ID Exam 1 Flashcards
Systemic inflammatory response syndrome (SIRS) criteria
- Tachycardia (> 90BPM)
- Tachypnea (> 20 RPM)
- Fever ( >38C or <36C)
- Increased/decreased WBC count (> 12,000 or <4,000 or >10% immature forms (bands))
Normal WBC count
4,500-11,000 cells/mm3
(represents total number of WBC - neutrophils, lymphocytes, monocytes, eosinophils, basophils)
Non-infectious causes of elevated WBC count
steroids, leukemia, stress, pregnancy, RA
Percentage of mature neutrophils (PMNS, polys, segs) in normal WBC differential
36-73% (most common WBC)
Percentage of immature neutrophils (bands) in normal WBC differential
0-5%
(increased during infection = “left shift”)
Leukocytosis is associated with _________ infections (as opposed to lymphocytosis)
bacterial
Lymphocytosis is associated with _________, _________, and __________ infections
viral, fungal, tuberculosis
What is leukocytosis?
an increase of neutrophils +/- bands
What is leukopenia? It might be a sign of what?
abnormally low WBC, which may be a sign of overwhelming infection
ANC =
WBC x (% segs + % bands/100)
Neutropenia = ANC < ________
500 cells/mm3
(or if ANC is expected to decrease to < 500 in the next 48 hours)
ANC < 500 is associated with a substantial risk of __________
INFECTION (especially by opportunistic pathogens)
ESR normal values
0-15 mm/hr (males)
0-20 mm/hr (females)
CRP normal value
0-0.5 mg/dL
Procalcitonin normal level
<0.05 mcg/L
Procalcitonin is _____ specific for bacterial infections than ESR and CRP
more
PCT < 0.25mcg/L =
low risk of infection
PCT > 0.5 mcg/L =
antibiotics should be continued
Serial measurements of PCT every 1-2 days are useful for what?
to assess response to therapy and when to discontinue antibiotics
Allergenicity of B-lactams
They acylate host cell proteins which raise antibodies that result in an allergic reaction
What chemical feature of penicillins confer resistance to degradation under acidic conditions?
The electronegativity of the substituent on the side chain carbonyl - if it reduces nucleophilicity/takes electron density away from carbonyl oxygen atom = stabilization
Which has a thicker peptidoglycan cell wall?
Gram (+)
In which type of bacteria are beta-lactamases confined to the periplasmic space?
Gram (-)
In Gram (-) cells, peptidoglycan is bridged between the terminal D-Ala and the ______ residue
DAP (mesodiaminopimelic acid) residue
In Gram (+) cells, peptidoglycan is bridged between the terminal D-Ala and the ______ residue
L-lysine
How many cell membranes do gram (+) bacteria have?
one
How many cell membranes do gram (-) bacteria have?
two - more complex cell wall that is lipoidal
What catalyzes penicillin degradation and should therefore be kept away from penicillin solutions?
Heavy metal ions
As lipophilicity of penicillins ________, serum protein binding increases
increase
As serum protein binding of pencillins increases, bioavailability ___________
decreases
How does renal disease affect half-life of penicillins?
prolonged
How does administration of probenecid with penicillins affect their half-life?
increases because they are competing for the anionic tubular secretion in the kidneys
Which is more stable in the stomach: Pen G or Pen V?
Pen V
Pen G antimicrobial spectrum
Gram (+) cocci
Is Pen G sensitive to B-lactamases?
Yes
Pen G precautions
should be used with caution in individuals with history of significant allergies or asthma
What chemical feature of methicillin confers resistance to Beta-lactamases?
The B-lactam carbonyl is sterically hindered (to a nucleophilic attack)
B-Lactamase-sensitive penicillins
Pen G
Pen V
Amoxicillin
Ampicillin
B-Lactamase-resistant parenteral penicillins
Methicillin
Nafcillin
B-lactamase-resistant oral penicillins
Oxacillin (d/c for oral use)
Cloxacillin (d/c for oral use)
Dicloxacillin
Which is more stable in acid: methicillin of nafcillin?
