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.
Aminoglycoside drugs
Amikacin
Gentamicin sulfate
Tobramycin sulfate
neomycin
Amikacin
aminoglycoside
Monitor for casts in urine and increases in BUN/Creat
dosage may need to be adjusted in critically ill patients
can be administered IV, IM, SQ q 24 hrs
Gentamicin Sulfate
Aminoglycoside
Monitor for casts in urine and increases in BUN/Creat
Can be administered IV, IM, SQ, q 24 hours
Tobramycin sulfate
Amino glycoside
Monitor for casts in urine and increases in BUN/Creat
Can be administered IV, IM, SQ q24 hours
Neomycin
Aminoglycoside
Used to treat hepatic encephalopathy
Minimal GI absorption
administer PO q 6-12 hrs
Fluoroquinolones
Mechanism of action
effectiveness and resistance
synthetic antimicrobials
Inhibit bacterial DNA gyrase which prevents bacterial DNA synthesis, replication and division, resulting in cell death
Bactericidal
Widest spectrum against gram-negative bacteria
Incomplete effectiveness against gram-positive and anaerobic bacteria
RESISTANCE TO FLUOROQUINOLONES CAN DEVELOP DURING THE COURSE OF THE TREATMENT
Fluroquinolones
metabolism and elimination
hepatic metabolism and excreted in bile +/- urine either unchanged or as metabolites
Most are eliminated by the kidneys
Half-life depends on renal elimination and dose
Resistance to fluroquinolones
increasing rate of resistance
attributed to widespread use of fluoroquinolones
Use of fluoroquinolones can lead to development of resistance to other antimicrobial classes
Fluoroquinolones should not be used as 1st line treatment. (exception - pyelonephritis, lower respiratory tract infections, bacterial prostatitis, hepatobiliary infections).
Adverse effects of fluoroquinolones
GI upset: V/D, nausea, abdominal cramping
Neurologic: rapid administration risk CNS adverse effects including seizures
It may lower the seizure threshold; therefore, do not use or use it with extreme caution in patients with seizure disorders.
Juveniles: cartilage defects - not recommended in growing animals
retinopathy: irreversible blindness in cats
Rapid IV administration may result in histamine release in dogs
Can chelate with positively charged ions - contains beta-keto acid group that can bind to and chelate with positively charged ions; most profoundly seen with aluminum and copper, but can also happen with magnesium and calcium
Cardiovascular signs can result in hypotension, bradycardia, prolonged QT
Rare reports of fluoroquinolones used in patients with necrotizing fasciitis resulted in activating bacteriophage, rapid bacterial cell lysis, and release of bacteriophage superantigen and the potential sequelae of toxic shock syndrome.
Enrofloxacin
2nd fluoroquinolone
only one available as injectable for dogs and cats
generally safe, though adverse effects can be permanent
Adverse effects can include:
- blindness in cats
- cartilage defects in juvenile animals
Max dose in cats if 5mg/kg q24hrs
primary metabolite of enrofloxacin is ciprofloxacin.
Marbofloxacin
2nd gen fluroquinolone
longest post-antibiotic effect and half-life
No clinical trials support the translation of long half-life to superior antimicrobial efficacy.
Pradofloxacine
3rd gen fluoroquinolone
Labeled for use in cats 12 weeks +, off-label for dogs (use in dogs associated with bone marrow suppression)
broad spectrum activity including many anaerobic bacteria
High potency with lower MIC values when compared with other fluoroquinolones
Ciprofloxacin
2nd gen fluoroquinolone
not labeled for veterinary use
Significantly higher doses needed in dogs than in humans and even so does not always achieve desired serum levels
Moxifloxacin
4th gen fluoroquinolones
improved activity against gram-positive and gram-negative
only used in human medicine
Metronidazole
drug class
Indications and mechanism of action
nitromidazole antimicrobial
Indicated to treat most gram-positive anaerobic and all gram negative anaerobic organisms
At higher dosages - effective against protoozoal diseases (giardia, amebiasis, trichomoniasis); however higher doses associated with CNS adverse effects
Concentration dependent
Within the bacteria: reduced and incorporates into bacterial DNA causing loss in helical structure
inhibits nucleic acid synthesis
results in cell death
Bactericidal
Metronidazole
Bioavailability, distribution, elimination
Good oral bioavailability
Excellent tissue distribution with good penetration to BBB and CSF
Elimination is dose dependent with renal and biliary routes
Hepatic metabolism –> dose reduction with liver dysfunction
Use with caution in patients with neurologic disease
Metronidazole
Adverse effects
GI upset
neurologic signs associated with higher doses and prolonged use
Clinical signs: vertical nystagmus, ataxia, paraparesis, tetraparesis, hypermetria, head tilt, tremors
Treatment: discontinue therapy and provide supportive care (IV fluids, antiemetics, sedatives PRN). Most patients improve within 3 days.
