Bacterial infections and Abx Flashcards
Describe the layers of gram positive and gram negative bacterias’ cell wall
gram positive:
* thick outer peptidoglycan wall and one inner phospholipid membrane
gram negative
* thin peptidoglycan wall surrounded by an inner and an outer phospholipid membrane
* lipopolysacchardie layer on the outside
What are the most common Staph bacteria isolated from dogs and cats?
dogs: Staphylococcus pseudointermedius, S. schleiferi
cats: S. pseudointermedius
Which Staph species indicates transfer from people?
Staphylococcus aureus
What are the most common bacteria to cause postsurgical infections?
Staphylococcus
Name 2 bacteria producing urease enzymes, leading to struvite infections
S pseudointermedius
Proteus mirabilis
Which S species are coagulase positive versus negative? What does this indicate?
S pseudointermedius - coagulase positive
S schleiferi - depending on subsp can be either
S aureus - most coagulase positive
virulence factor - low virulence if negative
coagulase induces blood clotting and fibrin clots covering bacteria can help avoid phagocytosis
How do Staph appear microscopically?
perfectly round and clustered
How do Streptococcus bacteria appear on cytology?
round and in chains
What does usually determine the virulence of Streptococci?
differentiate between
* alpha (partial) hemolytic
* beta (complete) hemolytic
* gamma (non) hemolytic
beta hemolytic bacteria most virulent
What is the most common Streptococcus species isolated in dogs and cats?
- Streptococcus canis
beta-hemolytic
part of the normal canine flora
can cause pneumonia, UTIs, wound infections
associated with toxic shock syndrome and necrotizing fasciitis
Why are Fluoroquinolones use contraindicated in Streptococcus canis infections?
can induce bacteriophage and increase the risk of toxic shock syndrome and necrotizing fasciitis
What bacteria has been associated with outbreaks of hemorrhagic pneumonia in dogs in shelter setting?
Streptococcus equi subsp zooepidemicus
What are the most common Enterococcus isolates in dogs and cats, where are they normal inhabitants?
E faecalis
E faceium
gastrointestinal tract
What are infections caused by Enteroccous and how are they treated?
UTIs, cholangiohepatitis, wound infections
E. faecalis - less resistant, tx of choice penicillin
E. faecium - more resistant
What classes of abx are enteroccus species generally resistant to?
- cephalosporins
- fluoroquinolones
- low dose aminoglycosides
- sulfonamides
- macrolides
What are 3 members of the Actinomycetales order?
- Actinomyces
- Nocardia
- Mycobacterium
Actinomyces - normal oral flora
Nocardia and Mycobacterium - environemnt
Actinomyces/Nocardia common pyothorax isolates
Mycobacterium infections rare
What is the treatment of choice for Actinomyces, Nocardia, or Mycobacterium?
Actinomyces - Penicillin, high dose and frequency
Nocardia - TMS
Mycobacterium - macrolide (clarithromycin)
What predisposes to Clostridium difficile diarrhea?
previous abx tx
What is caused by adherent-invasive E.coli? How is the condition treated?
Granulomatous colitis
enrofloxacin at 10-20 mg/kg q24h for 8 weeks
What is Pseudomonas aeruginosa resistant to and how are infections treated?
Resistant to:
* aminopenicillins
* most cephalopsorins
* TMS
* chloramphenicol
* tetracyclines
* often acquired resistance to aminoglycosides and fluoroquinolones
treatment with anti-pseudomonal beta-lactams i.e., ceftazidime, pipercaillin => reserve for life-threatening systemic infections
What Pasteurella spp. are isolated in dogs and cats and what kind of infections do they usually cause?
P. multicide, P. canis => normal flora of oral cavity and upper respiratory tract
can cause bite wound infections and pneumonia
best tretment: penicillins or aminopenicillins
What is the most sensitive diagnostic for Bartonellosis?
PCR followng enrichment culture
What is increaesed time to antibiotic therapy in sepsis associated with?
