Lecture 5: Microbiology -- Antibacterial Drugs 2

Front 1

Basic idea of:

inhibitors of cell wall synthesis

Back 1

No cell wall --> osmotic lysis --> cell death

Front 2

What types of bacteria are resistant?

Specify 2

Back 2

L-forms of bacteria -- have no cell wall
Ones in the kidney -- osmotic pressure is HIGH so they don't get lysed!

Mycoplasma, and ..?

Front 3

Cell Wall Synthesis:

carrier compound?
major enzyme?

Back 3

isoprenyl-phosphate
peptidoglycan synthase: catalyzed crosslinking (transpeptidation) of peptidoglycan strands by connecting D-ala with 3rd AA of other strand

Front 4

Bacitracin -- does what?

Back 4

Binds isoprenyl phosphate -- can't carry peptide

Front 5

Vancomycin -- does what?

Back 5

inhibts peptidoglycan synthazse from growing chain

Front 6

beta-Lactams:

mech? similar to what? resistance how?

Back 6

Inhibit transpeptidation rxn via binding penicillin-binding proteins (PBPs), of which many many exist

they are structurally similar to D-ala dipeptide?

resistance via production of beta-lactamases which break the beta-Lactam ring

Front 7

Penicillins: from Fleming, 1928

Mech:

Static/Cidal?

Selective why?

Back 7

Beta-lactam
Mimics D-Ala-D-Ala strucutre of pentapeptide of peptidoglycan, competitively tying up transpeptidase (PBP)

Cidal

All beta-lactams inhibit cell wall syth, which doesn't effect euks

Front 8

Generic Structure of Penicillin:

overview
name parts (2)

Back 8

Two rings, one with carboxylic acid = Thiazolidone Ring (5 members)

And one with C=O and amidase which is Beta-Lactam Ring (4 members) which has beta-lactamase activity

Front 9

Penicillin resistance via?

Back 9

beta-lactamase produced by bacteria: causes penicillin to change so it doesn't look like D-ala-D-ala

does this by hydrolyzing it into di-carboxylic acid

Front 10

Penicillin G

spectrum?
good for?

Back 10

Natural penicillin
1st Gen

Narrow Spectrum

Staph. aureus: Good for Gram + non-beta-lactamase but not for Gram + with beta-lactamase (99%)

Streptocuccus Group A: good

Only good for a few gram negative, pretty bad though.

summary: Strep Group A, Gram pos staph aureus w/o resistance (rare)

Front 11

Cloxacillin

type, good for what?
spectrum narrow or broad? what can't it help?

MRSA?
name another drug in this category

Back 11

Anti-staphylococcal Penicillin = beta-lactamase resistant

Good for: staph. aureus +beta-lactamase

MRSA resistant to it though -- b/c it changes PBPs affinity for beta-lactam, so it doesn't try to change the drug just the body rxn to it. MRSA is resistant to ALL beta-lactams!

narrow spectrum -- **useless for gram negatives

another drug -- Methylcyline

Front 12

Which drugs good for streptococci?

Back 12

All of these beta-lactamases are, even non-resistant typs like Penicillin G

Front 13

Ampicillin

type, good for what?
spectrum narrow or broad?
another drug is category?

Back 13

Amino-penicillin, like amoxicillin

*Good for Gram negative E. Coli, H. influenza -- which are non-beta-lactamase bugs

*Bad for Gram negative Pseudomonas aeruginosa

*No good for beta-lactamase positive strains of staph. aureus

broader spectrum

Front 14

Piperacillin

type, good for what?
spectrum narrow or broad?

Back 14

anti-pseudomonal penicillin

*Good for Gram negative Pseudomonas aeruginosa

and for E. Coli and other gram-negs

pretty bad for +beta-lactamases

extended spectrum

Front 15

Can Gram positive or Gram negative bacteria produce beta-lactamase for resistance?

