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INFECTIOUS DZ > Antibiotics, Antifungals, Antivirals > Flashcards

Antibiotics, Antifungals, Antivirals Flashcards

1
Q

Penicillin - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Penicillins
Ampicillin - some G- coverage
Ticarcillin - more G- and less G+ (antipseudomonal, extended spectrum)
Amoxyclav - broadest spectrum

Inhibit synthesis of peptidoglycan cross linking in cell wall. Therefor G+ affected > G- and those without peptidoglycan wall are innately resistant
Time dependent - keep at high levels for longer time.
Wide distribution but poor entry into brain/prostate
Renally excreted, concentrate in urine

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2
Q

Cephalosporins - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

1st gen = cephalexin (G+ and anaerobic G-)
3rd gen = ceftiofur, cefovecin (no penicillinase/B lactamase coverage)

Inhibit cell wall synthesis by blocking peptidoglycan cross linking
Time dependent
Wide distribution but do not penetrate BBB or prostate
Renally excreted

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3
Q

Carbapenems - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Imipenem
Inhibit cell wall peptidoglycan cross linking, highly resistant to B lactamases.
Broad spectrum of activity due to penetration of G- outer membrane
Restricted drug
Renal excretion can be nephrotoxic, GI upsets

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4
Q

Vancomycin - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

A glycopeptide drug
inhibit peptidoglycan synthesis (not cross linking like other drugs) preventing cell wall synthesis.
Restricted use, MRS
renally excreted
Anaphylaxis after IV infusion in humans

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5
Q

Quinolones - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Enro, Marbo, pradofloxacin
Bind DNA gyrase and topoisomerase - disrupting bacterial DNA synthesis and negative supercoiling
CONCENTRATION DEPENDENT
Staph and Pseudomonas require highest doses
Lipophilic with good tissue penetration, can also attain high intracellular concentrations.
G- > G+ > atypical. No anaerobic coverage.
Metabolised to ciprofloxacin and excreted in urine

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6
Q

Rifamycins - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Rifampin
Inhibit DNA-dependent RNA synthesis
CONCENTRATION dependent
Highly lipid soluble, good intracellular concentrations for treating mycobacterial infections
Atypical infection used in multiagent therapy. Some G+ and G- activity

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7
Q

Aminoglycosides - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Gentamicin, amikacin, Neomycin
Protein synthesis inhibitor - binds 30S subunit
Requires O2 to enter cytoplasm (which also disrupts cell wall)
CONCENTRATION dependent
Poorly lipid soluble, does not readily penetrate many tissues or secretions. Excreted by kidney and can be nephrotoxic (concentrate here)
G- and resistant staph infections. No anaerobic coverage.

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8
Q

TETRACYCLINES - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Doxycycline, minocycline
Inhibits bacterial ribosomal 30S subunit, bacteriostatic effect
Good tissue penetration particularly lung, and also some into CNS
TIME DEPENDENT (concentration at high doses).
Excreted in urine
Covers most quadrants, doxycycline has increased anaerobe coverage.
In particular effective against Mycoplasma and Rickettsial disease.

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9
Q

Macrolides - drug examples, MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Clindamycin, azithromycin, erythromycin
Inhibit protein synthesis binding to 50SA subunit in bacterial ribosomes.
TIME DEPENDENT
High lipid solubility and good penetration of tissue including CNS
Good G+ coverage, poor G- coverage and excellent for intracellular disease as concentrates in leukocytes.
Can have very long tissue retention

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10
Q

TMS - MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Trimethoprim inhibits dihydrofolate reductase, sulphonamide inhibits bacterial folate synthesis (PABA). Synergistic actions
CONCENTRATION DEPENDENT
Good tissue penetration, lipophilic, weak base can enter prostate.
Broad spectrum, though less active against anaerobes, and innate resistance in enterococcus infection despite in vitro efficacy.

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11
Q

Metronidazole - MOA, time/concentration dependent, tissue penetration, excretion, spectrum

A

Activated in bacterial cytoplasm to nitroso free radical that damages DNA

Good absorption and lipophilic,
Used for Tx of anaerobic infections and some protozoal disease
Poor coverage of aerobic or atypical intracellular infections.

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12
Q

Mechanism of resistance to B lactams

A
  • production of B lactamases (common in G- to have extended spectrum that also effects cephalosporins)
  • Many Bacteroides ahve inherent resistance
  • reduced porin expression
  • G+ bacteria modify peptidoglycan proteins preventing binding
  • multidrug efflux pumps
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13
Q

Mechanism of resistance to Cephalosporins

A
  • extended spectrum B-lactamase (ESBL) in G-
  • reduced uptake
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14
Q

Mechanism of resistance to carbapenems

A
  • production of carbapenemases identified in Klebsiella sp
  • reduced uptake
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15
Q

Mechanism of resistance to fluoroquinolones

A
  • DNA gyrase modification in G- bact
  • Drug acetylation
  • Multi-drug efflux pumps
    Often resistance to one results in all of this class being impaired (less so for pradofloxacin)
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16
Q

