Antimicrobials Flashcards
What is the percent of time the concentration of penicillins / cephalosporins / carbapenems should be above the minimum inhibitory concentration (MIC) for clinical cure? What is recommended in critical patients?
- Penicillins: 50-60%
- Cephalosporins: 60-70%
- Carbapenems: 30-40%
For critical patients, suggest this time should be 100% and concentration should potentially be even > 4 x MIC
What specific parameters does the efficiency of time-dependent / concentration-dependent antimicrobials depend on
- Time-dependent: percent of time the antimicrobial concentration is above the minimum inhibitory concentration (MIC)
- Concentration-dependent: ratio of maximum concentration (Cmax) to MIC or ratio of area under the curve over 24h to MIC
What is the recommended ratio of maximum concentration (Cmax) over MIC for concentration-dependent antibiotics in critical patients
Cmax : MIC > 8
In terms of dose and frequency, how should you approach time va concentration dependent antibiotics in critical illness?
Time dependent: High dose with frequent administrations
Concentration dependent: High dose with longer intervals between doses
What dosing adjustments are required for patients with fluid overload / hypoalbuminemia
- Fluid overload -> increase dose of concentration dependent antibiotics / increase dose or frequency of time dependent antibiotics IF using hydrophilic antibiotic
- Hypoalbuminemia -> no change for concentration dependent antibiotics (might have increase efficiency), increase dose or frequency for time dependent antibiotics (will have increased renal excretion) IF using a highly protein-bound antibiotic
If a patient develops AKI, after how long should antimicrobial doses be adjusted
After 48h if AKI is persistent (unless it is an antibiotic with small therapeutic index then might need to be adjusted earlier)
What phenomenon can decrease antimicrobial levels in critical patients
Augmented renal clearance (increased creatinine clearance with increased substance removal by kidneys) -> patients with normal creatinine should be dosed at high end of range
How much decrease in liver function does it take for metabolism of antimicrobials to be significantly affected
At least 90%
For amikacin, ampicillin/sulbactam, cefazolin, ceftazidime, clindamycin, doxycycline, enrofloxacin, gentamicin, meropenem, piperacillin / tazobactam, and vancomycin: indicate if they time / concentration dependent, hydrophilic / lipophilic, protein bound (>70%), and have renal / hepatic elimination
See table
What are the 3 possible patterns of administration of beta-lactams with some pros and cons
- Standard infusion over 15-30 min
- Most commonly done, easy
- Likely sufficient for most patients - Prolonged / extended infusion over 3h
- Allows more time spent over MIC
- Conflicting results in humans with some showing improved mortality compared to standard infusion
- Could help for less susceptible pathogens (P aeruginosa)
- Can interfere with administration of other medications - Continuous infusion (with initial bolus)
- Could allow to spend 100% of time over MIC
- More constant dosing
- Requires less total daily dose
- Interferes with administration of other medications
- Need to stop CRI for procedures, to go outside, etc.
- In case of augmented renal clearance, patient could be under MIC all the time
What is the default recommended duration of antibimicrobials for patients in the ICU? What could require longer treatment?
7 days
Longer treatment required in case of persistent neutropenia, source of persistent infection that cannot be removed (implants, endocarditis), P aeruginosa infection
Mechanism of action of beta-lactams
Beta-lactam ring binds to PBP (penicillin-binding protein) -> inhibits transpeptidase enzymes -> inhibit production of peptidoglycan -> disruption of cell wall, bacterial lysis
What are mechanisms of resistance to beta-lactams
- Beta-lactamases -> inactivate antimicrobial by degrading beta-lactam ring
- Penicillinases
- AmpC-type cephalosporinases
- Extended spectrum beta-lactamases (ESBLs)
- Carbapenemases - Alterations in PBP (penicillin binding proteins) -> alteration in PBP2a in MRSA (mecA gene)
- Antimicrobial efflux pumps
- Changes to porins in bacterial cell wall
What beta-lactams have activity against P aeruginosa? What are other antimicrobial options?
