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73 Cards in this Set
- Front
- Back
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List the various drug classes of bacterial cell wall inhibitors. |
B-lactams: - Penicillins - Oxapenams - Cephalosporins - Carbapenems - Monobactams Non-B-lactam: - (cyclopeptide) Vancomycin |
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What do penicillins, oxapenams, cephalosporins, carbapenems and monobactams have in common? |
Beta-lactam ring in their structure. |
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What is the mode of action (MOA) of the penicillins? |
1. Bind covalently to transpeptidase (aka penicillin-binding protein, PBP) in bacteria --> block cross-linking of terminal peptide components of polymer chains in peptidoglycan ie. block transpeptidation --> inhibit peptidoglycan synthesis 2. Inactivate inhibitor of murein hydrolase (found normally in bacteria, responsible for degradation of murein in peptidoglycan cell wall) --> autolysis of bacterial cell wall (SAME MOA as the other B-lactams except oxapenams, which have an additional primary MOA) |
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Name the different types of penicillins and their anti-microbial spectrum. Distinguish whether they are B-lactamase sensitive or resistant. |
1. Penicillins - Narrow spectrum (mainly gram pos) - B-lactamase sensitive - eg. Penicillin G (benzylpenicillin), Penicillin V 2. Staphylococcal penicillins - Very narrow spectrum (targets mainly Staph, Strep, Pneumococci) - B-lactamase resistant - eg. Cloxacillin, Flucloxacillin 3. Extended spectrum penicillins - Wide spectrum (mainly gram pos, some gram neg) - B-lactamase sensitive - eg. Amoxicillin, ampicillin, piperacillin, methicillin (no longer used due to MRSA) |
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What drug class is usually used together with the penicillins? |
Oxapenams. |
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What is co-amoxiclav (Augmentin)? |
Co-amoxiclav = Clavulanic acid (oxapenam) + amoxicillin (extended spectrum penicillin) |
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How does co-amoxiclav work? |
Co-amoxiclav = Clavulanic acid (oxapenam) + amoxicillin (extended spectrum penicillin) Amoxicillin binds covalently to transpeptidase (aka penicillin-binding protein, PBP) in bacteria --> block transpeptidation --> inhibit peptidoglycan synthesis. Amoxicillin also inactivates the inhibitor of murein hydrolase (found normally in bacteria, responsible for degradation of murein in peptidoglycan cell wall) --> autolysis of bacterial cell wall However, amoxicillin is B-lactamase-sensitive. Thus, it is used in combination with an oxapenam. Clavulanic acid forms a complex with bacterial B-lactamase to inactivate it --> preventing B-lactamase from destroying a co-administered B-lactam (high affinity for B-lactamase). |
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Why is a macrolide commonly combined with a penicillin in the empirical treatment of community acquired pneumonia? (EXAM QN) |
Toachieve broader spectrum of coverage. Most common cause of community acquired pneumonia isthe gram +ve organisms, esp. strep pneumonia, which is sensitive to penicillin.Erythromycin provides coverage for the causes of atypical pneumonia (legionella, mycoplasma - MYCOPLASMA IS MOST COMMON CAUSE OF ATYPICAL PNEUMONIA) as well as gram –veand gram +ve bacteria. Penicillin might also have some synergistic effectswith erythromycin. Penicillin can damage the cell wall so that erythromycin can penetrate. |
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What are some mechanisms of bacterial resistance against the penicillins? |
1. Antibiotic inactivated (IMPT, most common) - through production of B-lactamase --> destroys the B-lactam ring --> destroys penicillin's ability for bacterial transpeptidase/PBP (thus, we have co-amoxiclav) 2. Altered binding target (IMPT) - through mutation of transpeptidase gene --> altered transpeptidase enzyme such that penicillin cannot bind (seen in MRSA) 3. Reduced permeability to drug via reduced/altered porins for gram neg bacteria 4. Presence of efflux pumps |
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What is the spectrum of activity of Penicillin G (benzylpenicillin)? |
Narrow spectrum. Mainly gram pos + a few gram neg |
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What is the spectrum of activity of Staphylococcal penicillins? |
Very narrow spectrum. A few gram positives (B-lactamase producing strains): - Staphylococci (mainly) - Streptococci - Pneumococcus (S. pneumonia) |
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What is the spectrum of activity of the extended spectrum penicillins? |
Gram pos + more gram neg than the other penicillin |
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What is one use of amoxicillin? |
Used in combination with omeprazole and metronidazole as part of triple therapy against Helicobacter pylori. |
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How is amoxicillin and ampicillin administered? |
IV and oral (excellent bioavailability due to acid stability) |
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What is the difference in the way ampicillin and amoxicillin is taken orally? |
