Antibiotics Flashcards
What determines the antimicrobial spectrum of penicillins?
Side chains attached to the B-lactam ring
Bacterial strategies of resistance against penicilins
B-lactamase to break B-lactam ring
Reduce bacterial permeability to limit intracellular concentration
Increase extrusion of penicillin
What would be used in addition to penicillin in severe pneumonia?
Macrolide
Contraindications of penicillins
- Allergy to B-lactam antibiotics
- Renal impairment
- Those at risk of C.diff (amoxicillin kills gut flora)
- Prior flucloxacillin-related hepatotoxicity (flucloxacillin)
How many days does a penicillin skin rash take to present after first exposure?
7-10 days
What immunoglobulin mediates an immediate anaphylactic reaction?
IgE
How often do penicillins need to be administered?
4-6 hourly due to short plasma half-life of 30-60mins
ROA for benzylpenicillin
IV or IM - GI absorption is prevented by hydrolysis by gastric acid
Therefore prescribed for the treatment of severe infections usually at high dose
ROA for penicillin V
Oral - less severe infections
What would you use to treat a young person with a sore throat of unknown cause?
Penicillin V - NOT AMOXICILLIN due to rash associated with amoxicillin & EBV
Penicillin V is mainly used to treat 3 conditions
Strep throat
Otitis media
Cellulitis
Penicillin V is active against Gram…
Positive bacteria - streptococcus pyogenes (i.e. group A streptococcus) - skin flora
Co-amoxiclav is active against
Gram-positive (like other penicillins) - Strep pneumoniae
Gram-negative (addition of amino group to the B-lactam side chain) - Haem influenzae
B-lactamase-producing bacteria (addition of clavulanic acid) - Staph aureus, Gram-negative anaerobes
Empirical treatment of pneumonia
Amoxicillin - covers Gram-positive (Strep pneumoniae) and Gram-negative (Haem influenzae)
UTIs are most commonly caused by
E. coli (treat with amoxicillin, trimethoprim or nitrofurantoin)
What is the interaction between penicillins and methotrexate?
Penicillins reduce renal excretion of methotrexate, increasing the risk of toxicity
What is the interaction between penicillins & warfarin?
Broad spectrum penicillins (e.g. amoxicillin) kill normal gut flora that synthesises vitamin K, and therefore enhance the anticoagulant effect of warfarin
Dose & ROA of amoxicillin for severe infections
1g 8-hourly IV
IV to oral switch after 48hrs if clinically indicated
Dose & ROA of amoxicillin for mild-to-moderate infection
250-500mg 8-hourly oral
How is the prescription of co-amoxiclav written?
e.g. 500/125
500mg amoxicillin + 125mg clavulanic acid
For piperacillin, what has the slide chain of broad-spectrum penicillins been converted to? Why is this beneficial?
It has been converted to a form of urea. This improves affinity to penicillin-binding proteins, thus increasing the spectrum to include Pseudomonas aeruginosa
What is the benefit of tazobactam?
B-lactamase inhibitor, so is active against B-lactamase-producing bacteria, e.g. Staph aureus, Gram-negative anaerobes
Is Haemophilus influenzae Gram-positive or Gram-negative?
Negative
Type of infections where antipseudomonal penicillins are used (e.g. Tazocin)
Severe infections, particularly where there is a broad spectrum of potential pathogens (including Pseudomonas aeruginosa), antibiotic resistance is likely (e.g. hospital-acquired infection) or if patients are immunocompromised
Dose & ROA for Tazocin
4g piperacillin + 500mg tazobactam (4.5g)
IV infusion every 6-8hrs - 5-14 days with no oral switch possible
What is flucloxacillin active against?
B-lactamase-producing staphylococci because it has an acyl side chain that protects the B-lactam ring from B-lactamases
How is MRSA resistant against flucloxacillin?
Resists the actions of flucloxacillin by reducing penicillin-binding activity
How are penicillins excreted?
Rapid renal excretion means that the plasma half-life is short. Therefore need to be administered 4-6hourly
Side effects of penicillins
- Minor GI upset (common)
- CNS toxicity (convulsion & coma) can occur with high doses + when renal impairment delays excretion
- Antibiotic associated colitis, i.e. C. difficile (broad spectrum)
- Liver toxicity (rare but serious)
ROA for flucloxacillin
Severe infections/systemically unwell - IV injection or infusion (1-2g)
Cellulitis - oral (250-500mg)
What is the antimicrobial effect of carbapenems & cephalosporins due to?
B-lactam ring
Are penicillins or cephalosporins & carbapenems more resistant to B-lactamases?