- Penicillins: ticarcillin and piperacillin
- Cephalosporins: ceftazidime, 4th generation cephalosporins (cefepime, cefpirome, cefquinome)
- Monobactams: aztreonam
- Carbapenems: imipenem, meropenem
Others:
- Fluoroquinolones (usually in combination)
- Aminoglycosides
- Doxycycline (sometimes)
What bacteria are considered resistant to carbapenems
- Enterococcus spp
- MRSA
What is a possible toxicity of imipenem (that meropenem does not have)
Renal toxicity
Mechanism of action of beta-lactamase inhibitors. What are the 3 beta-lactamase inhibitors and which ones are more efficient?
Weak beta-lactam antibiotics -> their beta-lactam rings irreversibly bind to beta-lactamase and allow the combined antimicrobial to bind PBPs
- Clavulanic acid
- Sulbactam
- Tazobactam
(Clavulanic acid and tazobactam more efficient)
What beta-lactams can cover MRSA / ESBL bacteria / AmpC bacteria
- MRSA -> none
- ESBL bacteria -> carbapenems, some beta-lactamases (pip-tazo, cefoxitin)
- AmpC bacteria -> carbapenems
Name 2 adverse effects of beta-lactams
- Type I hypersensitivity (urticaria, anaphylaxis)
- Type II hypersensitivity (IMHA, ITP, immune-mediated neutropenia)
What bacteria commonly have AmpC resistance
“HECK YES”: Hafnia, Enterobacter cloacae (++), Citrobacter freundii, Klebsiella aerogenes, Yersinia enterocolitica
+ Serratia, Pseudomonas
Mechanism of action of aminoglycosides
Inhibition of bacterial protein synthesis by binding to ribosome 30S subunit (A site of 16S ribosomal RNA) -> faulty proteins -> cessation of ribosomal activity
Enter bacterial cells in 3 stages:
1 = ionic binding with LPS or phospholipids -> entry in cell
2 = insertion of faulty proteins in membrane -> increased permeability (slow and aerobic energy-dependent)
3 = rapid entry of aminoglycosides through new channels
What antimicrobials could have a synergistic action with aminoglycosides
Beta-lactams (altered bacterial wall -> increased permeability for aminoglycoside entry)
What are mechanisms of resistance to aminoglycosides and bacteria in which they are found
- Enzymatic mutation of aminoglycosides (intracellular aminoglycoside modifying enzymes: acetyltransferases, phosphotransferases, nucleotidyltransferases)
* Can be found in all bacteria - Target modification (change in 16S RNA)
* Found in P aeruginosa, Klebsiella, E Coli, Proteus, Mycobacterium - Increase in efflux (pumps)
* Found in Pseudomonas, Acinetobacter, E Coli
Intrinsic resistance of anaerobes and facultative anaerobes (Enterococcus faecalis and faecium)
Name 3 adverse effects of aminoglycosides
- Nephrotoxicity (tubular necrosis)
- Ototoxicity
- Neuromuscular junction toxicity
What is the recommended dosing frequency of aminoglycosides? Why?
Once a day
Concentration-dependent with post-antibiotic effect -> does not need to have high concentration for a long time
Toxicity dependent on trough levels -> need to be low for some time in the day
Mechanism of action of fluoroquinolones
Inhibition of topoisomerase IV and DNA gyrase -> inhibition of DNA synthesis, replication and division
Effect on topoisomerase IV predominant in Gram +, effect on DNA gyrase predominant in Gram -
What is the risk with use of fluoroquinolones at the low end of the dosing range
Selection of resistant mutants (E Coli ++), acquisition of resistance is possible in the patient during the antibiotic course
What Cmax/MIC and AUC/MIC ratios are recommended for fluoroquinolones
Cmax/MIC > 10
AUC/MIC > 125
Which fluoroquinolone is reported to have the best action against P aeruginosa
Marbofloxacin
Mechanism of action of metronidazole
Incorporation into bacterial DNA -> loss of helical structure -> inhibition of nucleic acid synthesis
Also has immunomodulatory and anti-inflammatory effects in GI
Mechanism of action of chloramphenicol
Inhibition of bacterial protein synthesis by binding to ribosome 50S subunit -> block elongation
What antibiotics should chloramphenicol not be used with
Clindamycin and macrolides (have similar binding site -> competition)
What are adverse effects of chloramphenicol? What species is most sensitive?
