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PHCY220 > CD > Flashcards

CD Flashcards

1
Q

How to classify antibiotics

A
  1. by their spectrum of activity
  2. by their effect on bacteria
  3. by their mechanism of action
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2
Q

Bacteriostatic v bactericidal

A

BacterioSTATIC = inhibits bacteria growth & replication

BacterioCIDAL - kills bacteria, needs to be present at adequate conc.

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3
Q

What are class I antibiotic drugs

A

not good target
host & organism are similar
bacteria can use alternative energy source

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4
Q

What are class II antibiotic drugs

A

better bet
unique pathways or differing sensitivities
synthesis of essential growth factors

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5
Q

What are class III antibiotic drugs

A

good target
assembly of macromolecules (DNA, RNA, proteins)

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6
Q

What is the general rule to tell whether an antibiotic is bacterioCIDAL or BacterioSTATIC?

A
  • antibiotics that interfere with cell wall synthesis OR inhibit crucial enzymes → are generally bacterioCIDAL
  • antibiotics that inhibit protein synthesis → tend to be bacterioSTATIC
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7
Q

TYPE A unwanted effects of antibiotics

A

dose dependant, predictable, based on pharmacology & route
GI toxicity
affect good & bad bacteria
change to microbiota/flora (e.g. c. diff.)
nausea, pain, vomitting, diarrhoea
nephrotoxicity
with antibiotics metabolised/excreted by kidney

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8
Q

TYPE B unwanted effects of antibiotics

A

idiosyncratic reactions → cannot be predicted by pharmacology
RARE → don’t occur in most patients at any dose
can affect any organ system, but usually:
skin (rashes, eruption, itching)
liver (hepatoxicity)
blood cells (haematological toxicity, e.g. anemia)

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9
Q

TRIMETHOPRIM
(general + pharmacokinetics)

A
  • bacterioSTATIC (gram +/-)
  • inhibits key enzyme in folate synthesis (dihydrofolate reductase)
  • good oral bioavailability, fully absorbed in GI tract
  • high conc. in lungs, kidney, CSF
  • long half life, eliminated by kidney (t1/2 = 24h)
  • synergy with sulphonamides! → sulphamethoxazone + trimethoprim = co-trimoxazole
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10
Q

TRIMETHOPRIM
(unwanted effects)

A
  • nausea, vomitting
  • long term use → megoblasmic anemia, folate deficiency
  • rashes
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11
Q

TRIMETHOPRIM
(clinical uses)

A

NEVER USE IN PREGNANCY
* UTIs
* as cotrimoxazole → bronchitis (if patient can’t have penicillin), UTIs, ear infections, travellers diarrhoea

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12
Q

QUINOLONES
(general + pharmacokinetics)

A

e.g. ciprofloxacin, norfloxacin, moxifloxacin, levofloxacin
* bacterioCIDAL (broad spectrum, G- > G+)
* inhibits DNA gyrase (G-), inhibits topoisomerase IV (G+)
* well absorbed orally
* acummulates in kidney, prostate, lung
* doesn’t cross BBB (except ofloxacin)
* excreted predominately by the kidney

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13
Q

QUINOLONES
(unwanted effects)

A
  • usually mild, reversible effects
  • most frequent → skin rashes, GI (ciprofloxacin, c. diff. colitis)
  • rare → increased risk of tendon rupture (eldery + corticosteriods), arthopathy (young patients), QT prolongation
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14
Q

QUINOLONES
(clinical use)

A
  • rarely first line → reserved for serious infections
  • prostatisis, bone & joint infections (if no alternatives), gonhorrhoea
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15
Q

QUINOLONE
(interactions)

A

quinolones → partly metabolised in liver → therefore potential for a no. of diff. reactions!!!
* Al & Mg containing antacids inhibit absorption
* Ciprofloxacin is a moderate inhibitor of CYP1A2 & increases plasma conc. of other drugs metabolised by this enzyme
- clozapine, olanzapine (antipsychotics → QT prolongation)
- Tizanidine (alpha2 agonist, muscle relaxant in MS → weakness, bradycardia)

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16
Q

QUINOLONE
(interactions)

A

quinolones → partly metabolised in liver → therefore potential for a no. of diff. reactions!!!
* Al & Mg containing antacids inhibit absorption
* Ciprofloxacin is a moderate inhibitor of CYP1A2 & increases plasma conc. of other drugs metabolised by this enzyme
- clozapine, olanzapine (antipsychotics → QT prolongation)
- Tizanidine (alpha2 agonist, muscle relaxant in MS → weakness, bradycardia)

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17
Q

TETRACYCLINE
(general + pharmacokinetics)

A

e.g. doxycycline, minocycline
* bacterioSTATIC (broad spectrum)
* widely used → binds to 30s subunit & inhibits binding of aa-tRNA
* given orally or i.v. (parentally)
* absorption irregular, incomplete → better taken on an empty stomach
* chelate with metal ions, when given with dairy, antacids, Fe supplements → decreases absorption
* renal excretion: dox → unchanged in bile, mino → hepatic metabolism

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18
Q

TETRACYCLINE
(unwanted effects)

A
  • GI disturbances
  • photosensitivity
  • oesophagitis (doxycycline)
  • Ca2+ chelation → deposition in bones & teeth, can cause discolouration
  • AVOID IN CHILDREN, PREGNANCY
  • hepatotoxicity (renal failure, parental)
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19
Q

TETRACYCLINES
(clinical use)

A
  • declined due to resistance, but staging a comeback
  • respiratory infections → chronic bronchitis, community acquired pneumonia (CAP)
  • acne
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20
Q

AMINOGLYCOSIDES
(general + pharmacokinetics)

A

e.g. gentamicin, tobramycin
* bacterioCIDAL (many G-, some G+)
* irreversibily inhibits 30s subunit causing misreading of codons on mRNA → leading to improper protein expression
* given i.v. or i.m. (NOT absorbed in GI tract)
* elimination entirely by glomerular filtration in the kidney
* renal failure → leads to accumulation
* need to monitor conc. in serum to prevent toxicity → >48h therapy, therapeutic dose monitoring (TDM)

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21
Q

AMINOGLYCOSIDES
(unwanted effects)

A
  • most common in elderly, renal impairment
  • ototoxicity 2-45% (cochlea, vestibular), is dose dependant
  • nephrotoxicity 10-25% (tubule damage), more likely to occur if dehydration, pregnancy, hepatic dysfunction, NSAIDs, diuretics
  • rare but serious → paralysis from neuromuscular blockage
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22
Q

AMINOGLYCOSIDES
(clinical use)

A
  • reversed for hospital only serious infections
  • pneunomia, meningitis
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23
Q

MACROLIDES
(general + pharmacokinetics)

A

e.g. erythromycin, roxithromycin, azithromycin, clarithromycin
* bacterioSTATIC (most active against G+)
* reversible to 50s subunit
* administered orally or i.v.
* short t1/2 (axithromycin longer >12h)
* hepatic metabolism
* CYP1A2, 3A4 inhibitors → affect the bioavailability of other drugs

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24
Q

MACROLIDES
(drug interactions)

A

erythromycin, clarithromycin inhibit CYP3A4 & 1A2 → which increase the plasma conc. & effects of:
* benzodiazepines (e.g. triazolam) → excess sleepiness
* antipsychotics (e.g. clozapine) → blood, cardiac toxicity
* simvastatin → rhabdomyolysis
* warfarin → risk of bleeding

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25
Q

MACROLIDES
(unwanted effects)

A
  • GI effects (erythromycin > others)
  • cardiac toxicity → causing arrythmias, QT prolongation
  • hepatotoxicity
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26
Q

MACROLIDES
(clinical use)

A
  • respiratory infections (Pertussis, Legionella)
  • chlamydia
  • myoplasma infections
  • skin infections
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27
Q

PENCILLINS
(general + pharmacokinetics)

A

e.g. amoxicillin, flucoxacillin
* bacterioCIDAL (G-)
* frequently administered with a beta lactamase inhibitor
* oral use (amoxicillin absorption greater than ampicillin)
* [therapeutic] in joint, pleural (lung), pericardial (around the heart), fluid & bile
* rapid renal elination → high drug conc. in urine
* short t1/2 (30-60mins)

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28
Q

PENICILLIN
(unwanted effects)

A
  • normally well tolerated, high therapeutic index (TI)
  • hypersensitivity (1-10% chance)
  • hapten carrier conjugates promote immune response
  • anaphylaxis, itching, rash
  • GI → change in gut flora
  • diarrhoea, c. difficile colitis
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29
Q

PENICILLIN
(clinical use)

A
  • upper respiratory tract infections (URTIs)
  • urinary tract infections (UTIs)
  • salmonella infections
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30
Q

what antibotic class acts synergistically with aminoglycosides like gentamicin?

A

Penicillins

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31
Q

CEPHALOSPORINS
(generations & e.g.s)

A

cefalexin (1st gen)
cefaclor (2nd gen)
ceftriaxone (3rd gen)
cefepime (4th gen)
ceftaroline (5th gen)
* as generation increases → increased activity for G-, increased BBB penetration, longer t1/2 (cetriazone > 8h)

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32
Q

CEPHALOSPORINS
(general + pharmacokinetics)

A
  • bacterioCIDAL (G-)
  • more resistant to beta lactamase than penicillins
  • similar MOA to penicillins
  • oral absorption (except ceftriaxone = i.v. or i.m.)
  • renal excretion, dose adjust in renal insufficiency (ceftriaxone doesn’t need as much)
  • conc. high in synovial, pericardial fluid
  • ceftriaxone has sufficient CNS pentration for meningitis Tx
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33
Q

CEPHALOSPORINS
(unwanted effects)

A
  • hypersensitivity: similar to penicillins
  • anaphylaxis, bronchospasm, urticaridal (immediate)
  • maculopapular (delayed)
  • cross-reactivity with penicillins
  • hepatotoxicity (low compared to aminoglycosides)
  • antibiotic-associated colitis (with broad spectrum agents)
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34
Q

CEPHALOSPORINS
(clinical use)

A
  • skin, soft tissue infections (1st gen)
  • pneumonia, resistant/pregnancy UTIs (2nd gen)
  • gonorrhoea, meningitis, CAP (3rd gen)
  • hospital acquired (nosocomial) infections (4th gen)
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35
Q

CARBAPENEMS
(general + pharmacokinetics)

A

e.g. imipenem, meropenem, ertapenem
* bacterioCIDAL??
* similar mechanism to penicillins
* very resistant to beta lactamase & have the broadest antimicrobial spectrum than other beta lactams or antibiotics
* poor oral bioavailability → therefore usually given parentally (i.v. or i.m.)
* renal excretion, short t1/2 (except ertapenam, once daily dosing)
* imipenem: rapid hydrolysis, partial inactivation (kidney) given with cilastatin (dihydropeptidase inhibitor)

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36
Q

CARBAPENEMS
(unwanted effects)

A
  • similar to other beta lactams
  • nausea & vomitting
  • neurotoxicity, seizures (high dose, renal failure, CNS injury/disease)
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37
Q

CARBAPENEMS
(clinical use)

A
  • severe hospital acquired infections! (MRSA)
  • septicaema
  • hospital-acquired pneuomonia
  • intra-abdominal infections
  • complicated UTIs
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38
Q

