Antimicrobials and Antifungals Flashcards
Antimicrobial stewardship and deescalation (3 key components)
- optimize antimicrobial use
- minimize the duration of prescription
- Re-escalating antimicrobial therapy when culture and susceptibility results have returned
Exceptions to 7 day administration of antimicrobials
- endocarditis
- prosthetic implants
- persistent neutropenia
Time dependent antimicrobials efficacy
only efficacious when [drug] in plasma is above the MINIMUM INHIBITORY CONCENTRATION (MIC) for that pathogens.
Note: in critically ill patients, ft>MIC may be 100%
ft>MIC
percentage of time drug concentration is above the minimum inhibitory concentration.
Concentration dependent antimicrobials
usually bind irreversibly to their target
their efficacy is usually predicted by comparing the maximum concentration (Cmax) to the MIC)
Critical illness Cmax:MIC should be >8
How might fluid overload affect antimicrobial pharmacokinetics?
Depending on if the antimicrobial is hydrophilic or lipophilic
Volume of distribution of the antimicrobial will be affected
e.g. If the antimicrobial is hydrophilic, the net effect of volume distribution is higher, decreasing [antimicrobial] in plasma –> decreasing [antimicrobial] in target tissue
Effects of AKI on antimicrobial elimination and considerations
AKI –> elimination via kidney is decreased therefore fT>MIC is increased.
However, must consider risk of toxicity is increased due to drug accumulation
Effects of augmented renal clearance (ARC) on antimicrobial elimination
Augmented renal clearance –> increased removal of substrate by the kidneys
Antimicrobials may remain at subtherapeutic levels resulting in worsening patient outcomes
Incidence not studied in VetMed.
Effects of hepatic dysfunction on antimicrobial administration
Antimicrobial clearance may be decreased for hepatically metabolized drugs.
(Usually takes reduction of 90% of liver) –> therefore patients in fulminant liver failure = consider dose reduction
Generally no change needed if biochem panel shows hepatic dysfunction.
What are the 4 classes of Beta-lactams?
Penicillins
cephalosporin
carbapenam
monobactam
Beta-lactams distinguishing feature and mechanism of action
beta lactam ring
effects exerted by disrupting the synthesis of the cell wall during bacterial replication by binding to the “penicillin-binding proteins” (PBP)
when beta lactam ring binds to PBP –> results in degradation of cell wall and imparis synthesis of new cell wall leaving bacteria exposed to local environment and resulting in bacterial lysis
Beta lactams are bactericidal
Four factors that influence resistance to beta lactams
alterations to PBP
development of antimicrobial efflux pumps
changes to porins in bacterial cell wall
inactivation by beta lactamases –> can be acquired or intrinsic resistance
Penicillins
Beta-lactam
Gram positive and anaerobic coverage
Minimal gram negative coverage
Able to kill enteric flora which can cause vomiting and diarrhea.
C
Penicillin excretion
Excreted unchanged in urine
highly effective in UTI
Penicillin Drugs
benzylpenicillin (Pen-G), phenoxymethylpenicillin (penicillin V), procaine penicillin, benzathine penicillin (pen B)
Cloxacillin, methicillin, oxacillin
Beta-lactamase resistant
Most effective against gram positive aerobes and anaerobes.
Cephalosporin
Beta-lactam
5 generations: grouped into generations based on their relative spectrum of activation
lower the generation, the better gram positive spectrum
the higher the generation, the better gram negative coverage
more stable against beta lactamases than penicillins
1st generation Cephalosporin
beta-lactam
effective against variety of gram positive
limited activity against anaerobic bacteria.
