Pharmacology - Antimicrobials Flashcards
How does Chloramphenicol work and what are some adverse effects
Mechanism:
Potent inhibitor of protein synthesis by binding to ribosome RNA 50s
Spectrum:
aerobic and anaerobic gram positive and negative, not active against chlamydia
Side effects:
gray baby syndrome
bone marrow suppression
nausea, vomiting, diarrhoea
Name some macrolides and describe their mechanism of action and spectrum
erythromycin, clarithromycin, azithromycin
Mechanism:
inhibit bacterial protein synthesis by binding to ribosomal RNA 50s
Spectrum:
Gram positive: strep, staphy, corynebacteria
Gram negative: neisseria, bordatella pertussis, treponema, campylobacter, chlamydia, legionella
other: mycoplasma (no cell wall)
Adverse effects:
anorexia, nausea, vomiting, diarrhoea
inhibit P450 enzymes
liver toxicity
What is the mechanism of action, indications and side effects of Azithromycin
Mechanism of action:
macrolide antibiotic acting by inhibiting protein synthesis by inhibiting RNA (50s)
Spectrum: haemophilus influenzae, chlamydia, mycobacteria, staph, strep, legionella
Side effect:
prolong QT interval
How does azithromycin differ from other macrolides
high tissue penetration
long elimination t1/2 (2-4 days)
single daily dosing
highly active against chlamydia
What is the mechanism, drug interactions and use of Erythromycin
Mechanism:
macrolide antibiotic that inhibits RNA protein synthesis by binding to 50s subunit
bacteriostatic but may be bacteriocidal at high concentrations
Hepatic inhibitor of CYP3A4
increases concentrations of: benzodiazepines, carbemazepine, digoxin, warfarin
Use:
corynebacteria infection, respiratory infection, ocular infection, chlamydia
What is the mechanism of action, spectrum and side effects of Flucloxacillin
Mechanism:
Beta lactam antibiotic
inhibits growth by binding to active site of penicillin binding protein
interferes with transpeptidation of bacterial cell wall synthesis, bactericidal
Spectrum:
staphylococci
streptococci
not MRSA, not anaerobes, not gram negatives
Side effects:
allergy/anaphylaxis
GI upset
nephritis
cholestatic jaundice
urticaria
What is the mechanism of action of Penicillin
beta lactam antibiotic
inhibits growth by binding to active site of penicillin binding protein
interferes with transpeptidation of bacterial cell wall synthesis
bactericidal
What are the pharmacokinetics of Penicillin
oral absorption impaired by food
wide distribution
poor CSF penetration (unless inflammation)
excreted into sputum and breast milk
rapidly excreted by kidney, need renal dose adjustment
What is the mechanism of resistance of Penicillin
inactivation by beta lactamase
modification of target PBP
impaired penetration of drug
antibiotics efflux pump
What are the clinical manifestations of a Penicillin allergy
anaphylaxis
fever
rash
serum sickness
steven johnson syndrome
What is the antimicrobial spectrum of Penicillin G
streptococci
meningococci
enterococci
some pneumococci
treponema pallidum
What antibiotics are used in staphylococcal infections
antistaphylococcal penicillins:
flucloxacillin, dicloxacillin, nafcillin
cephalosporins:
cephazolin, cephalexin
What is the mechanism of resistance in methicillin resistant staph aureus
- beta lactam agents normally bind to penicillin binding proteins
- MRSA produce penicillin binding proteins that have a low affinity for binding beta lactam agents
What is the mechanism of action of Cephalosporins?
beta lactam class
act by inhibiting cell wall synthesis
bactericidal
How are Cephalosporins classified
1st - very active against gram positive cocci (staph and strep), ex. cephazolin, cephalexin
2nd - active against same as 1st with extended gram negative cover, ex. cefaclor, cefuroxime
3rd - expanded gram negative, some active against pseudomonas, some cross BBB, ex, cefotaxime, ceftriaxone
4th - good activity against pseudomonas, cross BBB, ex. cefepime
Side effects of cephalosporins
Anaphylaxis
cross allergy with penicillin
rash
nephritis
haemolytic anaemia
thrombophlebitis
What type of antibiotic is cephazolin, how does it work and what is its spectrum
first generation cephalosporin
beta lactam agent, act by inhibiting cell wall synthesis
Spectrum:
very active against gram positive cocci (staph and strep)
Why are third generation cephalosporins used in CNS infections
expanded gram negative
some cross BBB
good toxicity profile
What pathogens responsible for CNS infection are not covered by Cephalosporins
HSV
listeria
resistant e coli
What is the relationship between Penicillin allergy and Cephalosporin allergy
5-10% cross allergenicity
What is the mechanism of action of ceftriaxone
Third generation cephalosporin
beta lactam
bacteriocidal
inhibits transpeptidation reaction of cell wall synthesis
What are the pharmacokinetics of ceftriaxone
t1/2 7-8 hours (given 1x/day)
excretion through biliary tract
no renal adjustment required
crosses the blood brain barrier
