antibiotics pharmacology Flashcards
Describe the mechanism of action of penicillins
● Bacteriocidal
● Inhibition of bacterial cell wall synthesis
● Covalent binding to penicillin binding proteins
● Interfere with cross linking and formation of peptidoglycan
How does resistance to penicillins occur?
● Inactivation by beta-lactamase
● Modification of target penicillin binding proteins
● Impaired penetration of drug
● Efflux pumps
What is the microbial spectrum of penicillin G?
● Streptococci, meningococci, enterococci, some pneumococci
● Treponema pallidum
● Clostridia
● Non beta lactamase producing staph
What are the manifestations of penicillin allergy?
● Anaphylaxis
● Fever
● Skin pathology – rash, Steven Johnson Syndrome
What are some other side effects of penicillin?
● Renal failure
● Seizure at high doses
● GI disturbance
● Hepatitis
How are penicillins eliminated in the body?
● Renal excretion and active secretion
● Biliary secretion
How does probenecid alter the elimination of some penicillins?
● Inhibits secretion of weak acid from the proximal tubule.
What circumstances encourage the development of bacterial resistance to
antimicrobial agents?
ntimicrobial agents?
● Resistance is an example of natural selection and arises through spontaneous
mutations or DNA exchange between bacteria.
● It is promoted by :
● Dirty hospital environments with multiple species of bacteria cp-existing and
exchanging between hospital patients, the environment and staff.
● A course of antibiotics that only partially treats an infection - can result from both
overuse and underuse of antibiotics.
● Total consumption of antibiotics in a human population os the critical factor in
development of resistant strains.
What is the MOA of flucloxacillin?
● Bacteriocidal, beta lactam antibiotic
● Inhibits bacterial cell growth by binding to the active site of penicillin binding
proteins
● Interferes with cell wall synthesis which leads to cell death
What microorganisms are susceptible to flucloxacillin?
● Staphylococci (including beta lactamase producing) and streptococci.
● No activity against enterococci, anaerobes, gram negatives or MRSA.
What are the side effects of flucloxacillin?
● Allergy/anaphylaxis, GIT upset, cholestasis, interstitial nephritis, neutropaenia,
serum sickness
What is the frequency of cross allergenicity between flucloxacillin and
cephalosporins?
● 5-10%
Why is oral fluclox given before meals?
● It is inactivated by gastric acid and binds to food proteins which can decrease
absorption
What is the MOA of cephalosporins?
● Bacteriocidal, beta lactam antibiotic
● Inhibit bacterial cell wall synthesis by halting peptidoglycan synthesis
How are they classified and give an example of each class
● 1st generation – cephalexin and cefazolin. Active against gram positive cocci.
Not active against pseudomonas.
● 2nd generation – Added gram negative coverage. Cefuroxime, Cefaclor
● 3rd generation – Crosses BBB, more gram neg coverage. Ceftriaxone and
Ceftazidime which works against Pseudomonas.
● 4th generation – Extended gram negative cover, more resistant to beta
lactamase, pseudomonas cover, crosses BBB. Cefepime
Are there any CNS infections that cephalosporins do not cover?
Listeria, resistant strains of pneumococci and e.coli
What are the adverse effects of cephalosporins?
Hypersensitivity reaction similar to penicillin, 5-10% cross reactivity. Fever, skin
rashes, neutropaenia, haemolytic anaemia. Can cause interstitial nephritis and
ATN.
Can you Explain the microbial spectrum of activity of ceftriaxone?
● Not usual degraded by beta lactamases, so a broader spectrum of activity
● Expanded gram negative cover and crosses the blood brain barrier
● Active against neisseria and haemophilus
● Not active against pseudomonas
What is the clinical relevance of ceftriaxones half life?
Half life is 7-8 hours so it may be administered once daily
What is the mechanism of action of vancomycin?
● Bacteriocidal antibiotic.
● Inhibits cell wall synthesis by binding to peptidoglycan pentopeptide.
● Prevents cross linking of the wall, which leads to weakening of the wall and cell
membrane
What are the target organisms of vancomycin
● Gram positive staph including MRSA and enterococci
● Gram positive anaerobes like clostridium difficile
Which clinical conditions require dose adjustment?
Renal impairment and obesity
What class of antibiotic is gentamicin?
● Aminoglycoside
What is its mechanism of action?
● Bacteriostatic.
● Acts by binding irreversibly to the 30s subunit of the bacterial ribosome, inhibiting
protein synthesis in 3 ways;
● By interfering with the initiation complex of peptide formation
● Inducing misreading of mRNA to produce non functional proteins
● Causing the breakup of polysomes to non-functioning monosomes
● Exhibits concentration dependent killing and post antibiotic effect
Please describe the pharmacokinetics of gentamicin
● A: IV, IM, inhalational or topical (poor PO absorption)
● D: Small volume of distribution, <10% protein bound, achieves high
concentrations in renal cortex
● M: Not metabolised
● E: Renal dependent elimination, glomerular filtration. Half life 2-3 hours, given
daily. Dose adjustment required for renal failure.