drugs: cefazolin, cephalexin, cefadroxil
2nd generation Cephalosporins
moderate gram positive and gram negative
increase spectrum against anaerobes
drugs: cefoxitan, cefotetan, cefuroxime
3rd generation cephalosporins
Broad spectrum activity with resistance to many beta lactamases
relies on normal plasma albumin for effective therapeutic serum levels
Good penetration of CSF
drugs: ceftiofur, cefotaxime, ceftazidime, cefovecin(Convenia - 1 injection for 14 days), cefpodoxime (only drug in this gen available as oral medication)
4th generation cephalosporin
excellent activity against enteric organisms
drugs: cefepime, cefpirome and cefquinome
5th generation cephalosproin
only 1 drug: ceftaroline
spectrum of action similar to 3rd gen - good gram positive coverage
retains efficacy to Staphylococcus spp. that are resistant to methicillin
Monobactams
Drug: Aztreonam
Gram Negative coverage
Not used much in vetmed
Carbapenems
broad spectrum
resistant to many beta lactamases
considered top tier antimicrobial goup and should not be used empirically
Drugs: imipenem, doripenem, ertapenem and meropenem
Imipenem
Carbapenem beta lactam antimicrobial
nephrotoxic - drug degrades in renal tubule by kidney enzyme dehydropeptidase 1
Administer with Cilastatin to prevent degradation
associated with seizures in humans
Meropenem
Carbapenem beta lactam antimicrobial
not nephrotoxic
Beta-lactamase inhibitors (3)
clavulanic acid
sulbactam
tazobactam
bind irreversibly to beta lactamases so when administered with a beta lactam, the beta lactam can bind to bacterial PBP.
Beta lactam adverse effects
Toxicity to beta lactam group considered very low.
Potential adverse reactions:
Type 1 hypersensitivity from urticaria to anaphylaxis - frequency unknown in small animals (occurs in 0.7%-10% of people receiving penicillin
Type 2 hypersensitivity can also occur – hemolytic anemia, thrombocytopenia and neutropenia reported
Type 4 reactions usually manifest as cutaneous disease
Can rigger immune-mediated reactions such as IMHA
Can kill neric flora which cause nausea, vomiting, diarrhea
High doses can result in seizures and other neurologic diseases (more likely if brain diseases already present)
Aminoglycosides
Antimicrobial used to treat gram negative infections
Rely on aerobic bacterial metabolism
parenteral administration only
requires monitoring of renal function
Exhibit synergistic bactericidal effects when administered in combination with beta lactams
Aminoglycosides mechanism of action (3 stage model theory)
Inhibit bacterial protein synthesis by binding to ribosome resulting in faulty protein.
further synthesis increases aminoglycoside uptake by the cell which eventually leads to complete cessation of ribosomal activity.
Stage 1: outer bacterial lipopolysaccharide membranes are negatively charged while aminoglycoside is positively charged. Ionic binding allows aminoglycoside entry into cell and increase cell wall permeability
Stage 2: Energy dependent phase Faulty protein synthesis inserted into cytoplasmic membrane of bacteria allowing for more aminoglycoside entry (slow process and relies on ATP hydrolysis –> therefore reduced activity in anaerobic conditions). This stage can be blocked by inhibitors of oxidative phosphorylation or electron transport
Stage 3: Aminoglycoside accumulate quickly after nonspecific membrane channels inserted –> increasing rate of mistranslation of protein synthesis
3 mechanisms of actions to aminoglycoside resistance + intrinsic resistance
- enzymatic mutation of aminoglycoside molecules
- target modification in ribosomal 30s subunit structure
- increase in aminoglycoside efflux
- intrinsic resistance to anaerobes
Aminoglycoside absorption, distribution, metabolism and elimination
Absorption: water soluble; poorly absorbed from GI tract therefore must be administered parenterally
Distribution: primarily extravascular - can reach bone, synovial fluids, peritoneal fluid (especially if inflammation present). Distribution to bronchial secretions is good. Does not penetrate cell membranes well because of positive charge. Not recommended for CNS, eyes or prostate.
Elimination: primarily through kidneys unchanged by glomerular filtration.
Aminoglycosides Adverse Effects
Aminoglycosides readily taken up by cells in proximal tubules and in ears
5-15% will suffer aminoglycoside induced nephrotoxicity (excreted through kidneys)
Nephrotoxicity:
dose dependent
majority of aminoglycoside is excreted but small amount is absorbed by renal tubules
Necrotic cells slough into tubular lumen which can result in obstruction
Underlying renal dysfunction predisposes patient to aminoglycoside induced nephrotoxicity
Often damage is reversible if caught early.
Ototoxicity:
hair cells update drug resulting in cell death and inflammation
dose and duration dependent
Ototoxicity is not reversible
Neuromuscular blockade
Rarely reported, but can be severe enough to cause respiratory depression
@ high doses - calcium release impaired at level of neuromuscular junction –> hypocalcemia. Concurrent use of neuromuscular blockade medications or myorelaxants may augment effets.