- increased mortality
- increased rate of AKI
- increased rate of organ dysfunction
- increased length of hospitalization
Explain how to use the MIC information for dosing regiments of time-dependent or concentration dependent antibiotics
Minimum inhibitory concentration - i.e., the lower the MIC the more susceptible
time-dependent abx - reversibly act on abx - i.e., want to minimize the time the plasma cc is less than MIC
* fT > MIC is the percent of time the plasma drug concentration is above the MIC
* ideally 100% for critically ill patients
* non critically ill: 50-60% penicillins, 60-70% cephalosporins, 30-40% carbapenems
concentration-dependent abx - irreversibly bind to abx
* want Cmax to be over MIC
* post-antibiotic effect
* Cmax:MIC should be 8 in critically ill patients
Explain how fluid overload may alter the PK of antibiotics and how to address this
increases the Vd - especially for hydrophilic antibiotics (e.g., beta lactams)
=> lower plasma cc => lower target tissue cc
- increase dose and frequency for time-dependent abx
- increase dose for concentration-dependent abx
Explain how hypoalbuminemia may affect the PK of abx
- increases the volume of distribution for hydrophilic abx
- increases renal clearance for abx that are usually mostly protein-bound
- increases fraction of free/active compound
net effect of hypoalbuminemia
* time-dependent => decreased efficacy because of fast elimination
* concentration-dependent => increased efficancy due to increased Cmax
- time-dependent antibiotics => increase dose or frequency
- concentration-dependent => no change needed
- not highly protein-bound => no change needed
In what ways can kidney disease affect antimicrobial PK?
AKI
* decreased renal clearance
* incresed fT>MIC
* higher risk of toxicity
* if high therapeutic index => likely safe, if narrow therapeutic index => frequency reduction or avoid drug overdose
Augmented renal clearance (ARC)
* may need to increase dose and frequency
* difficult to identify - need to measure renal creatinine clearance (>120-150 mL/minute people)
How does hepatic disease affect antimicrobial PK?
hepatic dysfunction would need reduction of at least 90% of metabolic capacity to substantially alter antimicrobial clearance
unlikely to play a role in most patients
Which group of beta lactams is MRSA resistant to?
all, except 5th gen cephalosporin (ceftaroline)
Name 4 classes of beta lactams
- penicillins
- cephalosporins
- monobactams
- carbapenems
Are beta lactams bacteriostatic or bactericidal?
bactericidal
Describe how beta lactams excert antibiotic properties
beta-lactam rings binds to penicillin-binding protein (PBP) –> inactivates transpeptidase enzymes –> bacteria can not build peptidoglycan layer –> defects –> permeability –> lysis
Name 4 ways of beta lactam resistance by bacteria
- antimicrobial efflux pump
- changes to porins in cell walls
- PBP mutation
- beta-lactamases
Name 4 systems of beta-lactamases
- penicillinases
- AmpC-type cephalosporinases
- extended spectrum beta-lactamases
- carbapenemases
How does MRSA exert its resistance
PBP2a mutation - beta-lactam ring cannot bind
MacA gene
Explain how beta lactams distribute in tissues. Which tissues do not typically achieve high concentration?
hydrophilic weak acid => cannot cross cell membranes, stays in EC space but with high Vd - interstitial cc will reach same as serum levels
tissue exceptions: ocular, reproductive, CNS
How are beta lactams excreted?
urine - high cc in urine!
Name 2 beta-lactams with a higher half-life
cefpodoxime
cefovecin
high protein-binding
Compare the spectrum of:
* penicillin
* aminopenicillins
* 1st through 5th gen Cephalosporins
- Penicillin - gram positive and anaerobic but minimal gram negative
- aminopenicillins - same gram positive and anerobic but better gram negative than penicillin
- 1st gen ceph: good gram positive, gram neg similar to aminopenicillins
- 2nd gen ceph: moderate gram pos and neg coverage, increased anerobe spectrum compared to 1st gen ceph
- 3rd gen ceph: broad spectrum, resistant against many beta-lactamases, ceftazidime covers P. aeroginosa and can reach CSF
- 4th gen ceph: good against enteric organism
- 5th gen ceph: covers MRSA
List examples for the 5 generations of cephalosporins
- 1st gen: cefazolin, cephalexin
- 2nd gen: cefoxitan
- 3rd gen: cefpodoxime, cefovecin, ceftiofur, ceftazidime
- 4th gen: cefquinome
- 5th gen: ceftaroline
What is the coverage of monobactams?