Bone marrow suppression, peripheral neuropathy, GI signs
Cats more sensitive (because metabolized by glucuronidation)
Mechanism of action of clindamycin
Inhibition of bacterial protein synthesis by binding to ribosome 50S subunit -> inhibition of peptidyl transferase
Mechanism of action of doxycycline
Inhibition of bacterial protein synthesis by binding to ribosome 30S subunit -> block elongation
Mechanism of action of trimethoprim - sulphonamides
Inhibition of folic acid production
Sulfonamide = competitive analog to P aminobenzoic acid (PABA) -> inhibits folic acid production
Trimethoprim dihydrofolate reductase -> inhibits folic acid reduction
What are adverse effects of TMS? What breeds are more sensitive?
- Hypersensitivity -> fever, polyarthropathies, pancreatitis, hepatitis, glomerulonephritis, IMHA, ITP
- Doberman Pinschers, Samoyeds, Miniature Schnauzers more sensitive
- KCS (duration-dependent, irreversible)
- Bone marrow suppression
- Acute hepatic necrosis (rare but severe)
- Decrease in thyroid hormones
- Hypoglycemia
Name 2 antimicrobial options to treat vancomycin-resistant Staphylococcus or vancomycin-resistant Enterococcus
Linezolid (oxalidinone) and daptomycin (lipopeptide)
What is the most concerning adverse effect of rifampin
Hepatotoxicity
What are usual treatment options for E faecalis / E faecium
- E faecalis: ampicillin, doxycycline, chloramphenicol
- E facecium (highly resistant): sometimes ampicillin, vancomycin (reserved drug), linezolid (reserved drug), nitrofurantoin for cystitis
What are treatment options for Actinomyces
- Ampicillin / amoxicillin (> 20 mg/kg q6-8h)
- Doxycycline, clindamycin
Need to treat for several weeks
What are treatment options for Nocardia
- TMS
- Second line: ormetoprim - sulfadimethoxine
- Other options: 3rd generation cephalosporins, amoxicillin q6h, doxycycline, amikacin
Mechanism of action of amphotericin B
Binds to ergosterol in fungal cell membranes -> increases membrane permeability to cause cell death
What is the main toxicity of amphotericin B
Nephrotoxicity due to binding of cholesterol in proximal tubular cells
(liposomal amphotericin B is less toxic)
Mechanism of action of azole antifungals
Inhibition of lanosterol 14alpha-demethylase (fungal P-450 enzyme in charge of the development of ergosterol in fungal cell walls) ->fungistatic
What are the 2 families of azole antifungals with examples
- Imidazoles (ketoconazole, clotrimazole, enilconazole)
- Triazoles (itraconazole, fluconazole, voriconazole)
What is the mechanism of hepatotoxicity in azole antifungals
Inhibition of patient’s P-450 enzymes (variable specificity for fungal P-450 enzymes)
-> also causes a change in drug metabolism over time
For what antifungal should compounded formulations not be used due to poor availability
Itraconazole
What antifungal(s) can cross the blood-brain barrier and blood-aqueous barrier
- Fluconazole (best)
- Voriconazole (partially)
What azole antifungal has less hepatotoxicity
Fluconazole (elimination is partially renal)
(Ketoconazole > itraconazole > fluconazole)
What is the beyond-use-date of aqueous compounded oral antimicrobial formulations
No more than 14 days, stored at cold temperatures
(could be less for some antimicrobials)
What are common treatment options for MRSP / MRSA
- Amikacin
- Chloramphenicol
- Linezolid
- Rifampin
(- Sometimes doxycyclin, TMS)
(- Sometimes fluoroquinolones but in vivo susceptibility may not be great)
What category of antibiotics has the longest post-antibiotic effect
Concentration-dependent antibiotics (usually minimal for time-dependent)
What are antimicrobial breakpoints and how are they determined
Thresholds of MIC (minimum inhibitory concentration) that determine susceptibility or resistance of a bacteria to an antibiotic.