Back 15

both!!! more common in positive though

Front 16

MRSA resistance mech

Back 16

production of altered PBPs with low affinity for ALL beta-lactam drugs

Front 17

Penicillin Spectrum overview:

Natural Penicillin
Anti-staph Penicillin
Amino-Penicillin
Anti-Pseudomonal Penicillin

Back 17

All work on Streptococci and on Gram Positive non-resistant Staph. In addition:

Natural -- only Gram Postitive nonresistant
Anti-Staph -- All Gram positive including resistant Staph.
Amino -- Gram Negative E. Coli but not Gram Negative Pseudomonas. No help to resistant Gram Positive
Anti-Pseudo -- only one to work for Gram Neg Pseudomonas; also works for E. Coli

Front 18

Clinical Use:

for Streptococcus pneuomiae which causes? (4)

for what else? one other bug with two diseases and then two other diseases

Back 18

pneuomnia, meningitis, otitis media, bacteremia

Haemophilus influenza which causes meningitis and epiglottitis

STDs -- syphilis

UTIs

Front 19

Penicillin Resistance Mechs: (4)

Back 19

beta-lactamases

altered PBPs (MRSA)

altered porins (gram neg)

enhanced efflux pump mechs

Front 20

PK:
absorption
distribution
metabolism
excretion

Back 20

A - oral or non-oral
D - no CNS entry due to BBB; unless meningitis present which breaks epithelial TJs and allows CSF entry
M - none
E - Renall; **short half-life

Front 21

Penicillin Toxicity:

Back 21

nontoxic overall

renal sometimes

*Hypersensitivity rxs*

Front 22

Rough Half Life of:

Pen G (IV) vs. V (oral) vs. G (oral)

RF?

Back 22

Pen G < V < G.oral -- but all between 1-2 hrs

note -- prevention of rheumatic fever via benzathine pen G which has longer half life

Front 23

Penicillins are Time:

independent drugs?
dependent drugs?

Back 23

DEPENDENT! -- concentrations in blood must be maintained long enough to inhibit cell wall synth and kill all bacteria

so continuous infusions needed since concentration goes down quickly

Front 24

Cephalosporins:

Mech
Selectivity

Back 24

Mech -- same as penicillins

sel -- resistant to beta-lactamases breaking down drug.

there are specific cephalosprinases that break the beta-lactam ring of cephalosporins down

Front 25

How many generations of Cephalosporins are there?

Trends from oldest to most recent:
wrt gram pos/neg/pseudmonals

Back 25

4 generations

Over time:
Increase Gram Neg Activity
Decrease Gram Pos Activity (esp. for staphylococcus)
Increase Spectrum
Increase anti-pseudomonal activity mostly (except ceftriaxone)

Front 26

Cefalozin:

which generation?
Effective for what type of orgs?

Back 26

1st gen, therefore good for Gram Positive (and some gram neg)

Front 27

Second Gen... no specific drugs

Back 27

better at gram negatives like H. influenza

Front 28

Ceftazidime:

which generation?
Effective for what type of orgs?

Back 28

3rd generation

especially effective for Pseudomonas

Front 29

Ceftriaxone:

which generation?
Effective for what type of orgs?
excretion?

Back 29

3rd gen

exception to the rule: not effective against pseudomonas

but still greater gram neg activity
biliary + rental excretion

Front 30

Cefepime

which generation?
Effective for what type of orgs?

Back 30

4th Gen
effective against pseudomonas
resistance to beta-lactamase breakdown
best one of all ceph's for Gram Neg

Front 31

Cephalosporins:

PK (ADMET)

Back 31

PK similar to penicillin generally

A -- oral and pareteral (non-oral); 3rd/4th IV
D -- Wide: 3/4th cross BBB itno CSF
M -- none
E -- Renal. Ceftriaxone biliary too.
T -- non-toxic, except hypersensitity cross-sensititivy with penicillin

Front 32

Carbapenems:

name one:
when used? exception?

Back 32

Imipenem
"Restricted Agent" only used for nosocomial infections
*esp. Pseudonomas
exception -- Ertapenem

Front 33

Imipenem:

spectrum
mech
effected by beta-lacatamases how?

