Antibiotics I and II Flashcards
1
Q
Cell Wall Synthesis Inhibitors
A
- Beta Lactams
- Vancomycin
2
Q
Bacteriostatic Abx
A
Erythromycin (macrolides)
Clindamycin
Sulfamethoxazole
Trimethoprim
a
Tetracyclines
i
Chloramphrenicol
3
Q
Bactericidal Abx
Really Very Fine At Bug Murder
A
- Rifampin
- Vancomycin
- Fluroquinolones
- Aminoglycosides
- Beta Lactams
- Metrondiazole
4
Q
Beta Lactams
A
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams (Aztreonam IV)
5
Q
Three Phases of Cell Wall Synthesis
A
- Cytosolic Phase - make the precursuor sugars
- Membrane - synthesize disaccharide building blocks
- External Phase - synthesize and cross link the strands
C Me, Feel Me, Touch Me, Hear Me……
6
Q
External Phase and Action of Abx
A
- gucosyltransferase (peptidoglycan synthetase) polymerizes disacchardies to make polysaccharide backbone
* Blocked by Vancomycin - Peptidoglycan transpeptidase (PBP) creates Gly cross-links
- Blocked by B-lactams - all bind to PBP
- implication is only active when the cell wall is being syntheized (growing bacteria)
7
Q
Penicillins
A
- Penicillin G (IV) and Penicillin VK (PO)
- Nafcillin (IV)
- Dicloxacillin (PO)
- Amoxicillin and Augmentin
- Ampicillin and (Amp/Sub)
- Piperacillin (Pip/Tazo)
8
Q
Cephalosporins
A
- Cefazolin - IV(1st)
- Cephalexin - PO (1st)
- Ceftriaxone - IV (3rd)
- Ceftazidime - IV (3rd)
- 5 generations. successive generations have increased Gram -ve activity, and less Gram +ve activity
9
Q
Carbapenems
A
- Imipenem
- Meropenem
10
Q
Monobactams
A
Aztreonam
11
Q
Beta Lactam - Mechanism of action
A
- Binds PT and it is irreversible covalent bond (looks like D-ala/D-ala of subtrate)
- Cell wall is defective. A lytic enzyme attempts to repair it and gets overly activated, causing cell lysis
12
Q
B-Lactam Resistance Mechanisms
A
- Physical Barrier - have an outer cell membrane (gram negative)
- Mutant Porin - some B-lactams can go through outer cell membrane through porins, so mutate those
- Efflux Pump - pump the b-lactams out of cell
- Inactivation - Beta-lactamases bind and inactivate (e.g., penicillinases, B-lactamases)
- mutate transpeptidase-PB-2a (MecA gene) does not bind B-lactams (MRSA)
13
Q
Penicilln G and VK
A
- susceptible Gram +ves aerobes and anerobes
- strep., meningococci, enterococci, oral anerobes, syphilis
- inactivated by gastric acid
- poor penetration into the CNS
- renal secretion into the proximal tubule (Vd is small)
14
Q
Adverse Effects of Penicillin
A
- direct tox. is low
- kills good gut bacteria (acidophilus prevents)
- superinfection (c. diff.)
