Respiratory System- Cell Wall Synthesis Inhibitors By Boy Bridges

Front 1

Respiratory System- Cell Wall Synthesis Inhibitors by Boy Bridges

Back 1

Respiratory System- Cell Wall Synthesis Inhibitors by Boy Bridges

Front 2

How do Beta-lactams work?

Back 2

1.They bind to Penicillin Binding Proteins (PBP)
2.PBP is unable to crosslink peptidoglycan chains
3.Bacteria are unable to synthesize a stable cell wall
4.Weakened cell wall leads to lysis of bacteria from osmotic pressure

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Name the Penicillins

Back 3

penicillin G
penicillin V

Front 4

Antistaphylococcal penicillins

Back 4

nafcillin
oxacillin
cloxacillin
dicloxacillin
methicillin

Front 5

Extended-spectrum penicillins

Back 5

ampicillin
amoxicillin

Front 6

Antipseudomonal penicillins

Back 6

ticarcillin
piperacillin

Front 7

Cephalosporins: First Generation

Back 7

Cephalexin
Cefazolin

Front 8

Cephalosporins: Second Generation

Back 8

Cefoxitin
Cefaclor
Cefprozil

Front 9

Cephalosporins: Third Generation

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Ceftriaxone
Ceftazidime
Cefotaxime
Cefdinir

Front 10

Cephalosporins: 4th generation

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Cefepime

Front 11

Carbapenems

Back 11

Imipenem (+ cilastatin)

Front 12

Monobactams

Back 12

Aztreonam

Front 13

Beta-lactamase inhibitors

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Clavulanic acid
Sulbactam
Tazobactam

Front 14

Other cell wall/membrane inhibitors

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Vancomycin
Bacitracin

Front 15

What's that important structure of the Gram positive cell wall that we'll pay attention to?

Back 15

The thick homogeneous sheath of peptidoglycan (aka murein).
-peptide cross-links predominate
-includes teichoic acid and lipoteichoic acid
--functions in cell wall maintenance and enlargement during cell division; move cations across the cell envelope; stimulate a specific immune response
-gives the cell wall rigidity against osmotic pressure.
-drugs prevent this cross-link from forming

Front 16

What's so important about the alanine-alanine?

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it's important for the mechanism of action as well as resistance for drugs.

We first need to change the naturally occurring L-alanine to an unnaturally occurring D-alanine

Front 17

What are the 3 stages of cell wall synthesis?

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Stage 1: occurs in cytoplasm – provides building blocks
Stage 2: occurs as building blocks pass through the plasma membrane
3rd stage: Occurs outside the plasma membrane and involves cross-linking of peptidylglycan strands

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What does vancomycin do?

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binds (recognizes) to the ala-ala and prevents the cross-links from forming. since the ala-ala has this huge drug on it now, the enzymes used to form the peptide and sugar cross-links can't get in there.

a target-directed mechanism of resistance is here, when the bacteria changes the last amino acid from an alanine to something else, so vancomycin won't recognize it anymore.

Front 19

What does bacitracin do?

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prevents the membrane-bound carrier protein (bactoprenol) from recycling

Front 20

What combines 2 amino acids?

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a transpeptidase, a penicillin binding protein. so if you inhibit this PBP, you prevent those amino acid chains from joining together, the cell gets weak from lack of cross-links, and it lyses. this is how penicillin, cephalosporin, etc work.

Front 21

How does penicillin work specifically.

Back 21

since penicillin is structurally similar to to alanine-alanine, the transpeptidase will bind to THIS instead of the real ala-ala. this is in comparison to the vancomycin which binds to ala-ala.

Front 22

What do beta-lactams do?

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-beta-lactams block transpeptidation step …block cross linking of peptidylglycan chains

-All beta-lactam antibiotics bind to PBPs and inhibit cell wall synthesis

Front 23

Describe PBPs (penicillin-binding proteins aka transpeptidases)

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There are a large number of different PBPs

Usually several types in each organism

Can be membrane-bound or cytoplasmic

Have diverse functions:
--catalyze transpeptidase reaction
--maintain shape
--form septums during division
--inhibit autolytic enzymes

Front 24

Beta-lactams are _____-dependent killers.

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Beta-lactams are …“time-dependent” killers
-Effect is directly proportional to amount of TIME the drug concentration at the site of infection is ABOVE the MIC of the organism

Front 25

You want the drug concentration at the site of infection to always...

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be above the MIC between doses


*adding more drug won't kill more bug. massively increasing the amount of drug at the same length of time has no effect on efficacy. it's time-dependent. not concentration dependent.

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What are the 4 beta-lactams?