Cephalosporins - B-lactam ring is fused with dihydrothiazine ring
Carbapenems - B-lactam ring fused with unique hydroxyethyl side chain
Generations of cephalosporins 1-5 have increasing activity against Gram-
Negative
When are carbapenems & cephalosporins used?
Severe complicated infections - due to broad-spectrum
Antibiotic-resistant organisms
Contraindications of carbapenems & cephalosporins
Allergy to penicillin, carbapenems or cephalosporins
Risk of C. difficile
Epilepsy (carbapenems)
Renal impairment
Side effects of carbapenems & cephalosporins
GI upset
Antibiotic associated colitis (C. diff) due to broad spectrum
Hypersensitivity similar to penicillins
CNS toxicity & seizures
Which antibiotics enhance the anticoagulant effect of warfarin & why?
Broad-spectrum penicillins, carbapenems & cephalosporins, trimethoprim, tetracyclines.
Kills normal gut flora which synthesises vitamin K
Is Streptococcus pneumoniae Gram-positive or Gram-negative?
Positive
Interactions of cephalosporins (2)
Warfarin - potentiates anti-coagulant effect
Aminoglycosides - increase nephrotoxicity
ROA of cephalosporins
IV for severe infections (e.g. cefotaxime 2g for meningitis)
Oral - only some available orally
Bolus infusion or injection
IM
ROA of carbapenems
Only available for IV administration (injection or infusion)
How does trimethoprim work?
Bacteriostatic: inhibits bacterial folate synthesis, which prevents DNA synthesis
What is the spectrum of activity of trimethoprim?
Broad spectrum of activity against Gram-positive & Gram-negative bacteria, particularly enterobacteria, e.g. E. coli
Why is the clinical utility of trimethoprim reduced?
Widespread bacterial resistance
Indication for co-trimoxazole (Septrin)
Pneumocystis pneumonia (opportunistic lung infection) in people with immunosuppression
Which drugs are contraindicated in pregnancy?
- Trimethoprim (folate antagonism is associated with increased risk of foetal abnormalities in the first trimester)
- Nitrofurantoin (towards term)
- Tetracyclines
Contra-indications of trimethoprim
Pregnancy (first trimester) Folate deficiency Renal impairment (dose reduction as unchanged in the urine)
Side effects of trimethoprim
Most common = GI upset (nausea, vomiting, sore mouth)
Skin rash
Severe hypersensitivity reactions
Impaired haematopoeisis (megaloblastic anaemia, leucopenia, thrombocytopenia) - folate antagonist so monitor FBC if used long-term
Hyperkalaemia
Trimethoprim interactions (3)
- Potassium-elevating drugs - ARBs, ACEi
- Folate antagonists - methotrexate, phenytoin
- Enhances warfarin effect
Elimination of trimethoprim
Mostly excreted unchanged into the urine
Why is trimethoprim less effective in people with renal impairment?
It competes with creatinine for secretion into the renal tubules (see a reversible rise in serum creatinine in healthy individuals without renal impairment)
What causes bacterial cell death with nitrofurantoin?
Its active metabolite, which is metabolised by nitrofuran reductase
What is nitrofurantoin active against?
Gram-positive (Staph saprophyticus) and Gram-negative (E.coli) organisms that commonly cause UTIs
What makes certain bacteria resistant to nitrofurantoin?
Those with reduced nitrofuran reductase activity
Why is nitrofurantoin unsuitable for pyelonephritis or other complicated UTIs?
Tissue concentrations of nitrofurantoin are very low - reaches therapeutic concentrations in urine through renal excretion
Why should nitrofurantoin not be given to babies (3months)?
Haemolytic anaemia - Immature RBCs are unable to mop up nitrofurantoin-stimulated superoxides, which damage RBCs
Usual treatment duration for trimethoprim or nitrofurantoin
3-7 days - infection severity determines duration
Something harmless to warn patients about with nitrofurantoin
Urine may turn dark yellow or brown
Which 3 types of antibiotics bind to ribosomal subunits 30S and 50S?
30S - tetracyclines (e..g doxycycine), aminoglycosides (e.g. gentamicin)
50S - macrolides (clarithromycin, erythromycin, etc.)
Purpose of binding to 30S
Inhibits protein synthesis by preventing binding of tRNA to mRNA, which prevents addition of new amino acids to the growing polypeptide chain
Indications for tetracyclines
Acne vulgaris
LRTIs - infective exacerbations of COPD, pneumonia, atypical pneumonia
Chlamydia
Side effects of doxycycline
Most common = GI upset
Hypersensitivity reactions
Oesophageal irritation, ulceration, dysphagia
Photosensitivity & sun burn
Absorption of tetracyclines is prevented if given within 2 hours of…
Calcium (so don’t take with milk), Antacids or Iron
Because it binds to divalent cations
Why does the mechanism of action of aminoglycosides mean they are active against Gram-negative aerobes, staphylococci & mycobacteria (e.g. TB), and NOT against streptococci & anaerobic bacteria
Enter bacterial cells via an oxygen-dependent transport system, which streptococci & anaerobic bacteria do not have
Is Pseudomonas aeruginosa Gram-positive or Gram-negative?