Nafcillin
B-lactamase sensitive, broad-spectrum, oral penicillins
Ampicillin
Amoxicillin
Ampicillin antibacterial spectrum
Gram (+) and Gram (-)
Which has better oral absorption: ampicillin or amoxicillin?
Amoxicillin
Mechanism of action of B-lactamase inhibitors
They acylate the serine hydroxyl group in the active site of the B-lactamase
B-lactamase-sensitive, broad-spectrum, parenteral penicillin
Piperacillin
Why does piperacillin, a acylureidopenicillin, have enhanced potency?
Because the added side chain fragment resembles a longer section of the peptidoglycan chain
Cephalosporins mechanism of action
Reaction with transpeptidases (penicillin binding proteins) that results in inhibition of peptidoglycan cross-linking (same as penicillins)
Allergic reactions to cephalosporins is ______ common than with penicillins
LESS common (and less severe)
What is the general trend from first generation to third generation cephalosporins?
enhanced Gram-negative activity and a loss of efficacy toward Gram-positive bacteria
What is the structural difference between orally active and parenteral cephalosporins?
Orally active cephalosporins have unreactive C-3 substituents
What side chain do first-generation orally active cephalosporins have at C-3?
Methyl group
Why are syn oxime ethers (at the C-7 side chain) more resistant to B-lactamase hydrolysis than anti oxime ethers?
The syn oxime ether hangs under the carbonyl protecting it from attack
What effect does the large oxime ether at C-7 on ceftazidime have on stability vs B-lactamases?
Enhanced stability/more resistant
What effects does the charged pyridinium ring ring at C-3 on ceftazidime have on aqueous solubility and B-lactam reactivty?
Enhances aqueous solubility and makes it parenterally active (too reactive for oral use)
What effect does the charged methylpyrrolidine on cefepime have on reactivity and antibiotic spectrum?
-Increased reactivity (good leaving group) making it parenterally active
-More activity against gram (-) organisms because porins are polar
Why can’t thienamycin be used as a drug?
Too reactive, the primary amino group attacks the B-lactam ring intermolecularly
Why are carbapenems more reactive than penicillins?
The sulfur in penicillins is replaced by a carbon, which causes an increase in the ring strain of the b-lactam ring (since the carbon is smaller than sulfur)
What unique feature does imipenem have against B-lactamases?
It reacts and inhibits B-lactamases
Why is cilastatin administered with imipenem?
Imipenem is hydrolyzed by renal dehydropeptidase-1, and cilastatin is dehydropeptidase-1 inhibitor
What structural feature do monobactams have that replaces the carboxyl group in penicillins and cephalosporins?
sulfamic acid - which allows them to be biologically active
Antibiotic spectrum of monobactams
Almost completely gram (-) bacteria
How does the sulfamic acid in monobactams affect reactivity?
The electronegativity of the sulfamic acid activates the beta-lactam ring to react with the penicillin-binding proteins
Cross allergenicity of monobactams with penicillins and cephalosporins
Has not been reported except with ceftazidime which an identical oxime ether sidechain
What type of bacteria does vancomycin cover? Why?
Gram (+) because it is too big to get through porins of gram (-) bacteria
Vancomycin mechanism of action
Binds to the D-ala-D-ala terminus of peptidoglycan - inhibits Gram (+) cell wall synthesis
Mechanism of bacterial resistance against vancomycin
Mutation of D-ala-D-ala to D-ala-D-lactate - vancomycin has 1000 times less affinity for D-ala-D-lactate and will therefore not bind
Main toxic effects of vancomycin
- Hypersensitivity rxn resulting in red skin rash - “red man syndrome”
- Nephrotoxicity
- Ototoxicity
Vancomycin therapeutic uses
- Given orally for c. diff (after flagyl treatment is ineffective)
- MRSA
How is vancomycin eliminated?