Mechanism of resistance to TMS

A
  • Altered folate synthesis proteins (PABA) prevents drug binding and activity
  • Efflux Pumps
  • intrinsic in Pseudomonas
17
Q

Mechanisms of ABx resistance

A

Antibiotic degrading enzymes (B lactamase, ESBL; fluoroquinolone acetylation)

Efflux pumps (drug specific or non-specific multidrug effluxx pumps)

Target Modification (altered penicillin binding protein, ribosomal change, DNA gyrase change)

Limiting Drug uptake (reduced porin expression in G-; biofilms)

18
Q

Mechanism of resistance to Aminoglycosides

A
  • phosphorylation causing inactivation
  • changes to cell wall polarity
  • Ribosomal mutations
  • Anaerobe and Enterococcus intrinsic resistance
19
Q

Mechanism of resistance to Rifampin

A
  • mutation causing altered RNA polymerase binding site
20
Q

Mechanism of resistance to tetracyclines

A
  • Change of ribosomal binding site
  • reduced uptake through porins
  • oxidation of drug
  • efflux pumps
21
Q

Mechanism of resistance to Macrolides/lincosamides

A
  • Ribosomal mutation/conformational change
  • Efflux pumps
22
Q

MIC test principles and limitations

A

Uses a gel plate with gradient of drug concentrations to inhibit bacterial growth
The lowest concentration at which growth is inhibited is the MIC.
Bacteria that grow at higher concnetrations are considered resistant
Concentrations reported are based on PLASMA/SERUM levels of drug that are normally reached (not tissue specific)

  • underestimates activity of drug at lower than MIC
  • underestimates activity of drug that concentrates at site where drug is more concentrated (ie urine excretion)
  • overestimates efficacy of drug that cannot penetrate certain tissues due to physiological or pathological processes
23
Q

What is breakpoint

A

Calculated from MIC, pharmacokinetics and clinical data for the drug used in field conditions.
Determine the efficacy of a particular drug dose and target tissue site.
Much of the tissue specific and disease specific data for animals is not known so human values used and may not be transferrable.

Drugs with breakpoint close to MIC are less likely to be effective in vivo

24
Q

What is the 90:60 rule in antimicrobial susceptibility

A

That for a given bacteria treated to antimicrobial it is sensitive to 90% of patients will respond favourably.
For a bacteria resistant to an antimicrobial administered ~60% of patients will still respond to therapy.

Not confirmed or challenged in vet med.

25
Q

Reasons for ABx stewardship and scope of its use

A

ACVIm 2015 guidelines, AAFP, AAHA Guidelines
Also think ISCAID Resp/Urinary guides
- strong evidence in human med that ABx use contributes to AMD development. Limited/circumstantial evidence this could cause resistant infection in small animals
- Low to moderate evidence of ABx causing resistance in animal med, but given human evidence is likely to be the case. Also recent publications on outbreak of carbapenem resistant ESBL E. coli in veterinary hospitals where there was over-prescription of this antimicrobial. vet hospitalisation was also a key risk factor of presence of AMR in prospective longitudinal study oin Switzerland
- Aim is through modification of use of medications we can reduce this risk

26
Q

Main Stewardship goals for ABx

A
  1. Prevent disease occurrence/reecurrence
    (vaccination, husbandry, address predisposing health issues)
  2. Reduce ABx use
    (confirm bacterial cause - not all fever is bacterial; consider if culture results are clinically relevant)
  3. Improved ABx use
    - consider site of action, pathogen susceptibility and patient facotrs in prescription
    - duration should be until clinical/microbiological cure is documented, extended courses are not needed even in MDR infections (if using appropriate ABx)
    - Strive for definitive diagnosis of infection
    - De-escalate based on C+S
    - Recommended laboratory withholding of sensitivity data for more critical antimicrobials.
    - restrict ABX to prescription only (OTC may increase risk of inappropriate use though no data to back this up)
27
Q

What practices are discouraged by stewardship guidelines

A
  • longer treatments are NOT need for MDR infections
  • Use of human generic ABx shoul dbe avoided due to unknown PK/PD data
  • in-house cultures due to risk of misdiagnosis, culture of contaminants and biosafety
  • Screening cultures not recommended (think subclinical UTI)
  • Avoid use of ABx for their immunomodulatory or other effects.
28
Q

AZOLES - types, MOA, AEs, Spectrum, Penetration

A

All inhibit fungal ergosterol synthesis (key component of cell wall). More efficacy against yeast, intrinsic resistance in fungi that lack this cell wall component.
GIVE THEM WITH FOOD TO IMPROVE ABSORPTION
ANTACIDS IMPAIR ABSORPTION

Ketoconazole - first gen drug. Can inhibit normal steroid hormone production, induce liver toxicity.
Tx of malassezia but not Aspergillus
Good tissue penetration but not CSF
Clotrimazole - ver poor bioavailability, use topically can be effective

Itraconazole - effective for Crypto, some Asper coverage and most other molds. Poor CNS penetration.
GI and hepatic adverse effects - dose dependent. Vasculitis in cats
No urine excretion

Fluconazole - no Asper coverage, narrower spectrum of other fungi. Good tissue distribution, can enter CNS for Crypto
GI and hepatic side effects

Posaconazole - broad spectrum and good tissue penetration (perhaps not as good into CNS). GI upsets are main reported AE but uncommon. Mild liver enzyme increase not affecting treatment.

