Antibiotics

Question 1

Betalactams

Answer 1

Penicillins, Cephalosporins, Carbapenems
Inhibit bacterial cell wall synthesis by binding to the penicillin binding protein in the cell wall
Some bacteria have adapted by having beta lactamases (ESBL) which hydrolyze the Beta lactam ring so that it cannot bind except to the carbapenems-> led to betalactamase inhibitors
Time Dependent (T> MIC)
- May also have PAE that helps with AUC/MIC
- Critical infections can use CRI to achieve 100% time >MIC
Bactericidal
However require the bacteria to be actively growing (ie are inhibited in presence of bacteriostatic antimicrobials and those that inhibit cell growth (ie ribosome formation))
Water soluble so they are widely distributed when administered IV but crossing of biological membranes (eyes, brain, testes, prostate) is limited unless barrier is dirupted
Concentrate in the urine!!! (like by 7x)

Question 2

MRS

Answer 2

In addition to ESBLs, bacteria can also alter their binding proteins. The most important instance of this is the Staphylococcus gene MecA that codes for a PBP-2a which confers resistance to all classes of B lactams, except for 5th generation cephalosporins. These are known as Methicillin-Resistant Staphylococci

Question 3

Penicillins

Answer 3

Penicillin G:
- Gram positive (except some Staphs) & anaerobes
- Synergistic with aminoglycosides
- Drug of choice for streptococcus (necrotizing fasciitis), clostridial infection, & actinomycosis.
Extended spectrum Penicillins (Amoxicillin & ampicillin):
- Less gram positive & anaerobic activity but much more gram negative activity.
- Ampicillin has poor oral bioavailability
- Often combined with a B-lactamase inhibitor such as clavulanic acid or sulbactam which helps extend coverage of all (gram +/- & anaerobes).
Antipseudomonal Penicillin (ticarcillin, piperacillin):
- Greater activity against pseudomonas & proteus spp.

Question 4

Clavamox

Answer 4

Amoxicillin - penicillin - Bacterial cell wall inhibitor
Clavulanate- beta lactamase inhibitor
Bactericidal
Time dependent
Good gram positive, okay gram negative, gets most anaerobes
S/E: the usual

Question 5

Clindamycin

Answer 5

Lincosamide - inhibits protein synthesis by binding to 50s ribosomal subunit
Bactericidal
Time dependent
toxo, neo, babesia, and hepatozoon
Drug of choice for anaerobes
Drug of choice for toxo
Good gram positive except variable resistance by staph so use erythromycin susceptibility, good for anaerobes, almost no gram negative
lipophilic and so wide volume of distribution
penetrates bone, abscesses, bile, & prostate
S/E- the usual GI upset

Question 6

Cephalexin/Cefazolin

Answer 6

first generation cephalosporin - bacterial cell well inhibitor!
bactericidal
time dependent
Mostly gram positives, few gram negatives, & no anaerobes
S/E- the usual

Question 7

Cefoxitin

Answer 7

second generation cephalosporin - bacterial cell wall inhibitor
bactericidal
time dependent
Enhanced stability against B-lactamases
Mostly gram positives but more gram negatives than first generation cephs
S/E - the usual

Question 8

Cefpodoxime, Ceftazidime, Cefovecin (Convenia)

Answer 8

third generation cephalosporins - bacterial cell wall inhibitor
Each member has a specific spectrum of action
- Ceftazidime has a high specificity for and spectrum of action against gram negative infections & is the treatment of choice for empiric therapy of CNS infections.
- Cefpodoxime has a similar spectrum of action as first generation
bactericidal
time dependent
good gram positives, good gram negatives
S/E - the usual

Question 9

Meropenem, Imipenem

Answer 9

Carbapenems
In the betalactam family but is not affected by betalactamse inhibition
Methicillin resistance includes to carbapenems
Bactericidal
Time dependent
truly equally broad spectrum

