Sketchy Pharma Antimicrobials Flashcards
1
Q
Mechanism of Beta-lactam abx
A
Beta-lactams bind to penicillin binding proteins (PBPs) on bacterial cell walls to interfere w/ transpeptidation of peptidoglycan synthesis
-PBP required to cross-link peptidoglycan, so penicillins binds to PBPs to prevent this
Prevent cell wall synthesis => bacteriocidal
2
Q
Main indication for Penicillin
A
Penicillin mainly for Gram positive cocci, mainly strep
Oral Penicillin (PenG) uses: GAS pharyngitis, rheumatic fever
3
Q
Other indications for Penicillin
(a) Against what gram negative
(b) What infxn from dog bites
(c) Against what filamentous rod
(d) Against what cause of food poisoning
A
Penicillin indications in addition to strep throat
(a) Penicillin works against neisseria meningitis! (gram negative)
(b) Pasteurella from dog bites
(c) Actinomyces israelii (skin infxn after jaw trauma)
(d) C. perfinges- so can use IV PenG for gas gangrene
4
Q
MC cause of resistance to penicillin
A
Beta-lactamases, expressed by plasmid genes, that cleave the beta-lactam ring
5
Q
Shared side effects of penicillin-class of abxs
A
Beta-lactams (Penicillins, Cephalosporins)
- Hypersensitivity reactions
- Interstitial nephritis
- Autoimmune hemolytic anemia
6
Q
Explain how the structure of Nafcillin changes its coverage
A
Nafcillin has a large R-group side chain on its beta-lactam ring that doesn’t allow beta-lactamase to cleave it => nafcillin is effective against beta-lactamase producing staph species (MSSA)
7
Q
Mechanism of resistance of MRSA to Nafcillin
A
MRSA: staph species that contain altered PBPs (penicillin binding proteins) that have low affinity for Nafcillin => Nafcillin can’t bind and kill the bacteria
8
Q
First line indications for Naficillin
A
MSSA- think Staph aureus (‘Naf for staph’) endocarditis/osteomyelitis/folliculitis/abscess
9
Q
Differentiate ampicillin and amoxicillin
A
Ampicillin- IV administration
-combined w/ sulbactam (Unasyn) to cleave beta-lactamase
Amoxicillin- PO
-combined w/ clavulnate (augmentin)
10
Q
Indications of amoxicillin
(a) Main indications
(b) Why useful for ppx in aspenic pts
A
Amoxicillin = extended-spectrum penicillin
(a) Strep throat, otitis media, sinusitis
(b) Covers encapsulated bacteria H. influenza and S. pneumo
11
Q
First line abx for
(a) Ppx in asplenic pts
(b) Staph endocarditis
(c) Syphilis
A
First line abx for
(a) Ppx in aspenia = Amoxicillin = extended-spectrum penicillin
(b) Staph endocarditis = Nafcillin
(c) Syphilis = single dose IV penicillin
12
Q
First line abx for
(a) Intrapartum GBS ppx
(b) Ppx before dental procedure in pts at high risk for endocarditis
(c) Listeria meningitis
(d) Gonorrhea
A
First line abx for
(a) Intrapartum GBS ppx = PenG
(b) Ppx for dental procedure in pts w/ artificial heart valves = Amoxicillin b/c covers S. pneumo
(c) Listeria meningitis = Ampicillin (IV extended coverage penicillin)
(d) Gonorrhea tx w/ single dose of IV ceftriaxone
13
Q
Beta-lactam abx associated w/
(a) Rash in pt w/ infectious mononucleosis
(b) Drug induced liver injury
A
(a) Amoxicillin and ampicillin are associated w/ rash in pts w/ EBV
- also associated w/ SJS
(b) Amoxicillin has high association w/ DILI
14
Q
Key indications for Piperacillin and Ticarcillin
A
Piperacillin (combined w/ tazobactam = Zosyn) and Ticarcillin are extended-spectrum penicillins w/ coverage of pseudomonas and anaerobes
-so used as empiric tx for HCAP and sepsis
15
Q
Name the three combo drugs of penicillin and beta-lactamase inhibitor
A
Combo drugs
- Amoxicillin w/ clavulate = Augmentin (PO)
- Ampicillin w/ tazobactam = Unasyn
- Piperacillin w/ tazobactam = Zosyn
16
Q
Mechanism of action of cephalosporins
A
Cephalosporins are beta-lactams, so still same mechanism as Penicillin, Nafcillin, Ampicillin etc
Bacteriocidal- halt peptidoglycan synthesis by binding PBP (penicillin binding proteins)
17
Q
1st gen cephalosporins
(a) Main indication
(b) Extent of G- coverage
A
1st gen cephalosporins = Cephalexin and Cefazolin (Keflex): mainly gram positive coverage w/ tiny bit of gram negative
(a) Surigcal infection ppx, cellulitis and abscess from Strep/Staph
(b) Covers PEK organisms that cause UTI: Proteus, E. Coli, Klebsiella
18
Q
Name the 2nd gen cephalosporins
A
2nd gen cephalosporins = Cefuroxime, Cefotetan, Cefoxitin
Covers same as first gen (staph/strep w/ Klebsiella Proteus E. coli) plus HENS: H. flu, neisseria, and serratia
19
Q
3rd gen cephalosporins
A
3rd gen cephalosporins = Ceftraixone, Cefotaxime, Ceftazidime
20
Q
Name the 3 components of empiric meningitis tx in 68 yo M
A
Empiric tx of meningitis
- Ceftriaxone for broad gram negative coverage w/ good CNS penetration
- Vanc for MRSA coverage