MONOBACTAMS
(general + pharmacokinetics)

A

e.g. aztreonam
* bacterioCIDAL?? (only G-) limited spectrum
* interacts with PBPs & causes formation of long filamentous bacteria
* resistant to many beta lactamases
* antimicrobial activity more like aminoglycosides

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39
Q

MONOBACTAMS
(unwanted effects)

A
  • generally well tolerated
  • similar to other beta lactans
  • little cross-reactivity with penicillins/cephalosporins (except ceftazidine, structurally similar)
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40
Q

MONOBACTAMS
(clinical use)

A
  • only useful for G- infections!
  • pseudomonas aeruginosa
  • haemophilis influenza
  • neisseria meningitidis
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41
Q

GLYCOPEPTIDES
(general + pharmacokinetics)

A

e.g. vancomycin, teicoplanin, daptomycin
* bacterioCIDAL (active against G+ infections (MRSA))
* prevent addition of murein monomers to peptide chain
* poor oral absorption → i.v., t1/2 = 8h (teicoplanin = i.m.)
* excreted orally
* dose adjustment in renal impairment! → drug conc. plasma monitoring for vancomycin to minimise toxicity

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42
Q

GLYCOPEPTIDES
(unwanted effects)

A
  • nephtrotoxicity (worse + aminoglycoside)
  • hypersensitivity, rashes, SJS/TEN
    ‘red man syndrome’ (rapid i.v. injection >500mg/h → histamine release) (with vancomycin)
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43
Q

GLYCOPEPTIDES
(clinical use)

A
  • serious G+ infection
  • MRSA
  • Bacterial endocarditis
  • C. difficle colitis (oral admin
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44
Q

COMMENSALISM, COLONISATION & DISEASE

A
  • commensalism → microbes do not cause disease, e.g. normal microflora
  • colonisation → may not cause disease
  • disease → damage resulting from infection with a harmful microbe (pathogen)
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45
Q

features of commensals

A
  • low virulence
  • normal microflora
  • mostly protective → beneficial role
  • can/may cause disease if colonise a sterile area (e.g. via a wound) in a susceptible host
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46
Q

features of pathogens

A
  • disease causing microbes
  • multiple virulence factors → toxins, adhesion molecules, immune response modifiers
  • virulence factors allow them to cause disease in many hosts
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47
Q

examples of individual host factors

that increase susceptibility to infection

A
  • age (neonates & eldery)
  • pregnancy
  • nutrition (malnutrition & alcoholism)
  • illness (e.g. diabetes, cancer, liver disease)
  • immunosuppressive drugs
  • chemotherapy
  • atmospheric pollution
  • surgery/trauma
  • physical defects
  • stress
  • immune diseases (acquired or genetic)
  • gender/genetic predisposition
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48
Q

dependants of infection

A
  1. the pathogen (virulence factors)
  2. the host (susceptibility)
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49
Q

signs vs symptoms (in fever)

A
  • signs → measurable (observation, lab tests), objective, physical changes
  • symptoms → felt & reported by the individual, subjective, cannot be measured
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50
Q

Fever from infection
(how it arises)

A
  • a response to LPS (endotoxin) aka an ‘endogenous pyrogen’
  • LPS stimulates the pyrogenic response (fever response)
  • early warning for immune system
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51
Q

beneficial effects of fever

A
  • designed to enhance immune function
  • accelerates immune response → increased phagocytosis, T-helper cell adherance
  • prolongs/reduces growth of invading microoganism
  • reduced TNF⍺ & IFNɣ
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52
Q

detrimental effects of fever

A
  • increased metabolic demand & oxygen consumption
  • source of patients discomfort?
  • children’s seizures? (controversial)
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53
Q

what are the NICE guidelines

A
  • assessment criteria for fever in under 5’s
  • green (low risk), amber (intermediate risk), red (high risk)
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54
Q

what is the definition of antimicrobial therapy

A

specific therapy to kill microbes/inhibit their growth

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55
Q

what is the definition of an antibacterial

A

substance (biological or chemical) that inhibits the growth of bacteria (bacteriostatic) or kills them (bacteriocidal)

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56
Q

definition of antibiotic

A

subset of antibacterials
produced by microorganisms

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57
Q

characteristics of bacteria

A
  • are prokaryotes
  • NO nucleus, double stranded DNA genome in cytoplasm
  • NO cellular organelles (i.e. mitochondria, ER)
  • cell wall
  • +/- capsules, spore forming
  • unicellular
  • extra-chromosomal DNA (plasmids)
  • reproduce by binary fission, logarithmic growth
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58
Q

characteristics of bacteria that are selective drug targets

A
  • folate pathway
  • bacterial cell wall
  • outer membrane
  • protein synthesis
  • replication
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59
Q

how does the folate pathway of bacteria make a good drug target?

A
  • folate pathway → used in making DNA & proteins
  • humans get folic acid from our diet BUT bacteria make their own dihydrofolate (DHF) → selective target for sulfonamides
  • trimethoprim = a dihydrofolate reductase (DHFR) inhibitor → higher affinity for the bacterial enzyme
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60
Q

how does the bacterial cell wall make a good drug target?

A
  • human cells don’t have a wall, just a membrane → therefore can target bacterial cell wall
  • major component = peptidoglycan
  • synthesis of peptidoglycan is a major drug target (β-lactams, glycopeptides)
  • bacterial cell wall = a 3D meshwork of peptide crosslinked sugar molecules
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61
Q

difference between gram + & - bacterial cell walls

A
  • G + cell walls have a thick peptidoglycan cross linking layer
  • G- cell walls more complex
  • G- cell walls have an outer membrane → is a barrier to some antimicrobals
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62
Q

how does bacterial protein synthesis make a good drug target?

A
  • process the same in pro & eukaryotes BUT ribosomal subunits are different
  • eukaryokes → 40s & 60s
  • prokaryokes → 30s & 50s
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63
Q

how does bacterial replication make a good drug target

A
  • differences in some enzymes
  • DNA gyrase (quinolones)
  • RNA polymerase (rifapicin)
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64
Q

Characteristics of Fungi

A
  • are eukaryotes (& so are humans)
  • bigger than bacteria
  • have nucleus & cellular organelles
  • unicellular
  • miotic division → division time 20hr
  • cell wall
  • NO extra-chromosomal DNA
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65
Q

How does the fungi cell membrane make a good drug target?

A
  • cell membrane contains ergosterol rather than cholesterol
  • can inhibit sterol synthesis (azoles & allylamines)
  • or selectively bind to ergosterol & influence cell membrane permeability (polyene anti-fungals e.g. amphotericin B)
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66
Q

How does the fungi cell wall make a good drug target?

A
  • fungi cell wall is a complex network of proteins & carbohydrates → glucan & chitan provide strength
  • can have glucan synthesis inhibitors (echinocandins)
  • or chitin synthase inhibitors (nikkomycin & polyoxins)
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67
Q

β lactam antibiotics include?

A
  • Penicillins
  • Cephalosporins
  • Monobactems
  • Carbapenems
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68
Q

β lactam antibiotics
(general)

A
  • useful, most frequently prescribed
  • all have a common β lactam ring
  • are all exclusviely bacteriocidal
  • either inhibit peptidoglycan synthesis OR target other penicillin-binding proteins
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69
Q

what are PBPs?

A
  • PBPs → penicillin-binding proteins
  • all bacteria have several
  • e.g. maintance of shape, etc.
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70
Q

Factors influencing β lactam activity

A

1. resistance
2. enzymatic degradation
G+ produce & secrete large amounts of β lactamases, G- produce smaller amounts in periplasmic space
3. biofilm formation
e.g. catheters, prosthetic joints & heart values
produce more polysaccharide, slower growing → less sensitive
4. density & age of infection
number or resistant bacteria
antibiotics most active in logarithmic growth phase

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71
Q

what does β lactamase do?

A
  • breaks down the β lactam ring of β lactam antibiotics
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72
Q

β lactamase inhibitors

A
  • molecules that can inactivate β lactamases
  • e.g. clavulanic acid, tazobactam
  • prevents the destruction of β lactam antibiotics
  • mostly active against plasma-encoded β lactamases
  • inactive against type I chromosomal β lactamases induced in G- bacteria
  • improve the spectrum of penicillins
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73
Q

Staphs (staphylococci)

A
  • G+ cocci
  • grape like clusters
  • produce microcapsules → help invade the immune system
  • produce numerous toxins → causes increased or decreased virulence
  • faculatatively resistant → can cope with low oxygen, thus can penetrate into deep tissue
  • multi-drug resistant
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74
Q

Strep (Streptococci)

A
  • G+ cocci
  • chain forming
    *produce microcapsules → help invade the immune system
  • produce numerous toxins → causes increased or decreased virulence
  • faculatatively resistant → can cope with low oxygen, thus can penetrate into deep tissue
  • penicillin sensitive
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75
Q

cogulase negative vs cogulase positive staphylococcus

A
  • cogulase = enzyme that breaks down components in blood
  • cogulase positive → more virulent (better human pathogens)
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76
Q

Staphylococcus aureus

A
  • distingushed by the golden colour of colonies, has coagulase enzyme
  • wide range of infections (range from benign to life-threatening)
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77
Q

Type of infections from staphylococcus aureus

A
  • skin and soft tissue infections (SSTI)
  • joints, bone (osteoarticular)
  • blood, lung, heart
  • GI, urinary, reproductive tract, mastitis…
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78
Q

epidemiology of staphylococcus aureus

A
  • carried by 30-50% of people
  • carriage increases risk of infection!
  • carriage is increased in populations with high rates of smoking
  • infections also via exposure to a carrier (community or hospital) or an environmental source
  • drug resistance → β-lactamase inactivates pencillin; mecA gene encodes low-affinity penicillin-binding protein, VanA modifies the target
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79
Q

pathogenesis of Staphylococcus aureus

A
  • damage to an epithelial barrier → colonisation of bacteria in tissue or boood
  • phagocytosis of bacteria by macrophages
  • activated macrophages attract neutrophils which secrete mediators (ROS, MPO, NETS)
  • bacteria fight back → destroy NETS, produce toxins & superantigens
  • abscesses form to contain bacteria, do not always work → spread to blood …
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80
Q

what impacts staphylococcus aureus infection?

A
  • host factors
  • bacterial factors
  • social/environmental factors
  • healthcare inequities
  • medical procedures, devices (sutures, catheters, valves, joints) → biofilm formation
    leading cause of bacteremia (blood bourne infections)
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81
Q

how is streptococcus classified?