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Pencillins
Cephalosporins
Monobactams
Carbapenems

*all share a similar structure. there's a beta- lactam bond between the carboxy and the nitrogen, and this is what the bacteria attacks, and what needs to be in tact for bacterial activity (need that 4-membered ring)

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What's the R side chain?

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determines spectrum of antibacterial activity and pharmacological properties (e.g., affinity for PBP, resistance to penicillinase, ability to penetrate G- outer membrane, resistance to stomach acid, PK)

Front 28

General properties of penicillins

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-A beta-lactam antibiotic
-Prevent cell wall synthesis leading to lysis of the cell
-All are bactericidal

Front 29

Pen G vs Pen V

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Pen G
-acid labile
-poor oral bioavailability

Pen V
more stable in acid
-so “better” oral availability
Remember: V is not IV

Front 30

When to use a penicillin G and why?

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Always consider using a penicillin if …
-the organism is susceptible
-can reach the site of infection
-the patient is not ALLERGIC

Because:
-of the low costs
-of the low toxicity and large TI

Front 31

What do we use Pen G against?

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Pen G (narrow spectrum)
-mostly gram positives  (both cocci and rods)
-a few gram negatives (like Neisseriae meningococci and gonococci)
-some anaerobes and spirochetes (syphilis)

There is acquired resistance for staph a (>90%), strep (5%), most neisseria gonococci

Front 32

Pen G has a wide body distribution, but where doesn't it go?

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since the concentrations in fluids and tissues differ widely, pharmacological sanctuaries exist in the:
-prostate
-ocular
-CSF (BBB..except during inflammation or meningitis where there's a loss of BBB integrity)

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What't the halflife like for Pen G, and how can it be altered?

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… short t1/2 (30 min)
Quickly eliminated by renal tubular secretion active transport pump

Probenecid can slow the process
-blocks renal tubular secretion of penicillin
-it is a competitive inhibitor
-rarely used for this purpose anymore

Front 34

What is procaine and benzathine used for?

Back 34

so you don't turn your pt into a pin cushion (decrease injection frequency)

taken IM, there is a slow release from the injection site, yields low but prolonged drug levels, and they are also known as repository penicillins

*works because penicillin is a time-dependent drug.

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Adverse Effects of Penicillin G

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-Lowest toxicity potential of all antimicrobials

-Allergic (hypersensitivity) Reactions
--Most common adverse effect
--Most commonly reported medication allergy
-----self-reported by at least 10% of patients
-----~85 - 90 % are NOT allergic & able to tolerate penicillins
-----Can be any of the 4 types of Gell and Coombs hypersensitivity reactions

-Manifest with a wide range of symptoms
From rash … to anaphylaxis (pretty rare)

Front 36

Tell me, what is Penicilloic Acid?

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Penicilloic acid
-breakdown product of pen G
-acts as a hapten
-the major determinant
--at least 25% due to other minor metabolites

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Does skin testing always identify an allergic patient?

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No, sir. Skin testing MIGHT identify an allergic patient. The kit may recognize only a particular hapten, so the patient may actually be allergic to a minor metabolite that the kit does not recognize.

*cross-sensitivity with other penicillins

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What are the non-allergic adverse effects of Penicillin G?

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Diarrhea and GI intolerance

NEUROTOXICITY
-Most likely at high concentrations (intrathecal admin or renal failure)
Increased CNS activity … SEIZURES

Superinfections
-more common with broad spectrum agents (e.g. cephlasporins)

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talk about Penicillin G resistance

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Many G- are resistant (Pen G can’t get in)

Penicillinase production: most common resistance component ( G+ & G- )

Cell lysis cascade not activated (autolysis)
certain strep, staph, listeria

Mycoplasma don’t have cell walls (no target)

For some, transpeptidases are mutated
Beta-lactams can’t bind to target (MRSA)

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What are the two types of beta-lactamase resistance?

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Chromosome encoded
-characteristic of entire species
-synthesis may be inducible in the presence of antibiotic

Plasmid encoded
-characteristic of an individual strain rather than the species
-constitutively expressed
-most mediate resistance to penicillins and 1st & 2nd generation cephalosporins

Front 41

Where are beta-lactamases for gram positives and gram negatives?

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The attack point is the beta lactam ring ... which is essential for PBP binding ... and antimicrobial effects

In gram positives they are:
-Secreted to outside of cell wall
-Produced in high concentration in some
-Primarily plasmid (R) factor transmitted

In gram negatives they are:
-In periplasmic space and high concentrations

Front 42

What can ESBLs hydrolyze?