What are the indications for ceftriaxone
gram positive and extended gram negative over second generation
not active against pseudomonas
effective against haemophilus and neisseria
not degraded by beta lactamase
What is the mechanism of action and target organisms of Vancomycin
Mechanism:
inhibit cell wall synthesis by inhibiting transglycosylase enzyme
bactericidal
Spectrum:
gram positive aerobes (beta lactamase producing organisms, MRSA)
gram positive anaerobes (c difficile)
-dose adjust in renal impairment and obesity
Adverse effects of Vancomycin
local phlebitis
chills, fever
flushing due to histamine release (red man syndrome)
ototoxicity (rare)
renal issues
What is the mechanism, pharmacokinetics, resistance and adverse effects of tetracyclines
-mechanism: inhibit protein synthesis by binding to RNA 30s, bacteriostatic
-pharmacokinetics: variable, depending on which drug
generally greater than 60% absorbed, impaired by food, calcium, dairy products, alkaline pH
40-80% protein bound
widely distributed in tissues except CSF
undergo hepatic metabolism, excreted in bile and urine
-resistance: impaired influx, interference with binding to ribosomes, enzymatic inactivation
-contraindication for use: pregnancy, children < 8 years, breast feeding
What is the mechanism, pharmacokinetics and use of Doxycyline
Mechanism:
inhibit protein synthesis by binding to RNA 30s, bacteriostatic
Pharmacokinetics:
95-100% oral absorption
not impaired by food
40-80% protein bound
no CSF penetration
t1/2 shortened by hepatic induction
excreted in bile and urine
Spectrum:
rickettsiae
mycoplasma
chlamydia,
pirochetes
vibrio
h pylori
active in malaria
Side effects:
photosensitivity
discoloration of teeth
nausea and vomiting
What is the mechanism of action of Gentamicin
aminoglycoside
irreversible inhibition of protein synthesis by binding to RNA 30s
initial event is passive diffusion via porin channels across outer membrane, then O2-dependant transport
What are the pharmocokinetics of Gentamicin
poor oral absorption
small volume of distribution
low protein binding
t1/2 2-3 hours
highly polar so does not enter cells readily
concentration dependent killing
CSF 20% of plasma levels
cleared by kidney
excreted unchanged
renal adjustment dose required
Uses and side effects of gentamicin
Spectrum:
gram negative (e coli, pseudomonas, proteus, klebsiella, serratia)
gram positive
no anaerobic activity
Resistance:
production of enzyme that inactivates drug
impaired cell entry
deletion of receptor on 30s
Side effects:
reversible nephrotoxicity
irreversible ototoxicity (vestibular dysfunction)
prolongs NM blockade
What are the benefits of once daily dosing of Gentamicin (how does it improve clinical effectiveness)
- concentration dependant killing: at increased concentration, increased number of bacteria killed as faster rate
- reduced toxicity: less time above critical concentration level
- post antibiotic effect: activity lasts longer than detectable serum levels
How do Penicillins enhance efficacy of Gentamicin
penetration of cell enhanced by inhibition of cell wall synthesis by penicillins
What is the mechanism of action of Fluroquinolones (Ciprofloxacin, Norfloxacin)
Blocks DNA synthesis by inhibiting bacterial topoisomerase II (DNA gyrase) and IV
What are the pharmacokinetics of Fluroquinolones
Well absorbed, IV or PO
High bioavailability
renal excretion - need to adjust dose in renal failure
Uses of fluroquinolones + side effects
Spectrum:
excellent gram negative
good gram positive
Uses:
UTI
sometimes TB
campylobacter
typhoid fever
anthrax
eradication of meningococcal carrier state
side effects: may damage growing cartilage in children less than 18 years old, prolongs QTC, tendon rupture
Compare Norfloxacin to Ciprofloxacin:
Ciprofloxacin has greater activity against gram negatives and positives
What is the mechanism of action of sulfonamides
reversibly block folic acid synthesis by blocking dihydropteroate synthase
Why is Trimethoprim co-administered with sulfonamides
antibacterial synergism:
block sequential steps in folic acid synthesis by blocking dihydrofolate reductase
What is the mechanism of action of Trimethoprim and how does resistance occur
inhibits bacterial dihydrofolate reductase, which inhibits folic acid synthesis and thus purine synthesis
Resistance:
reduced cell permeability
increased production of enzyme DHF reductase
alteration of binding site
Which drugs can be used against Pseudomonas?
- Aminoglycosides e.g. Gentamicin
- Quinolones e.g. Ciprofloxacin
- Cephalosporins e.g. Ceftazadime, Cefepime
- Carbapenems e.g. Meropenem
- Monobactams e.g. Aztreonam
What are the four drugs used for treatment of TB?
Rifampicin
Isoniazid
Pyrazinamide
Ethambutol
What are the important principles of treatment of TB?
- Multiple drugs (usually all 4) are used initially
- Prolonged course of ~ 6 months
- Isoniazid and rifampicin are the most active agents
How does Rifampicin work and why is it used?