- Ampicillin for Listeria coverage since over 65
21
Q
Distinguish the two types of 3rd gen cephalosporins
A
3rd gen cephalosporins: Ceftraixone and Cefotaxime great for meningitis, cross BBB
But then Ceftazidime is special b/c it covers pseudomonas! So use Ceftrazidime for HCAP and ventilator-associated pneumonia
22
Q
Differentiate 4th and 5th generation cephalosporins
A
4th gen cephalosporin = Cefepime- broad spectrum w/ good CNS penetration (tx meningitis) and covers pseudomonas
-but still no MRSA coverage
5th gen cephalosporin = Ceftaroline- Cefepime plus MRSA coverage!!!!! Can bind to the altered PBPs of MRSA
23
Q
Main side effects of cephalosporins
A
Cephalosporins are beta-lactams (like penicillin, ampicillin, nafcillin, aztreonam, imipenem) so have the same major side effects
- Hypersensitivity- cross reactive w/ penicillin allergy
- so if pts have IgE against Penicillin, more likely they’ll also have type I hypersensitivity against cephalosporins - interstitial nephritis
- autoimmune hemolytic anemia
24
Q
Explain the progression as you get to higher generations of cephalosporins
A
Start w/ mainly G+ coverage, get increasingly more G- up to 3rd gen which has big G- coverage
Then 4th gen has broad G+ and G- coverage (broad spectrum), while 5th gen is everything + MRSA
25
Mechanism of
(a) Aztreonam
(b) Vancomycin
Mechanisms
(a) Aztreonam = monobactam, beta lactam abx => bacteriocidal by binding PBPs to half peptidoglycan wall synthesis
(b) Vancomycin directly binds D-ALA-D-ALA oligopeptide of the cell wall (not indirectly by binding PBPs)
- this is why Vanc is effective against MRSA, which has altered PBPs
26
Mechanism of
(a) Imipenem, Meropenem
(b) Daptomycin
Mechanisms
(a) Carbapenems are beta-lactams => bacteriocidal by binding PBPs to half peptidoglycan wall synthesis
(b) Daptomycin works against gram positives by inserting its lipid tail into the membrane and causing depolarization => bacteriocidal
27
Which abx requires co-administration w/ Cilastatin
Cilastatin = dehydropeptidase enzyme inhibitor
Co-administer cilastatin w/ Imipenem b/c otherwise Imipenem gets inactivated by dehydropeptidase in the renal tubules
28
Explain the mechanism by which certain enterococci strains are resistant to vancomycin
VRE gain resistant b/c of altered peptidoglycan (cell wall) structure
Normally peptidoglycan is D-ALA-D-ALA chains, while VRE have D-ALA-D-LAC chains instead => Vanc can't bind :-(
29
Why are vanc troughs monitored?
Vanc levels are measured b/c the drug is 90% excreted by glomerular filtration, which can greatly vary from person to person and w/ certain concomitant medications etc
So want high enough levels to penetrate tissues but don't want to cause toxicitiy (thrombophlebitis, nephrotoxicity, ototoxicity) => monitor levels
30
Vancomycin side effects
Vancomycin side effects
- Red man infusion syndrome
- thrombophlebitis
- rare: ototoxicity and nephrotoxicity
31
Buzzword w/ abx
| a) Red man syndrome
(b
Buzzword
(a) Red man syndrome = infusion syndrome from histamine release 2/2 vancomycin
32
Side effect of daptomycin that requires monitoring
Daptomycin is associated w/ myopathy, requiring monitoring of CPK levels in pts on chronic daptomycin tx
33
Indications for Daptomycin
Daptomycin (depolarizes cell membranes of G+) for VRE, vanc resistant strep, MRSA bacteremia, MRSA endocarditis
NOT for MRSA pneumonia!!! inactivated by pulmonary surfactant
34
Which MRSA infection is Daptomycin contraindicated in?
Well not contraindicated in by Daptomycin is ineffective against MRSA pneumonia b/c Daptomycin is inactivated by pulmonary surfactant
35
Which MRSA infection is Daptomycin contraindicated in?
Well not contraindicated in by Daptomycin is ineffective against MRSA pneumonia b/c Daptomycin is inactivated by pulmonary surfactant
36
Name the beta-lactam abx classes
Tons of beta-lactams: all w/ the same mechanism = bind to PBPs (penicillin binding proteins) to inhibit peptidoglycan wall synthesis = bacteriocidal
```
Penicillin
Nafcillin, Oxacillin
Amoxicillin, Ampicillin, Piperacillin, Ticarcillin
Cephalosporins (all 5 generations)
Monobactams (aztreonam)
Carbapenems
```
37
Name abx that target the cell wall but are not beta-lactams
Vancomycin- binds directly to D-ALA-D-ALA instead of PBPs (penicillin binding proteins)
Daptomycin- depolarizes the cell membrane by inserting its lipid tail
38
Name abx that target the cell wall but are not beta-lactams
Vancomycin- binds directly to D-ALA-D-ALA instead of PBPs (penicillin binding proteins)
Daptomycin- depolarizes the cell membrane by inserting its lipid tail
39
Mechanism of tetracyclines
(a) What else has a similar mechanism?
