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:
bone marrow suppression: aplsatic anaemia
nausea, vomiting, diarrhoea
allergy/anaphylaxis
gray baby syndrome
Name some macrolides and describe their mechanism of action, spectrum and side effects.
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:
allergy: rash, anaphylaxis
CVS: prolong QT interval
CNS: headache, dizziness, altered taste and smell
GIT: n/v/d, abdo pain
Liver: deranged LFT, hepatitis
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 (diphtheria), 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/anaerobes/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
- PO, IV or IM administration
- Absorption:
Impaired by food in most, administer 1-2 hours before a meal - Distribution:
Wide, most tissues have similiar concentrations to serum
Concentrated in sputum and breast milk = 3-15% of serum
Eye, prostate and CNS = poor penetration
With active inflammation of meninges, penetration for treatment can be achieved - Metabolism:
Half-life of Penicillin G is 30 minutes, or up to 10 hours in renal failure - Excretion:
Renal – 90% tubular secretion, 10% glomerular filtration = dose adjustment in renal impairment
Nafcillin is primarily biliary excretion, and oxacillin, dicloxacillin and cloxacillin have both renal and liver elimination, thus no dose adjustment required in renal failure
Blood levels of all penicillins can be raised by probenecid, which impairs renal tubular secretion of weak acids such as beta-lactam compounds
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 (type 1)
fever
rash
serum sickness (type 3)
stevens johnson syndrome (type 4)
What is the antimicrobial spectrum of Penicillin G
streptococci
meningococci
enterococci
some pneumococci
treponema pallidum
(P-STEM: penicillin is the first antibiotics where many others stem from)
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, target PBP
- act by inhibiting cell wall synthesis, disruption of peptidoglycan cross linking
- 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
First Generation = “FA/PHA” Second Generation = “Everything Else” Third Generation = “ONE/TEN/IME” Fourth Generation = “PI” Fifth Generation = “ROL”
Side effects of cephalosporins
- Hypersensitivity: allergy/anaphylaxis, swelling/rash/hives, cross-reactivity with penicillin
- Haematological: Drug-Induced Immune Haemolytic Anaemia (DIIHA), rarely DITP
- GIT: n & v, abdo pain, C. diff diarrhoea & pseudomembranous colitis
- Kidney: increased nephrotoxicity of aminoglycosides, nephritis
- Infusion 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
IV administration
Crosses BBB
Half-life 7-8 hours, allows daily dosing
Mixed clearance with biliary excretion
No dose adjustment required in renal failure
What are the indications for ceftriaxone?
- 3rd gen cephalosporin, with gram positive and expanded gram negative coverage
- less active against staph c.f. 1st/2nd gen
- not degraded by beta lactamase
- effective against beta lactamase producing strains of Haemophilus and Neisseria, penicillin-resistant pneumococcus
- not active against Pseudomonas, Listeria, Enterobacter
What is the mechanism of action and target organisms of Vancomycin
Glycopeptide antibiotic
Mechanism:
- inhibit cell wall synthesis by inhibiting transglycosylase by binding to peptidoglycan pentapeptide (PPP)
- bactericidal
Spectrum:
- gram positive aerobes (beta lactamase producing organisms, MRSA, Enterococci, meningitis by penicillin-resistant pneumonoccus in combination with ceftriaxone)
- gram positive anaerobes (C difficile)
Dose adjust in renal impairment and obesity, Red man syndrome, vesicant
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: - tetracycline, broad spectrum - inhibit protein synthesis by binding to 30s ribosome subunit - bacteriostatic
Pharmacokinetics:
- absorption: PO or IV, 100% oral absorption, not impaired by food
- distribution: 40-80% protein bound, poor CSF penetration
- metabolism: liver, t1/2 shortened by hepatic enzyme induction
- elimination: excreted in bile and urine
Spectrum:
Effective against various gram positive & gram negative bacteria, Rickettsia, Chlamydia, Mycoplasma pneumoniae
Clinical uses:
- Combination therapy to treat H Pylori
- Community-acquired pneumonia
- Exacerbation of COPD
- Malaria
- Acne
Side effects:
- GI upset: nausea and vomiting
- deranged LFTs
- photosensitivity
- enamel dysplasia, discoloration of teeth, bony deformity in children (calcium binding)
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 at faster rate
- post antibiotic effect: activity lasts longer than detectable serum levels
- reduced toxicity: less time above critical concentration level (renal/ototoxicity)
- simplified administration and reduced monitoring
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.
Both are fluroquinolones.
Cipro has greater activity against gram negatives and positives (broader spectrum), better oral availability, and longer half life.
What is the mechanism of action of sulfonamides
reversibly block folic acid synthesis by blocking dihydropteroate synthase
e.g. sulfamethoxazole, sulfasalazine
Why is Trimethoprim co-administered with sulfonamides
antibacterial synergism:
block sequential steps in folic acid dependent purine synthesis
The combination is frequently bactericidal
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 by inhibiting bacterial DNA-dependent RNA polymerase, interferes with RNA synthesis
- Clinical indications include TB, eradication of meningococcus, Haemophilus influenzae and Staphylococcal colonisation, 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
(Ansamycin abx - inhibits bacterial RNA synthesis)
- orange discolouration of body fluids
- rash
- hepatitis & cholestatic jaundice
- nephritis
- thrombocytopaenia
- flu-like syndrome with intermittent dosing (if given less than twice per week)
CYP enzyme 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
- Inhibition of mycolic acid synthesis, which are required to build cell walls – cell wall discruption, bactericidal
- Readily absorbed orally and wide distribution, 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?
Polyenes (Nystatin, Amphotericin B) Azoles (Ketoconazole, Fluconazole) Allyamines (Terbinafine) Echinocandins (Caspofungin, Micafungin, Anidulafungin) Pyrimidine analogs (Flucytosine)
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?
- Selectively absorbed by anaerobic bacteria and sensitive protozoa
- Bacteroides, Fusobacterium, Clostridium, Trichomonas, Giardia, Amoeba
- 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
Adjuvant therapy is where chemotherapy is administered after surgery
Neoadjuvant therapy refers to the use of chemotherapy in patients who present with localised cancer e.g. chemotherapy + radiotherapy
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
30s: Aminoglycosides, Tetracyclines
50s: Chloramphenicol, Erythromycin (macrolides), Lincosamides (clindamycin), Linezolid