- colitis
- thrombophlebitis
- CNS - tremors/convulsions (high doses)
- hypersensitivity
15
Q
Penicillin Hypersensitivity
A
- overdiagnosed, prevalence 1%
- Classification
- Immediate (0-30 minutes) acute anaphylactic reaction
- Accelerated (1-72 hrs) - similar to immediate, but milder. hypotension and death are rare
- Delayed (3-30 days) - usually self-limiting involving skin reactions BUT Stevens-Johnson Syndrome (mild form of TEN)
16
Q
Penicillinase Resistant Penicillins
A
- use with penicillinase producing strains of of gram +ve (Strep. and MSSA)
- Nafcillin (IV) - variable GI absorption, excreted via bile, not kidney
- Dicloxacillin (PO QID) - skin infections
17
Q
Extended Spectrum - Aminopenicillins
A
- Amoxicilln (PO TID or BID) -
- gram +ve and -ve organims
- H. influenzae, E. coli, Listeria, Proteus mirabilis, Salmonella, Shigella, enterococci
- acid-stable, well absorbed
- Better GI absorption, can give with food
- rare, non-allergic rash
- GI distress and diarrhea
- Ampicillin (PO QID IV) -
- more GI distress
- delayed hypersensitivity reactions and non-immune skin reactions
18
Q
Extended Spectrum Antipseudomonal Penicillins
A
Piperacillin
- must be IV or IM (bug usually from ventilator anyway)
- plasma concentrations not proportional to dose
- sensitive to B-lactamases
19
Q
Penicillin + B-lactamase inhibitor
A
- Amoxicillin/Clavulanic Acid (Augmentin)
- Ampicillin/Sulbactam
- Piperacillin/Tazobactam
- clavulanic acid - suicide inhibitor of B-lactamase
- only inhibits some types of B-lactamases
20
Q
Cephalosporins - Resistance/Suscep.
A
- Resistant to penicillinase
- Gen. 1-2 inactivated by “broad spectrum” B-lactamases
- Gen 1-3 inactivated by extended spectrum B-lactamases (ESBLs)
- Gen 1-4 do not bind PB2a (MRSA)
21
Q
Cephalasporins - Phys Disp.
A
- Gens 1 & 2 - poor CNS penetration
- Gen 3 - good CNS penetration
- well absorbed orally, not affected by food
- t1/2 of 0.5-2 hours
- excreted mostly by kidney (probenicid delays renal tubular secretion)
22
Q
Cephalosporins - Adverse Effects
A
- Hypersensitivity - cross-reactivity with other cephalosporins and with penicillins (cautious use with those who have a mild/moderate allergy to penicillin)
- mild nephrotoxicity - enhances nephrotoxicity of aminoglycosides
- thrombophlebitis with IV
- diarrhea
- superinfection
23
Q
Cephalosporins - Gen I
A
- primarily for gram +
- skin, soft tissue infections
- Cefazolin (IV) - often preferred for surgery prophylaxis. penetrates most tissues, excreted by kidney and has longer 1/2 life
- Cephalexin (PO) - similar spectrum of activity to cefazolin
24
Q
Cephalosporin - Gen 3
A
- Reserved for very serious polymicrobial infections
- often used with an aminoglycoside
- susceptible to extended spectrum B-lactamases
- Ceftriaxone (IV) - good CNS penetration; gonorrhea, Lyme disease (severe) and meningitis
- Ceftazidime (IV) - t1/2 is 1-2 hours. Penetrates CNS and has good activity against Pseudomonas (turns on a dime)
25
Carbapenems
Imipenem-cilastatin & Meropenem -
* broadest activity of all antibiotics
* Most gram + and - rods
* Pseudomonas
* reserved for very serious polymicrobial infections
* resistant to many ESBLs
26
Imipenem/Cilastatin
* no oral absorption
* rapidly hyrdolyzed by renal enzyme dihydropeptidase I
* cilastatin (inhibitor of dihydropep I)
* renal excretion - modify dose for patients with renal insufficienty
27
Meropenem
* similar to imipenem
* not hydrolyzed by dehydropeptidase I
* cilastatin not required
28
Monobactams
Aztreonam (only one we need to know)
* restistant to beta lactamases
* gram -ve bacteria (aerobic rods)
* good activity against entero and Pseudomonas
* 2nd line to aminoglycosides
* hypersensitivity rxns, but little cross-reactivity
* thrombophlebitis at IV site
29
Vancomycin - General
* A glycopeptide
* Only kills gram +
* inhibits glucosyltransferase (PS) that adds dissaccharide subunit to growing sugar polymer
* does this by binding to terminal D-ala-D-ala residues to inhibit GT
* Resistance: terminal D-Ala mutated to D-lactate
* reserve for MRSA/C. diff
* IV unless for C. Diff (then oral)
* excreted by kidney 90%
* long t1/2 in anephric patients
30
Vancomycin - Adverse Effects
* irritating to tissues (thrombophlebitis)
* chills, fever
* ototoxicity (large doses or other otoxin)
* flushing (red man syndrome - rapid infusion)
* nephrotoxicity at highter doses
31
What do we have for Vancomycin resistance?