Back 42

Extended Spectrum Beta Lactamases
Efficiently hydrolyze:
Penicillins
Cephalosporins (capable of cleaving later generations)
Monobactams (aztreonam)
Note: the beta-lactamases we noted previously DO NOT typically cleave later-generation cephalosporins and aztreonam (that’s why they were developed)

Primarily seen in gram negative bacilli

Klebsiella pneumoniae and E coli
most common ESBL producers but many others demonstrated

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What are our MSSA drugs of choice?

Back 43

For Methicillin-Sensitive Staphylococcus Aureus, we shall use oxacillin and nafcillin (but won't work against MRSA because the target is alterned)

Resistant to breakdown by b-lactamase
-Contains bulky side chain
-doesn’t fit into b-lactamase active site

Extends their spectrum to include b-lactamase producing staphylococci

Front 44

Adverse effects of oxacillin and nafcillin?

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Adverse effects similar to Pen G

BUT ... this group may cause:
-blood dyscrasias (agranulocytosis)
-acute interstitial nephritis
-hepatotoxicity (oxacillin only)

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Which are the extended spectrum penicillins?

Back 45

ampicillin and amoxicillin

Penetrate gram negatives more readily, so often used for G- infections
E coli, N. meningitidis

Broad spectrum
-Not effective against beta-lactamase producers
-Beta-lactamase inhibitors extend spectrum

Administered by most routes but ....
-Amoxicillin has better bioavailability than Amp
-Amox: one of the oral pens that food does not interfere with absorption

Front 46

What do we use these extended spectrum penicillins?

Back 46

HELPSS:
H influenzae, E. coli, Listeria sp., Proteus, Salmonella, Shigella (Amp)

Clinical uses include things such as:
-Pneumonia, UTIs, Otitis, Sinusitis
-Ampicillin is frequently used (synergistic) with an aminoglycoside (Gentamycin) for broad range coverage in serious infections
-Ampicillin is DOC for Listeria meningitis

Front 47

Synergy between antibiotics

Back 47

Single agents:
bacteriostatic or not effective

Drug combination:
bactericidal


*also can give extended coverage

Front 48

What are the antipseudomonal penicillins

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ticarcillin and puperacillin

Sensitive to b-lactamase breakdown
-b-lactamase inhibitors may be added to extend spectrum

Spectrum is similar to that of ampicillin but extends to include other gram negatives
-Spectrum is Pen G + HELPSS + Pseudomonas*, Klebsiella, and Serratia

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Clinical Uses of Ticarcillin & Piperacillin

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Due to the ease of resistance emergence with Pseudomonas
-These agents are often used in combination with an aminoglycoside ...

Clinical uses:
-Useful in a wide range of infections like pneumonia, UTIs, peritonitis
-Often used in immunocompromised pts

Piperacillin – broadest spectrum of the penicillins when used in combo with b-lactamase inhibitor (tazobactam)

Front 50

Adverse Effects of Ticarcillin & Piperacillin

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Adverse effects ... like that of Pen G but …
-Superinfection more likely
-Can potentiate aminoglycoside-associated nephrotoxicity
-Sodium overload potential
--Look out for pts with CHF or renal insufficiency
--Parenteral preps contain sodium

Front 51

Resistance and antipseudomonal penicillins...

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Since they act on both G+ & G- ... more resistance mechanisms may be involved

Gram positive mechanisms
-beta lactamases outside cell wall
-changes in PBP (target)

Gram negative mechanisms
-Change in entry through porins
-Beta lactamases (periplasmic space)
-Efflux pump

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As you go up in generations, the effectiveness of cephalosporins against gram negatives...

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increases.

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As you go up in generations, the effect of cephalosporins on gram positives...

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decreases.

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General Properties of cephalosporins

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-Mechanism of action same as penicillins … bactericidal
-Kinetics determined by R groups (different generations) … some orally effective
-Most drugs eliminated by kidneys … a few are more dependent on metabolism
-Spectrum … generally like ampicillin (G+ & HELPSS) ... but varies with generation
-Not active against enterococcus or MRSA

Front 55

Cephalosporin resistance

Back 55

Resistance – similar to penicillins
-Penicillinases and cephalosporinases
-In general … cephs are more resistant to breakdown by these enzymes
--Klebsiella, E Coli, Pseudomonas, Enterobacter, (ESBL can breakdown penicillins & cephs)

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Cephalosporins Adverse effects

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ALLERGIC reactions
-Cephs < pens; Some cross-sensitivity (~10%)

Some unique AEs (generation specific)

Superinfections – cephs account for large % of reported cases (due to very frequent use)

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Clinical indications of cephalosporins