Tetracycliines (Doxycycline, Mincecycline) enter the bacteria and reversibly bind to the 30S subunit to inhibit translocation, bacteriostatic
(a) Aminoglycosides also bind to 30S ribosomal subunit, but they're bacteriocidal
40
2 abx used for moderate to severe acne
Tetracyclines (doxycycline)- skin anaerobes, bacteriostatic, inhibits bacterial protein synthesis by binding to 30S subunit
Clindamycin, kills off the cutaneous anaerobic flora, bacteriostatic, inhibits bacterial protein synthesis by binding to 50S subunit
41
What two populations are tetracyclines contraindicated in?
Tetracyclines are contraindicated in children under 8 and pregnant women
Children b/c tetracyclines bind to newly formed bone and teeth => classically causes teeth discoloration
Teratogenic b/c binds Ca2+ in fetal teeth and bone => malformations
42
What abx can you not take with milk or ferrous sulfate?
Avoid milk, ferrous sulfate, and antacids w/ tetracycline b/c tetracyclines are absorbed by divalent cations (Ca2+, Fe2+, Mg2+) in the gut which decreases absorption
43
What abx is associated w/ Fanconi syndrome
Fanconi syndrome- causes a type 2 renal tubular acidosis- is associated w/ use of expired tetracyclines
44
Explain the mechanism of bacterial resistance to tetracyclines
Tetracyclines work by binding bacterial ribosomal 30S subunit, which requires them to be inside the cell
Resistance develops by efflux pumps that literally pump the abx out of the bacteria, or by alteration of the ribosomal subunit
45
Main indications for Doxycycline
Doxycycline first line for
- Rickettsia (rocky mtn spotted fever), also covers other tick borne illness (Ehrlichia, francisella, Borrelia bergdorferi- use in early Lyme's disease)
- community acquired pneumonia from atypical bugs (mycoplasma and chlamydia)
- zoonotics: Brucella, Coxiella (Q-fever), Yersinia (black plague)
Does cover MRSA (but not first line)
46
Which antibiotic that inhibits bacterial protein synthesis is bacteriocidal
Only abx w/ mechanism of inhibiting protein synthesis that is bacteriocidal = aminoglycosides (streptomycin, gentamycin, tobramicin, amikacin)
47
Side effects of doxycycline
Photosensitivity and GI (N, V, D)
48
Drugs for tx of atypical (walking) pneumonia
Tetracyclines (doxycycline, inhibit bacterial protein synthesis by binding to 30S) covers mycoplasma and chlamydia atypical pneumonia
Macrolides (Azithromycin, inhibit bacterial protein synthesis by binding to 50S) covers mycoplasma, legionella, and chlamydia pneumonia
49
Mechanism of macrolides
Macrolides = Azithromycin, Clarythromycin, Erythromycin
Bacteriostatic, inhibit 50S subunit
50
Tx of community acquired pneumonia in pts w/ penicillin allergy
Macrolides (Azithromycin): good coverage of S. pneumo, H. influenza, and Moraxella catarrhalis
51
Mechanism of the triple therapy used for H. pylori eradication
H. pylori triple therapy
1. PPI to reduce acid production which is elevated due to the infection
2. Clarythromycin = macrolide abx, bacteriostatic, inhibits bacterial protein synthesis by binding 50S
3. Amoxicillin = extended-coverage beta-lactam, bacteriostatic, inhibits cell wall synthesis
52
Abx of choice for
(a) Cat scratch fever
(b) Congenital conjunctivitis
Abx of choice for
(a) Cat scratch fever 2/2 bartonella henselae = Azithromycin (macrolide)
(b) Congenital conjunctivitis- think gonorrohea and chlamydia, tx w/ erythromycin (macrolide)
53
Abx of choice for
(a) Diptheria
(b) Aspiration pneumonia c/b abscess formation
Abx of choice for
(a) 'Bull's neck' from C. diptheria = erythromycin (macrolide)
(b) Really good oral anaerobic coverage w/ great abscess penetration = clindamycin (own class, bacteriostatic, inhibits 50S)
54
Abx of choice for polymicrobial infections of the female genital tract such as endometriosis or infected retained products of conception
Want broad coverage: gentamycin plus clindamycin
- Gentamycin
- clindamycin = inhibits bacterial protein synthesis by binding 50S
55
Two txs for gas gangrene/myonecrosis
Clostridium perfinges (G+ bacilli) can cause gas gangrene/myonecrosis
Tx w/ IV PenG (beta lactam, inhibits cell wall synthesis, bacteriocidal) or clindamycin (inhibits protein synthesis by binding 50S, bacteriostatic)
56
Tx for bordetella pertussis
Azithromycin = Macrolide abx, inhibits bacterial protein synthesis by binding to 50S
Use Azithromycin over Erythro or Clarythromycin in infants under 1 mo
-can also give Azithromycin for pertussis ppx to close contacts
57
In addition to metronidazole, what abx covers gardenerella vaginosis?