Established by the CLSI (Clinical and laboratory standard institute) based on routine antibiotic doses and bioavailability (usually determined for blood concentrations but could also use urine)
MIC for a cultured bacteria is then measured (susceptibility testing -> if MIC < breakpoint then bacteria is susceptible, if > then it is resistant
- Can have dose-dependent breakpoints when different doses of an antibiotic can be used (eg. for fluoroquinolones)
What antimicrobials have the best penetration in lungs
Small lipophilic molecules -> fluoroquinolones, aminoglycosides, clindamycin, macrolides (not beta-lactams but cephalosporins better than penicillins)
What antimicrobials have a good CNS penetration
- TMS
- Fluoroquinolones
- Chloramphenicol
- Metronidazole
- Rifampin
Moderate penetration
- Beta-lactams (cephalosporins better)
- Doxycycline
+/- Clindamycin
What antimicrobials have a good prostate penetration
- Fluoroquinolones
- TMS
- Clindamycin
- Macrolides
Moderate penetration:
- Tetracyclines
- Chloramphenicol
What antimicrobials have a good ocular penetration
- Fluoroquinolones
- TMS
- Carbapenems
- Clindamycin
Moderate penetration:
- 3rd generation cephalosporins
- Macrolides
What are 4 characteristics of antibiotic choice in a deescalation approach?
- Intravenous
- Bactericidal
- Able to penetrate tissue of interest
- Broad spectrum
What is broad spectrum therapy vs combination therapy?
Broad spectrum: use of 1 or more antimicrobial agents with the specific intent of broadening the range of potential pathogens covered
Combination therapy: The use of multiple antimicrobials with the specific intent of covering the pathogen for a ssynergistic effect
What are the concentration dependent antibiotics?
- Aminoglycosides
- Fluoroquinolones
- Metronidazole
- Doxy depending on serum level
List 3 lipophilic antibiotics
- Clindamycine
- Doxyxycline
- Enrofloxacin
Which antibiotics undergo hepatic elimination?
Clindamycin
Doxycycline
Which of the aminoglycosides is most nephrotoxic?
Gentamicine
What are expected UA changes in a patient with aminoglycoside toxicity?
- Glucosuria without hyperglycemia
- Proteinuria
- Presence of granular casts
What organs do fluoroquinolone penetrate well?
Kidneys, lungs, prostate
Urine, bile
What are antimicrobial options for pseudomonas?
Piperacilline
Aminoglycosides
Carbapenem
Ceftazidime
+/- fluoroquinolone (marbo?)
Which antibiotic undergoes glucuronidation in the liver and should therefore be avoided in cats?
Chloramphenicol
Define MIC, breakpoint, susceptible, intermediate and resistant
MIC: Minimum inhibitory concentration = minimum bacterial concentration required to prevent bacterial growth
Breakpoint: Highest concentration of a drug that can safely be used in a patient to determine susceptibility - may change based on species and tissue/location
Susceptible: MIC is less than breakpoint
Intermediate: MIC approaches breakpoint (antibiotic may be effective with bigger dose)
Resistant: MIC is greater than breakpoint
The greater the difference between MIC and breakpoint, the better!
–> don’t compare MIC between antibiotics but rather the difference between MIC and breakpoint for that specific antibiotic in that tissue