Linezolid - protein synthesis
Daptomycin - membrane depolarizer (pore former)
32
Oxazolidinone - Linezolid
* Gram +
* very limited indications (2nd/3rd line) when vancomycin is contraindicated
* unique mechanism of action (no cross-resistance) blocks initiation of protein synthesis
* binds to 23s RNA of 50s subunit
* prevents formation of the 70s complex
* inhibits protein synthesis
33
Linezolid - Resistance
* due to mutation in the 23s RNA
* reported for enterococci
* agent of last resort!
34
Linezolid - Phys Disp
- oral and parenteral - can give with food
- metabolized in liver, excreted in urine
(no need to adjust for renal patients)
35
Linezolid - Adverse Reactions
* nausea, vomiting, diarrhea, headache, rash
* myelosuprpresion
* oral contains phenylalanine
* peripheral and optic neuropathy with prolonged use (reversible)
36
Linezolid - Drug Interactions
* mild inhibitor of MAO - hypertension if taken with foods rich in tyramine
* watch SSRIs and drugs with pseudophedrine
* No interactions with Cyp3A4 or others
37
Cyclic Lipopeptide - Daptomycin
* Gram +ves
* very limited indications (3rd/4th line) - only when vancomycin and linezolid are contraindicated
38
Daptomycin - Mechanism
* needs Ca2+
* targets cell membrane by oligomerizing with Ca2+ and forms pores in membrane that allow K+ to leave
* cell death
39
Daptomycin - Clearance and AE
* excreted unchanged in urine (need to adjust for renal pts)
* IV only
* muscle weakness (no with statins)
* fever, headache, insomnia dizziness, rash
40
What are the alternatives to wall agent abx?
* Protein synthesis (translocation) inhibitors
* Macrolides (gram +/-)
* erythromycin
* clarithromycin (PO)
* Azithromycin (PO, IV)
* lincosaminde (anaerobes)
* clindamycin (PO, IV)
* DNA breaker
* Nitroimidazole (anaerobes)
* Metronidazole (PO, IV)
41
What are the Macrolides?
* Clarithromycin (PO)
* Azithromycin (PO, IV)
* Erythromycin - Don't use
42
Nitroimidazole-Metrondiazole
* used for anerobes and C. diff bowel surgery
* flagyl is trade name
* disrupts DNA by forming covalent bonds that fragment DNA
* resistance - has reduced levels of nitroreductase
43
Lincosamide - Clindamycin
* PO or IV
* most +ve aerobes
* most +ve and -ve anerobes (oral\>bowel)
* Can be used for MRSA
44
Clindamycin - Resistance and Phys. Disp.
* If you are resistant to clindomycin, you are resistant to macrolides. converse not necessarily true
* oral and parenteral
* no CNS penetration
* metabolized by liver (watch in severe hepatic disease)
45
Clindamycin - AE
* diarrhea, nausea
* Pseudomembranous colitis (usually C. diff. which is resistant to clinda)
* potentially fatal
* treated with oral metronidazole or oral vancomycin or fecal transplant
46
Macrolide-Azithromycin
* penetrates tissues well and stays there
* t1/2 3 days
* food and antacids decrease bioavailability
* no CYP-450, so no drug-drug
* cross-resistance with erythromycin
47
Macrolide-Clarithromycin
* more stable to acid than eryth
* metabolized by liver (dosage reduced for hepatic pts)
* eliminated by kidney (dosage reduction for renal pts)
Adverse Effects
* high doses reversible hearing loss
* teratogenic - no in pregnancy or kids
* inhibits CY34A (drug-drug interaction)
48
Macrolides - Mechanism
* Inhibit Protein Synthesis
* premature release of polypeptides by preventing translocation
* Gram +ve cocci and bacilli
* inactive against mot gram -ve bacilli
* allergy to penicillin alternative
49
What is MLS resistance?