Amoxicillin - can be taken with food Ampicillin - taken before or after food |
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How does penicillin compare with the other antibiotics in terms of toxicity? |
Least toxic of all the antibiotics; safest |
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List the toxic effects of penicillins. |
1. Allergy/hypersensitivity - range from minor rash to life-threatening anaphylaxis - 10% mortality 2. Neurotoxicity - When blood levels are elevated in renal-impaired patients - convulsions, confusion, hallucinations 3. Clostridium difficile-associated diarrhoea (CDAD), antibiotic-associated pseudomembranous colitis (AAPMC) - can occur with ampicillin (extended spectrum penicillin) 4. Anosmia |
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Explain how penicillin can lead to allergy/hypersensitivity as a toxic effect. |
Degradation products of penicillin act as haptens which combine with host cell proteins --> form an antigenic entity --> trigger immune response |
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List examples of oxapenams. |
1. Clavulanic acid 2. Sulbactam 3. Tazobactam |
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What is the mode of action of oxapenams? |
1. Forms a complex with bacterial B-lactamase to inactivate it --> preventing B-lactamase from destroying a co-administered B-lactam (high affinity for B-lactamase) 2. Also has similar mechanism as the other B-lactams, but has weak anti-bacterial activity on its own |
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What are the clinical uses of oxampenams?
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Used together with penicillins which are B-lactamse sensitive.
1. Co-amoxiclav (Augmentin): clavulanic acid + amoxicillin - MUST KNOW 2. Sultamicillin (Unasyn): salbactam + ampicillin 3. Tazocin: tazobactam + piperacillin |
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What is the MOA of Cephalosporins? |
(same as penicillins) 1. Bind to transpeptidase enzyme (PBP) in bacteria --> block cross-linking of terminal peptide components of polymer chains in peptidoglycan ie. block transpeptidation --> inhibit peptidoglycan synthesis 2. Inactivate the inhibitor of murein hydrolase (found normally in bacteria, responsible for degradation of murein in peptidoglycan cell wall) --> autolysis of bacterial cell wall |
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What are examples of the 3rd generation cephalosporins? |
Ceftriaxone Ceftazidime Cefotaxime |
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How is ceftriaxone and the other 3rd gen cephalosporins administered? |
IV and IM. |
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What is an example of a 4th generation cephalosporin? |
Cefepime (IV or IM) |
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What is the anti-bacterial spectrum of cephalosporins? |
Gram positive and gram negative (vary among generations). |
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How does B-lactamase-resistance change from generation 1 to 4 of the cephalosporins? |
Increases. 1st gen - low resistance 2nd gen - moderate resistance 3rd gen - higher resistance 4th gen - highest resistance |
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How does distribution to CSF change from generation 1 to 4 of the cephalosporins? |
Increases. 1st and 2nd gen - poor CSF penetration (poor treatment for meningitis) 3rd gen and 4th gen - good CSF penetration |
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How does activity against gram negative bacteria change from generation 1 to 4 of the cephalosporins? |
Increases. 1st gen - low activity 2nd and 3rd gen - higher activity 4th gen - highest activity |
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What is the mechanism of bacterial resistance against the cephalosporins? |
1. Extended spectrum B-lactamases (ESBL) --> destroy the beta-lactam ring in the structure of cephalosporins --> can no longer bind to transpeptidase to inhibit cross-linking of terminal peptide components of linear polymers of peptidoglycan i.e. can no longer inhibit transpeptidation --> can no longer inhibit peptidoglycan cell wall synthesis 2. Intrinsically resistant bacterial - Listeria monocytogenes and enterococci |
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What do the cephalosporins have in common with the penicillins wrt metabolism? |
Minimal hepatic metabolism. |
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How are cephalosporins excreted? What is the one exception? |
Mainly renal tubular secretion. Exception: Ceftriaxone. 40% excreted in bile ie. Hepatic elimination. (Thus must monitor liver enzymes AST and ALT) |
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What is one precaution when administering ceftriaxone? |
Ceftriaxone powder should not be reconstituted in Ca2+ containing diluents nor given with Ca2+ containing solutions --> avoid formation of potentially fatal precipitates in lungs and kidneys (prevent acute renal failure) |
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What are the clinical uses of cephalosporins? |
to treat: 1. septicemia 2. meningitis (3rd gen cephalosporin + vancomycin to treat pneumococcal meningitis) 3. Otitis, sinusitis, pneumonia - cefuroxime (2nd gen) 4. UTI, esp during pregnancy 5. Biliary tract infection 6. Surgical prophylaxis - cefazolin (1st gen) |