Gardenerella vaginosis = anaerobe, can also be covered by clindamycin which has great anaerobe coverage
'clindamycin for anaerobes above the diaphragm (oral anaerobes that cause aspiration pneumonia), metronidazole for anaerobes below the diaphragm
58
Abx w/ highest risk of C. Dif
Clindamycin = MC implicated in pseudomembranous colitis 2/2 C. Dif
Mechanism of clindamycin = inhibits bacterial protein synthesis by binding 50S
59
Name the abx not used in the US, but often used in third world countries to combat meningitis outbreaks
Chloramphenicol
-bacteriostatic inhibitor of microbial protein synthesis
Super duper cheap, but not used here b/c of side effects: hematologic (aplastic anemia), gray-baby syndrome
60
Mechanism of
(a) Linzeolid
(b) Streptomycin
(c) Isoniazid
Mechanisms
(a) Linezolid = bacteriostatic, binds 50S to prevent formation of initiation complex => inhibiting bacterial protein synthesis
(b) Streptomycin = type of aminoglycoside => bacteriocidal protein synthesis inhibitor
(c) Isoniazid = inhibits synthesis of mycolic acid (necessary component of mycobacterium cell wall, what makes it stain acid fast positive)
61
Mechanism of
(a) Gentamycin/Tobramycin
(b) Rifampin
Mechanisms
(a) Gentamycin/Tobramycin are aminoglycosdies that are bacteriocidal inhibitors of bacterial protein synthesis
(b) Rifampin binds to bacterial-dependent RNA polymerase to prevent RNA production
62
When are the following used a single agents
(a) Isoniazid
(b) Rifampin
Often used in combo to prevent resistance, but can be used alone in certain circumstances
(a) Isoniazid tx alone for tx of latent Tb to prevent reactivation
(b) Rifampin can be used as monotherapy to prevent meningitis (2/2 H. influenza and N. meningitis) in close contacts
63
Abx to use w/ caution in pts w/ depression
Linezolid, is a partial inhibitor of MAO, so can precipitate serotonin syndrome if used w/ other 5-HT agents
64
2 agents effective against VRE
1. Daptomycin: cell wall inhibitor by depolarizing cell membrane, bacteriocidal
2. Linezolid- bacteriostatic, inhibits protein synthesis by binding to 50S to prevent formation of initiation complex
65
Toxicities of Linezolid
Linezolid toxicities
1. Hematologic
- MC thrombocytopenia, also anemia and neutropenia
2. Neuropathy: optic neuropathy and peripheral neuropathy
66
Main indications for Linezolid
Linezolid (bacteriostatic inhibitor of bacterial protein synthesis)
For serious/nosocomal G+ infections
- nosocomial pneumonia
- complicated cellulitis from MRSA or VRE
67
Mechanism of
(a) Aminoglycosides
(b) Ethambutol
Mechanism
(a) Aminoglycosides = bactericidal inhibitors of bacterial protein synthesis
(b) Ethambutol blocks arabinosyl transferase to inhibit carbohydrate formation at the cell wall
68
Mechanism of all RI and E RIPE agents
Mechanisms:
- Rifampin works by inhibit RNA polymerase
- Isoniazid inhibits mycolid acid (cell wall component) synthesis
- Pyrazinamide: mechanism unknown
- Ethambutol blocks arabinosyl transferase, inhibiting carb formation at the cell wall
69
Which class of abx are often coupled w/ cell wall active drugs
Aminoglycosides are actively transported across cell membrane by an O2 dependent process (hence efficacy against aerobic bacteria), but need to get past cell wall first => pair w/ beta-lactam or Vancomycin
70
2 indications of streptomycin
Streptomycin (aminoglycoside- bacteriocidal bacterial protein synthesis inhibitor)
1. tularemia by Francisella tularensis (rabbits)
2. black plague by yersinia pestis
71
Benefit of Amikacin over Gentamycin and Tobramycin
All 3 are aminoglycosides (bacteriocidal bacterial protein synthesis inhibitors)
But Gentamycin and Tobramycin are inactivated by certain acetylation enzymes found in enterococci species => require high doses, while Amikacin is resistant to that enzyme
72
Main toxicities of Amikacin
Amikacin (big gun aminoglycoside) toxicities:
- ototoxicity that often presents as vistibular disturbance: dizziness, ataxia
- nephropathy: ATN- brown muddy fasts
73
2 contraindications to aminoglycoside therapy
1. Pregnancy- can cause ototoxicity (deafness) in newborn
| 2. Myasthenia Gravis b/c aminoglycosides have rare side effect of neuromuscular blockade
74
Main side effects of isoniazid
Isoniazid = INH 'injury to nerves and hepatocytes'
- Peripheral neuropathy (2/2 B6 deficiency), ataxia, paresthesias
- expect asympatomatic rise is aminotransferases
75
Mechanism by which bacteria develop resistance to
(a) Isoniazid
(b) Rifampin
(a) Isoniazid is activated by KatG (catalase peroxidase) made by bacteria, so mutations that downregulate KatG expression confer resistance to isoniazid
(b) Bacteria can mutate their RNA polymerase => Rifampin can't bind
76
What to co-administer w/ isoniazid
Coadminister pyridioxine (vit B6) w/ isoniazid to prevent side effect of periphery neuropathy
77
Describe the effect of RIPE drugs on cyt p450
Isoniazid inhibits cyt p450 => can increase levels of drugs metabolized by cyt p450 (ex: wafarin, AEDs)
While Rifampin is a potent cyt p450 inducer/activator
78
Less common side effects of isoniazid
(a) Autoimmune
(b) pH abnormality
(c) CNS
Isoniazid (inhibit mycolic acid synthesis) less common side effects (aside from peripheral neuropathy and elevated LFTs)
(a) Drug-induced lupus
(b) Metabolic acidosis (MUD PILES)
(c) Seizures
79
What makes isoniazid metabolism clinical relevant?