Question 10

Enrofloxacin

Answer 10

Fluoroquinolone (2nd gen including Marbo & Ciprofloxacin, 3rd gen - Prado with increased gram positive and anaerobic coverage, 4th) - inhibit bacterial DNA sequencing via inhibiting gyrase (Gram -) and topoisomerase (gram +, newer gen better at this) IV
Bactericidal
Concentration dependent - Want the Cmax to be > 8-10x > than the MIC and the AUC to be as long above MIC as possible
Great activity against Gram negatives
+/- Gram positives with newer quinolones
No anaerobic coverage
Good activity against many intracellular pathogens due to penetration of phagocytic cells
- Mycoplasma (pradofloxacin preferred for M. haemofelis), Mycobacteria, Rickettsia, Chlamydia, Brucella
Cross the urine, prostate, lung, bile, BBB, bone, inflamm. cells
great bioavailability orally, lipophilic, low protein binding
partially metabolized by the liver and then excreted in urine (and bile). Decrease dosing frequency in liver and kidney disease
post-antibiotic effect lasts 8 hrs
Antacids & sucralfate near admin decrease absorption
S/E: cartilage damage in young growing animals (Inhibition of proteoglycan synthesis, magnesium chelation, and mitochondrial dehydrogenase activity), Irreversible, dose-related blindness from retinal degeneration in cats (enro > marbo, promote MRS resistance, GI signs
Fast IV admin can be associated with seizures, Histamine release, hypotension, bradycardia, and prolonged QT interval. Also seizures from Inhibition of Y-aminobutyric acid receptors & stimulation of N-methyl-d-aspartate receptors in the CNS

Question 11

Flouroquinolone resistance

Answer 11

Staphylococcus, E.coli, pseudomonas, salmonella
chromosomal point mutations - quinolone resistance-determining region” in the genes encoding DNA gyrase & top IV
Loss of/or reduction in outer membrane porin 1a (OmpF) reduces accumulation of drug within the cytoplasm.
increased expression energy-dependent efflux systems (AcrA-AcrB-TolC) that actively pump drug across cell membrane and out of the cell - Ecoli & salmonella
Plasmid-mediated resistance

Question 12

Amikacin, Gentamicin

Answer 12

Aminoglycoside - impair protein synthesis via bindings to 30s ribosomal subunits
Great gram negatives, no anaerobes (require aerobic conditions to get into cells, don’t penetrate abscesses)
- (Klebsiella (particularly amikacin), Enterobacter, Pseudomonas (particularly amikacin), E.coli)
Some activity against Mycoplasma (lacks a cell wall), Yersinia Pestis (plague), Brucella, & Francisella tularensis (tularemia or rabbit fever)
Bactericidal
Concentration Dependent
Synergistic with betalactams
Water soluble (thus renally excreted) but can penetrate bones, joints, and pulmonary parenchyma but not bronchi
S/E: Nephrotoxicity (proximal renal tubule - Bind to tubular epithelial cells, accumulate in lysosomes causing their rupture and damage to surrounding structures.
Decreases GFR starting around day 5-7 (max toxicity @ day 9) and causes polyuric renal insufficiency. Can be reversible if caught early & drug is discontinued). Mx best with daily urine sediment evaluation (w/in 1-2 hrs collection) for presence of granular/cellular casts, glucosuria & tubular proteinuria. - Azotemia too late
Ototoxicity- drug accumulates within the inner ear cochlear and vestibular apparatus causing irreversible destruction of sensory hair cells
Oral neomycin suppresses bacterial growth in the large bowel but otherwise poor oral absorption
IV is preferred. Avoid with solutions containing calcium, sodium bicarb, heparin, & penicillin.
Can be given IM or SQ but there is discomfort at injection site & less-predictable absorption.
Post antibiotic effect and adaptive resistance (bacteria downregulate uptake of additional doses) leads to preferred once daily high dosing but TDM is recommended
Neuromuscular junction- If patient has myasthenia gravis or is receiving NM blocking agents)
Reversibly interferes with release/uptake of Ach at the NMJ. Inhibits calcium movement into the nerve terminal during depolarization -> inhibits subsequent release of Ach. Tx calcium +/- neostigmine

Question 13

Concentration dependent drugs (aminoglycosides, fluoroquinolones)

Answer 13

Concentration-dependent bactericidal activity is optimized by achieving a Cmax that is 8-10 times greater than the MIC.
The Cmax to MIC ratio is referred to as the inhibitory quotient.