A
  • classified based on ability to rupture red blood cells (hemolysis) & traditionally of cell wall polysaccharides (lancefield group)
  • streptococcus pyogenes causes most serious infections
  • now being replaced by sequencing the emm gene, encodes the highly polymorphic M surface protein
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82
Q

streptococus pyogenes - is what group & hemolysis

A

lancefield group A, β hemolysis

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83
Q

Group A streptococcus (GAS)
general

A
  • have many virulence factors including capsules, toxins & superantigens
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84
Q

Streptococcal pathogensis

A

multiple virulence factors inpact on pathogenesis
* direct tissue damage
* induction of coagulopathy → helps bacteria to cause infection
* inactivation of cytokines & immune cells
extensive tissue damage, bacteremia, organ damage

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85
Q

Group A streptococcus → S. pyogenes

A
  • GAS colonizes epithelial surfaces
  • most disease is from superficial infections but can be serious
  • **invasive disease follows a breach of epithelia ** → variety of disease with high morbidity & mortality
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86
Q

Group A streptococcus → S. pyogenes
(infection epidemology)

A
  • rates higher with social deprivation
  • pateinst die within 7 days of infection
  • most common invasive dieseases = SSTI & bacteremia
  • may be complicated by development of STSS (streptococcal toxic shock syndrome)
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87
Q

Serious Skin Infections

A
  • opportunistic skin pathogens → S. aureus & S. pyogenes
  • risk groups for invasive disease → skin lesions, very young, eldery, immune compromised
  • morbidity → organ failure & amptutation
  • rate in NZ kids higher than similar countries
  • higher incidence in boys
  • highest in pre-school aged children
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88
Q

Cellulitis

A
  • bacterial infection of the skin & sub cutaneous tissue (fascia, muscles, tendons)
  • commonly caused S, pyogenes, S. aureus
    organism must gain entry through a wound (cut, abrasion, burn, sting, bite, surgery)
    commonly occurs in the extremities
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89
Q

Cellulitis (presentation & diagnosis)

A
  • presentation → ill defined lesions, red, painful, swollen, may/may not have systemic symptoms (fever, chills, regional lymphadenopathy)
  • diagnosis → biopsy, culture only used in situations where complications may occur
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90
Q

treatment of cellulitis

A
  • uncomplicated cellulitis → (small area of involvement, no risk factors, no systemic symptoms, minimal pain) = oral antibiotics
  • complicated cellulitis → (systemic symptoms & risk factors) = hospitalisation, i.v. antibiotics, surgical drainage/debridement
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91
Q

Toxic Shock Syndrome

A
  • caused by release of Staph & Strep toxic “superantigens”
  • widespread immune system activation → cytokine storm → multi organ failure & high mortality
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92
Q

symptoms of toxic shock syndrome

A
  • early symptoms → redness, swelling & pain at wound site (starts off like a normal skin infection!)
  • late symptoms → plumet in BP, issues with organs, etc..
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93
Q

treatment of toxic shock syndrome

A
  • treatment is aggressive
  • supportive care
  • antibiotics
  • wound care (drainage &/or debridement)
  • IVIG?
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94
Q

Necrotising Fasciitis ‘flesh eating bacteria’

A
  • tissue infection in which extensive necrosis accompanies the cellulitis
  • massive destruction of soft tissue, damage to blood vessels, muscle liquefaction
  • potentially fatal
  • also known as streptococcal gangrene
  • cause by S. pyrogenes & S. aureus
  • organism must gain entry through a wound
  • risk factors → age, vascular disease, diabetes, immune suppression
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95
Q

Symptoms of Necrotising Fasciitis

A
  • early symptoms → slight tramua → local discomfort in area of tramua, general malaise, headache, fever, joint & muscle pain
  • advanced symptoms → pain gets worse, seem out of proportion to the small wound visible, blisters, skin & tissue looks dead
  • critcal symptoms → disease progresses, less local pain, more systemic symptoms from bacterial toxins, coma & death
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96
Q

treatment of Necrotising Fasciitis

A
  • seek treatment early!
  • hospitalisation, i.v. antibiotics, supportive therapy, surgical drainage & debridement
  • amputation
  • costemic surgery → skin grafts
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97
Q

S. aureus vaccine

A
  • development has been difficult!
  • pfizer vaccine got antibody production but NO protection from infection
  • NO VACCINE → because the infection is so variable
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98
Q

GAS (s. pyogenes) vaccine

A
  • working on a vaccine since the 1940’s…
  • whole cell vaccines → too many side effects & no protetction
  • still NO vaccine
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99
Q

fungal infections (general)

A
  • aka mycoses
  • are widespread
  • associated with skin & mucous membranes
  • in temperature climates (like NZ) fungal infections are usually associated with the skin
  • minor in healthy individuals
  • only when in immunocompromised patients or when they gain access to the systemic circulation, they can become lifethreatening
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100
Q

Clinically important fungi

A
  • yeast → unicellular, simple, single cellular organisms
  • mould → a growth phase of the yeast
  • aspergillus fumigatis (opportunistic pathogens)
  • candida albicans (opportunistic pathogens)
  • cryptococcus neoformans (opportunistic pathogens)
  • coccocidoides immitis (systemic)
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101
Q

Trizalones (antifungal agent)
examples

A
  • examples → fluconazole, itraconazole, miconazole, voriconazole, posaconazole
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102
Q

Trizalones (antifungal agent)
mechanism

A
  • inhibit microsmola CYP (14-⍺-sterol demthylase) → impairs ergosterol synthesis
  • some increase permeability of plasma membrane (conc. dependent, topical use)
  • fungiSTATIC (broad spectrum)
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103
Q

Trizalones (antifungal agent)
pharmacokinetics

A
  • orally or i.v. (miconazole generally topical/oral gel)
  • itraconazole absorption variable, extensive hepactic metabolism
  • short t1/2 (6-8h) → miconazole, voriconazole
  • long t1/2 (30-40h) → fluconazole, itraconazole, posaconazole
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104
Q

Trizalones (antifungal agent)
unwanted effects

A

generally mild
* nausea
* headache
* abdominal pain
* rare → allergic skin reactions (SJS = stevens-johnson syndrome)
* AVOID DURING PREGNANCY

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105
Q

Trizalones (antifungal agent)
therapeutic use

A
  • candidiasis → miconazole, only topical use
  • cryptococcal meningitis (AIDS)
  • invasive aspergillosis → voriconazole
  • prophylaxis against candidiasis, aspergillosis in patients with neutropenia or GVHD (graft vs host disease)
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106
Q

Trizalones (antifungal agent)
clinically important intertactions

A
  • azoles interact with hepatic CYPs as substrates AND inhibitors
  • azoles can increase [drug] in plasma of some co-administered drugs
  • other co-administered drugs can decrease [drug] in plasma of azoles
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107
Q

clotrimazole

A
  • OTC **topical **treatment
  • superficial fungal infections → thrush (candidiasis), tinea, funal keratitis, nappy rash
  • interferes with aa transport into fungus!
  • small amount absorbed is metabolised by livre & excreted in bile
  • may still be used to treat yeast infections in pregnant women!
  • may cause stinging, redness, itching
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108
Q

polyenes (antifungal antibiotics)

A

polyenes are naturally occuring antifungals produced particular strains of bacteria

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109
Q

amphotericin (B)
antifungal antibiotic
mechanism

A
  • is the ‘gold standard’ polyene antibiotic (streptomyces)
  • binds to ergosterol in fungal membrane
  • relative specificity
  • forms pores/channels → increases permeability, leakage
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110
Q

amphotericin (B)
antifungal antibiotic
pharmacokinetics

A
  • GI absorption of all amophotericin B formulations is none exsistant
  • used topically & systemically → slow i.v. infusion (lipid formulations)
  • highly protein bound
  • excreted very slowly by kidneys
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111
Q

amphotericin (B)
antifungal antibiotic
unwanted effects

A
  • most common, most severe = renal toxicity (80% of patients)
  • hypokalemia (20%)
  • acute response to i.v. → fevers, chills, worst with collodial dispersion, least with liposomal
  • irritant, thrombophlebitis
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112
Q

amphotericin (B)
antifungal antibiotic
therapetic use

A
  • candida oesophagitis (HIV/AIDS)
  • mucormycosis (weakened immune system, e.g. organ transplant)
  • meningitis
  • cryptococcus
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113
Q

Nystatin
antifungal antibiotic
mechanism

A
  • useful for topical use, superficial infections
  • tetraene macrolide (streptomyces noursei)
  • structurally similar to amphotericin → same MoA
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114
Q

Nystatin
antifungal antibiotic
pharmacokinetics

A
  • not absorbed from the GI tract, skin, or vagina
  • good for ‘topical’ use
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115
Q

Nystatin
antifungal antibiotic
unwanted effects

A
  • none of note!
  • allergic reactions very uncommon
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116
Q

Nystatin
antifungal antibiotic
therapeutic use

A
  • only for candidiasis (thrush)
  • supplied in preparations for cutaneous, vaginal, or oral administration
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117
Q

echinocandins
semisynthetic antifungal
examples

A
  • examples → caspofungin, micafungin, anidulafungin
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118
Q

echinocandins
semisynthetic antifungal
mechanism

A
  • inhibit synthesis 1,3-β-glucans → decrease structural integrity → death
  • fungiCIDAL
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119
Q

echinocandins
semisynthetic antifungal
pharmacokinetics

A
  • no oral bioavailability (size), given i.v.
  • extensive protein binding (>97%)
  • don’t penetrate into CSF
  • no renal clearance
  • (little effect on [drug] in plasma in renal impairment)
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120
Q

echinocandins
semisynthetic antifungal
unwanted effects

A
  • remarkably well tolerated
  • phlebitis (inflammation of veins) at injection site (caspofungin)
  • histamine-like effects (rapid infusion)
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121
Q

echinocandins
semisynthetic antifungal
therapeutic use

A

deeply invasive candidiasis
salvage therapy for invasive aspergillosis

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122
Q

echinocandins
semisynthetic antifungal
clinically important interactions

A

particularly for immunocompromised patients
1. caspofungin & micafungin are mild inhibitors of CYP3A4 (increase [drug] in plasma of immunosuppresant tracolimus, an anti rejection drug used in organ transplant patients)
2. drugs that are inducers of CYP3A4 (rifampicin, an antibiotic for TB, decreases [drug] in plasma of caspofungin)

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123
Q

flucytosine
antifungal agent
mechanism

A
  • unapproved medicine
  • inhibited DNA synthesis in fungal cells (converts to 5-FU)
  • limited spectrum
  • combined with amphotericin &/or azoles
  • resistance common
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124
Q

flucytosine
antifungal agent
pharmacokinetics

A
  • given by i.v. or orally
  • t1/2 approx. 3-5h
  • 90% excreted unchanged by kidney
  • dosage should be reduced in renal impairment
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125
Q

flucytosine
antifungal agent
unwanted effects

A

infrequent
* GI disturbances
* anaemia
* neutropenia
* alopecia
more significant in patients with AIDS?

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126
Q

flucytosine
antifungal agent
therapeutic use

A
  • with Ampho B for → serious fungal infections
  • cryptococcal meningitis in patients with AIDS
  • canididiasis
  • alone or w/ other antifungals for →chromomycosis (skin infection foun in subtropical & tropical areas)
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127
Q

Terbinafine (Lamisil)
antifungal agent
mechansim

A
  • selective inhibitor of squalene epoxidase (ergosterol synthesis)
  • highly lipophillic & keratinophilic → will preferentially accumulate in skin, nails, & hair
  • fungiCIDAL
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128
Q

Terbinafine (Lamisil)
antifungal agent
pharmacokinetics

A
  • topical or oral
  • well absorbed (decreased bioavailability due to first pass metabolism)
  • metabolised in liver, excreted in urine
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129
Q

Terbinafine (Lamisil)
antifungal agent
unwanted effects

A

well tolerated
* low incidence of GI distress, headache or rash
* not recommended in hepatic failure → check LFTs
* SYSTEMIC THERAPY AVOIDED DURING PREGNANCY

rifampin (antibiotic) decreases [terbinafine]
cimetidine (acid reducer) increases [terbinafine]

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130
Q

Terbinafine (Lamisil)
antifungal agent
therapeutic use

A
  • nail onychomycosis (oral)
  • tinea (cream or spray)
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131
Q

antimicrobials vs other drugs

how are antimicrobials different

A

antimicrobials are different to other medicines as they don’t just affect the patient receiving treatment!
they also affect the patient’s immediate community & the global community
* they have a societal impact!!