gram negative
poor gram pos or anaerobe coverage
List 2 examples of carbapenems and compare their risks of adverse effects
imipenem
maropenem
imipenem nephrotoxic and can cause seizures
Compare the efficacy of clavulanic acid and sulbactam
clavulanic acid is significantly more effective than sulbactam
Are aminoglycosides bactericidal or bacertiostatic?
bactericidal
What is the general coverage of aminoglycosides?
good gram negative, some gram positive, no anaerobes
What class of antibiotics combines well with aminoglycosides (synergistic effects)?
beta-lactams - break the cell membrane and help aminoglycosides reach the intracellular space of bacteria faster
Describe how aminoglycosides kill bacteria
binding to ribosome 30S subunit - specifically high affinity for the A site on the 16S ribosomal RNA => alters its conformation => tRNA binds => causes mRNA misreading
=> lead to faulty protein synthesis => cessation of ribosomal activity
Describe how aminoglycosides cross the cell membranes of bacteria
three phases of aminoglycosides crossing cell membrane
Stage I:
positively charged aminoglycosides binding with the negatively charged lipopolysaccharide layer => ionic binding increases wall permeability
(gram pos => ionic binding to phospholipids)
Stage II: small amounts have reached cell and caused faulty protein synthesis => these proteins insert themselves into the cytoplasmic membranes => membrane channels => more aminoglycoside entering
ATP-dependent process
Stage III: large amount of aminoglycosides enter bacterial cells via previously formed channels
List the ways bacteria can use to build resistance against aminoglycosides
- aminoglycoside efflux pumps
- intrinsically resistant: anaerobes - aminoglycosides need O2 for active cell membrane crossing
- enzymatic mutation of aminoglycosdies - AME (intracellular aminoglycoside modifying enzymes) causing structural modifications rendering aminoglycosides unable to bind to the A site
- target modification - change of the 16S rRNA - either via mutation or enzymatic modificaiton
describe the Vd, bioavailability, protein-binding, and chemical properties of aminoglycoside
low volume of distribution
low protein binding
weak base, polar, hydrophilic/water-soluble
poor bioavailability
Explain the PK/PD targets for aminoglycosides
concentration-dependent abx
want Cmax 8-10 times MIC
or AUC over MIC ration >75
post-antibiotic effect - suspected to be partially from enhancing leukocyte activity
Describe how aminoglycosides excert renal damage
freely filtered by the glomerulus - some reabsorbed in the proximal tubules - enter cells via pinocytosis => causes necrosis of the tubular cells due to changes in water and solute transport
sloughing tubular cells create casts –> can obstruct tubules and increased pressure within the bowman’s space –> decreasing GFR
List the following by most to least nephrotoxic: amikacin, gentamicin, tobramycin
dog: gentamicin, tobyamycin, amikacin
cats: tobramycin, gentamicin, amikacin
What conditions can increase the risk of nephrotoxicity from aminoglycosides?
- preexisting renal disease, e.g., CKD
- concurrent drug administration with renal effects (e.g., NSAIDs)
- conditions lowering GFR (pregnancy or old age)
- metabolic acidosis - will increase tubular uptake
What are the recommended trough concentrations for amikacin and gentamicin?
amikacin < 2.5 mcg/mL
gentamicin < 1 mcg/mL
list ways to monitor patients for nephrotoxicity when receiving aminoglycosides
- UA - glucosuria (w/o hyperglycemia) or proteinuria
- granular casts
biomarkers: uNGAL, uNGAL to creatinine ratio, urinary cystatin C
Other than the kidneys, what other organ systems may be affected by adverse effects from aminoglycosides?
- ototoxicity - taken up by cells in the ears and causing necrosis,
- CSN - impairment of Ca release at the neuromuscular junction - neuromuscular blockage
Are fluoroquinolones bacteriostatic or bactericidal?
bactericidal
Describe in detail how Fluoroquinolones affect bacteria. Which effect targets gram neg versus pos bacteria?