Question 14

Doxycycline

Answer 14

Tetracycline (Minocycline, etc.) - inhibits protein synthesis via 30s ribosomal subunit
Bacteriostatic! > cidal
Both concentration < time dependent
Fairly broad spectrum and anaerobes
Drug of choice for lyme, brucella, and many rickettsial diseases in dogs, lepto, bordetella, myocplasma!
gets mycoplasma, rickettisal diseases, penetrates into lung well, chlamydia, spirochetes
Excellent tissue penetration to the prostate, bile, lung, & bronchial secretions
Anti-inflammatory, immunomodulatory, inhibits collagenase activity, and aids in wound healing.
not renally excreted so safe in kidney cases
S/E - esophageal irritation/stricture in cats, enamel discoloration in young animals, GI side effects, caution when given IV

Question 15

Erythromycin, Azithromycin

Answer 15

Macrolides
Erythromycin in the GI tract as a prokinetic
Azithromycin in the eyes?
Time dependent

Question 16

TMS

Answer 16

Potentiated Sulfonamide - inhibits two steps of folic acid synthesis needed for bacterial replication
sulfamethoxazole, sulfadiazine, & sulfadimethoxine (SDM) potentiated with trimethoprim
Decent gram negative, staph, no anaerobes. gets toxo and protozoa
BacteriCIDAL
Time Dependent! however tissue concentrations remain high enough to usually allow for once daily dosing
treatment of prostate, urinary, GI, CNS, bone, joint, skin, soft tissue, & respiratory
S/E: idiosyncratic KCS mo later, hepatotoxicity, anemia, proteinuria, decreased thyroxine production, idiosyncratic hypersensitivity (Fever, polyarthropathy (large breed dogs), hepatotoxicity, skin eruptions, thrombocytopenia, neutropenia, & hemolytic anemia), DO NOT GIVE TO DOBERMAN, azotemia in cats long term use

Question 17

Chloramphenicol

Answer 17

Florfenicol - inhibits protein synthesis via 50s ribosomal subunit
Bactericidal or static
Broad spectrum + spirochetes, rickettsiae, chlamydiae, & mycoplasma. Generally not effective against Pseudomonas or predictably against Ehrlichia or in CNS infection.
Inhibits cytochrome p450 - raises levels of opiates, benzos, propofol
Penetrates tissues
Reserved for serious MDR infections
metabolized by the liver so use w caution
S/E: aplastic anemia in humans, bone marrow suppression, hepatotoxicity, GI side effects, hindlimb signs in large breeds,

Question 18

Metronidazole

Answer 18

Nitroimidazole - Disrupts nucleic acid synthesis
Bactericidal
Concentration dependent
low protein binding, gets to important sites including CSF, bile, and abscesses
Effective against many obligate anaerobes (gram negative Bacteroides & gram positive Clostridium, Peptostreptococcus) & some protozoa (Giardia)
Immunomodulatory effects (inflammatory enteropathies & gingivostomatitis)
Self-limiting, dose & duration neurotoxicity (seizures, cerebellar dysfunction, etc.)
Patients with severe hepatic disease metabolize metronidazole slowly.

Question 19

Vancomycin

Answer 19

Bactericidal
Glycopeptide that binds peptide precursors in bacterial cell wall
prevents cross linking of peptidoglycan side chains thereby inhibiting bacterial cell wall synthesis.
Active against many aerobic & anaerobic gram positive infections
Not orally absorbed across intestinal wall so limited to parenteral administration
May not reach therapeutic levels in pleural effusion or bile
Exclusively eliminated by the kidney
Dosage should be adjusted with renal dysfunction
May potentiate aminoglycoside nephrotoxicity
Rapide IV infusion can cause histamine release (give slowly, premed)
Optimal dosing regimes (usually TID) and TDM unknown
Very important in the treatment of B lactam resistant staph and enterococcal infections in human medicine so ALWAYS last line of defense for super MDR gram positive cocci in veterinary medicine