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132
Q

goals of antimicrobial therapy
(3)

A
  • cure a diagnosed infection (individual)
  • reduce morbidity & mortality (individual)
  • prevent spread of disease (societal)
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133
Q

what are the first two steps when you think a patient is infected?

A
  1. obtain a thorough history of the patient’s symptoms (patient report) & presentation
  2. are there tests (signs, clinical finding) which may indicate an infective process?

both signs and symptoms are helpful - but not specific to infection!!

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134
Q

what is the only specific sign of infection?

A

a positive culture

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135
Q

what is empiric therapy?

A
  • empiric therapy is medical treatment or therapy based on experience &, more specifically, therapy begun on the basis of a clinical “educated guess” in the absence of complete or perfect imformation”
  • it covers a variety of organisms that are possible suspected causes of infection (hedging bets)
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136
Q

what are the 6 steps to initiating antimicrobial treatment?

A
  1. consider patient symptoms
  2. consider signs/tests
  3. consider risk factors for infections
  4. suspected source
  5. antimicrobial treatment needed?
  6. culture/swab/viral PCR
  7. begin empiric antimicrobial therapy
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137
Q

what are the 3 types of factors empiric antibiotic therapy is selected based upon?

A

bug, drug and patient

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138
Q

empiric therapy - what are the infection factors (bug)?

A
  • likely organism & location
  • severuty of infection → systemic? localised?
139
Q

empiric therapy - what are the antimicrobial factors (drug)?

A
  • spectrum of activity (broad vs narrow)
  • PK/PD: distribution, half life
  • toxicity & ADR profile (risk/benefit)
  • local sensitivities
  • formulations available
  • funding considerations
140
Q

empiric therapy - what are the patient factors (patient)?

A

MOST IMPORTANT CONSIDERATION!!
* allergy status
* age → neonates, eldery
* renal & hepatic function
* co-morbidities (including immunosuppression)
* prenancy/breastfeeding
* history of MDR infection
* drug interactions
* clinical setting: inpatient/outpatient
* site of infection: e.g. CNS infection vs eye infection

141
Q

what is de-escalate therapy?

A

narrowing the antimicrobial spectrum (target)

142
Q

why de-escalate therapy?

A

aim of de-escalation is to reduce the risk of antimicrobial resistance (AMR) & improves efficacy by selecting therapy that targets specific infective organisms

143
Q

when choose de-escalation therapy?

A
  • once cultures & sensitivities are back
  • patient is clincially improving (if not → aim for broader coverage)
144
Q

therapeutic drug monitoring

A
  • serum levels (peaks & troughs) - conc. dependant
  • serum levels (AUC) - time dependent
145
Q

duration of antimicrobial treatment?

A
  • most common infections have a standard treatment regimen → refer to local guidelines
  • guidelines typically provide a range → this requires the use of clinical judgement (severirty of infection, location of infection, & drug tolerability)
146
Q

what to consider when treatment fails

A
  • was it truely an infection?
  • was the empiric therapy appropriate (i.e. appropriate spectrum for supected organism?, dose & frequency?)
  • recurrent infection?
  • was the patient compliant?
  • antimicrobial resistance? → review cultures
147
Q

what to do when treatment fails?

A
  • review antimicrobial choice, sensitivity
  • review antimicrobial dose, route & interactions
  • review antimicrobial duration
  • consult AMS team
  • if non-compliance is apparent, consider why? - e.g. dose frequency, pill burden, special instructions, intolerance
148
Q

important things to note about antimicrobial guidelines

A
  • they are GUIDES
  • they ASSIST in provision of patient care
  • CLINICAL JUDEMENT & PATIENT CENTRED CARE MUST STILL BE APPLIED
  • there is no “one size fits all”
149
Q

what is a Hui?

A

a “meeting”

150
Q

what is a Pōwhiri?

A
  • a formal welcome
  • has to be on a marae - or a maori immensed place
151
Q

what is a whakatau?

A

a formal welcome of the marae

152
Q

what are the 4 key elements that the “hui process” contains?

A
  1. mihimihi
  2. whakawhanaungatanga
  3. kaupapa
  4. whakamutunga
153
Q

what is mihimihi - & how is this applied in pharmacy setting

A
  • first element of of the hui process
  • intial greeting & engagement
  • pharmacists clearly introduce themselves & describe their role & the specific purpose of engagement. They should also confirm that patient identfies as Maori
154
Q

what is whakawhanaungatanga - & how is this applied in pharmacy setting

A
  • second element of hui process
  • making a connection i.e. connecting at a personal level
  • requires pharmacist to draw on their understanding of te ao Maori & relevant patient & whanau maori beliefs, values, experiences
    *
155
Q

what is kaupapa - & how is this applied in pharmacy setting

A
  • 3rd element of the hui process
  • attending to the main purpose of the encounter
  • in pharmacy: the point at which the focus moves to history taking or whatever the clincal task at hand is (e.g. counselling)
156
Q

what is whakamutunga - & how is this applied in pharmacy setting

A
  • finial element of the hui process
  • concluding the encounter
  • ensure you have understood what the patient has said, ensure patient understands what you have said, ensure patient is clear about the next steps
157
Q

how does antibiotic resistance develop?

A
  • mainly becuase of the spread of bacterial resistance
  • bacteria can be innately resistant to an antimicrobial or resistance can develop (be accquired) due to a genetic mutation
158
Q

why does accuired resistance develop so quickly?

A

due to unique properties of bacterial replication
* reproduce quickly →vertical transmission of mutations that provide a survival advangtage e.g. AMR &…
* extra-chromosomal DNA (plasmids) facilitates spread of AMR horizontally, within & between bacterial species (conjugation, transformation, transduction)
* many types of resistance can & will develop

159
Q

Plasmids & anantimicrobial resistance (AMR)

A
  • 1959 → found that AMR was being readily transferred from 1 bacteria to another → through plasmids!
  • found that genes conferring resistance could be carried on plasmids → a single plasmid may contain more than 1 resistance gene
  • can transfer across species
160
Q

innate/intrinsic resistance

A

innate/instrinic resistance is due to → an inherant feature of the bacteria
e.g…
* drug target is not present
* bacteria may have efflux pumps which removes the drug
* drug can’t cross the outer membrane (OM) of G- bacteria

161
Q

accquired resistance: 1. drug accumulation

A

decrease entry (influx)
accquired mutations that:
* reduce the no. of pores
* change the type of pore
* impair pore function
increased exit (efflux)
* genes for efflux pumps can be encoded on plasmis & cause accquired AMR as bacteria gain new efflux pumps
* mutations can also increase expression of pumps

162
Q

acquired resistance: 2. the target

A

another way the bacteria can become resistant is if the target is mutated is someway so that the antimicrobial agent can no longer have it’s effect - e.g.
* replace the target → via gene transfer with a new target that has low affinity for the drug
* modification of the target → via mutation of the binding site while retaining function
* protection of the target → dislodge drug or compete with drug for target
* overproduce the target → via mutation to retain function

163
Q

acquired resistance: 3. the drug

A

can develop resistance if the bacteria develop some sort of mutation that will alter the drug
acquires an enzyme that:
inactivates/breaks down the drug
* many enzymes indentified, chromosome & plasmid encoded, transfer quickly
* e.g. β-lactamases, carbapenemases
changes/modifies the drug
* modifies the drug through the addition of acyl, phosphate, nucleotidyl & ribitoyl groups
* can no longer interact with target
* large antibiotics (aminoglycosides) more susceptible

164
Q

in drugs with multiple MoAs - does drug resistance develop faster or slower?

A

SLOWER

165
Q

what social factors impact on the development of drug resistance?

A
  • misuse/overuse of antibiotics
  • OTC supply of antibiotics
  • incorrect prescribing (viral infections)
  • empirical use of antibiotics
  • prophylactic use
  • increased use of broad specturm antibiotics
  • use of antibiotics in animal feeds
  • not taking the entire course of antibiotics???
166
Q

not taking the entire course of antibiotics?

A
  • common misconception → has no impact on resistance!!
  • may impact on disease control
  • dose & complicance more important as regards to resistance
  • i.e. resistance develops when you have subtherapeutic levels of antibiotic
167
Q

do fungi become multi-drug resistant (MDR)?

A

YES → but not such a big problem as with bacteria
* as bacterial replication rate is much faster
* bacteria can transfer resistance on plasmids
* bacterial replication is more mutation-prone

168
Q

drug resistance & fungi → mechanisms

A

same types of mechanisms as in bacteria
* drug target alteration
* drug target overexpression
* efflux pump overexpression

169
Q

Multi-drug resistance to candidia

A
  • systemic infections with azole resistant candida are becoming increasingly common
  • now also developing resistance to polyenes & flucytosine
  • less resistance to amphotericin B!
  • OPTIONS → more drug/better delivery, combination therapy, new drugs, new therapies
170
Q

Looking after you health → why people might not exercise?

A
  • disabilities (mental & physical health)
  • disabilities exacerbated by lack of money (e.g. foot problems, inability to afford special shoes)
  • care of childern & others
  • work → long hours, physcial exhaustion
171
Q

Looking after you health → why people might not eat healthy food?

A
  • insufficient income & rising prices
  • food as the last item of expenditure
  • shared kitchen in boarding house etc.
  • lack of storage & preparation space
172
Q

Looking after you health → why people might have too much stress?

A

multiple sources of stress
* poverty
* poor physical health
* waiting for healthcare
* access to healthcare
* house insecurity
* mental health problems
* past trauma
* worrying about the future for youself, childern & grand children

173
Q

Looking after you health → why people might not seek healthcare?

A
  • busy, stressful lives
  • knowledge of how health system works
  • frustration & distrust in the health system
  • difficulties with arranging & attending appoinments
174
Q

Looking after you health → financial barriers to appointments & medicines

A
  • may be unable to afford appointments & medicines
  • may be in debt to medical practise, pharmacy
  • shame/stigma
175
Q

principles of communication: giving feedback

A
  • respectful
  • positive
  • encouraging
  • supportive
176
Q

principles of communication: receiving feedback

A

receive it understanding it is intended to help you on your learning journey
* listen
* be open
* understand the message
* reflect
* decide

177
Q

code of health & disability services - consumer’s rights (3 main ones)

A
  • right 5 → right to effective communication
  • right 6 → right to be fully informed
  • right 7 → right to make an informed choice & give informed consent
178
Q

principles of communication: what are the three steps to better health literacy?