Chloramphenicol
drug class
mechanism of actions
Phenicol
Bacteriostatic
Inhibit protein synthesis by binding to 50S ribosomal subunit
In mammalian cells, can also inhibit mitochondrial protein synthesis (especially erythropoietic cells).
Chloramphenicol effectiveness
Gram-positive
Gram-negative
anaerobic
intracellular organisms such as: Chlamydia, mycoplasma and rickettsia
Not effective against pseudomonas aeruginosa
Chloramphenicol
bioavailability, metabolism and elimination
Good bioavailability through oral administration and tissue distribution
Penetrates CNS
Limited prostate
Hepatic metabolism –> dose reduction with liver dysfunction
Excreted in kidneys in mostly inactive form
Chloramphenicol
Toxicity
Dose-dependent bone marrow suppression in humans, dogs and cats (cats more sensitive)
DO NOT SPLIT
DO NOT PULVERIZE
Caretakers to wear gloves
Dogs: hind end weakness and GI signs
Chloramphenicol + drugs requiring CYP450 (phenobarbital)
Chloramphenicol is a potent inhibitor of CYP450.
Drugs that require CYP450 may need dose adjust to prevent toxicity.
Chloramphenicols + concurrent antimicrobials of other classes
Competitive inhibitors of 50S ribosomal subunits
Do not give chloramphenicols with lincosamides and macrolides
Tetracyclines bind to 30S subunit
Therefore Chloramphenicols may act synergistically with tetracyclines
Clindamycin
drug class
Mechanism of action
Lincosamide Antimicrobial
binds to 50S subunit of ribosome
Bacteriostatic and time dependent
Clindamycin effectivness
Effective against gram-positive aerobes and anaerobes
Effective against mycoplasma and toxoplasmosis
Clindamycin bioavailability
Distribution, metabolism and elimination
Good bioavailability after oral administration. Can also be administered SQ and IV
Good tissue distribution especially to skin and bone
penetrates CNS
penetrates blood prostate barrier –> good for gram-positive bacterial prostatitis
penetrates biofilms –> use for gingivitis, and peridontal disease
Clindamycin
Side effects
Overall rare
Humans: overgrowth of C. diff
Doxycycline
drug class
Mechanism of actions
Tetracycline
inhibits protein synthesis by binding to 30S ribosomal subunit
bacteriostatic
Lipid soluble –> greater bacterial penetration
Doxycycline
effectiveness
1st line therapy for tick borne rickettsial diseases
felin upper airway
canine respiratory
Gram-positive, gram-negative, mycoplasma, chlamydia, rickettsial, spirochetes
not considered effective against anaerobic infections
Doxycycline resistance
found in all bacteria secondary to presence of efflux pumps
alterations to binding sites
bacterial enzymatic destruction
Doxycycline
bioavailability
distribution, metabolism and elimination
high bioavailability
drug is lipophilic so will also distribute into placenta and milk
limited in prostate
highly protein bound
30%-40% CSF
elimination: mostly unknown with 16% in urine unchanged
predominance for intestinal elimination and enterohepatic recirculation
Doxycycline Adverse effects
Adverse effects more likely with decrease in rental function.
Give with food to decrease GI upset
Associated with ESOPHAGEAL EROSION - follow with 6ml water
Incorporates into bone and enamel resulting in discoloration
IV Doxycycline needs to be diluted and ideally given through central line to reduce risk of thrombophlebitis
Give over 1 hour as anaphylactic shock has been reported
Rarely hepatotoxic
Doxycycline
Concurrent administration of medications and fluids
should not be administered with antacids, aspirin or calcium containing fluids as it chelates with cations
May bind to cholestyramine because of its lipophilic nature
Sulfonamides and trimethoprim
individually - bacteriostatic
used together = bactericidal and time dependent
work on different stages of bacterial folic acid production
Combo therapy 1:5 trimethoprim: sulfonamide
Sulfonamides and trimethoprim
effectivess
broad spectrum
gram-positive, gram-negative and anaerobes
Ineffective against mycoplasma and rickettsial disease
Sulfonamides and trimethoprim
distribution, metabolism and elimination
goo tissue distribution to include CNS for sulfadiazine and prostate for trimethoprim
Both drugs undergo hepatic metabolism
metabolites thought to be responsible for allergic and idiosyncratic reactions
Both active drug and metabolites renally excreted
TMS highly concentrated in urine therefore considered 1st line therapy for bacterial cystitis
Sulfonamides and trimethoprim
Adverse effects
allogenic, immunogenic and toxic metabolites (Dobermans, Samoyeds and Mini schnauzers more sensitive)
hypersensitivity reactions: fever, polyarthritis, pancreatitis, hepatitis, glomerulonephritis, anemia, ITP, mucosal skin lesions.