Isoniazid is metabolized by liver enzyme N-acetyltransferase
-certain ppl are slow acetylators => have increased risk of side effects such as vit B6 deficiency peripheral neuropathy
80
Main side effect of
(a) Rifampin
(b) Ethambutol
Main side effect of
(a) Rifampin therapy = benign orange-red discoloration of body fluids
- urine, sweat, saliva
(b) Ethambutol = optic neuritis => reduced visual acuity and red/green color blindness
81
Side effects of pyrazinamide
Pyrazinamide
- severe hepatotoxicity, can even cause hepatic necrosis
- hyperuricemia, can precipitate acute gouty attacks
82
Main side effect of RIPE therapy
Hepatotoxicity
83
Abx that is associated w/
(a) Red/green color blindness
(b) Red/orange discoloration of body fluids
(c) Increased side effects in slow acetylators
(a) Red/green color blindness 2/2 optic neuritis seen w/ Ethambutol therapy
(b) Red/orange discoloration of urine, saliva, sweat from Rifampin
(c) Isoniazid metabolized by N-acetyltransferase in the liver, so slow acetylators have increased risk of side effects of isoniazid therapy (peripheral neuropathy)
84
Bactrum mechanism
Bactrum = combo drug w/ synergistic activity (bacteriostatic alone, bacteriocidal togther), blocks folate synthesis at two sequential steps
- SMX (sulfa drug) = PABA analog that blocks PABA --> DHF
- TMP blocks dihydrofolate reductase to block DHF --> THF
85
HIV ppx
(a) CD4 200
(b) CD4 100
(c) CD 50
Once CD4 count reaches under
(a) 200- ppx w/ Bactrum against PJP (pneumocystis jirovecii pneumonia)
(b) 100- ppx w/ Bactrum against toxoplasmosis
(c) 50- ppx w/ Azithromycin against MAC
86
Bactrum coverage
(a) First line for what?
(b) Important G pos coverage
(c) Filamentous rod
Bactrum coverage
(a) First line for UTIs (good gram neg coverage), also tx acute prostatitis
(b) Covers MRSA!
(c) Covers nocardia (partially acid fast filamentous rod)
87
Which abx to really avoid alcohol on
Metronidazole 2/2 disulfiram-like reaction: flushing, tachycardia, palpitations, N/V in response to EtOH
88
Teratogenic effects of
(a) TMP-SMX
(b) Fluoroquinolones
(a) Bactrum teratogenic during first trimester due to folate inhibition => increased risk neural tube defects
(b) Fluoroquinolones contraindicated in pregnancy and children under 10 2/2 cartilage damage/arthropathy
89
Use of bactrum in HIV pts
Bactrum used to tx and ppx for PJP (pneumocystis jirovecii pneumonia)
Also bactrum for CD4 under 100 for toxo ppx
90
Main adverse effect of bactrum therapy
Pancytopenia 2/2 folate inhibition
| -can cause megalobalstic anemia
91
General side effects common to all sulfa drugs
- hypersensitivity rxn (2nd MC abx to cause hypersensitivity rxn behind penicillins)
- SJS/TEN risk
- hemolytic anemia in G6PD deficiency
- type IV renal tubular acidosis => hyperkalemia
- interstitial nephritis
- photosensitivity
92
Explain why sulfa drugs have a ton ton of drug interactions
Sulfa drugs do 2 things: (1) inhibit cyt p450 (20 displace drugs from albumin
=> increase in concentration of many drugs (ex: warfarin)
93
Why are sulfonamides contraindicated in
(a) First trimester
(b) Third trimester
Sulfa drugs
(a) Increase risk neural tube defects 2/2 inhibition of folate synthesis
(b) Third trimester- displaces unconjugated bili from albumin => increased risk of kernicterus in neonates
94
Mechanism of fluoroquinolones
Fluoroquinolones are bacteriocidal, inhibit bacterial topoisomerase DNA gyrase => inhibits bacterial replication
DNA gyrase needed to relieve strain during unwinding and replication
95
Tx of complicated vs. uncomplicated UTI
Uncomplicated UTI- tx w/ Batrum (good G- coverage)
Complicated UTI first line is fluoroquinolones (ciprofloxacin)- complicated meaning in diabetic pt or pt w/ h/o urinary obstruction b/c want to cover for pseudomonas
96
Empiric tx for pyelonephritis