90% glomerular filtration
Oritavancin, Telavancin, and Dalbavancin antibiotic spectrum
Gram (+), including MRSA
Which drugs are lipoglycopeptides?
oritavancin, telavancin, dalbavancin
Lipoglycopeptide antibiotic mechanism of action
Binds to D-ala-D-ala terminus of peptidoglycan inhibiting cell wall synthesis - identical to vancomycin
How do the half-lives of oritavancin and dalbavancin differ from those of vancomycin and televancin? Why?
Greatly increased - this is because of their lipophilic side chains which increases protein binding
Which structural feature of quinupristin and dalfopristin allow for salt formation and enhance water solubility?
The amino side chains (R-NH2)
Quinupristin and dalfoprisitin: bacteriostatic or bactericidal?
Bacteriostatic on their own
Synercid therapeutic uses
- Vancomycin-resistant Enterococcus faecium bacteremia and UTIs
- Skin infections caused by MRSA
*NOT effective against Enterococcus faecalis
Quinupristin mechanism of action
binds in the ribosomal tunnel and causes blockage of tunnel
Dalfopristin mechanism of action
binds to the 23S portion of the 50s ribosomal subunit, enhancing the binding of quinupristin
Streptogramin drug interactions
streptogramins inhibit CYP3A4 so drugs metabolized by CYP3A4 i.e. cyclosporine and macrolides
Streptogramin resistance mechanisms
- Quinupristin ONLY - Adenine methylation of A2058 (this makes Synercid bacteriostatic)
- Continued use of streptogramins in animal feeds
Linezolid mechanism of action
It acts early on the 50S subunit which prevents formation of the 70S initiation complex - it interacts specifically with 23S rRNA
Linezolid therapeutics uses
- Vancomycin-resistant Enterococcus faecium
- Nosocominal pneuomonia caused by MRSA
- Skin infections caused by MRSA
Why should linezolid only be used to treat or prevent infections that are proven/strongly suspected to be caused by multi-drug resistant Gram (+) bacteria?
To reduce the development of drug-resistant bacteria and maintain the effectiveness of linezolid
Resistance mechanism to linezolid
G -> U substitution in the 23S rRNA at position 2576 - results in reduced affinity of linezolid to the 50S subunit
Linezolid side effects
- GI: N/V/D
- Tongue discoloration or oral thrush
How is linezolid metabolized?
- The morpholine ring undergoes oxidation
- 30% is excreted in urine as parent drug
Linezolid is _____% bioavailable after oral administration
100%
Linezolid drug interactions
- it inhibits monoamine oxidase - therefore may interact with adrenergic and serotonergic drugs
- Pseudoephedrine - caution in patients with HTN
- Foods rich in tyramine
Tedizolid is _____ potent that linezolid
MORE
Aminoglycoside mechanism of action
Inhibits protein synthesis by binding to 30S ribosomal subunit, specifically 16S rRNA forming the A site
Symptoms of aminoglycoside ototoxicity
- high-frequency hearing loss
- vertigo
- loss of balance
- ataxia
- tinnitus
Which toxicity caused by aminoglycosides is irreversible: ototoxicity or nephrotoxicity?
ototoxicity
Resistance mechanisms to aminoglycosides
Bacteria inactivate aminoglycosides by acetylation, adenylation, and phosphorylation
(aminoglycosides are not metabolized in humans, as opposed to bacteria)
Concurrent use of which drugs with aminoglycosides may potentiate nephrotoxicity?
-Loop diuretics
-Vancomycin
-Amphotericin
How are curare-like effects caused by aminoglycosides treated?
respiratory paralysis usually reversed by neostigmine or calcium gluconate
What might cause aminoglycoside toxicities?
- large doses
- treatment > 5 days
- eldery patients
- renal impairment
What are the core structures of aminoglycosides?
- streptidine
- 2-deoxystreptamine
Aminoglycoside antibiotic spectrum
broad spectrum Gram (+) and Gram (-), but is almost always reserved for Gram (-)
Why should penicillins and aminoglycosides not be administered in same solution?