What microorganisms is gentamicin active against?
● Gram negative bacteria – e.coli, pseudomonas, proteus, klebsiella, serratia
● Gram positive – staph, strep (in combination with beta lactams)
● No anaerobic activity
What are the advantages of a single daily dosing regimen for gentamicin?
● Decreased toxicity time – less time above critical level for toxicity than multiple
dose schedule
● Concentration dependent killing (at increased concentration can kill more
bacteria at a faster rate)
● Post antibiotic effect (effects last longer than detectable serum levels)
● Easier to do outpatient therapy
● Cost effective
● Less nursing time
● What are the adverse effects of gentamicin?
● Nephrotoxic, ototoxic, prolongs neuromuscular blockade
How do penicillins enhance the efficacy of gentamicin?
Transport of gentamicin into the cell is enhanced by penicillins because they act
on the cell wall.
How does resistance to gentamicin develop?
● Transferase enzyme that inactivates drug
● Impaired cell entry via cell wall changes
● Alteration of ribosomal receptor proteins
Doxycycline
What is the MOA of doxycycline?
● Bacteriostatic
● Protein synthesis inhibitor - binds to the 30s subunit of a ribosome
● Blocks the binding of tRNA to mRNA ribosome complex and stops the addition of
amino- acids to the peptide.
● Inhibits protein synthesis in malaria, where it is active against erythrocytic
shizonts of all malaria parasites. Used for prophylaxis.
What are the pharmacokinetics of tetracyclines?
● A: generally well absorbed (>60% bioavailability) but absorption inhibited by
food, calcium, dairy products and alkaline pH.
● D: Distributed widely to tissues except the CSF, crosses the placenta and can
chelate to Ca in teeth and bones. 40-80% protein bound.
● M: Concentrated in bile, undergo enterohepatic circulation.
● E: Excreted in the bile and urine. Except for doxycycline which has no renal
elimination.
What are the side effects of doxycycline?
● GI - nausea and vomiting
● Skin photosensitivity
● Hepatotoxicity
● Discolouration of teeth and bones (binds calcium in forming teeth ad bones so
cannot be used in pregnancy or children <8yrs)
● Intracranial hypertension
Other than malaria, what are the other indications for doxycycline?
● Respiratory infections
● STIs (chlamydia, syphilis)
● Skin infections (acne)
● Rickettsia (Q Fever)
● Vibrio species (Cholera)
● Antihelminthis
● Anthrax
● Some gram negatives but not routinely used
What is the mechanism of action of chloramphenicol?
● Chloramphenicol is bacteriostatic
● It directly interferes with substrate binding in the 50S subunit of the ribosome to
block protein synthesis
What are the side effects of chloramphenicol?
● GIT: Nausea, vomiting, diarrhoea
● Bone marrow suppression
● Gray baby syndrome in newborns
● Drug interactions with phenytoin, warfarin
Chloramphenicol
Which bacteria is it active against?
Aerobic and anaerobic gram positive and negative. Rickettsia but not chlamydia
Can you list some examples of macrolide antibiotics?
Erythromycin, roxithromycin, azithromycin, clarithromycin
Describe the MOA of macrolides
Bacteriostatic - at high concentrations can be bacteriocidal to some orgaisms
● Inhibit bacterial protein synthesis by binding to the 50s subunit of the ribosome,
blocking transpeptidation
What organisms are macrolides effective against?
● Gram positive organisms like staph, strep, pneumococcus
● Atypicals: mycoplasma, legionella, chlamydia, listeria and some mycobacteria
● Gram negative organisms: Neisseria, pertussis, treponema pallidum,
campylobacter
What are the adverse effects of erythromycin?
● GI upset – anorexia, nausea, vomiting
● Liver toxicity – acute hepatitis
● Allergic reaction – fever, rash
● Drug interaction via P450 enzymes
What is the mechanism of the drug interactions with erythromycin and give some
examples?
● Erythromycin inhibits hepatic enzymes, inhibiting the metabolism of other drugs
and causing increased activity.
● Examples include benzodiazepines, digoxin, warfarin, theophylline
How does azithromycin differ from other macrolides?
● Higher tissue penetration
● Long elimination half life (2-4 days rather than 2-4 hours)
● Single daily dosing
● More effective against chlamydia, haemophilus
● Less effective against staph and strep
● Excreted unchanged in the urine
● No inhibition of of hepatic P450 so drug interactions are uncommon
● Prolongs the QT interval
Ciprofloxacin
● Describe the pharmacokinetics of ciprofloxacin
● A: PO or IV administration, bioavailability >80%
● D: 20 - 40% protein bound
● E: Elimination half life 3-5 hours, renal elimination, requires dose adjustment in
renal failure.