Pyelonephritis empiric tx = ciprofloxacin (fluoroquinolone, inhibits DNA gyrase to inhibit bacterial DNA replication)
97
Main indication for fluoroquinolones
Fluoroquinolones have great gram negative coverage
- GI gram neg bacilli: Shigella, Salmonella, E. Coli, campylobacter
- complicated UTI and pyelonephritis b/c pseudomonal coverage
- Gram neg osteomyelitis b/c good bone penetration: specifically salmonella osteo in SCD
98
Gram positive coverage of fluoroquinolones
Fluoroquinolones (ciprofloxacin) covers bacillus anthracis (necrotizing, hemorrhagic pneumonia)
99
Name the respiratory fluoroquinolones
(a) Indications
Respiratory fluoroquinolones = Levofloxacin and Moxifloxacin
(a) community acquired pneumonia (S. pneumonia) and atypical pneumonia (mycoplasma and legionella)
100
Two classes of abx that shouldn't be taken with milk
Both fluoroquinolones (Cipro, levofloxacin, moxifloxacin) and tetracycline absorption are inhibited by divalent cations (Mg, Ca, Fe) => leave a few hours btwn drug and drinking milk
101
Two classes of abx that can prolong QT interval
Both fluoroquinolones (Cipro, levofloxacin) and macrolides (Azithromycin, Clarithrymycin) can prolong QT => increase risk of Torsades
102
Rare but specific side effect of fluoroquinolones
Fluoroquinolones (cipro, levofloxacin, moxifloxain) carry risk of tendon damage/rupture and cartilage damage/arthropathy
-esp in elderly and pts on chronic steroids
103
Metronidazole
(a) Main indication
(b) 2 protozoa
Metronidazole
(a) Polymycrobial anaerobic infxns (ex: intraabdominal), vaginitis from Trich, BV by gradnerella
- "clindamycin for anaerobes above the diaphragm, metronidazole for anaerobes below the diaphragm"
(b) 2 protozoa: entamoeba histolytica and Giardia
104
2 female GU indications of Metronidazole
Metronidazole for tx of
1. vaginitis/cervicitis from Trichomonas
2. bacterial vaginosis from gardnerella
105
Triple therapy H. pylori regimen for pt w/ Penicillin allergy
H. pylori regular triple therapy: PPI, Amoxillin, Clarithrymycin
Amox allergy => can replace amox w/ metronidazole
106
Mechanism of
(a) Zidovudine
(b) Ritonavir
(c) Efaverenz
Mechanism
(a) Zidovudine = prototype NRTI
(b) Ritonavir = protease inhibitor 'navir'
(c) Efaverenz = NNRTI (non-nucleoside reverse transcriptase inhibitor)
107
Mechanism of
(a) Lamivudine
(b) Navirapine
(c) Maraviroc
Mechanism
(a) Lamivudine = NRTI (like Emtrictiabine, Zidovudine, stavidine, didanosine)
(b) Navirapine = NNRTI
(c) Maraviroc = entry inhibitor by binding CCR5
108
Mechanism of
(a) Enfuvirtide
(b) Raltegravir
(c) Indinavir
Mechanism
(a) Enfuvirtide = fusion inhibitor, binds pg41
(b) Raltegravir = integrase inhibitor
109
3 groups of cells invaded by HIV
HIV infects
1. CD4 T cells
2. Macrophages
3. Dendritic cells
110
Relevance of HIV env gene
(a) Env mutations infer mutations against what?
HIV env gene codes for gp41 and gp120 surface glycoproteins
-first gp120 binds CCR5 and CXCR4 for viral entry, then gp41 facilitates HIV fusion
(a) So env mutations => resistance against entry inhibitors (Maraviroc- bind CCR5 to prevent gp120 binding) and fusion inhibitors (Enfuvirtide- binds gp41)
111
HIV proteins (and the genes that encode them) responsible for
(A) Entry
(b) Fusion
(c) Integration
HIV proteins
(a) Entry by gp120 coded for by HIV env gene
(b) Fusion by gp41 also coded for by HIV env gene
(c) Integration by integrase coded by HIV pol gene
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Relevance of HIV pol gene
(a) Pol mutations infer mutations against what?
HIV pol gene codes for: reverse transcriptase, integrase, protease
(a) Pol mutation can confer resistance to NRTI (Zidovudine), NNRTI (Nevirapine), integrase inhibitor (Raltegravir) and protease inhibitors (Indinavir, Ritonovir)
113
Which HIV drug most directly prevents the transcription of HIV mRA?