A
  1. find out what people know → determines baseline understanding
  2. build health literacy skills & knowledge → links new info to what the person already knows
  3. check you were clear (&, if not, go back to step 2) → use the teach-back method
179
Q

Gathering Info - SCHOLAR:

A
  • what are the** symptoms**?
  • what are the characteristics of the symptoms?
  • what is the history of the symptoms?
  • when was the onset?
  • what factors aggravate the symptoms?
  • what factors remit the symptoms?
180
Q

Gathering Info - MAC(S)

A
  • medicines
  • allergies & adverse effects
  • medical conditions
  • social history (if relevant)
181
Q

Pharmacokinetics vs Pharamcodynamics

A
  • Pharmacokinetics = the change in conc. ovr time in the plasma after administration of the drug → ‘what the body does to the drug’
  • Pharmacodynamics = usually the effect of the drug conc. on the body → ‘what the drug does to the body’
182
Q

minimum bactericidal concentration (MBC)

A
  • the lowest conc. of antibiotic required to kill a particular bacterium
183
Q

Minimum inhibitory concentration (MIC)

A
  • lowest conc. of an antimicrobial that will inhibit the visible growth of a microorganism after overnight incubation
184
Q

Gentamicin

A
  • an aminoglycoside → used for serious infections due to aerobic G- baccilli
  • generally the starting dose is 5-7 mg/kg IBW (ideal body weight) given once daily
185
Q

Gentamicin PK

A
  • Administration - Usually give by IV infusion over 30 mins
  • Data fits a one-compartment model
  • Renally cleared (NOT metabolised) - base dose on ideal body weight (IBW)
  • CL = 4L/h = 80% of GFR
  • V = 18L = Extracellular fluid volume (EFV)
  • t1/2 = 3.1h, almost completely eliminated between doses!
  • F = 0 so there is no oral formulation
186
Q

Gentamicin PD effect on microorganisms

A

PD effect on microorganisms:
* conc.-dependent bactericidal effect → optimise the Cmax (peak) for max. bactericidal effect
* post-antibiotic effect (PAE) → effect on the bug continues when drug is not there!
* adaptive resistance

187
Q

Gentimicin PD effect on the body (side effects)

A
  • uptake to the kidneys & cochlear → prolonged high concentrations lead to toxicity
188
Q

genamicin bacterial kill trend

A
  • concentration-dependent killing!
  • bigger Cmax = bigger bacterial kill
  • extent & rate of bacterial kill is related to Cmax!
189
Q

Gentamicin conc.-time curve

A
  • antimicrobials are usually regarded as bactericidal if the MBC is no more than 4 times the MIC
190
Q

Aminoglycoside toxicity (know this!)

A
  • nephrotoxicity (4-40%) → kidney damage in the tubules, usually reversible
  • ototoxicity (1-20%) → sensory & vestibular (cochlear) damage, usually NOT reversible
  • due to the uptake into the kidneys & cochlear
  • toxicity is rare if doses are adjusted appropriately!
191
Q

risk factors predisposing patients to gentamicin toxicity (major & minor)

A

major
* duration of treatment
* dose
minor
* liver disease
* prior aminoglycoside exposure
* female
* other nephrotoxic drugs

192
Q

goal of gentamicin treatment

A
  • to reach the highest Cmax:MIC ratio within an acceptable exposure level
  • Cmax less than 10mg/L (at least 4-5x the MIC)
  • Cmin more than 0.5mg/L
  • AUC of 70 to 100mg/L.h
  • the aim is to ensure that high peak levels are acheived (conc.-dependant kill) but that drug is cleared before the next dose
193
Q

Flucloxacillin

A
  • a penicillin - used for minor & serious infections due to aerobic G+ baccilli
  • used for Staph. spp, Strep. spp
  • has better activity against beta-lactamase producing bacteria
  • often given in community setting (PO) for uncomplicated, but also given in hospital (PO or IV) for complicated infections
194
Q

Flucoxacillin
administration

A

PO, or IV push over 3-5mins or IM

195
Q

Flucloxacillin PK

A
  • fe = 0.7
  • CL (total) = 8.2 L/h
  • CL (renal) = 5.4 L/h
  • V = 10 L
  • t1/2 = 50 min
  • F = 0.3 (affected by food)
  • only 30% of an oral dose is absorbed, rest is degraded in gut or unabsorbed. If taken with food the F is reduced by 20%
196
Q

Conc.-time profile → after 0.5g Flucoxacillin given as a 3min IV push

A
  • even though it has a short half-life, the conc. is above the MIC for the whole dosing interval
  • the conc.s are very high (80-100 mg/L) on average, & the Cmax greatly exceeds the MIC of the organism
197
Q

Flucloxacillin PD

A

kill kinetics of flucloxacillin (& all beta-lactams) dependent on time above MIC - needs to be 40% or more
* time-dependent bactericidal effect (time above MIC)
* no post-antibiotic effect
* minimal toxicity - some bleeding at high doses
* doses generally provide a much higher conc. than the MIC in order to account for the short half-life

198
Q

Goal of Flucloxacillin treatment

A
  • choosing a dosing regimen where the conc. is above the MIC for the longest period of time
  • current thinking is that a successful dosing regimen where the plasma conc. is above the MIC for at least 40% of the dose interval
  • so can give as a constant infusion
199
Q

time-dependent dosing antibiotics

A
  • beta-lactams
  • macrolides
  • tetracyclines
    conc.s above MIC for as much as possible of the dose interval
200
Q

conc.-dependent dosing antibiotics

A
  • aminoglycosides
  • fluroquinolones
    highest Cmax to MIC ratio as possible
201
Q

AUC-dependent dosing antibiotics

A
  • vancomycin
    optimise ratio of AUC to MIC
202
Q

how does antimicrobial resistance (AMR) occur?

A

antimicrobial resistance occurs when microorganisms such as bacteria, viruses, fungi & parasites change in ways that render the medications used to cure the infections they cause ineffective - WHO

203
Q

outcomes of antimicrobial resistance (AMR)

A
  • public health crisis
  • morbidity/mortality
  • spread of disease
  • cost: individual, healthcare system & societal
204
Q

why does antibiotic resistance matter?

A
  • reduced efficacy when using 2nd line antimicrobials
  • higher toxicity & rates of adverse effects from the use of 2nd line agents
  • patient cost/inconvenience with hospital visits for antimicrobial therapy (affecting rural/low socioeconomic groups disproportionately)
  • longer hospital stays
  • poorer outcomes from surgery (e.g. joint replacement), cancer care & other interventions
  • increased mortality
  • elevated healthcare costs
205
Q

WHO Global Action Plan (2015) for AMR (5 points)

A
  1. improve awareness & understanding of antimicrobial resistance (through effective communication, education & training)
  2. strengthen the knowledge & evidence base (through surveillance & research)
  3. reduce the incidence of infection (through effective sanitation, hygiene & infection prevention measures)
  4. **optimise the use of antimicrobial medicines **in human & animal health
  5. develop an economic case for sustainable investment (that takes account of the needs of all countries, & increase investment in new medicines, diagnosis tools, vaccines & other interventions)
206
Q

NZ AMR Action Plan (4 points)

A
  1. awareness & understanding
  2. surveillance & research
  3. infection prevention & control
  4. antimicrobial stewardship
207
Q

what is antimicrobial stewardship?

A

“to optimise the use of antimicrobial agents in the prevention & treatment of infections, & minimise the potential harms that may result from their use including AMR, adverse drug reactions & excessive healthcare surveillance of the quantity & quality of antimicrobial use, education & training, & implementation of quality improvement initiatives”
* AMS directly addresses objective 4 of the NZ AMR action plan, & WHO action plan

208
Q

AMS Interventions

A

usually fall into two categories:
1.** broad**, higher level activities→ how can we impact the use of antimicrobial agents to a specific population?
2. specific, ground level activities → looking at individual patient context

209
Q

what are broad AMS interventions? (3)

A
  1. guideline & clinical pathway development & review
    * develop local empiric antibiotic guidlines
    * base on evidenced based medicine & local antibiotic sensitivies
    * promotes appropriate use
    * antibiograms
  2. antimicrobial restrictions
    * certain medicines require specialist approval before use
  3. auditing
    * surveillence of restrictions
    * what is being used & why?
    * used to measure effectiveness of interventions
210
Q

antibiograms

A

utilised in practise to:
* inform empiric guideline creation
* rationalise antibiotic use through targeted therapy (de-escaltion)
* improve treatment outcomes
* slow down antimicrobial resistance

211
Q

specific interventions “ground level” (8)

A

IV to PO (oral) switch
* using PO where appropriate, reduces needs for IV line (risks associated)
dose optimisation
* therapeutic drug monitoring (TDM)
* avoid sub-therapeutic treatment (right dose, route, duration)
eliminate duplicates
* rationalise combination therapy to avoid overlappomh spectrum
de-escaltion
* cultures
* empiric therapy → targeted therapy
duration (hospital charts)
* indicates duration or review date
* automatic-stop orders (e.g. perioperative)
interactions
* review for interactions that may increase or decrease the dose requirement
allergy warnings
* very important with b-lactam agents
document indication on chart or script
* poromotes thoughtful prescribing, facilitates clear assessment of suitability of treatment & compliance with best practise

212
Q

AMS intervention EDUCATION - how to apply to public

A
  • lay language
  • written info to describe the WHY & HOW
  • personalise the message
213
Q

topical formulation - SOLUTION

A
  • water or alcoholic lotion containing a dissolved powder
214
Q

topical formulation - LOTION

A
  • usually considered thicker than a solution & more likely to contain oil as well as water or alcohol. A shake lotion separates into parts with time so needs to be shaken to suspension before use
  • thinner than cream, therefore easy to spread over large area
215
Q

topical formulation - CREAM

A
  • thicker than a lotion, maintaining its shape, e.g. a 50/50 emulsion of water & oil. Requires preservative to extend shelf life. Often moisturising
216
Q

topical formulation - OINTMENT

A
  • semi-solid, water-free or nearly water-free (80% oil)
  • greasy, sticky, emollient, protective, occusive.
  • no need for preservative, so contact allergy is rare
  • not that nice to use, as very oily, but good for night time use
217
Q

topical formulation - GEL

A
  • aqueous or alcoholic monophasic semisolid emulsion, often based on cellulose & liquefies upon contact with skin. Often includes preservatives & fragrances
  • often good for treating hairy areas
218
Q

topical formulation -PASTE

A
  • a concentrated supsension of oil water & powder
  • good for treating particular areas
219
Q

dermatology - which formulation to use - for which condition?

A
  • wet, oozy skin conditions → creams, lotions, pastes →not as occlusive
  • dry, scaly conditions → oinments, oils →more occlusive, hydrating
  • inflamed skin → wet compress, soaks, then creams or ointments
  • crack & sores → bland, basic formulations → avoid alcohol or acidic
220
Q

dermatology - which formulation to use - for which site?