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What are the toxic effects of cephalosporins? |
1. Allergy/hypersensitivity (as with penicillins) 2. GI disturbances (for oral administration) - diarrhoea, AAPMC, CDAD (wide spectrum nature of cephalosporins select for resistant Clostridium difficile in gut) 3. Thrombophlebitis (for IV infusion) |
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Why should patients with history of allergy to penicillins not be given cephalosporins? (exam qn) |
Due to cross-reactivity between penicillins and cephalosporins. |
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Describe how IV cephalosporins can cause thrombophlebitis. Explain the dangers of this. |
The drug can alter or irritate the tunica intimate of vein --> predisposes vein to thrombosis. Embolism can occur, leading to AMI, stroke etc. |
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How can the risk of thrombophlebitis be minimised? |
- infuse drug slowly - in diluted form - by rotating infusion site |
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What is the MOA of carbapenems? |
1. Bind covalently to transpeptidase (aka penicillin-binding protein, PBP) in bacteria --> block cross-linking of terminal peptide components of polymer chains in peptidoglycan ie. block transpeptidation --> inhibit peptidoglycan synthesis 2. Inactivate inhibitor of murein hydrolase (found normally in bacteria, responsible for degradation of murein in peptidoglycan cell wall) --> autolysis of bacterial cell wall (SAME MOA as the other B-lactams except oxapenams, which have an additional primary MOA) |
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List examples of carbapenems. |
1. Imipenem 2. Meropenem 3. Tienam = Imipenem + cilastatin (inhibitor of renal dehydropeptidase) |
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How are carbapenems administered? |
All IV, but imipenem can be administered via IM as well. (parenteral, as carbapenems have poor oral bioavailability) |
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Can carbapenem penetrate the CSF? |
Yes |
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What is the spectrum of anti-microbial activity of carbapenems? |
- Wide spectrum (gram pos and gram neg) - broader than most other antimicrobials - most effective B-lactam against anaerobes - especially able to penetrate outer cell membrane of gram neg bacteria |
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What is the mechanism of bacterial resistance against carbapenems? |
Production of carbapenemase (beta-lactamase) --> destroy the beta-lactam ring in the structure of carbapenems --> can no longer bind to transpeptidase to inhibit cross-linking of terminal peptide components of linear polymers of peptidoglycan i.e. can no longer inhibit transpeptidation --> can no longer inhibit peptidoglycan cell wall synthesis |
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What bacteria have become resistant to carbapenems? |
- MRSA - C. difficile - Burkholderia cepacia - Sternotrophomonas maltophilia |
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What is the difference in metabolism between imipenem and meropenem? |
Imipenem is metabolised to inactive metabolites in renal tubular cells by dehydropeptidase VS Meropenem is not metabolised (but excreted unchanged in urine) |
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How does Tienam work? |
Tienam = Imipenem + cilastatin Imipenem is metabolised by dehydropeptidase to inactive metabolites in the renal tubule cells. Thus, it is used together with cilastatin, an inhibitor of renal dehydropeptidase. This prolongs the time imipenem remains in the blood to exert effects. |
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What are the clinical uses of imipenem/Tienam? |
To treat: - mixed infections (aerobic and anaerobic infections e.g. open abdominal wound/surgery) - Pseudomonas infections - Enterobacter infections |
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What are the clinical uses of meropenem? |
- meningitis in children (> 3mths old) - intra-abdominal sepsis, skin infections in children and adults |
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List the toxicities of carbapenems. |
1. Rashes 2. GI disturbances (nausea, vomiting, diarrhoea) 3. Superinfections (4% of patients on imipenem, Tienam) 4. Neurotoxicity (when blood levels are elevated, as in renal failure) - seizures |
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What is the MOA of monobactams? |
1. Bind covalently to transpeptidase (aka penicillin-binding protein, PBP) in bacteria --> block cross-linking of terminal peptide components of polymer chains in peptidoglycan ie. block transpeptidation --> inhibit peptidoglycan synthesis 2. Inactivate inhibitor of murein hydrolase (found normally in bacteria, responsible for degradation of murein in peptidoglycan cell wall) --> autolysis of bacterial cell wall (SAME MOA as the other B-lactams except oxapenams, which have an additional primary MOA) |
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What is the only commercially available monobactam? |
Aztreonam |