Voriconazole - broadest spectrum, best penetration. V $$
Cytp450 inducer, may cause GI upset and liver tox.

29
Q

Amphotericin MOA, Uses, Spectrum AEs

A

Irreversibly binds fungal wall sterols forming a pore which leaches intracellular electrolytes and neutrients
Also has immunomodulatory effects on macrophage activity increase

Used for progressive, severe systemic fungal infections.
Broad spectrum.

Given IV or SC. Use lipid complexed formulation to reduce AE
AEs: nephrotoxicity through reduced renal blood flow and possible inherent toxicity to tubular cells. May cause RTA. Also GI upsets and cardiac arrhythmias reported.

30
Q

Terbinafine MOA, Spectrum, Uses, AEs

A

Reversible inhibition of squalene cyclase in fungal ergosterol synthesis for cell wall.
Has synergistic effects with azole antifungals.
Concentrates in the skin and hair.
Used primarily as a single agent for dermatophytes but can enhance efficacy of azoles in treatment of systemic infections

AEs: GI upset, liver toxicity, periocular swellings

31
Q

Recent findings of comparative absorption of itraconazole compounded formulations

A

2 JAAHA studies
- compounded formulation had significantly lower, and subtherapeutic in 12%) levels compared to generic or brand name formulations. Some on brand name/generic had potentially toxic serum levels

  • randomised crossover design trial comparing compounded to namebrand formula. Found compounded formulations poorly absorbed. But also that liquid formulations were much better absorbed than formulated capsules.resulting in a need for lower dose of liquid formulations
32
Q

Antivirals used to treat FIP and their MOA, AEs

A

GS and Remdes - nucleoside analogues. Small molecules that enter cells and interfere with viral synthersis incorporating into transcript and causing termination of synthesis
Good oral bioavailability (unpublished); AEs: injection site pain/inflammation, urolithiasis

Molnupiravir - prodrug that is converted to active nucleoside analogue that causes translation mutations in viral RNA transcription –> lethal mutagenesis
PK and PD not published in cats (very small study) anecdotally may cause more side effects.
Used as back up for GS/Rem if treatment failure

33
Q

Antiretrovirals used in FIV/FeLV and evidence

A

Zidovudine and Fozivudine
both are nucleoside analogues that inhibit viral replication
Fozivudine is preferentially activated by lymphocytes so has less haematological AEs compared to Zidovudine which can cause non regenerative anaemia.
Limited evidence of efficacy, may reduce viral load in affected cats, and/or help improve QoL by impairing secondary infections. As these are viruses many cats live with and not develop secondary complications it is difficult to know true impact of these treatments without longitudinal prospective trials in a large cohort

34
Q

MOA, AEs, Indications of Acyclovir and Famciclovir

A

Thymidine kinase activated drug, TK is produced by viral infected cells and then other cellular machinery further activates the product resulting in accumulation of ac tive metabolite in virally infected cells. The active metabolite interferes with viral DNA synthesis

Acyclovir caused severe AEs when used parenterally, and poor efficacy topically
Famciclovir is better tolerated and can help to reduce disease severity (though limited evidence ofr this).

35
Q

MOA of IFN-omega and uses

A

Not a direct antiviral but inhibits host cell mRNA translation proteins that virus hijacks for replication thus inhibiting viral replication. May also non-specifically enhance immune defence.

Improved clinical signs and decreased viral shedding in 16 FIV/FeLV cats
May also reduce clinical signs and mortality associated with canine/feline parvo
May be that effects are more on inhibition of 2ry infections than on interference with the parvovirus itself.

36
Q

Clofazime MOA, uses, AEs

A

Binds to mycobacterial DNA and inhibits replication, ineffective against other bacteria and fungi.
May also work on Leishmaniasis
Used in various mycobacterial infections ideally based on sensitivity testing
AEs: changes colour of secretions to orange, GI upset, possible hepatotoxicity (limited information)

37
Q

Pyrantel MOA, uses, excretion, AEs

A

Tx of ascarids and hookworms in dogs and cats (Toxocara, Uncinaria, Ancylostoma)
Cholinergic agonist that inhibits nicotinic receptors of parasites to act as a neuromuscular blocking agent
Poorly absorbed from GIT, acts locally on intestinal worms.
Rare AEs: vomiting, diarrhoea, anorexia short lived

38
Q

Doramectin - MOA, uses, AEs

A

An avermectin that affects chloride channel activity in the nervous system of nematodes/arthropods causing parasite paralysis and death

Used off label in treatment of Spirocerca lupi infections and some mites

May see mydriasis, lethargy, blindness. Avoide in MDR1 dogs.

39
Q

Mefloquin MOA, uses, AEs

A

human antimalarial drug that reduces viral load by preventing cell lysis and thus completion of viral replication

Continuous administration necessary as does not stop viral replication.

AEs: vomiting, increase SDMA possible renal damage.

INFECTIOUS DZ (7 decks)

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