Used as ‘a last resort’, in resistant strains of E Coli and Klebsiella Pneumoniae, although resistant strains are now emerging.

Question 37

What are the classes of antifungals?

Answer 37

Azoles - active against yeasts and can be with molds. Inhibit cell membrane synthesis. An example is fluconazole which is used to treat Candida. Itraconazole is also active against Aspergillus. Polyenes - inhibit cell membrane function. Nystation is used for topical treatment of candida. Amphotericin for IV treatment of systemic fungal infection (e.g. aspergillus).

Question 38

What are the main antivirals used?

Answer 38

Aciclovir - when phosphorylated, inhibits viral DNA polymerase, used for herpes simplex (genital herpes, encephalitis) and varicella zoster (chicken pox, shingles) Oseltamivir (‘Tamiflu’) - inhibits viral neuraminidase, used in cases of Influenza A & B

Question 39

What is metronidazole?

Answer 39

An agent with antibacterial and antiprotozoal properties. Active against anaerobic bacteria but also effective against protozoa: amoebae (dysentery & systemic), giardia (diarrhoea), trichomonas (vaginitis)