Back 33

Broad -- pos/neg
Binds PBPs of Gram Negative Bacteria

not effected by them- stable. Exception: carbepenemases = extended spectrum beta-lactamases (ESBLs)

Front 34

carbepenemases

Back 34

extended spectrum beta-lactamases (ESBLs) that cause resistance to Imipenem/carbapenems

Front 35

carbapenem PK: absorption?

Back 35

IV only!

Front 36

Monobactams:
ex of one:

Back 36

Aztreonam

Front 37

Aztreonam

type:
used against?
rxn to resistance?
PK -- absorption?

Back 37

monobactam
effective against: aerobic gram neg orgs
stable to beta-lactamases
but many resistance gram neg strains now with ESBLs to break down aztreonam

IV or IM injection only

Front 38

Beta-Lacatamase Inhibitors:

Mech:
used how?

Back 38

suicide inactivators of beta-lactamases

given in conjunction with beta-lactam antibiotics

*not all beta-lactamases inhibited by these

Front 39

Which Beta-Lacatamase Inhibitor is taken orally?

With what antibiotic?

Name the other two Beta-Lacatamase Inhibitors:

Back 39

Clavulanate

Amoxacillin

SulBACTUM and tazoBACTUM -- given via IV

Front 40

Vancomycin:

mech:
cidal/static?

Back 40

inhibits peptidoglycan sythetase: by binding to the carboxyl terminus of D-ala-D-ala

this inhibts polymerization of peptidogylcan following the isoprenyl phosphate lipid carrier bringing it to cell exterior

cidal

Front 41

Vancomycin:

resistance?

Back 41

Major clinical problem

Bacteria change to D-ala-D-xxx (lac/ser) so Vancomycin doesn't bind as well

Front 42

Vancomycin:

spectrum/clinical use:

Absorption/Toxicitiy:

Back 42

Spectrum is narrow: Only Gram positive staph or streptococci

Large size of molecule means it can't penetrate outer membrane of gram negs

use: MRSA infections

PK -- IV, except for Clostridium difficle when it's given orally. oral use results in rapid resistance

not metabolized
Toxicitiy -- hearing loss

Front 43

Metronidazole

Back 43

better choice than vancomycin for C. difficle (pseudomembranous collitis)

Front 44

Bacitracin

mech:
spectrum:
use:
Aborption:

Back 44

binds isoprenyl phosphate lipid carrier to inhibit its dephosphorlyation and re-use

spectrum -- gram positive
use: TOPICAL infections of skin, eye
A -- only topical; not oral, not IV

Front 45

Polimixins:

mech:
spectrum:
cidal/static:

Back 45

Damage cell membrane -- polypeptide cationic detergent puts holes in cell membrane so cytoplasm leaks out

only Gram Neg (gram pos have too thick a cell wall)

cidal

Front 46

Polimixins:

use:
aborption:

Back 46

Pseudomonal infections in ears, eyes by TOPICAL administartion

Front 47

Daptomycin:

mech:
cidal/static:
time frame:

Back 47

lipopeptide inserts tail into cell membrane causing Ca dependent cell membrane depolarization, K ion efflux.

cidal w/ rapid action

Front 48

Daptomycin:

spectrum:
clinical:

Back 48

Only Gram POSTIVE (in gram neg gets stuck in 2nd membrane)

use: VRE, MRSA (resistant bugs)
Restricted Drug
Used for serious skin infections

Front 49

Daptomycin:

resistance:
Absorption:

Back 49

no resistance yet

IV once a day (8 hr half life)

Front 50

Daptomycin:

if you increase dose of this then...

if you take someone off this drug then...

Back 50

you increase killing of cells -- Concentration Dependent activity

it has post-antibiotic effects -- even after its out of your system, it helps

Front 51

Polimixins vs. Daptomycin

Back 51

Gram Neg vs. Gram Pos

polypeptide vs. lipopeptide

topical vs. IV

Front 52

Colistin

Back 52

type of polimixins given via IV