Cell Wall Agents
What is the difference between gram negative and gram positive bacteria? What effects does this have on antibiotics?
Gram positive bacteria have a thick peptidoglycan layer on the outside of their membrane, while gram negative bacteria have a thinner peptidoglycan layer sandwiched between two phospholipid membranes. This means that antibiotics that target peptidoglycan or it’s synthesis are typically inactive against gram negatives because they cannot penetrate deep enough.
What two mechanisms of action does Bactrim combine?
The sulfamethoxazole portion of bactrim targets folic acid synthesis via dihydropteroate synthetase and the trimethoprim portion targets folate utilization via dihydrofolate reductase.
Where do the different antifungals (allyl amines, azoles, and morphlines) target in the synthesis of ergosterol?
Allyl amines target squalene epoxidase, azoles target CYP450 demthylase, and morpholines target delta14 reductase and delta 8-7 isomerase.
What types of host defenses does a human have?
Physical barriers like skin, hardship environments like the stomach, forced elimination via urine/feces, and the immune response.
Describe the three different types of PD killing properties.
Concentration dependent - the higher the concentration of the antibiotic, the more microbes killed.
Time dependent - The longer the antibiotic concentration is over the MIC, the more killing.
AUC:MIC ratio - Microbe killing effect is a function of both concentration and time, higher concentrations for longer result in greater killing
Name one common resistance mechanism against beta lactam antibiotics and how it works.
Beta lactamases - an enzyme secreted by some bacteria that renders beta lactams inactive by cleaving them as the beta lactam bond.
Mutations of transpeptidase - a mutation of the enzyme that build peptidoglycan prevents penicillin antibiotics from binding
Which antibiotics target the 30s subunit of the ribosome?
What is the difference between nucleoside and non-nucleoside antiviral drugs?
Nucleoside drugs bind to the DNA chain and prevent elongation/synthesis of the chain, while non-nucleoside drugs bind to reverse transcriptase in order to prevent viral RNA from binding in the first place.
Why is the MIC of a pathogen relevant to care?
MIC represents the lowest concentration of drug that will result in killing of the pathogen, and each pathogen carries a unique MIC based on resistance mechanisms. Administering a drug below the MIC will not resolve the infection.
What is post-antibiotic effect and what does it mean for antibiotic dosing?
The post-antibiotic effect describes continued bacterial suppression even after concentration falls below the MIC. This usually allows for longer dosing intervals (q12h instead of q8h)
What is the spectrum of activity of each generation of cephalosporin?
1st generation - gram positive microbes, think staph and strep (cefazolin, cephalexin)
2nd generation - begin to expand to some gram negative microbes, such as E. coli, klebsiella, proteus, less activity against gram positives now (cefuroxime)
3rd generation - incredibly well rounded gram negative and gram positive coverage, microbes above as well as H. Influenzae, serratia, enterobacter, and more (ceftriaxone)
After 3rd generation it becomes harder to fit into categories. “4th generation” adds pseudomonas coverage (cefepime) and “5th generation” adds MRSA coverage (ceftaroline)
Interaction with what can reduce the bioavailability of flouroquinolones? How do we prevent this?
Interaction with certain cations (calcium, iron, aluminum) cause a chelation reaction which reduces bioavailability. On order to prevent this, we must separate administration by at least 2 hours.
What side effects may occur when taking fluconazole?
Standard adverse effects occur such as nausea/vomiting, headache, diarrhea. More rare adverse effects include alopecia, infant deformities, and QTc prolongation.
What are the pros and cons of PCR identification testing?
Pros - the most sensitive test and results only take a few hours. May also identify slow growing organisms
Cons - Not always sufficiently discriminating, requires a high level of expertise, and expensive.
Knowing beta lactam feature time dependent killing, what would be the “most effective” administration method? (Although not always possible or recommended)
Prolonged IV administration of a beta lactam over the MIC would result in consistent long term killing of pathogen.
What benefit does ertapenem have over imipenem or carbapenem?
Ertapenem has a longer half-life that allows for once daily dosing. Ertapenem also has good activity against anaerobes making it good for intra-abdominal infections.
What infections is nitrofurantoin effective for and why?
Nitrofurantoin is only effective for lower urinary tract infections because it only builds up an effective concentration in the bladder, not the plasma or kidneys.
How do protease inhibitors work and which viral infections do they fight?
Protease inhibitors prevent the final step in viral protein synthesis where the protease cleaves long strand bifunctional proteins into functional proteins. These drugs are relevant to the treatment of HIV adn HepC.
What are 3 different resistance mechanisms that can be transferred via plasmid?
Plasmids can encode for antibiotic degrading enzymes, antibiotic altering enzymes, and antibiotic effluent pumps.
How do we perform AUC dosing in practice?
We use surrogate markers peak and trough concentration. By knowing the peak and trough we can get a rough idea of AUC.
What is the mechanism of nephrotoxicity from Vancomycin?
Nephrotoxicity from vancomycin is postulated to be due to oxidative stress and and drug accumulation. Antioxidants are therefore presumed to help prevent nephrotoxicity as well as other agents that increase renal excretion of the drug.
What are three potentially serious side effects of aminoglycosides?
Ototoxicity, nephrotoxicity, and neuromuscular blockade.
Under what conditions is oseltamivir effective and how effective is it?
Oseltamivir is seen to be effective typically only when taken within the first 48 hours of exposure, and treatment can reduce duration of illness by 1-2 days and reduce risk of complications.
Name 4 resistance mechanisms conferred by pathogen mutation.
Mutations in DNA gyrase affecting flouroquinolones, mutations of the gram positive cell wall affecting Vancomycin, alterations in the phospholipid call membrane affecting daptomycin, changes to PBP affecting beta lactams, and changes to the ribosomes affecting tetracyclines, macrolides, other protein synthesis antibiotics.
How long does it usually take to achieve steady state vancomycin and when should you draw the trough level?
Vancomycin is typically at steady state after 3 doses (24-36 hours) and the trough should be drawn just before the 4th dose.