- Rifampicin works to inhibit RNA synthesis
- Clinical indications include TB, meningococcal carriage and prophylactic agent for Haemophilus influenzae and Staphylococcal carriage, in combination therapy for osteomyelitis and prosthetic valve endocarditis
Pharmacokinetics of Rifampicin?
- Readily absorbed orally and widely distributed
- Enters the CSF only when the meninges are inflamed
- Excreted through liver and bile
Side effects of Rifampicin
orange coloured urine/sweat/tears
rashes
thrombocytopaenia
nephritis
hepatitis, cholestatic jaundice
Can also cause a flu like illness if administered less than twice weekly, with fever, chills, myalgias, anaemia and thrombocytopaenia
CYP-450 inducer - increased elimination of anti-coagulants, methadone, contraceptives and some anticonvulsants
What is the main side effect of ethambutol to be aware of?
Optic neuritis
How does Isoniazid work?
- Most active drug
- Inhibits synthesis of mycolic acids, which are required to build cell walls – inhibits cell wall synthesis
- Readily absorbed orally and wide distribution, including into CSF
- Metabolised by liver and excreted in urine
- Adverse reactions include provocation of vitamin B6 deficiency (therefore recommended to give doses of pyridoxine in patients at high risk for neuropathy), Isoniazid-induced hepatitis, tinnitus, fever and skin rashes
What are the different classes of anti-fungal medications for systemic infections?
Azoles (Ketoconazole, Fluconazole)
Echinocandins (Caspofungin, Micafungin, Anidulafungin)
Polyenes (Amphotericin B, Terbinafine)
Mucocutaneous infections (Griseofulvin, Terbinafine)
Topical therapy (Nystatin, Topical azoles e.g. Clotrimazole, Topical allylamines e.g. Terbinafine)
What agents are used to treated HSV and VZV?
Acyclovir
Valacyclovir
Famciclovir
What are the indications for Acyclovir in the ED?
- Viral encephalitis
- Shingles (i.e. VZV)
- Patients with HIV
- Genital herpes
Describe the mechanism of action of Acyclovir
DNA polymerase inhibitor which inhibits DNA synthesis
What agents can be used to treat CMV?
- Valganciclovir
- Ganciclovir
- Foscarnet
- Cifofivir
What is the mechanism of action, pharmacokinetics and indications for Acyclovir
-mechanism: inhibition of viral DNA synthesis by inhibiting viral DNA polymerase
-pharmacokinetics: short half life of 2.5 hours (5 x daily dosing), low oral bioavailability, excreted unchanged
wide distribution and CSF levels of 20-50%
- indications: HSV encephalitis, VZV, HIV, genital herpes
- side effects: nausea, vomiting, diarrhoea, headache, reversible renal toxicity, tremour, delirium, seizures
List some anti-influenza agents
oseltamivir
amantadine
Details about Oseltamivir
-mechanism: neuraminidase inhibitors, disrupt viral replication, active against influenza a and b
-indication: uncomplicated influenza, 5 day course if given within 36-48 hours of symptoms onset
shortens duration and lessens severity of illness
- use in ED: high risk groups, elderly, pregnant women, immunocompromised
- prevention with vaccination is preferred
What are the mechanisms of action of Metronidazole?
- Anti-protozoal agent with potent anti-anerobic actions e.g. Bacteriodes, Fusobacterium, Clostridium, Trichomoniasis, Giardiasis, Amoebiasis
- Disruption of the electron transport chain
How does Mupirocin work? What is it used for?
- Mupirocin is active against GP cocci, including MSSA and MRSA
- Inhibits Staphylococcal tRNA synthetase
- Topical treatment for minor skin infections and ? Staph carriage
What are the different chemotherapy options?
Primary chemotherapy refers to chemotherapy administered as the primary treatment in patients who present with advanced disease for which no alternative treatment exists e.g. chemotherapy
Neoadjuvant therapy refers to the use of chemotherapy in patients who present with localised cancer e.g. chemotherapy + radiotherapy
Adjuvant therapy is where chemotherapy is administered after surgery
What are some common anti-helminthic drugs?
- Albendazole
- Ivermectin
- Praziquantel
What are the indications for Pentamidine?
anti-protozoal
indications:
Pneumocystis jiroveci
Trypanosomal infections
Interferes with nuclear metabolism
What drugs are used for malaria prophylaxis?
- Chloroquine → areas without resistance P. falciparum e.g. Central America, Dominican Republic, Egypt and most areas in the Middle East
- Malarone (Atovaquone and proguanil) and Mefloquine → areas with chloroquine-resistance P. falciparum e.g. all other areas except above and below
- Doxycycline → areas with multidrug-resistance P. falciparum e.g. Thailand
- Primaquine → terminal prophylaxis of P. vivax and P. ovale infections
CYP 450 Inducers
CYP 450 Inhibitors
Ribosome 30s v 50s inhibitors
Buy AT 30
CELL at 50
30: Amioglycasides, Teteracycline
50: Chloramphenicol, Erythromycin, Linezolid, Lincosamides (clindamycin)