A
  • thick skin (palms soles) → ointment or cream
  • skin folds → cream or lotion → not as occlusive
  • hairy areas → lotion, solution, gel, foam → not as messy
  • mucosal surfaces → non irritating, avoid alcohols & acidic preparations
  • large areas → lotions can be easier to apply
221
Q

histamine

A
  • histamine = mediator of immediate allergic (urticaria) & imflammatory conditions
  • also has a role in gastric acid secretion & functions as a neurotransmitter & neuromodulator
  • most histamine is stored in granules within mast cells or basophils → complexed with a protein (macroheparin)
  • stimuli trigger its release → then histamine exerts its effects
222
Q

histamine release

A
  • is released by exocytosis during inflammatory or allergic reactions
  • causes local increase in permeability of capillaries & venules → redness, itching, swelling
223
Q

histamine receptor subtypes

A
  • are all G-protein coupled receptors BUT act through different secondary messengers when activated
  • H1 & H3 elevate cyclic AMP
  • H3 & H4 stimulate phospholipase C
  • a rise in cytosolic Ca2+ initiates hisatmine release
224
Q

antihistamine drugs (acting at H1R) 1st vs 2nd gen

A
  • first gen. → more sedating, pharmacist only
  • second gen. → reduced distribution to the CNS - less sedating
225
Q

Antihistamines

A
  • reversible binding to the H1 receptor to prevent release of histamine
  • 1st gen H1 antagonists enter CNS readily, have anticholinergic side effects since they interact with muscarinic cholinergic receptors
  • the active metabolites of hydroxyzine, terfenadine, & loratine are available as drugs (cetirzine, fexofenadine, & desloratadine)
226
Q

what are inflammatory skin diseases

A
  • superficial inflammation of the skin
  • not causes by infectious agents!
  • are an immune dysfunction to innocuous foreign/external substances (allergens) or self-proteins (autoimmunity)
227
Q

what do inflammatory skin diseases involve?

A
  • immediate responses from granulocytes → mast cells, eosinophils, neutrophils, basophils
  • delayed/accquired response → helper T cells (Th cells), many diff. types with diff. roles
228
Q

T helper cell subsets

A
  • subsets have a physiological role & a pathological role
  • good & bad!
  • provide protection to pathogens & destroy transformed cells, BUT can also cause tissue destruction, remodelling, DNA mutation & cancer
229
Q

Acne (acne vulgaris)

A
  • very common skin disease, inflammation of sebaceous gland
  • common at puberty, also present in adults
230
Q

open vs closed comedone

A

closed comedone = white head
open comedone = black head

231
Q

acne - hyperseborrhoea
role of androgens

A
  • androgens → plays a crucial role in pathogenesis, does NOT develop in their absense
  • androgens stimulate the growth of sebaceous glands & stimulate sebum production
232
Q

acne - hyperseborrhoea
role of anabolic steroids

A
  • anabolic steroids further increase sebum production, estrogens decrease sebum production by decreasing androgen production
233
Q

acne - follicular keratinization

A
  • spontaneous changes in keratinocytes → increased turnover
  • altered pattern of kertinisation
  • keratinous material becomes denser, altered lipid metabolism
234
Q

commensal bacteria associated with sebaceous glands are…

A
  • Stap. epidermis → top of the follicle
  • Propionibacteria: P. acne, P. granulosome, P. parvum → lower, initiate inflammation through interaction with keratinocytes
235
Q

what increases likelihood of acne?

A
  • genetics
  • no link between ‘cleanliness’ & acne!
  • diet, stress, smoking → may impact
236
Q

acne - treatment

A
  • usually heal spontaneously, main treatment aim is to reduce scarring & prevent new lesions
  • CAM use is widespread → no good evidence to support use but gives a feeling of control & being more natural. Can have adverse effects
237
Q

Dermatitis - classifications

A
  • atopic dermatitis (atopic/allergic eczema) → allergic immune response
  • contact dermatitis (contact eczema) → can occur both allergic/atopic individuals & non-atopic individuals, some evidence for increased rate of ACD in atopic indiviudals
  • irritant contact dermatitis (ICD)
  • allergic contact dermatitis (ACD)
  • protein contact dermatitis (PCD)
238
Q

atopic dermatitis/eczema

A
  • commonly diagnosed in childhood
  • geographic variations in prevalence
  • complex disease → genes & environment
  • strongest risk factor = family history
239
Q

atopic dermatitis (AD) pathogenesis (acute & chronic)

A

acute
* allergens enter via damaged skin & stimulate release of inflammatory mediators from granulocytes
chronic
* driven by cytokines released by T cells
* keratinocyte (KC) dysfunction
* skin becomes thick

240
Q

probiotics in the treatment & prevention of atopic dermatitis

A
  • all studies reported some symptom reduction
  • impact depends on when used (in pregnancy, early or late)
  • depends on strains of Bifidobacterium & Lactobacillus used
  • minor adverse effects in healthy individuals
241
Q

Irritant contact dermatitis (ICD)

A
  • physical (UV, heat, cold, damp) or chemical (detergents, solvents, bleaches) agents causing direct irritation/injury
  • can be acute (mins to hours) or chronic/cumulative, mild or severe, recurrent
242
Q

allergic contact dermatitis (ACD)

A
  • immune response to small organic & inorganic allergens that can penetrate skin e.g. nickel
  • sensitizing phase (asymptomatic) of weeks to months then an inflammatory phase
  • T cell response
243
Q

Protein Contact Dermatitis (PCD)

A
  • immune response to large protein allergens
  • can NOT penetrate intact skin
  • sensitizing phase (asymptomatic) of weeks to months then an inflammatory phase
  • IgE & cellular response → similar to allergic dermatitis
244
Q

presentation of contact dermatitis

A
  • varied clinical presentation → erythema, scales, crusts, erosion
  • ICD usually dryer than ACD
245
Q

Nappy/Diaper rash (ammoniacal dermatitis)

A
  • ICD (irritant contact dermatitis) caused by irratants (ammonia in urine, proteolytic enzymes in faeces), friction, damp
  • redness, swelling, initially scaly, progresses to erosions, can be acute or chronic
  • complication is yeast infection (pustules) or bacterial (crusty) secondary infection
  • treatment if its uncomplicated → regular nappy changes, careful cleaning, barrier creams
  • treatment if its complicated → treat infections
246
Q

What is Urticaria

A
  • common
  • itchy weheals (hives), localised oedema of the upper dermais, or can occur in deeper dermal layers (angioedema)
  • can be acute or chronic → self resolving
247
Q

Urticaria (pathophysiology, causes, treatment)

A
  • pathophysiology → mediated by mast cell degranulation
  • causes → idiopathic/’one-off’, physical triggers - pressure (scratching), heat, cold, chemical contact, allergies
  • treatment → avoid triggers, pharmacotherapies
248
Q

Psoriasis vulgaris

A
  • chronic T cell mediated inflammatory disease that can develop into psoriatic arthritis (within 10 years)
  • onset in yoing adults
  • lesions variable, sharp boarders, erythema, scale, pustules
  • 1 in 4 patients experience psychosocial distress
  • common co-morbidities → psoriatic arthiritis (11-30%), CVD
249
Q

Psoriasis vulgaris (prevelance & risk factors)

A
  • higher prevelance in: adults, higher income contries
  • genetic pre-disposition
  • enviromental risk factors: medications, infection/GI dysbiosis?, trauma, smoking, alcohol
250
Q

psoriasis vulgaris - pathogenesis

A

initiation:
* damaged KC release ‘dangre’ molecules that activate DC, go to lymph node & activate T cells
* trigger??, antigen - self??
inflammation:
* Th cells release cytokines → activate KC, neutrophils, mast cells, macrophages
* dermal hyperplasia, impaired KC differentiation → plaque formation

251
Q

psoriasis vulgaris - treatment

A
  • pharmacotherapy
  • NO cure, just manage disease
  • initial treatments centered on lytic & anti-miotic drugs. Now targte very specific molecules of the immune system
  • probiotics, faceal microbiotic transplant?
252
Q

adrenal gland

A
  • job is to produce hormones & steriods
  • consists of the medulla & the cortex
  • medulla (core) → nerve endings → makes neurotransmitters
  • cortex (surrounding layer) → gland tissue
253
Q

what does the adrenal gland secrete? (5)

A
  • mineral corticoids
  • glucocorticoids
  • androgens
  • catecholamines
  • peptides
254
Q

cortisol

A
  • cortisol is the predominant corticosteriod secreted from the adrenal cortex
  • secreted according to a diurnal pattern (highest after wakening) under the influence of ACTH from the pituitary gland under the influence of CRH from the hypothalamus
    ACTH = adrenocorticotrophin
    CRH = corticotrophin releasing hormone
255
Q

Glucocortciods

A
  • secreted from → Zona fasciculate of the adrenal cortex
  • Cortisol half life = 70-90 mins
  • Mainly effect the metabolism of glucose via carbohydrate, protein and lipid metabolism
  • Control the carbohydrates, fats and other proteins within the system
  • Help with healing wounds of minimising pain in injury
256
Q

Mineralcorticoids

A
  • secreted from → Zona glomerulosa of the adrenal
  • half life = 20mins
  • main action on minerals like Na, K and H ions
  • Control of electrolytes and water balance of the body
257
Q

Hydrocortisone

A

is a corticosteriod naturally produced by the body

258
Q

regulation of cortisol sercretion (3 major mechanisms)

A
  1. diurnal variation
  2. stress (physical & psychological)
  3. negative feedback (helps to regulate the amount released)
259
Q

anti-inflammatory drugs → glucocorticoids
(examples & route of admin)

A

anti-inflammatory & immunosuppresant drugs
routes of administration:
* oral → prednisone, budesonide
* iv → methylprednisolone, hydrocortisone
* enema → hydrocortisone
* rectal foams → hydrocortisone
* topical → hydrocortisone & betamethasone

260
Q

glucocorticoid → mechanism of action

A
  • Activated GR complex up regulates the expression of anti-inflammatory proteins
  • Activated GR complex decreases the expression of pro-inflammatory proteins
261
Q

glucocorticoids PK

A
  • not stored - rate of synthesis = rate of release
  • synthesized rhythmically and controlled by irregular pulses of ACTH
  • influenced by light and major pulses occur in the morning and after meals
  • Glucocorticoids act via their receptors (GR) in the nucleus
  • GRs are widely distributed and located in almost all cells in the body
262
Q

steriod hormones & targeting of cellular effects

A
  • most physiological effects of glucocorticoids & mineralocorticoids hormones are mediated through binding to intracellular that operate as ligand-activated transcription factors to regulate gene expression
  • mineralocorticoid & glucocorticoid receptors are closely related & share similarities in their ligand & DNA binding domains
263
Q

mineralocorticoid & glucocorticoid receptors

A

are classified into:
* type 1 → specific for minieralocorticoids, but have high affinity for glucocorticoids
* type 2 → are specific for glucocorticoids & are expressed in virually ALL cells

264
Q

Long term risks of glucocorticoids

A

adrenal axis suppression
* risk of death with abrupt cessation of dosing
* requirement for dose-tapering
effects on carbs, protein and fat metabolism
effects on carb, protein & fat metabolism
* promotes gluconeogenesis
* can precipitate hyperglycemia
* skeletal msucle wasting
* hypertension (mineralocorticoid effects)
* redistribution of body fat (‘moon face’, ‘buffalo humps’)
* elevation of mood
* skin thinning
* acne
* bruising

265
Q

topical corticosteriods

A
  • are use for the treatment of inflammatory coniditions of the skin (other than those from infection!) → e.g. eczema, contact dermatitis, insect stings, & eczema of scabies
  • corticosteriods suppress the immune system
  • are not curative & on disocontinuation a rebound exacerbation of condition may occur
  • generally used to relieve symptoms & suppress signs of disorder (when other measures like emollients are ineffective)
  • can get different potencies! (mildly potent, potent, very potent)
266
Q

what counts as topical?

