DRUGS Flashcards
Polyenes (older)
- Example: conventional Amphotericin B
- Mechanism: Binds to sterols in cell membrane = increase membrane permeability and forms pores. Also has effects on inhibiting oxidation
- Not affected by hepatic or renal failure
- Poor penetration thru BBB
- Spectrum: broad with low resistance
- due to toxicity not often used. Still used
- for invasive candidiasis, cryptococcal meningitis in HIV and empiric therapy in selected cases
-
ADRs:
- Nephrotoxicity - up to 80% (HSCT pts greatest risk)
- Infusion reaction (fevers, chills, rigors, hypotension)
Flucytosine MOA
- converted by cytosine deaminase to 5-fluorouracil, which inhibits thymidylate synthase and disrupts fungal protein synthesis.
Capsofungin MOA
- Caspofungin inhibits synthesis of beta-glucan, a major fungal cell wall component.
Azoles MOA
- Example: Azole, fluconazole, posaconazole (best for zygomycosis), voriconazole (first line for invasive aspergillus)
- Spectrum - Broad: inc Aspergillus
- Mech: Inhibit C-14alpha demethylase which is required synthesis of ergosterol in fungal cell membranes –> breakdown. Then cell leakage and death occur by lytic activity of the host defence system.
- Contra/precaution: Peripheral neuropathy may worsen
- *ADRs**: Rash, HA, dizziness, GIT, hepatic derrangement, P450 inhibition
- Rare:
- thrombocytopenia (voriconazole), other blood dyscrasias
- Hepatotoxicity (30% with vori)
- Allergy
- Alopecia (prolonged courses)
- Peripheral neuropathy (prolonged courses)
- SCC in lung transplant recipients
- Voriconazole 30% visual changes - dose related, reversible
Terbinafine MOA
- Inhibits squalene epoxidase
Griseofulvin MOA
- interacts with microtubules to disrupt mitotic spindle.
Trimethoprim
- interferes with DNA synthesis by inhibiting dihydrofolate reductase may interact with methotrexate, which also inhibits dihydrofolate reductase
- AE: myelosuppression, transient rise in creatinine via competitively inhibits the tubular secretion of creatinine resulting in a temporary increase which reverses upon stopping the drug. HyperK
- Avoid in pregnancy
Primaquine
- used in non-falciparum malaria to destroy liver hypnozoites and prevent relapse.
- Should not be given to people with glucose-6- phosphate dehydrogenase (G6PD) deficiency due to the risk of haemolysis.
Vancomycin
- MoA: inhibits cell wall formation by binding to D-Ala-D-Ala moieties, preventing polymerization of peptidoglycans
- Mechanism of resistance: alteration to the terminal amino acid residues of the NAM/NAG-peptide subunits (normally D-alanyl-D-alanine) to which the antibiotic binds
- Adverse effects: nephrotoxicity ototoxicity thrombophlebitis red man syndrome; occurs on rapid infusion of vancomycin
Aminoglycosides
- Example: Gentamycin, Amikacin, Streptomycin
- Spectrum: Primarily Gram negative, gentamicin has pseudomonal cover
- Mech: irreversibly bind 30S ribosomal subunit = inhibit protein synthesis + damage cell membrane Concentration dependent bactericidal
- Contra: neuromuscular disease (myasthenia gravis), PHx vestibular/auditory toxicity
- Precaution: renal/elderly/preg
- ADRs: Renal, ototoxicity, neuromuscular blockade - inc resp depression Rx with Ca gluconate. Includes permanent deafness esp in DNA A1555G mutation
Voriconazole
- High cover spectrum
- Fluconazole resistant Candida
- Moulds
- Aspergillus spp (esp terreus)
- Fusarium
- Scedosporium apiospermum
Fluconazole
- Treatment of candidaemia in non-neutropenic patients who are haeomdynamically stable
- Sensitive Canidida
Itraconazole
- Broader spectrum -> yeasts and moulds
- Oral bioavailablity
- new formulaiton - suba-itraconzaole (pH polymeric matrix)
- Oral - signififcant GI side effects
- Drug-drug interactions
- Uses
- alt prophylaxis post allogenic HSCT
- Sequential therapy for IA (rarely with the advent of other azoles
- Alt 2nd or 3rd line agent for Scedosporium
- Alt for treatment of Dermatophytes
Carbapenems
- Example: Ertapenem, imipenem, meropenem
- Spectrum = BROAD: gram positive, negative, anaerobes, ESBLs, pseudomonas. No MRSA activity
- Mech: inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins
- Usually bactericidal
- Contra: avoid Rx with valproate (lowers Val)
-
ADRs: GIT, headache, C diff, anaphylaxis
- Imipenem: neurotoxicity
- Ertapenem: neurotoxicity inc seizures
- Stenotrophomonas maltophilia - intrinsically resistant and can be opportunistic infection with prolonged Rx
- Note Ertapenem does not have anti-pseudomonal activity
Tetracyclines
Example: Tetracycline, Doxycycline
- Mech: reversibly binding to 30S ribosome subunit - inhibits bacterial protein synthesis
- Bacteriostatic