Question 20

Polymixins

Answer 20

B (topical) & E - Mostly unclear MOA: cationic detergents interact with phospholipid cell membrane leading to increased cell wall permeability and cell death. Can also bind and neutralize LPS
Bactericidal
Active against many gram negative bacteria but no gram positives or anaerobes

Question 21

Rifampin

Answer 21

Blocks RNA polymerase
Bactericidal
Many gram negative > positives but no anaerobes
Do not use as monotherapy as resistance happens quickly
Currently the most active antibiotic to staph & MRS
S/E: hepatotoxicity if > 10mg/kg q24hrs <- d/c if any other elevations aside from mild ALP, rare hemolytic anemia and thrombocytopenia, reversible orange colored urine, tears and saliva

Question 22

Known risk factors for MDR

Answer 22

antibiotic use in the previous 3 months!!
in an MDR environment (hospital, etc.)
hospitalization > 5 days
indwelling catheter, bacterial translocation, invasive procedure

Question 23

Definition of MDR

Answer 23

Resistance to three or more classes of the drugs that the organism is usually susceptible to
Resistance to an antibiotic should be expected when the bacterial pop. >10^6-8 cfus no matter the nature of the organism (commensal vs infective)
Drug levels should > 8 to 10x the MIC to prevent emergence of resistant subpopulations

Question 24

Suspected bacterial population based on location

Answer 24

GI - Ecoli (negative), Enterococcus (positive), anaerobes
Urogenital - Ecoli - gram negative aerobe
Abdomen - gram negative aerobes > anaerobes
Anaerobes in deep isolated tissues, bones, and hollow organs

Question 25

Sinusoidal capillaries

Answer 25

no barrier to bound or unbound drug

Adrenal cortex, pituitary, liver, spleen

Question 26

Fenestrated capillaries

Answer 26

pores with no barrier to unbound drug
Kidneys & endocrine glands
Highly protein bound drugs, such as doxycycline, may require higher levels of the drug to reach therapeutic tissue penetration, which may not always be reflected in the MIC reported.

Question 27

Continuous, non-fenestrated capillaries

Answer 27

endothelial layer with tight junctions that inhibit drug penetration
Brain, CSF, Blood-bronchus barrier, testes, prostate, muscle & adipose tissues
Water soluble drugs (B lactams, aminoglycoside, & selected sulfonamides & tetracyclines) may need to have marked concentration increases
In human medicine only up to 30% of water soluble antimicrobials penetrated the bronchus-blood barrier as opposed to 30-80% of lipid-soluble drugs.
Some medications (ie macrolides) may have enhanced efficacy with accumulation of the active (or unbound) form of the drug in places of marked inflammation.

Question 28

Synergism

Answer 28

B lactam + aminoglycoside or fluoroquinolone or potentiated sulfonamide
Penicillin-induced cell wall failure increases aminoglycoside/fluoroquinolone/sulfa penetration into the cell
Can also be seen with aminoglycosides & vancomycin

Question 29

Volume of distribution

Answer 29

Degree of distribution to second and third compartments
Greater the Vd, the lower concentration remaining in plasma
Affected by the volume to which the drug is administered, bloodflow, lipophilicity, albumin, and degree of protein binding.
- Highly protein bound drugs do not leave plasma easily. Only the unbound form of the drug is considered active. so an MIC in plasma may not actually reflect tissue levels required to get MIC

Question 30

Volume of distribution in critical illness

Answer 30

• Blood flow is redirected in shock - can increase drug acc in the heart and brain
• Volume to which the drug is distributed - Aggressive fluid resuscitation, fluid accumulation within cavities or interstitium, the lipophilicity of the drug in cases of acc of fluids in peripheral tissues and body cavities - water-soluble drugs (Aminoglycosides, B lactams, etc.) may follow
• Hypoalbuminemia, independent of whether the drug is protein bound or not, peripheral fluid retention & increased volume of distribution. Some sources recommend dosage increases of 1.5-2 times.