DNA gyrase and Topoisomerase IV inhibition - * DNA gyrase needed for DNA supercoiling regulation => unable to transcript DNA normally
* Topoisomerase needed for unlinking DNA following replication (daughter cell replication)
- DNA gyrase inh - gram neg
- Tropoisomerase IV inh - gram pos
Describe the coverage by fluoroquinolones
Discuss sepcifically:
* gram pos/neg/anaerobes
* Pseudomonas aeruginosa
* Staph and Strep
* tick-borne diseases
* Mycoplasma
good against gram neg
some gram pos
no anaerobes except pradofloxacin
- some efficacy against P aeruginosa - but develops resistance fast
- Staph susceptible, most Strep resistant
- tick-borne commonly resistant
- cane move IC –> so okay for IC bacteria like Mycoplasma
What is the oral bioavailability of fluoroquinolones, how are they metabolized, and excreted?
great bioavailability
metabolized by the liver - cytochrome P450 pathway
excreted some in bile, mostly in urine
Are fluoroquinolones hydrophilic or lipophilic, how is their protein-binding and volume of distribution?
lipophilic
high Vd - i.e., distributes well into tissues
protein-binding variable (18%-35%)
How do antiacids affect enrofloxacins bioavailability?
- Sucralfate dose not affect it
- polyvalent cation antacids (e.g., mg, aluminum, Ca, etc.) can interfere
What are the PK targets of fluoroquinolones?
AUC24/MIC > 125
Cmax:MIC >10
AUC/MPC > 32-39 (depending on which fluoroquinolones)
MPC mutant prevention concentration
What are mechanisms by which bacteria become resistant to fluoroquinolones?
- increased efflux
- alterations of the antimicrobial targets (point mutations)
In what conditions are fluoroquinolones acceptable first-line agents?
- pyelonephritis
- prostatitis
- say pneumonia here, but check with consensus
- hepatobiliary infection suspected to not be anaerobe (unless prado used in cats) and neither Enterococcus induced
List adverse effects of fluoroquinolones
- GI
- seizures/tremors
- cartilage defects in juveniles
- irreversible blindness in cats
How are fluoroquinolones suspected to cause seizures
competitively inhibit GABA binding
What can too rapid IV infusion of fluoroquinolones cause?
histamine release
What is the primary metabolite of enrofloxacin?
cirpofloxacin
What is a specific adverse effect of pradofloxacin in dogs?
bone marrow suppression
What is mitronidazole’s Vd, bioavailability and tissue penetration?
high bioavailability (50-100%)
good tissue penetration and high Vd (reaches CSF and crosses BBB)
What class of antibiotic does Metronidazole belong to?
nitroimidazoles
Is metronidazole
* time-dependent/concentratio-dependent?
* bacteriostatic/bactericidal?
cc-dependent
bactericidal
How does metronidazole assert its action on bacteria?
- reduced by enzymes in the bacteria => produced product incoorporates into the DNA => cell death
What is the spectrum of metronidazole?
only anaerobes - nitrous reduction of metronidazole can only happen in anaerobic bacteria
also protozoals - but higher dosages (i.e., risk of CNS signs)
List the adverse effects of Metronidazole
- GI upset
- CNS toxicity (ataxia, nystagmus, tremors, etc.)
What is the mechanism of action of Chloramphenicol, is it bacteriostatic or bactericidal?
What other classes of antibiotics have the same mechanism of action?
bacteriostatic (time-dependent)
binds to the 50S ribosomal subunit - blocks elongation
same binding site: clindamycin, macrolides
What is the reason for Chloramphenicol’s high risk of toxicity?
it inhibits mitochondrial protein synthesis in mammalian cells (especially erythropoietic cells)
What is the spectrum of Chloramphenicol?
gram +/- and anaerobes
but common resistancies
What is the bioavailability, Vd and metabolism/excretion of Chloramphenicol?
good bioavailability, high Vd, most tissues except prostate only 60%
metabolized by liver - glucuronidation –> cats more sensitive to toxicities
renal excretion - inactive form
What class of antiobitics is clindamycin? Is is bacteriostatic/bactericidal, concentration/time dependent?