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What is the spectrum of anti-microbial activity of monobactams? |
Gram negative aerobic bacteria ONLY. (no activity against gram positive or anaerobic bacteria) |
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How are monobactams administered? |
Parenteral only: IM and IV. |
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Can monobactams penetrate the CSF? |
No, except in meningitis. |
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Elaborate on the metabolism and excretion of monobactams. |
metabolism - small amt of hepatic metabolism excretion - 60-70% renally excreted |
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Clinical uses of monobactams? |
Septicemia. |
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What are the toxicities caused by monobactams? |
1. Rashes (occasionally) 2. Transaminasemia (elevated serum ALT and AST) which is suggestive of hepatocyte damage |
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What are advantages of using monobactams compared to the other B-lactams? |
1. high therapeutic index 2. resistant to action of most B-lactamases 3. low/no cross-reactivity with penicillins, and thus can be used in penicillin-allergic patients |
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Compare the resistance of the classes of B-lactams to B-lactamases. |
Penicillins - sensitive Oxapenams ---- Cephalosporins - less sensitive than penicillins Carbapenems - highly resistant Monobactams - highly resistant |
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Name a non-B-lactam. |
Vancomycin (which is a cyclopeptide/glycopeptide). |
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Describe the MOA of vancomycin. |
Bind to D-alanine-D-alanine terminus of the pentapeptide --> block transglycosylation (which is responsible for the elongation of peptidoglycan) --> inhibit biosynthesis of peptidoglycan (at an earlier step than B-lactams) |
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What is the anti-microbial spectrum of vancomycin? |
Only gram positive bacteria (except Flavobacterium) - includes MDR bacteria like MRSA, B-lactamase producing Staphylococci, C. difficile |
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What is the mechanism for bacterial resistance against vancomycin? |
Mutation of terminal D-alanine (binding site) to D-lactate --> loss of high affinity binding of vancomycin to its target |
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What are some examples of vancomycin-resistant bacteria? |
VRE: vancomycin-resistant enterococcus (THUS metronidazole is the 1st choice for AAPMC and CDAD, as resistance can develop against vancomycin if used) VRSA: vancomycin-resistant Staphylococcus aureus |
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What are the clinical uses of vancomycin? |
1. MRSA sepsis or endocarditis (empiric antibiotic, given while awaiting lab diagnostics) 2. Enterococcal endocarditis (vancomycin + gentamicin) 3. Pneumococcal meningitis (vancomycin + ceftriaxone) 4. N. meningitides & H. influenza infections in infants (vancomycin + ceftriaxone) 5. 2nd line (oral) drug after metronidazole to create AAPMC and CDAD 6. Prophylaxis for - high cardiac risk penicillin-hypersensitive patients to protect against endocarditis following certain procedures where the likely organism would be S. aureus - major procedures involving implantation of prostheses in institutions with high rate of MRSA |
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What toxic effects can be caused by vancomycin? |
1. Red-neck/red man syndrome (rash above nipple line) 2. Nephrotoxicity and ototoxicity 3. Thrombophlebitis (with fever and chills) |
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Explain why red-neck/red man syndrome happens following vancomycin administration. |
Due to histamine release. |
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How can the red-neck/red man syndrome caused by vancomycin toxicity be prevented? |
1. Prolong duration of infusion (1-2h) of vancomycin 2. Adequate dilution 3. Administer antihistamines prior to infusion of vancomycin |
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Why is thrombophlebitis common in IV administration of vancomycin? |
Vancomycin has a high molecular weight (1500) |
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How is vancomycin administered? |
IV and oral. - Parenteral administration (IV) for systemic uses as it has poor oral bioavailability. - Vancomycin's poor oral bioavailability allows it to remain in the gut and thus be used to treat PMC or CDAC |
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Describe the pharmacokinetics of vancomycin. |
A: oral (poor bioavailability) or IV D: Widely distributed (including pleural, pericardial, ascitic fluids); cannot enter CSF (except in meningitis) M: no hepatic metabolism E: 90% excreted renally via filtration |
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Why should parenteral dose of vancomycin be reduced in renal impaired patients? |
90% of vancomycin is excreted renally via filtration and can lead to nephrotoxicity. Significant accumulation occurs in renal impairment( which increases the risk of nephrotoxicity), but vancomycin is difficult to remove via hemodialysis. |