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Can be useful alternative for penicillin allergic patients (if mildly allergic)

Often the greatest expenditures of hospital pharmacy (especially 3rd generation)

Frequently used for surgical prophylaxis (especially 1st generation)

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Cephalosporin generalizations

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-Gram negative coverage 3>2>1
-Gram positive coverage 1>2>3
-All are more resistant to b-lactamases than penicillins (all act on MSSA)
--Resistance to beta lactamases increase from 1st to 4th generation
-Half-life increases with generation (3>2>1)
-Renal elimination but 1>2>3
-CSF entry almost exclusively 3rd & 4th gen

*there are lots of exceptions

Front 59

Hypoprothrombinemia

Back 59

cephalosporin adverse effect:
Coagulation abnormalities
Disturbs synthesis of vitamin K-dependent clotting factors

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Alcohol intolerance

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CephalosporinsAdverse Effects:
disulfiram-like reaction
Disulfiram is an agent that inhibits alcohol dehydrogenase, causing an increase of acetaldehyde, the agent that causes hangovers

Due to methylthiotetrazole (MTT) group
Cefotetan (2nd generation)
Cefoperazone (3rd generation)

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Primary use for 1st generation cephalosporins

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-UTIs caused by Klebsiella and Pen/sulf resistant organisms

-staphylococcal or streptococcal infections; cellulitis or soft tissue infections
-PO: not for serious systemic infections
-Alternative for pts allergic to antistaphylococcal penicillins (eg oxacillin, nafcillin)


-Prophylaxis of surgical procedures (CEFAZOLIN)

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Primary use for 2nd generation cephalosporins

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UTIs,
soft tissue infections,
bone infections,
surgical prophylaxis

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Primary use for 3rd generation cephalosporins

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Nosocomial G- infections ... often in combination with AGs

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1st Generation Cephalosporins

Back 64

Kinetics similar to penicillin
Orally active
Short half-life and never crosses the BBB (can’t be used for bacterial meningitis)
very active against G+  plus Proteus, E. coli, Klebsiella (Pen G + PEcK)
Not effective against ... MRSA, enterococcus or pseudomonas

Front 65

What is the drug of choice for surgical phrophylaxis?

Back 65

cefazolin

Front 66

Adverse effects of first generation

Back 66

-Generally pretty safe
-Adverse effects similar to pens
-~ 1-10% cross-allergenicity with pens
-Blood dyscrasias
--neutropenia, thrombocytopenia, hypoprothrombinemia
(admin Vit K1)

Front 67

Kinetics of 2nd generation of cephalosporins

Back 67

Elimination half-life longer than 1st gen

All renally eliminated

Do not achieve adequate levels in CSF (don't cross BBB)

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Generalizations of 2nd generation cephalosporins

Back 68

-Like 1st generation … plus extended G- coverage
less effective on G+ more effective on G-
--G+ + H. influenza, Enterobacter, Neisseria, Proteus, E. coli, Klebsiella
--(G+ HEN PEcK)

-No activity against ... enterococci, MRSA, or pseudomonas

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Clinical use of 2nd generation cephalosporins

Back 69

Primarily used to treat
-sinusitis, bronchitis, otitis media
-lower respiratory tract infections
-mixed anaerobic infectionseg, peritonitis or diverticulitis
-surgical prophylaxis (no advantage over 1st gen)
-Lyme disease
-Gonorrhea

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Adverse effects of 2nd gen cephalosporins

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-Allergic reactions
-Blood dyscrasias (anemia, eosinophilia)
-Pseudomembranous colitis (a superinfection)

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What are the backbones of alternating sugars?

Back 71

N-acetylglucosamine- NAG
N-acetylmuramic acid- NAM

the amino acids hang below this.
a bridge of glycines connects adjacent amino acid chains

Front 72

What are some characteristics of 3rd generation cephalosporins?

Back 72

-mostly given parenterally
-readily cross the BBB
-longer half life
-excretion eliminated renally (except cetriaxone which is biliary)
-less effective on gram pos
-more effective on gram neg (pseudomonas, klebsiella DOC, e.coli DOC)

Front 73

are 3rd generation cephalosporins the DOC for gonorrhea and lyme disease?

Back 73

yeah.

Front 74

So what's the difference between 3rd and 4th generation?

Back 74

not much. 4th just has a wider spectrum, and more resistant to beta-lactamases.

more effective against pseudomonas, staph a, strep pneumo, haemophilus, and neisseria

Front 75

What's an important point that we should know about imipenem?

Back 75

it's bactericidal to almost all bacteria (but it's not a good DOC for a lot of things)

Front 76

What is the MoA of imipenem?