A
  • powder
  • paste
  • cream
  • lotion
  • oinment
  • drops
  • foam
267
Q

absorption rates in the skin

A
  • forearm absorbs 1%
  • armpit absorbs 4%
  • face absorbs 7%
  • eyelids & genitals absorb 30% (max)
  • palms absorb 0.1%
  • sole absorbs 0.05% (min)

the less absorption, the more potent of a steroid you can use (generally)
* minimal systemic absorption (i.e. into the body) → however after a few weeks treatment, tempory HPA axis suppression does occur, resolves upon cessation

268
Q

cutaneous adverse effects of topical corticosteriods

A

uncommon or rare if used appropriately
* skin thinning
* stretch marks
* easy bruising
* enlarged blood vessels
* susceptibility to skin infections
* localised increase in hair thickness & length
* allergy

269
Q

how to minimise adverse effects of topical corticosteriods

A
  • Apply to affected areas only
  • do not apply more frequently than twice daily
  • use the least potent formulation which is fully effective
  • use appropriate formulation for the area
  • use appropriate quantity
  • use for the shortest time possible
270
Q

athletes foot

A
  • aka ‘Tinea pedis’ a fungal infection
  • superfical mycosis → doesn’t go deep, doesn’t cause systemic infection
  • very common infection
  • prevalence rates 15-20%
  • common in tennage & adult males
  • rar in children under 12
271
Q

athletes foot → causitive agents and predisposing factors

A
  • causitive agents → Trichophyton rubrum, T. mentagrophytes, Epidermophyton floccosum
  • spores found in shoes, carpet, bath mats, showers (can survive for months)
  • is not highly infectious, but loves warm, moist enviro’s (inside sweaty shoes & shoes)
  • chronic recurrent disease
  • predisposing factors → immune deficiency, poor circulation, sweaty feet
272
Q

athletes foot (presentation, complications & treatment)

A
  • variable presentation
  • interdigitating, scaling, splitting
  • onychomycosis
  • ‘moccasin’ type → dry, scaly, red, itchy (heels, toes, side of feet)
  • blistering
  • complications → secondary bacterial infections in broke skin (needs to be treated)
  • treatment → OTC preparations
273
Q

Ringworm - Tinea Corpis

A
  • different causative agents → often zoonotic (from pets)
  • T. rubrum, Microsporum canis, T. verrucosum
  • can be acute or chronic
  • inflammed red patches, white healing midle, itchy, inflamed, pustular
  • commonly confused with non-fungal conditions such as impetigo, psoriasis, discoid eczema, allergic dermatitis
  • quick test to distinguish fungal & non-fungal conditions is to use a Wood’s light
274
Q

Tinea Capitis

A
  • scalp infection → inflammation, hair loss
  • common in school age children
  • in NZ commonly from infected cats → M. canis
  • transmissable via spores on hairbrushes, clothing
275
Q

treatment of tinea corpis & capitis

A
  • OTC ointments & shampoos (also for contacts who may be asymptomatic)
276
Q

viral infections → warts

A
  • warts (verruca vulgaris) are cutaneous tumors (benign) → caused by human pailliomarviruses (HPV)
  • very common, caused by a large no. of HPV, many different types of lessions
  • human to human transmission, long incubation time, also get auto-inoculation
  • differential diagnosis → if it looks like a wart it probably is, only refer eldery or immunocompromised patients with atypical warts
277
Q

treatment of warts

A
  • no therapy as will generally disappear by themsleves (but this may take years)
  • cosmetic removal or warts → laser, chemical, surgical removal
  • cytostatic agents, keratolytic agents
  • stimulate the immune system to kill warts → imiquimod cream
278
Q

viral infections - cold sores

A
  • causative agent → Herpes simplex virus Type 1 (HSV 1)
  • viruses are endemic, virus remains latent in nerve infections
  • 1º infection usually occurs in childhood, 7 day incubation, widespread sores (red bump, blister, crust, drops off 7-10 days) usually no scarring!
  • recurrence → fewer or no sores, sores maybe preceded by burning or itching
  • triggers for recurrance → sunlight, fever, menstruation, immune suppression
  • treatment → acyclovir
279
Q

viral infections → chickenpox

A
  • caused by varicella-zoster virus (VZV)
  • human reservoir
  • moderate to highly contagious, generally a self limiting infection
  • transmitted by airborne route → vesicles shed from skin
  • endemic in temperate countries
  • primary infection → varicella (chickenpox)
  • reactivation → herpes zoster (shingles)
280
Q

viral infections - chickenpox (chain of events)

A
  • 14-16 day incubation
  • prodromal phase (fever, malaise, fatique) then the rash
  • raised red bumps, scalp face & trunk (3-5 days, few to many)
  • itchy, fluid filled blisters → rupture, then scab over (24-48 hours - no longer infectious!)
281
Q

complications of chickenpox

A
  • most common → secondary bacterial infection of rash with a Staph. or Strep.
  • hospitalisations → overall rate 8.3/100,000
  • inequalities in hospitilisation
  • rate increasing? → support for inclusion of a vaccine on the nation immunisation schedule (NIS)
282
Q

chickenpox treatment

A
  • mild disease → supportive therapy only
  • prevention → live attenuated vaccine, Oka strain VV (Varilix) added to NZ schedule in July 2017
283
Q

examples of bacterial infections of the skin

A

superficial:
* follicle infections
* impetigo
* leprosy
invasive:
* cellulitis
* closteridial infections

284
Q

hair follicle infections

A
  • folliculitis (single infection), boils (multiple) → furuncles or carbuncles
  • hair follicile is infected generally by a bacteria (Staph. a.) but may be a fungal or viral infection
  • occurs commonly in → groin, armpits, scalp (moist, warm environment)
  • often occurs as a complication to acne or after waxing/shaving
285
Q

types of hair follicle infections

A
  • Folliculitis → localised small inflamed pustules, itchy or painful
  • bolis (furunculosis) → more severe, deeper infection of one or more follicles, often has a central yellow ‘plug’, bigger lesions, commonly in areas of friction, usually will drain themselves, systemic symptoms
  • Carbuncle → conglomeration of several furuncles → massive amounts of necrosis and bacteria (pus), systemic symptoms, will need to be drained
286
Q

hair follicle infections (treatment & complications)

A

treatment:
* depends on severity & if it needs drainage
* antibiotics → topical, local or i.v.
complications:
* rare, assocaited with severe infection → endocarditis, sinus thrombosis

287
Q

impetigo

A
  • Superficial infection of the epidermis caused by staphylococcus aureus or streptococci pyogenes
  • In NZ and Australia commonly known as ‘school sores’
  • Highly infectious
  • risk factors → broken skin (viral infections, trauma, scratching)
  • No systemic symptoms, resolves without scarring
288
Q

what are the 2 types of impetigo?

A

nonbullous (impetigo contagiosa):
* immine response to bacteria → vesicle to erosion to honey-coloured crust
* highly contagious often around nose & mouth
bullous:
* due to toxin, fluid filled blisters, when burst get crust
* less contagious
* can occur in armpits, neck folds, etc. (moist areas)

289
Q

impetigo (transmission)

A

autoinnoculation from nose, person to person, towels, face clothes

290
Q

impetigo (treatment & complications)

A
  • “clean, cut, cover”
  • topical or systemic antibiotics
  • child can return to school 24 hours after starting treatment
  • complications → systemic spread → glomerulonephritis (4%) or scarlet fever (rare)
291
Q

costridial skin infections

A
  • gram positive, anaerobic, rod shaped, spore forming & toxin producing
  • environmental infection of deep tissue through an open wound, no person-person transmission
  • minor cause of serious skin infections in NZ, vaccine for C. tetani
  • examples → C. tetani, C. perfringens
292
Q

C. tetani

A
  • 14-28 day infection
  • early symptoms → tissue infection, weakness, stiffness, cramps. late - spasms, seizures
  • 1% mortality for localised tissue infection, >60% for infection in neonates
  • After infection exotoxin is secreted binds to presynaptic nerve endings and prevents release of GABA and glycine - no inhibition - spasms and seizures
  • vaccine widely used
  • neonatal infection in low income country
293
Q

C. perfringens

A
  • risk factors → vascular disease, diabetes, trauma, surgery
  • necrotising disease similar to streptococcal NF but progresses faster,
  • major toxin is alpha-toxin
  • early → pale skin - fluid filled blisters - discharge - gas production
  • Late → severe pain, tachycardia, fever - progresses to hypotension and organ failure
  • iv antibiotics and debridement, hyperbaric oxygen therapy
294
Q

Leprosy (Hansen’s disease)

A
  • chronic, slow progressing, minimally contagious infection
  • caused by Mycobacterium leprae
  • curable
  • involves skin, mucosal membranes & nerve endings in skin
  • can infect any age group!
  • social implications → historically patients sent to leprosy colonines
  • transmission → person to person, respiratory?, insects?
  • 1991 WHO developed a program to eliminate leprosy
295
Q

pathogenesis of leprosy

A
  • most people will not be infected (<5%), rates increase with deprivation
  • long incubation time → average of 5 years
  • 2 main types of leprosy → tuberculoid & lepromatous (with 3 intermediate borderline classifications)
296
Q

Tuberculoid Leprosy

A
  • non-infectious
  • paucibacillary
  • small defined dry, scaly lesions, slow growing, hair loss
  • systemic nerve damage
  • trauma to extremities common!
297
Q

Lepromatous Leprosy

A
  • progressive
  • contagious infection
  • multibacillary
  • involement of the face, earlobes & nose
  • chronic nasal discharge
  • systemic nerve damage → slow to develop
298
Q

treatment of leprosy

A
  • are a number of antimicrobials available → e.f. dapsone, rifampicin, clofamizine
  • to combact resistance multi-drug therapy is used, generally for 12 months
  • plus surgical reconstruction
  • prevention → tuberculosis vaccine, bacillus calmette-guerin (BCG) has some efficacy
299
Q

topical vs. transdermal drug delivery

A
  • topical → is for the localised treatment of a dermatological condition e.g. Zinc & castor oil oinment, topical corticosteriods
  • transdermal → refers to producst that use the skin surfaces as a portal for systemic delivery of bioactives e.g. voltaren emugel
300
Q

what is the primary barrier to drug permeation?