Question 31

Elimination half-life of the drug

Answer 31

Inversely proportional to the clearance
Proportional to the volume of distribution
Affected by lipophilicity
- water soluble drugs such as aminogly and betalactams are renally excreted, acc in GFR
- lipid soluble drugs are usually reabsorbed by the renal tubules and so must be metabolized to be cleared thus they may acc in hepatic disease (and hypoalbuminemia)

Question 32

Minimum inhibitory concentration

Answer 32

Amount of drug that must be administered to inhibit the growth of bacteria in vitro

Question 33

MIC breakpoint

Answer 33

The breakpoint is the concentration of the drug in plasma for the standard dose and route
Doesn’t account for concentrations of the drug in intracellular (phagocytes), secluded (CSF, eye, prostate, abscessed) or excretory sites (urine, bile, etc.) or those that are highly bound to serum proteins.

Question 34

How to compare between drugs of an MIC report

Answer 34

You can either divide the breakpoint by the MIC to get an efficacy ratio. Use the drug with the greatest ratio
Or see how many dilutions you can go from the breakpoint to the MIC and pick the one that has the greatest number of dilutions (ie has the greatest concentration relative to the MIC)

Question 35

Time Dependent Pharmacodynamics

Answer 35

Act reversibly so the only time the drug is efficacious is the time spent above MIC, no matter the Cmax achieved
Therefore the frequency of dosing is most important
If bacteriostatic drug, also care about the area under the curve above the MIC because of PAE (post antibiotic effect)
Ex: B lactams

Question 36

Concentration Dependent Pharmacodynamics

Answer 36

bind irreversibly
efficacious when there is a sufficient concentration of the drug at the site so that all target microbes are bound so care about Cmax as well as the AUC above MIC
Their effectiveness is best measured by comparing the maximum concentration of the drug (area under the inhibitory curve) to the MIC.
Ex: aminoglycosides & fluoroquinolones

Question 37

Common Pathogens In Animals

Answer 37

Staph pseudintermedius - gram positive coccus aerobe (think skin!), found in the skin, perineum, nose nadmouth of healthy dogs. Pathogenic in skin wounds, ears, urine, bones, and post-surgical abscesses. necrotizing wounds and fasciitis
E.coli - gram negative rod, facultative anaerobe, coliform
Klebsiella pneumonia - gram negative rod, facultative anaerobe, coliform
Pasteurella multocida - gram NEGATIVE ANAEROBE from dog and cat mouths. most common organism in human bite wounds
B hemolytic Strep - gram positive aerobe
Pseudomonas aeruginosa - gram NEGATIVE mostly AEROBE, ubiguitous
Proteus mirabilis - gram negative facultative anaerobe, ubiquitus, urogenital infections
Enterobacter - gram negative, facultatively anaerobic, rod
Enterococcus - gram POSITIVE facultative anaerobic, cocci

Question 38

De-escalation of empirical polytherapy

Answer 38

guided by C&S - start thinking about it at the 72hr mark
Current guidelines from the Surviving Sepsis Campaign advise a 7–10 day course, unless clinically indicated otherwise (initial clinical failure, slow clinical response, undrainable foci of infection, immunologic deficiencies). Infections caused by Staphylococcus aureus or Pseudomonas aeruginosa may also warrant prolonged courses to avoid treatment failure, early relapses, or metastatic complications. A meta-analysis of critically ill human patients showed no difference in microbial eradication, clinical cure, STEWART AND ALLEN 235 or survival when using shorter antimicrobial regimens (5–7 days) compared to longer regimens (7–21 days).

Question 39

Changes to Vd in critically ill patients

Answer 39

The effect on changes to Vd is predominantly restricted to hydrophilic drugs (Table 1).2 For this reason it has been recommended to administer loading doses of hydrophilic antimicrobials in critically ill human patients to ensure that therapeutic concentrations are achieved.20 It has also been recommended to administer hydrophilic antimicrobials as extended infusions. The Vd for lipophilic drugs is usually high and often unchanged in critically ill patients compared to healthy volunteers.2 A loading dose has not been recommended for lipophilic drugs in septic patients.20 For all antimicrobial classes, including concentration-dependent antimicrobials, an increased Vd can prolong the time needed to reach therapeutic concentrations.

Question 40

ARC

Answer 40

Augmented renal clearance (ARC) is the pathologic phenomenon wherein the kidneys display increased filtering activity beyond that expected under normal physiological conditions of renal function.