KCS most common because of direct cytotoxic effects of sulfonamides on lacrimal gland
reversible with short treatments (<5 days), but may be irreversible with long term use.
decrease in thyroid hormone in dogs –> reversible
Macrolides
Drug examples
mechanism of actions
drugs: Erythromycin, azithromycin, clarithromycin
Mechanism of action: binds to 50S subunit inhibiting protein synthesis
Bacteriostatis
Macrolides effectiveness
Mainly effective against gram-positive bacteria and intracellular bacterial infections
limited effectiveness against Gram-negative bacteria
Not effective against anaerobic bacteria
Macrolides advantage
Alternative drug option for patients that cannot take beta-lactams (allergies)
Erythromycin
Macrolide
enteral and parenteral administration
rapid degradation by gastric acid when given orally
DO NOT CRUSH TABLETS b/c coating helps prevent rapid degradation
Drug of choice for Campylobacter jejuni
Azithromycin
Macrolide
Greater activity against gram-negative organisms
More stable in acid –> higher bioavailability when taken orally
Macrolides side effects
GI upset most commonly reported
also highly effective as a prokinetic when administered at subantimicrobial doses
Nitrofurantoin
Prescription based on culture and susceptibility and lack of any other viable alternative
treatment for multi drug resistant UTI
inhibits cell wall synthesis, bacterial protein and DNA synthesis
bactericidal
Gram Positive and gram negative
resistance is rare
side effects: irreversible peripheral neuropathies
use with caution in cats –> potential for hemolysis
Vancomycin
Prescription based on culture and susceptibility and lack of any other viable alternative
glycopeptide antibiotic
Reserved only for serious life-threatening multi-drug resistant gram-positive bacterial infections that cannot be treated with other agents (ie MRSA)
Mechanism of action: inhibits proper cell wall synthesis by binding to subunits preventing cross-link formation in peptidoglycan cell wall
Adverse effects: nephrotoxicity, ototoxicity
Rapid IV administration can be associated with histamine release
Extravasation can result in severe soft tissue damage
Rifampin
Prescription based on culture and susceptibility and lack of any other viable alternative
used to treat Methicillin-resistant staphylococcal pyodermas
Mechanism of action: inhibits RNA synthesis
Resistance develops in as short as 2 days when used as monotherapy
Use in combo with other drugs to decrease emergence to resistance
Rifampin + fluoroquinolone –> antagonistic
Fair to good oral bioavailability when fasted
Side effects: GI upset and hepatotoxicity
Pretreatment and weekly biochem monitoring for hepatotoxicity
Oxazolidinones
Prescription based on culture and susceptibility and lack of any other viable alternative
Linezolid - synthetic antibiotic
Treatment for multidrug resistant skin infections, pneumonia and bacteremia
Mechanism of action: binds to p-site of 50S ribsomal subunit –> inhibit protein synthesis
Bacteriostatic
effective against gram-positive, including methicillin and vancomycin resistant staphylococci
Anaerobic spectrum similar to clindamycin
Good bioavailability with tissue distribution to lungs, CSF , bones
well tolerated with dogs.
No studies on cat pharmacokinetics
Lipopeptides
Prescription based on culture and susceptibility and lack of any other viable alternative
Most recently discovered
Drug: Daptomycin
indicated for Gram-positive that are vancomycin resistant
effective against gram-positive and anaerobic
Mechanism of action: forms ion channels in cell membrane allowing it to depolarize and result in rapid cell death
Gram-negative organisms inherently resistant
Adverse effects: highly toxic, causes skeletal muscle damage
Antifungals (2 classes)
Polyene antibiotics
Azole derivatives
polyene antibiotics
two types
- amphotericin B
- lipid-complexed emphotericin B