Describe the mechanism of action of fluoroquinolones
● Blocks DNA synthesis by inhibiting bacterial topoisomerase II (also known as
DNA gyrase) and IV.
● Inhibition of Topoisomerase II - interferes with relaxation of supercoiled DNA,
required for normal transcription and replication
● Inhibition of Topoisomerase IV - interferes with separation of replicated
chromosomal DNA
What are the clinical uses of ciprofloxacin?
Used to treat UTIs, bacterial diarrhoea, soft tissue/bone/joint infections and
atypical pneumonias or respiratory infections
What is the microbial spectrum?
● Excellent gram negative activity, moderate gram positive activity
● Active against staph aureus, pseudomonas
● Agents of atypical pneumonia such as mycoplasma & chlamydia.
● Intracellular pathogens such as legionella & mycobacterium
● The drug of choice for treatment of anthrax
How does the antibacterial activity of ciprofloxacin differ from norfloxacin?
● Ciprofloxacin has a greater activity (4-8 times lower minimum inhibitory
concentration) against gram negatives and has a much greater activity against
gram positives
What are the potential adverse effects of fluoroquinolones
● Prolonged QT (with some)
● Nausea, vomiting, diarrhoea (including c.diff)
● Rash
● Abnormal LFTs
● Photosensitivity
● Hyperglycaemia in diabetes
● Damage to growing cartilage(not recommended for those <18 or in
pregnancy/lactation)
● Tendonitis and risk of tendon rupture
● Allergy
What is the mechanism of resistance to fluoroquinolones?
enzyme or a change to the permeability of the organism
What are the indications for acyclovir in the ED?
● HSV encephalitis
● Varicella Zoster
● Patients with HIV
● Neonatal HSV
Describe the mechanism of action of acyclovir
● Inhibition of viral DNA synthesis via irreversible binding to DNA polymerase.
● Incorporation into viral DNA with termination.
● Specificity for virus-infected cell (virus specific thymidine kinase)
Describe the pharmacokinetics of acyclovir
● Short half life of 2.5hrs ( 5 times daily dosing PO)
● Low PO bioavailability
● Excreted unchanged in the urine
● CSF concentration reaches 50% of plasma concentration
● Large volume of distribution
Name some side effects of acyclovir
● Nausea, vomiting, diarrhoea
● Reversible renal toxicity
● Neurological effects - tremor, delirium, seizures
List some anti-influenza agents
Oseltamivir, zanamivir, amantadine, rimantadine
What is the MOA of Osteltamivir/tamiflu?
● Neuraminidase inhibitor - disrupts viral replication and release.
● Active against influenza A and B
What is the relevance of these agents to emergency medicine?
● May be of use in higher risk groups i.e. pregnant women, immunocompromised
● Can limit the severity of disease in those infected
● Can be used in the early phases of a pandemic to limit spread and numbers
infected
Describe the mechanism of action of trimethoprim
● Selectively inhibits bacterial enzyme dihydrofolate
reductase, which is required for the conversion of
dihydrofolic acid to tetrafolic acid.
● By this mechanism it inhibits purine and DNA synthesis
in the bacterium.
● Less efficient at inhibiting the human version of this
enzyme.
What is the rationale for combining trimethoprim with
sulphonamides?
● Sulphonamides inhibit sequential steps in the DNA
synthesis pathway, leading to an enhanced effect.
● They inhibit the step before trimethoprim, which inhibits
the conversion of PABA to dihydrofolic acid.
● This means the combination is bacteriocidal, compared to the bacteriostatic
action of using just one.
Describe the pharmacokinetics of metronidazole
● A: Well absorbed orally with 99% PO bioavailability, can also be given IV
● D: Low protein binding 10 - 20%
● M: Metabolised in the liver, can accumulate in liver disease
● E: half life 7.5 hours, excreted by the kidney
What are the adverse effects of metronidazole
● GIT: nausea, diarrhoea, dry mouth, metallic taste
● Neuro: Headache, paraesthesia, dizziness
● Thrombophlebitis
● Disulfiram like effect so alcohol should be avoided
What is an antiseptic
A chemical disinfectant applied to living tissue which decreases the number of
organisms by killing, removing or diluting and has generally low toxicity to tissues.
Describe the actions and uses of chlorhexidine
● Low skin irritating capacity
● Low oral toxicity
● Active against bacteria (most effective against gram positive cocci)
● Not inhibited by blood or organic products
When is chlorhexidine contraindicated
● Middle ear surgery (can cause sensorineural deafness)
● Neurosurgery as can cause neural toxicity
● Allergy