They react with each other which inactivates them
Penicillin/aminoglycoside combination therapeutic use
bacterial endocarditis
Streptomycin therapeutic uses
- tuberculosis
- bubonic plague
- tularemia
Gentamicin therapeutic uses
- UTIs
- burns - topically
- joint and bone infections caused by Gram (-) infections
- pneumonias
- eye infections - ophthalmic
Tobramycin therapeutic uses
same as gentamicin:
1. UTIs
2. burns - topically
3. joint and bone infections caused by Gram (-) infections
4. pneumonias
5. eye infections - ophthalmic
AND gentamicin-resistant P. aeruginosa infections
Oral aminoglycosides
- Neomycin B
- Paromomycin
Amikacin therapeutic uses
- aminoglycoside-resistant nosocomial infections
- severe P. aeruginosa infections
- Mycobacterium tuberculosis
- Francisella tularensis
Neomycin therapeutic uses
- Suppress gut flora in traveler’s diarrhea
- Peritonitis prophylaxis prior to GI surgery
- Used as a topical ointment
Paramomycin therapeutic uses
- Suppress gut flora in traveler’s diarrhea
- Peritonitis prophylaxis prior to GI surgery
- Amoebic dysentery
- Dwarf and beef tapeworm
Plazomicin therapeutic uses
complicated UTIs + pyelonephritis caused by E. coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae
Why is gentamicin the most important aminoglycoside?
because it’s low cost and has reliable activity against the most resistant Gram (-) aerobes
How is tobramycin metabolized by bacteria?
- Adenylated at C2
- Acetylated at C3
Which part of the macrolide structure is important for activity?
the desosamine sugar
Which bacteria have intrinsic resistance to macrolides by not allowing entry of these drugs?
Pseudomonas spp. and Enterobacter spp.
Macrolides mechanism of action
bind to the P site of the ribosome inhibiting translocation of growing peptide from the A site to P site
What is the main route of erythromycin metabolism?
Demethylation in the liver
Macrolides side effects
- 14-membered macrolides can cause vomiting, gastric cramps, abdominal pain
- Minor to severe allergic skin reactions
- Long term use (10-20 days) can cause reversible cholestatic hepatitis - manifests as jaundice with cramping/nausea/fever
- Erythromycin may increase risk of pyloric stenosis in children
Clindamycin mechanism of action
inhibit protein synthesis by binding to 50S subunit of ribosome - similar to macrolides MOA and has same binding site as erythromycin
Clindamycin antibiotic spectrum
Aerobic gram (+) cocci
Anaerobic gram (-) bacilli
Clindamycin therapeutic uses
- Topically for acne
- Bone infections from S. aureus
- Bacterial vaginosis (cream)
- Lung abscesses + pleural space infections
- MRSA
- Used in AIDS patients with encephalitis caused by Toxoplasma gondii
What side effect of clindamycin limits its use?
Pseudomembranous colitis caused by C. diff
How is clindamycin metabolized?
by cytochrome P450 enzymes in the liver to inactive metabolites
Where is clindamycin absorbed?
90% is absorbed in GI tract
What is the preferred route of tetracyclines?
oral
Why should tetracyclines not be administered to children who are forming their permanent teeth?
tetracyclines chelate calcium during formation of teeth resulting in permanently brown or gray teeth
Epimerization of tetracycline is ______ in the solid state and _________ at pH ___
slow in solid state
most rapid at pH 4
Why is 4-epianhydrotetracycline toxic?
it’s toxic to the kidneys and can produce a Fanconi-like syndrome
Why do minocycline and doxycycline lack the renal toxicity risk of tetracycline?
they lack a C-6 hydroxyl group (which causes the dehydration reaction)
Tetracyclines mechanism of action
binds to 30S subunit blocking the attachment of tRNA to A site of ribosome
What might lower absorption of tetracyclines by about 20-50%?
food and milk
Why is doxycycline the tetracycline of choice?
It has no potential for 4-epianhydrotetracycline toxicity and produces fewer GI symptoms
Which tetracyclines are teratogenic?
omadacycline and sarecycline