- Contra/Precaution: SLE (may worsen), contraindicated with oral retinoids (increased risk of BIH), children (discolour teeth, reduce bone growth)
- Safe in first 18 weeks of pregnancy
- ADRs: GIT, tooth discolouration, reduced bone growth in kids <8, photosensitivity
- Rare ADRs: photo-onycholysis/nail discolouration, oesophageal ulcers, C. diff, hepatitis/fatty liver, benign intracranial hypertension, allergy, TEN, worsening of SLE, serum sickness-like reactions
Mechanisms of Resistance
- Penicillins
- Aminoglycosides
- Chloramphenicol
- Tetracyclines
- Sulphonamides
- Vancomycin
Cephalosporins with anti-pseudomonal activity
Ceftazidime
Cefepime
Ceftolozane + Tazobactam
Trimethoprim and Sulfamethoxazole
- AKA co-trimoxazole or Bactrim
- Mech: competitively inhibit bacterial folate production essential for bacterial growth
- Bacteriostatic
- Use: Rx and prevention of PCP + other
-
Precaution:
- SLE may worsen
- may inactive PO typhoid vaccine
- Drugs that cause hyperkalemia
- increased risk of haemolysis in G6PD deficiency
- Contra: megaloblastic anaemia due to folate deficiency, severe hepatic or renal impairment
- Avoid use in pregnancy and BF
- ADRs: GIT, skin sensitivity, itch, fever, blood dyscrasias
- Rare ADRs: megaloblastic anaemia, methaemoglobinaemia, erythema, hypoglycaemia, hyponatraemia, hepatitis, crystalluria, urinary obstruction with anuria/oliguria, lowered mental acuity, depression, tremor, ataxia (after IV use in HIV patients), C diff, aseptic meningitis
Drug Profile: Ganciclovir
NOT AVAILABLE IN AUS
Mechanism: Guanine analogue
- Viral TKs selectively try to phosphorylate it - inhibits DNA polymerase and DNA synthesis of the virus
Formulation: IV or intravitrolly (bad PO bioavailability)
Indications: often induction prior to valgan
- Sight-threatening CMV retinitis in immunocompromised
- CMV pneumonitis in BM transplant recipients
- Prevention of CMV disease in BM/solid organ transplant patients
- Precaution
- Avoid use with imipenem - seizures
- BM suppression or cytopenia - ?more myelosuppression
- Renal
Not safe in pregnancy or breast feeding - teratogenic advise contraception
ADRs:
- Common (>1%) granulocytopenia, neutropenia, thrombocytopenia, anaemia, fever, GIT, raised LFTs, HA, confusion, hallucinations, seizures, pain and phlebitis at injection site (due to high pH), sweating, rash, itch, increased serum Cr and urea , infections, myalgia
- Infrequent (0.1–1%) chest pain, chills, mouth ulceration, cough, dry mouth, drowsiness, arthralgia
VICTOR Study:
PO Valgan vs Gan: Valganciclovir was non-inferior (but study biased to non-severe disease)
Mechanisms of Antibiotic Resistance
Mechanisms of Antibiotic Resistance
Mechanism of Vancomycin Resistance
Palivizumab
Ribavirin adverse effects
(used in Hep C)
Cephalosporins MoA
- *Examples: Cef-/Ceph-**
- *Spectrum:** varies with generation
- *ALL** are inactive against MRSA, listeria and enterococcus spp.
- *Mech:** Interfere with bacterial cell wall peptidoglycan synthesis by binding to penicillin-binding proteins = cell lysis and death
- *Bactericidal**
- *ADRs:** GIT, rash, allergy, super infection. Rare - neurotoxicity, blood dyscrasias, renal impairment
Monobactams - Aztreonam
Example: Aztreonam
Spectrum: effective only against aerobic Gram-negative bacteria (e.g., Neisseria, Pseudomonas).
Mech: inhibits bacterial cell wall synthesis by binding to penicillin-binding protein 3 of gram negative bacteria aerobes
Bactericidal
Precaution: may cross react with ceftazidime allergy
Safe in pregnancy/BF
ADR: GIT, rash, taste disturbance, HA, dizziness
Rare ADR: anaphylaxis, TEN, C. diff, blood dyscrasia and hepatitis
NOT for gram negative anaerobes or any gram positives
Very veeeeery limited cross reactivity with beta-lactams other than ceftazidime
Nitroimidazole antibiotics
Example: Metronidazole, Tinidazole
Spectrum - Broad: Gram positive+negative, anaerobes, protozoa (inc giardia), amoeba
Mech: ?metabolised to active metabolites which interfer with DNA synthesis
Contra/Precaution: neurotoxic, blood dyscrasias
ADRs: GIT, metallic taste > furry tongue/glossitis/stomatitis
Rare ADR - hypersensitivity, peripheral neuropathy, seizures, dark urine
Daptomycin
Mech: cyclic lipopeptide inserts in Gram-positive bacterial cytoplasmic membranes in presence of Ca, causing depolarisation and K+ efflux - impairs K+ dependent DNA, RNA and protein synthesis = cell death
Spectrum: Gram positives ONLY inc MRSA and VRE
Bactericidal
ADR: GIT, HA, rash
Importantly - parasthesia, myalgia and muscle weakness
Rare ADR: increased Cr, hypersensitivity, eosinophilic pneumonia, multi-organ hypersensitivity syndrome, Rhabdo, hepatoxicity, C. diff
Must measure baseline and min. weekly CK
Cannot be used in pulmonary infections - inactivated by surfactant