Back 76

similar to pens and cephs (binds to penicillin binding protein to prevent crosslinking)

-also it has a significant post anitbody effect (PAE). The lingering effect after the drug is dropped below the minimal inhibitory concentration.

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What's the primary use of imipenem?

Back 77

organisms resistant to other antimicrobials (eg extended spectrum beta lactamase-producing microbes)

-so you use this when all the other drugs aren't working, so it's not usually a DOC.

-empiric treatment of serious nosocomial and mixed infections caused by MDR aerobic and anaerobic enteric bacilli.

Front 78

What are the clinical uses of imipenem?

Back 78

mixed infections (on those pts on other antimicrobials, and the immunocompromised)

gram neg pneumonia and bacteremia, complicated UTIs, serious infections by pseudomonas

Front 79

ok, so imipenem is the DOC for what

Back 79

enterobacter infections

Front 80

what is cilastatin

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cilastatin inhibits the dipeptidase enzyme that slows down the breakdown (metabolism) of the imipenem (in the kidney) so it can achieve therapeutic concentrations.

this is necessary because imipenem usually has a short half life when broken down in the kidney

*this has nothing to do with blocking excretion. it's about blocking metabolism.

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what do you take with imipenem to fight against pseudomonas resistance?

Back 81

aminoglycoside

Front 82

What are the adverse effects of imipenem?

Back 82

-NVD most common
-seizures (especially if CNS lesions present or renal insufficiency)
-hypersensitivity (< 3%)
--cross reactive with pens

Front 83

What is the magic bullet for gram negatives?

Back 83

monobactams (aztreonam)

-same mechanism of action as other beta-lactams, but only binds to a PBP present in gram negatives

Front 84

are monobactams an alternative to aminiglycosides?

Back 84

yeah. the spectrum more closely resembles AGs.

Front 85

other monobactam details...

Back 85

-high degree of resistance to beta-lactamses (ie penicillinases and cephalosporinases)
-active against many MDR strains
-used for tx of serious g- infections
-no cross sensitivity with pens or cephs (use in allergic pts)

Front 86

and that's it for cell wall synthesis inhibitors

Back 86

now onto beta lactamase inhibitors and the 'others' and we're done

Front 87

so what does clavulanic acid do?

Back 87

prevents the breakdown of amoxacillin (for example) by competing for its binding with beta-lactamase (which wants to break it down). clavulanic acid has little to no antimicrobial effect, so it doesn't compete with amox for that, but it will keep amox from being broken down by beta lactamases, by inactivating it.

-it looks like penicillin and irreversibly binds to beta lactamase.

Front 88

are beta lactamases inhibitors active against plasmid-encoded beta lactamases?

Back 88

yeah. including enzymes active against ceftazidime and cefotaxime (3rd gen)

-but generally do not inhibit chromosomal beta-lactamases (induced in g- bacilli by 2nd and 3rd gen ceph)

Front 89

what is the only oral prep beta lactamase inhibitor combo?

Back 89

amoxicillin and clavulanic acid

Front 90

What does vancomycin do?

Back 90

binds tightly to alanine-alanine end of peptidoglycan pentapeptide
-inhibits transglycosylase
--prevents building block bound to phospholipid carrier from binding to growing peptidylglycan chain

*binds to ala-ala and prevents NAG and NAM from going into the cell wall

Front 91

so vancomycin is bactericidal, yeah?

Back 91

yes, but it's not a beta lactam.

-it's for oral use only to treat GI infections like colitis and enterocolitis

-otherwise it's given parenterally.

Front 92

is vancomycin good for gram+ or gram-?

Back 92

gram positives only.

-use limited to SERIOUS infections (MRSA drug of choice, enterococci, clostidium difficile alt choice)

Front 93

what is the DOC for pseudomembranous colitis?

Back 93

metronidazole. vancomycin is the alternative.

this is from an overgrowth of clostridium difficile.

Front 94

adverse effects of vancomycin?

Back 94

-ototoxiticity
-nephrotoxicity
-EXTREME FLUSHING with RAPID INFUSION
(red man or red neck syndrome, histamine release though not allergic (direct toxic effect on mast cells))

Front 95

What are the drug interactions of vancomycin?

Back 95

synergistic effects with aminoglycosides
--increased antimicrobial effects (enhances uptake of aminoglycosides)

Front 96

What type of bacteria is bacitracin good for?

Back 96

gram positives. once again, it's bactericidal, but not a beta lactam.

topical only (bc very nephrotoxic)

Front 97

what is the MoA of bacitracin?

Back 97

interferes with REGENERATION of membrane phospholipid carrier (bactoprenol)