HIV mRNA only made once cDNA has been incorporated into the host genome, so integrase inhibitors most directly inhibit mRNA transcription
Integrase inhibitor = Raltegravir
114
3 key enzymes coded for by HIV pol gene
HIV pol gene codes for
1. reverse transcriptase
2. integrase
3. protease
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Mechanism of NRTIs
NRTI = nucleoside reverse transcriptase inhibitors work as competitive inhibitors of RT
-these nucleoside/tide analogues lack 3' OH end needed for 3' to 5' phosphodiester bond => causes premature chain termination halting DNA synthesis
Nucleoside analogues require intracellular phosphorylation for activation
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Mechanism of NNRTIs
NNRTI = non-nucleside reverse transcriptase inhibitors
Bind directly to HIV reverse transcriptase => allosterically inhibiting RT to half DNA polymerase
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Contrast activation of NRTI and NNRTI
NRTI = nucleoside analogues that cause premature chain termination
-nucleosides require intracellular phosphorylation for activation
NNRTI = allosteric inhibition directly of DNA polymerase
-no intracellular activation required
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NRTI SEs
(a) pH disturbance
(b) Neuro finding
NRTI SEs
(a) Lactic acidosis
(b) Peripheral neuropathy: esp Lamivudine, Stavudine, Didanosine
119
Differentiate both NRTIs: Lamivudine and Tenofovir
Lamivudine is a nucleoside => requires intracellular phosphorylation for activation
While Tenofovir is a nucleotide => doesn't require any activation
Both Lamivudine and Tenofovir (NRTIs) are used in to tx Hep B
-recall Hep B has reverse transcriptase but isn't a retrovirus b/c doesn't integrate into host genome
120
Which NRTI is first line during pregnancy to reduce risk of HIV vertical transmission?
Zidovudine = NRTI given to pregnant F to reduce risk of vertical transmission
-can be taken regardless of viral load/CD4 count
121
Risk to mother of ZIdovudine therapy
Zidovudine = NRTI given to pregnant F to reduce risk of vertical transmission
-can be taken regardless of viral load/CD4 count
But carries real risk of myeosuppresion => granulocytopenia, anemia
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Which NRTI is known for causing
(a) Dose dependent pancreatitis
(b) Delayed hypersensitivity rash
(c) Hyperpigmentation of hands and soles
NRTI associated w/
(a) Dose dependent pancreatitis = Didanosine
(b) Delayed type IV hypersensitivity rash = Abacavir
(c) Hyperpigmentation of hands and soles = Entricitabine
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Main AE of NNRTI therapy
NNRTI therapy main SE = liver failure
- can occur w/in 6 weeks of starting therapy
- can be pretty severe, even fatal
124
Which class of antiretrovirals requires intracellular activation?
Only NRTIs that are nucleosides require intracellular activation by phosphorylation
So NRTIs that are nucleotides (tenofovir), NNRTI, protease inhibitors etc don't require activation
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Mechanism of protease inhibitors
Protease inhibitors inhibit proteases encoded for by DNA pol gene taht are required for cleavage of precursor polypeptide molecule needed to form a mature virion
So protease inhibitor causes virion to remain immature
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MC SE of protease inhibitors
SE of protease inhibitors = metabolic
- hyperglycemia 2/2 insulin resistance
- dyslipidemia
127
How to avoid interaction btwn Rifampin and protease inhibitors?
Rifampin is a potent cyt p450 activator, while protease inhibitors are metabolized by cyt p450 and also activate cyt p450
So Rifampin reduces the concentration of protease inhibitors so use together is contraindicated
-use Rifabutin instead = same mechanism of Rifampin w/ less cyt p450 induction
128
Backbone of ART
NRTIs
Usual initial therapy is 2 NRTIs w/ one additional drug
129
What stimulates endogenous interferon release?
(a) From what cells?
Interleukin signals from infected cells cause release of interferon (a) from virally infected cells
130
Indications for tx w/
(a) IFN-beta
(b) IFN-gamma
(a) IFN-beta used in tx of relapsing-type MS
(b) IFN-gamma to reduce recurrent infxns in chronic granulomatous disease (NADPH oxidase deficiency => defective oxygen-dependent killing)
131
Indications for IFN alpha therapy
(a) Main
(b) 3 malignancies
IFN alpha
(a) Used in tx of hep B and hep C
(b) 3 malignancies
1. malignant melanoma
2. Hairy cell leukemia
3. renal cell carcinoma
132
How to define success in tx of Hep C
No detectable HCV RNA for 6 months after stopping therapy = sustained virologic response
So SVR = goal of HCV therapy
133
Ribavirin mechanism of action
Ribavirin (used int traditional HCV tx) is a guanosine nucleoside analog
-requires intracellular phosphorylation before active
134
Ribavirin main indication
(a) Old indication
(b) Main side effect
Ribavirin = guanosine nucleoside analogue requiring intracellular phosphorylation
(a) Used in traditional tx regimen for Hep C (w/ interferon alpha)
(b) Main side effect = dose dependent hemolytic anemia
135
Mechanism of Hep C drugs
(a) Sofosbuvir
(b) Simeprevir