* MLS: Macrolides, Lincosamides and Streptogramins
* add methyl group to the biding site on the 50s ribosome = resistance to all
50
Protein Synthesis Inhibitors (Class)
Tetracyclines
Aminoglycosides
51
Urinary Tract Antiseptics
Nitrofurantonin
52
DNA Synthesis Inhibitors (Class)
Antifolates
Flruoquinolones
53
Protein Synthesis - Process
* f-met binds to 30s and then 50s binds ftmet in P-site
* makes a 70s ribosome
54
Translation and the Ribosome - Process
1. aminoacyl-tRNA binds to a vacant A-site and proofreading checks if base pair is correct
2. a. Peptide bond is formed (PT) b. aminoacyl-tRNA moves to P-site (translocation)
3. spent tRNA is ejected from E-site. ribosome resets
55
Buy AT 30, CCELL at 50
30s inhibitors
A=aminoglycosides
T=tetracyclines
50s
C=clindamycin
C=chloramphenicol
E=erythromycin
L=lincomycin
L=linezolid
56
Tetracyclines (abx you need to know)
* doxycycline
57
Tetracyclines - Mechanism of Action
* usually enter cell due to passive diffusion
* accumulates in bacteria, eukaryotes don't
* binds REVERSIBLY to the 30s
* blocks binding of the aminoacyl-tRNA to A site
* prevents addition of aa's
58
Resistance to Tetracyclines
3 mechanisms:
1. Efflux pumps
* TET(AE) efflux pump in gram -ve (DoxyR/TigS)
* TET(K) pump in staph (DoxyS/TigS)
2. 30s Ribosome protection
* TET(M) in gram +ve (DoxyR/TigS)
3. enzymatic inactivation by organism (acetylation)
NB: Tigecycline does not usually share cross-resistance
59
Tetracyclines - Coverage
* bacteriostatic
* gram +ve and -ve organisms
* NO to pseudomonas, proteus
* seldom first line, except Doxy:
* atypical pneumonia (mycoplasma)
* NGU (chlamydia)
* Rocky Mountain spotted fever
* lyme disease
60
Doxycycline - Properties
* BID oral or IV
* low renal clearance
* longer t1/2
* wider activity
61
Tetracyclines - ADME
* Doxycycline - 95-100% absorbed (can be taken with food) - longer 1/2 h=life
* Absorption impaired by divalent metals (chelate)
* distributed widely in bones and teeth, not in CSF (except Mino)
* Doxy eliminated by non-renal, so safest for renal pts
*
62
Tetracyclines: Toxicities
* modification of gut microflora
* superinfection (C. diff, staf, pseudomonas)
* Doxycycline at higher doeses produces vestibular dysfunction
* short shelf life - expired drugs cause renal tubular acidosis (Fanconi syndrome)
* tooth discoloration - no for kids less than 8
* impair bone growth in developing fetus
63
Aminoglycosides (ones you must know)
* gentamicin
* tobramycin
64
"mean" GNATS can NOT kill anaerobes
NOT - nephrotoxic, ototoxic, teratogen
GNATS - gentamicin, tobramycin (among others)
65
Aminoglycosides - Mechanism
binds 30s subunit
* blocks initiation of synthesis
* blocks A-site loading
* causes incorporation of incorrect aa
* impairs proofreading
* evidence suggests alteration to increase permeability and leaking of conents
* likes to stick to membranes
* **needs O2 to get accross membrane and uses H+ pump - low extracellular pH inhibits**
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