A
  • the stratum corneum (top layer of the skin)
301
Q

drug transport through the stratum corneum

A
  • rate-limiting process → diffusion
  • disease condition to treat → tinea, corns & calluses
302
Q

drug transport through the viable epidermis

A
  • rate-limiting step → diffusion
  • disease condition to treat → psoriasis, eczema
303
Q

drug transports through the dermis

A
  • rate-limiting step → blood supply & diffusion
  • disease condition to treat → psoriasis, eczema, urticaria
304
Q

drug transport through the systemic circulation

A
  • rate-limiting step → metabolism & excretion
  • disease condition to treat → hypertension, angina, nausea
305
Q

normal skin vs. atopic skin

A

atopic skin:
* not tightly packed → breakdown of skin layer
* The breakdown of the skin barrier means that irritants, allergens and pathogens can penetrate the skin causing inflammation and itching
* water is lost from the skin
* comeocytes shrink and gaps form between them
Atopic presenting skin symptoms →dry skin, inflammation and itching
normal skin:
* tightly packed
* penetration of irritants, allergens & pathogens is blocked by the natural skin barrier
* water is attracted into & retained within the comeocytes causing them to swell & sit together nicely

306
Q

atopic conditions → therapy

A

mainstay → hydration!
* moisturiser’s
* soap substitute
medicated products
* keratolytics (scaly)
* topical corticosteroids (inflammation)
* antipruritic (itch)
products (topical) types
* oils
* lotions
* creams
* oinments
pain relief (if required)

307
Q

moisturisers - humectants

A

reduce the lose of water (bond with water to withdraw moisture from deeper layers of the skin or from the atmosphere to the skin)
e.g. glycerine, hyaluronic acid, urea

308
Q

moisturisers - emollients

A
  • soften/smooth skin (‘fill’ voids between rough/peeling skin cells)
  • e.g. oils, shea/cocoa butter
309
Q

moisturisers - occlusive

A
  • form a barrier on the stratum corneum
  • e.g. vaseline (petroleum), mineral oil, lanolin, silicone
  • stops air escaping skin
310
Q

soap substitutes

A
  • typcally contain absorption bases (contain w/o emulsifying agent)
  • can absorb large amounts of water (approx. 50% their volume) & thereby produce w/o emulsions
311
Q

topical corticosteriods (CC’s)

A
  • synthetic analogues of cortisol (HC)
  • Anti-proliferative/anti-inflammatory actions → atopic condition e.g. eczema and psoriasis
  • Ideal topical CCs permeate SC into the dermis (not into systemic circulation) → governed by lipophilicity
  • Modification of ring structure ± side chains → potency and modulation of ADRs (side effects)
312
Q

modulating chemistry of CC’s

A

changing structure slightly will change action!
* HC backbone modified to change potency → OH group at C11 required for glucocorticoid activity
* double bond: C1-2 to → anti-inflammatory activity (e.g. HC → prednisolone)
* halogenation: (6⍺ or 9⍺ position, fluorination → increase potency/receptor affinity)
* esterification or addition of acetonide → increase lipophilicity → increase skin absorption

313
Q

potency & topical steroid formulations

A

efficacy (‘potency’) = potency (CCs chemisty) + vehicle (formulation)
* i.e. efficacy = pharmacological potency + ability to be absorbed & reach target cells

can have:
* very potent or superpotent
* potent (100-150 times as potent as hydrocortisone)
* moderate (2-25 times as potent as hydrocortisone)
* mild

314
Q

topical delivery: site of CCs action

A
  • need to get into the viable layers of the skin → e.g. the viable epidermis & dermis
  • glucocorticoid receptor (keratinocytes & fibroblasts)
315
Q

percutaneous absorption of CCs

A
  • skin properties dertermines bioavailablity
  • occulusive dressings → increase permeability < 10-fold, however decrease in use due to availability of super potent CCs
  • eyelids & genitals absorb the most → as skin is thinnest there
316
Q

topical CCs - role of vehicle

A

vehicle (formulations) play a key role in the appearance, feel & successful application of topical CCs
* physical form
* solubility
* rate of drug release
* degree of hydration
* chemical/physical stability
* physical and chemical interactions with the skin and active molecule
* location and extent of disease
* emollient properties

317
Q

formulation & potency of CCs

A

at any given strength of a corticosteroid → ointments > cream formulations > lotions
* i.e. ointments are always the MOST POTENT
* occlusive vehicles → trap transepidermal moistures → increase skin water content
* hydration of the SC → swells the membrane → increase drug permeability

318
Q

penetration enhancers

A
  • reversible decreases the barrier resistance of the SC without damaging any viable cells → increases drug absorption
  • e.g. interact with head group or insert between bilayer → affect lipid packing disorder
319
Q

betamethasone dipropionate
(e.g. disprosone vs diprosone OV)

A

(numbering = relative potency)
1. Diprosone OV ointment → e.g. propylene glycol
2. > Diprosone OV cream → e.g. propylene glycol
3. > Diprosone ointment → e.g. soft white paraffin; liquid paraffin
4. > Diprosone cream → e.g. cholrocrestol

320
Q

oinments as treatment

A
  • lubricant, decreases transepidermal H2O loss, occlusive → increase absorption
  • good for dry scaly lesions or non-hairy skin
  • BUT low patient acceptance
321
Q

creams as treatment

A
  • cosmetically appealing (can be washed off)
  • good for larger areas
322
Q

lotions as treatment

A
  • hairy areas/large areas have to be treated
  • cooling & drying effect (useful for treating moist lesions &/or pruritus)
323
Q

foams as treatment

A
  • spread readily & are easier to apply
  • complex delivery systems - so expensive!
324
Q

development of new anti-bactirial agents → problems & solutions

A

problems:
* regulatory requirements increase
* patents expire relatively soon after market introduction
* treatment times tend to decrease
* new drugs often reserved for special patients or situations
solutions:
* tax incentitives, patent extensions, academia-industry collaborations
* 2012 → FDA offered a series of marketing incentives for new antibiotics

325
Q

development of new anti-bacterial drugs - whats happening

A
  • quantity over quality?
  • limited number of new agents
  • pipeline mainly consists of derivatives of known drugs
  • many prone (to some degree) of existing cross-reactive resistance
  • incomplete coverage
  • not keeping up with resistance
326
Q

Teixobactin

A
  • new anti-bacterial agent → 2015
  • isolated from a soil organism (using new culturing technique) → binds to peptidogylcan precursor in gram +ve organisms, active against MRSA
  • Low (no) resistance? (as it binds to lipids!)
  • years away from clinic… issues → difficult to synthesize, low oral bioavailability
327
Q

alternative therapy examples (immunotherapy & ant-microbial therapies)

A

immunotherapy:
* cytokines
* TLR agonists
* antibodies
* vaccines
anti-microbial therapies:
* peptides
* bacteriophages
* predatory bacteria

328
Q

Immunotherapy:

A

**Prevent infection **
* boost immunity or provide immunity (passive immunisation) in vulnerable populations
* active immunisation
**Treat infection **
* act on the immune system to boost existing immune responses
* act on the pathogen directly
treat inflammation (pathology mediated by immune system)
* act on the immune system to modulate inflammation

329
Q

prophylactic vaccines

A
  • used to prevent disease in individuals & decrease spread through a community (herd immunity)
  • active immunization = vaccines on NZ immunisation schedule
  • passive immunisation = antibody given not not able/no time for active immunisation
330
Q

Therapeutic vaccines

A

used to treat individuals already sick, still experimental → HIV, hepatitis

331
Q

antibodies

A
  • use of antibodies was one of the first anti-microbial therapies
  • use before the discovery of antibiotics to treat disease such as diptheria, tatanus
  • excellent therapy
  • **reduce/remove/reverse toxicity **from exotoxins, immune mediators
  • kill → pathogens & pathogen infected cells
  • modulate cell activity
332
Q

therapeutic & prophylatic use of antibodies for infections

A
  • therapeutically → used to treat infectious disease → e.g. tatanus, diphtheria, rabies, anti-venom, new uses - hepatitis, RSV, meningitis, C. difficile
  • prophylatically → given to vulnerable populations (e.g. healthcare workers, leukemics, pregnant women), also known as passive immunisation
333
Q

antibodies & use in COVID

A
  • both polyclonal & monoclonal antibodies manufactured for use in prevention & early treatment of COVID
  • bind to virus & prevent infection of new cells
  • combinations of monoclonal antibiotics used to prevent selection of resistant virus
334
Q

limitations of antibody therapies

A
  • short term effect? (months)
  • anaphylaxis
  • unwanted activities
  • cost????
  • but their use is increasing…
335
Q

cytokines

A
  • soluble messengers of the immune system
  • proteins → need to be given by injection
  • most act as short range (cell -cell)
  • act at low concentration (10^-10 M)
  • short half life
  • multiple, overlapping activities
  • produced by many cells or few cells
  • potential therapeutic use in infections, cancer, autoimmunity
336
Q

clinical examples of cytokines

A

of the 130 known cytokines 18 are approved for human therapy as recombinant preparations
* Actimmune → trialed fro use in treating Mycobacterial infections in combination with Leukine
* Pegasys → pegylated to increase half life, for viral hepatitis
* neupogen & proleukin → in use or trialed for HIV

337
Q

limitations of cytokines

A
  • main limitation → toxicity - encapsulation?
  • lack of specificity
  • effect on pathogens → some cytokines can also act as growth factors for pathogens
  • short half life → pegylation
  • bioavailability
  • cost
338
Q

agonists for immune activating receptors

A
  • Pattern recognition receptors (PRR) on cells of innate immune system recognise conserved ‘patterns’ from microbes e.g. Toll-like and NOD - like receptors (TLRs and NLRs)
  • agonists can be used to stimulate innate immune response
  • antagonists can suppress pathological inflammation
339
Q

advantages or disadvantages of agonists for immune activating receptors

A
  • **advantages **→ target the host not the pathogen → no selective pressure/resistance
  • disadvantages → overactivation of innate immunity → pathologic inflammation, autoimmunity
340
Q

anti-microbial peptides

A
  • can be isolated from both eukaryotes and prokaryotes
  • new, natural ‘antibiotics’ from bacteria, sea sponges, trees, plants, animals, milk
  • small - 10-15 amino acids (aa) usually cationic
  • issues with bioavailability and stability
    resistance will develop
  • activity against bacteria, viruses and fungi
  • also have effects on the immune system
  • activity related to aa composition and properties (such as positive net charges, flexibility, size, hydrophobicity
341
Q

phage therapy

A
  • viruses of bacteria
  • specific host ranges
  • can kill bacteria very quickly → new phage produced within 30 minutes
  • first discovered in 1886
  • hot topic until the discovery of antibiotics
  • resurgence in research with the development of antibiotic resistance
342
Q

phage therapy - advantages & disadvantages

A
  • advantages → very specific, easy to grow & isolate, little toxicity (?), self-replicating & self-limiting, good biodistribution
  • disadvantages → bacteria develop resistance (therefore mixtures of phages are used), immune response to phages
343
Q

predatory bacteria

A
  • interesting alternative…
  • use with antimicrobials (are innately resistance to b-lactams and antifolates) and bacteriophages
  • Bdellovibrio and like organisms (BALOs) show particular promise
  • BALOs are motile bacteria that predate gram - bacteria for energy and nutrients
  • potentially useful for biofilms e.g. catheters, periodontal disease and other situations where antibacterials can’t gain access to infection - ocular infections, burns, infections in cystic fibrosis patients…
  • more research needed…
344
Q

if patient allergic to a penicillin (e.g. fluxcoxacillin) what antibiotic could you prescribe for a skin infection?

A
  • erythromycin

PHCY220 (3 decks)

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