Hep C drugs: traditional regimen of weekly pegylated interferon-alpha w/ daily ribavirin (guanosine nucleoside analogue)
Newer drugs
(a) Sofosbuvir = nucleoside analog that directly inhibits RNA production (directly inhibits RNA polymerase)
(b) Simeprevir = NS 3/4A protease inhibitor
136
Mechanism of acyclvoir
(a) How do they specifically target virally infected cells
Acyclovir = guanosine nucleoside analogue that halts viral DNA polymerase
(a) Only infects HSV infected cells b/c only hepatitis virus codes for the viral thymidine kinase needed for first phosphorylation (activation) step of acyclovir
- hence why acyclvoir isn't effective against CMV (CMV doesn't code for the necessary thymidine kinase)
137
Mechanism by which herpes strains can become resistant to acyclovir
If herpes virus mutates its thymidine kinase then it won't phosphorylate acyclovir => resistant
138
Drug of choice for
(a) Daily suppressive therapy for HSV
(b) HSV encephalitis
Drug of choice
(a) Valacyclvoir for HSV suppressive therapy in ppl w/ multiple yearly recurrence
- use val b/c better oral bioavailability
(b) HSV encephalitis- use IV acyclovir
139
2 drugs that can tx acyclovir-resistant strains of HSV
HSV can become resistant to acyclvoir by mutating its thymidine kinase => acyclovir can't get activated
So instead use Cidofovir or Foscarnet- which don't require phosphorylation by viral kinase => are active against both acyclovir and ganciclovir resistant strains of HSV, CMV, VZV
140
Mechanism of valacyclovir
Valacyclovir = pro-drug of acyclovir w/ better oral bioavailability
So same mechanism of acyclovir = guanosine nucleoside analogue requiring phosphorylation by HSV thymidine kinase first then two more phosphorylations by cellular kinases
Just better oral bioavailability than acyclvoir (b/c prodrug) but same mechanism
141
Interstitial nephritis
(a) Which anti-viral
(b) Which anti-bactierial
Interstitial nephritis = inflammation of the renal interstitium characteristic side effect of
(a) IV acyclovir
(b) Penicillins
142
Traditional tx regimen for Hep C
(a) Now what?
Traditional regimen = weekly pegylated interferon alpha w/ daily ribavirin
(a) But now we have protease inhibitors (SImeprevir) and polymerase inhibitors (Sofosbuvir) so trying to move towards interferon/ribavirin-free regimens
143
2 things to do before choosing treatment regimen for Hep C
1. Genotype the strain of Hep C
| 2. Indirectly (aka clinically, not w/ liver biopsy) degree of liver fibrosis
144
HIV pt noncompliant w/ meds p/w retinal infiltrates and retinal hemorrhage- most likely dx?
(a) Drug of choice
Dx = CMV retinitis, esp if CD4 under 50
| a) Tx w/ either IV ganciclovir or valganciclovir (better oral bioavailability w/ same efficacy
145
Mechanism of ganciclovir
Ganciclovir (like acyclovir) is a guanosine nucleoside analog
- first step of activation (first phosphorylation) is catalyzed by CMV-encoded viral kinase
- next two phosphorylations by host cellular kinases
So only active in CMV-infected cells b/c requires CMV-encoded viral kinase for first activation step
146
What differentiates acyclovir and ganciclovir?
Acyclvoir and ganciclovir are both guanosine nucleoside analogs that require 3 phosphorylations before are active to be incorporated into DNA synthesis (and therefore able to inhibit DNA polymerase)
Acyclovir requires activation by thymidine kinase encoded by HSV, while ganciclovir requires activation by viral kinase encoded by CMV (so they both only are active in cells infected by HSV and CMV respectively)
147
Who should get HSV ppx?
(a) Drug of choice
HSV ppx for mothers w/ active genital lesions to prevent vertical transmission, also in in high-risk immunocompromised or organ transplant pts
(a) Oral valayclovir daily
148
Who should get CMV ppx?
(a) Drug of choice
CMV ppx for solid-organ and bone marrow transplant pts, also some HIV pts w/ CD4 under 50 (risk of CMV retinitis, colitis, esophagitis)
(a) Valganciclovir b/c better oral bioavailability than ganciclovir
149
Main side effects of acyclovir and ganciclovir
Acyclovir- interstitial nephritis or crystalline nephropathy
Ganciclovir- bone marrow suppression
150
Danger of giving HIV pt on Zidovudine ganciclovir tx for CMV retinitis
Both Zidovudine (NRTI) and ganciclovir cause bone marrow suppression- additive bone marrow suppression when given together
151
Mechanism of Foscarnet vs. Cidofovir
(a) Main indication
Foscarnet and Cidofovir both directly inhibit viral DNA polymerase (don't require any phosphorylation/intracellular activation like acyclovir/ganciclovir)
(a) Use to tx acyclovir-resistant HSV strains and ganciclovir- resistant CMV striains
152
Which antiviral should be coadministered w/ Probenecid
Probenecid blocks tubular secretion of Cidofovir (direct viral DNA polymerase inhibitor) to reduce nephrotoxic effects
Probenecid also prevents excretion (and therefore increases plasma concentration) of tons of drugs: MTX, PCN, NSAIDs
153
Main side effects of the two drugs that are effective against acyclovir resistant HSV
Foscarnet and Cidofovir directly inhibit viral DNA polymerase => are active against acyclovir-resistant RSV and ganciclovir-resistant CMV
Main SE:
- Foscarnet: renal insufficiency and electrolyte disturbances that can lead to seizure
- Cidofovir: nephrotoxicity, reduce by coadministering w/ Probenecid