Gram-negative aerobe
Indications for gentamicin
Severe infections caused by Gram-negative aerobes:
Severe sepsis, Pyelonephritis, Intra-abdominal sepsis, Endocarditis
If the causative organism is unknown, what should gentamicin be combined with?
Penicillin and/or metronidazole - because lacks activity against streptococci or anaerobes
2 main side effects of gentamicin
Triggers apoptosis of specific epithelium, causing:
Nephrotoxicity (potentially reversible)
Ototoxicity (may be irreversible)
It is therefore important to monitor plasma drug concentrations, measure renal function, and ask patient daily if they have noticed any ear symptoms
ROA of gentamicin
IV infusion diluted with NaCl 0.9% to prevent exposure of ear to high concentration bolus - cannot be given orally as does not cross lipid membranes
What happens when macrolides bind to the 50S subunit?
Blocks translocation and therefore elongation
Spectrum of activity of erythromycin
Relatively broad spectrum against Gram-positive and some Gram-negative bacteria
Compared to erythromycin, clarithromycin has increased activity against…
Gram-negative bacteria (especially H. influenza) - it is synthetic
Triple therapy for H. pylori eradication
PPI + Clarithromycin + Amoxicillin or Metronidazole
Which macrolide produces the worst side effects?
Erythromycin
Antibiotics associated with increased risk of colitis - i.e. C. difficile infection
Amoxicillin, Tazocin, FLucloxacillin
Cephalosporins (& carbapenems)
Macrolides, e.g. Clarithromycin
Quinolones, e.g. Ciprofloxacin
Side effects of macrolides
GI upset when taken orally (N&V, abdominal pain, diarrhoea)
Thrombophlebitis when taken IV
Allergy
Antibiotic-Associated colitis
Liver abnormalities
Prolonged QT interval (predisposing to arrhythmias)
Otoxicity at high doses
Macrolides should be used with caution alongside drugs that prolong the QT interval
Amiodarone, antipsychotics, quinine, quinolines, SSRIs
Do erythrmoycin & clarithromycin inhibit or potentiate cytochrome P450?
Inhibit - therefore drugs metabolised by cytochrome P450 will have increased concentrations & risks of AEs - warfarin & bleeding, statins & myopathy
Elimination of macrolides
Mostly hepatic
What are quinolines particularly active against?
Gram-negative bacteria (urinary & GI infections)
Why are quinolines, e.g. ciprofloxacin, not used readily (reserved as second or third-line for UTIs, severe GI, LRTI)
Bacteria rapidly develop resistance to quinolines + it has an association with C. difficile
Metronidazole works by…
Entering bacterial cell walls by passive diffusion. Reduction generates a free radical that binds to DNA & causes bacterial death. (Aerobic bacteria are unable to reduce metronidazole)
Metronidazole is active against…
Anaerobes (Gram-positive & Gram-negative). Which is why it is an “anaerobic antimicrobial”
Infections that metronidazole is indicated for…
Gram-positive anaerobe: -C. difficile Gram-negative anaerobes: -Oral infections & aspiration pneumonia -Surgical & gynaecological infections Protozoal infections: -Trichomonal vaginal infection -Giardiasis
What cannot be consumed with metronidazole?
Alcohol (during or 48hrs afterwards) - flushing, headache, nausea, vomiting
Because it inhibits acetaldehyde dehydrogenase which is responsible for clearing the intermediate alcohol metabolite acetaldehyde from the body
Why is antimicrobial efficacy of metronnidazole reduced by phenytoin and rifampicin?
Induce cytochrome P450, which reduces plasma concentrations of metronidazole
ROA of metronidazole
Variety: oral, IV, rectal, gel
Glycopeptides (vancomycin) are active against?
Gram-positive bacteria only (aerobic & anaerobic)
Indications for glycopepetides
Gram-positive infection (e.g. endocarditis) & Antibiotic-associated colitis caused by C. difficile
Side effects of vancomycin
Thrombophlebitis at site of infusion Severe reactions if infused rapidly Hypersensitivity Nephrotoxicity Otoxicity Blood disorders
What is Augmentin?
Co-amoxiclav - i.e. contains penicillin