Lincosamide
bacteriostatic, time-dependent
What is the spectrum of clindamycin?
gram positives
anaerobes
Myocplasma
How is the tissue distribution of Clindamycin?
good distribution - therapeutic levels in CNS (toxoplasmosis!) - penetrates BBB
What is the mechanism of action of tetracyclines?
binds to the ribosomal 30S subunit - blocks tRNA bindings and elongation
Name an additional effect of doxycycline besides antimicrobial
inhibits matrix metalloproteinases - can potentially help in delayed wound healing but not proven
List the spectrum of tetracyclines
Gram pos, neg
vector-borne rickettsial
anaerobes
intracellular bacteria (E.g., mycoplasma)
What is the bioavailability, Vd, lipophilic/hydrophilic, and protein-binding of tetracyclines? How are they eliminated?
high bioavailability
high Vd
lipophilic
high protein-binding (99%)
unknown elimination (suspect hepatobiliary and enteric), only 19% in urine
List adverse effects of tetracyclines
esophagitis with subsequent strictures
GI upset
enamel discoloration of erupting teeth
thrombophlebitis from IV
rare: hepatotoxicity
What is the mechanism of action of TMS, is it bacteriostatic or bactericidal?
bactericidal in combination (time-dependent)
sulfadiazine and trimethoprim each alone would be bacteriostatic
causes inhibition of the folic acid production
* sulfonamide => competetive analog to P aminobenzoic acid (PABA)
* trimethoprim inhibits folic acid reduction
target different parts of the folic acid pathway
What is the ratio of TMS combination products?
1:5 trimethoprim to sulfonamide
What is the spectrum of TMS? How does it distribute in tissue?
gram +/-, anaerobes
ineffective against mycoplasma, P aeruginosa, rickettsial disease
good tissue distribution - sulfonamide reaches CNS, trimethoprim reaches prostate
How is TMS excreted?
renally - good for UTIs
List the adverse effects of TMS
- KCS
- immune-mediated disease
- hypersensitivity reactions (fever, pancreatitis, glomerulonephritis, etc.)
What are the most concerning adverse effects of nitrofurantoin?
dogs - irreversible neuropathy, severe, occurs delayed
cats - causes glutathione instability and can cause hemolysis
How should rifampin be administered?
always with another antibiotic! - otherwise resistance develops quickly (within 2 days)
What are the three types of resistance?
- inherent resistance (e.g., anaerobes to aminoglycosides)
- circumstantial resistance - i.e., culture says susceptible but not effective in vivo
- acquired resistance - phenotypic changes
How are multidrug resistant organisms (MDRO) defined?
resistant to at least 1 agent in 3 or more classes of antibiotics
What are XDR and PDR drugs?
XDR - extensively drug resistant - susceptible to only one or two classes of antimicrobials
PDR - pan drug resistant - resistant to all known licensed antimicrobials
What are risk factors for MDR infections?
- previous antimicrobial administration
- hospitalization
- duraiton of ICU stay
- surgical procedures
- MV
- predisposing diseases
What is the primary mechanism of acquired resistance by MRS?
acquisition of the mecA gene
What are MRS resistant to and what are options for empirical abx tx?
- all beta lactams except cetaroline (5th gen)
- frequently resistant to: clindamycin, fluoroquinolone, macrolides, TMS
empiric: vancomycin, aminoglycosides (but not good at penetrating purulent material or cellular debris)
What are Enterococci typically resistant to?
- cephalosporins
- clindamycin
- aminoglycosides
- Fluoroquinolones
- Carbapenems (E. faecium)
What are treatment options for Enterococcus spp.?
- Vancomycin
- combination of gentamycin and ampicillin
Note: Enterococcus spp. are not highly pathogenic, so treatment may not be always necessary
Note: don’t use amikacin or tobramycin with ampicillin - not synergistic
Which antibiotics is Pseudomonas aeruginosa most susceptible to?
- meropenem
- amikacin
What antibiotics is Pseudomonas aeruginosa typically resistant to?
almost all beta-lactams except piperacillin, ceftazidime, carbapenem
Compare the resistance of beta-lactamases versus ESBLs
beta-lactamases: penicillins, aminopenicillins, carboxypenicillins, narrow-spectrum cephalosporins
ESBLs: also third-gen cephalosporins
Tx of choice: carbapenems
