Lecture 38 & 41 - Intro to Anti-Microbials + Cell Envelope Anti-Microbials Flashcards by Benjamin Bloom

Name the 2 Folate Anti-Metabolites

Sulfonamides

Trimethoprim

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Sulfonamide:
Common Agent
Mechanism

Common Agent: Sulfamethoxazol

Mechanism: Analogous structure to PABA.
Inhibition of Dihydropteroate Synthetase

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Trimethoprim:

Mechanism

Inhibition of DIhydrofolate Reductase

Bacteriostatic when used alone

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TMP-SMX

What is it?
Spectrum/Clinical uses?
Is it bacterostatic or bacterocidal

Combination of Trimpethoprime + Sulfamethoxazole (1:5 ratio)

Spectrum:
-GN (but NOT pseudomonas)
- GP: Staphylococci;
Most Enterococci are resistant

Uses: UTI, GI, Respiratory

Bactericidal with Excellent Bioavailbility

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TMP-SMX: Adverse Events

Drug interactions

All abx: alteration of the micro-biota
Common: Rash, Nausea, Vom, HA
Uncommon: Hyperkalemia, hepatitis, pancreatitis
Rare: Steven’s Johnson, aplastic anemia, thrombocytopoenia,

Drug Interxn: Displaces warfarin and Pehytoi from Albumin

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Name the Classes of abx that are “DNA inhibitors”

Quinolones, Fluoroquinolones

- Nitrofurantoin

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Quinolones, Fluoroquinolones:
- Common Agents and their Mechanisms

Adverse Effects
Bactericidal or Static?
Resistance Mechanisms for Quinolones

Common Agents:

Ciprofloxacin - DNA Gyrase (topoisomerase II) inhibitor

Moxifloxacin
- Topo II and Topo IV Inhibitor

Stabilization of the Double Stranded DNA breaks – leading to chromosomal fragmentation

Adverse Effects: Overall quite well tolerated

Common: N, V, abd, HA, dizziness
Serious: Prolonged QT Syndrome

Bactericidal

Mutation to the Target: GryA, ParC
Plasmids, Efflux pumps

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Ciprofloxacin: Spectrum and Clinical uses

Moxifloxacin: Spectrum

Cipro Spectrum: GN, Atypicals
Clinical uses: UTIs

Moxi: GN, GP, anaerobic, atypicals
Poor penetration to the GU tract

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Nitrofurantoin -
Mechanism

Clinical Uses:

Adverse Effects:

Mechanism: Unknown damage to the DNA; also binds RNA and interfers with Translation

Clinical Uses: Exclusively Used for UTIs

Adverse Effects: Nausea, Pulmonary Fibrosis with prolonged use

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What abx are considered RNA inhbitors?

Rifamycins: Rifampin, Rifabutin, Rifaximin

Fidaxomicin

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Rifamycins -
Mechanism
Bacteriostatic or Cidal?
Adverse Effects?

Mechanism: Inhibition of RNA Polymerase

Bacteriostatic

GI: N, V, D, abd pain
Heme: Thrombocytopenia, anemia, hepatitis

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Spectrum In General:

Clinical Uses

What is different about Rifaximin

General: Broad Spectrum
- GP, GN, Mycobacterial

Clinical uses: Prophylaxis for N. meningitis, S. Aureus

Rifaximin: Not absorbed; only used GI (enteric) infections

Clinical uses: Traveler’s diarrhea

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Fidaxomicin: 
Mechanism 
Adverse Effects 
What's unique about it? 
Spectrum
Clinical uses

Mechanism: Blocks RNA polymerase; prevents formation of DNA complex

Adverse effects: None

Unique: Non-absorbed;

Spectrum: C. DIff Only; No GNs

Clinical use: Use for C. Diff. Only if relapse after Vanc therapy

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What Abx Classes Attack the Cell-Envelope?

Beta Lactams: PCN and derivatives, Cephalosporins, Carbapenams, Monobactams

Glyocopeptides

Cyclic Lipopeptides

Other (Polymyxins, bacitracin, fosfomycin)

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What is the General mechanism of Beta Lactam Agents

B-lactam ring
Resembles peptide
Mimics terminal D-ala-D-ala of peptidoglycan monomer (pentapeptide)
Penicillin binds to transpeptidases (PBPs) of bacterial cell – now these enzymes not available to from stabilizing cross-links
· Autolysins still break up cell wall – continual remodeling
· Weaker and weaker cell wall
Eventually leads to cell lysis from osmotic pressure – death

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Mechanisms of Resistance Against Beta Lactam Agents?

B-lactamases (inactivate it and break it)
· Enzymes that hydrolyze the beta-lactam ring
Penicillinases, cephalosporinases, carbepenemases
Extended-spectrum beta-lactamases (ESBL)

Modified PBP’s
- MRSA, encoded by mecA gene

Decreased permeability/porins 
· Avoid it – don’t let it in 
Efflux pumps (MDR)
· Avoid it – pump it out

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PCN (General)

Bactericidal or static?
Common Adverse Effects:

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Bactericidal
Adverse Effects:
hypersensitivity: Rash, hives, anaphylaxis, serum sickness, cytopenias, nephritis
Seizures are high doses

PCN (G)
- Spectrum

Clinical uses

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Gram negative: GN cocci only

Gram positive: cocci/anaerobes (good if resistance not present)

Infections caused by Streptococci
Dental abscesses/human bites (GP anaerobe)
Syphilis
IV Only

PCN - SemiSynthetics:
-Common Agents

Mechanism:

Common Resistances: what gene causes this?

Spectrum

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Nafcillin (IV)
Dicloxacillin (PO)
(Methicillin)

Penicillinase-resistant penicillins (pre-MRSA)
· Bulky “R” Group – can’t fit into many b-lactamases
· Still maintain b-lactam ring

Resistance due to altered PBP (new protein PBP2a) encoded by mecA gene
· MRSA

Spectrum:
Gram-positive ONLY
Cannot penetrate Gram-negative (thick OM)

Amino-PCNs
- Common agents

Mechanistic change
Spectrum of Activity

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Ampicillin (IV)
Amoxicillin (PO)

R-group more polar, allows penetration through some Gram-negative porins

GP: Strep and cocci
Some Gram-negative porins:
· H. flu, E. coli
· NOT Pseudomonas

Anti-Pseudomonal penicillins

Common Agents
Resistances
Spectrum of activity:

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Piperacillin (used with tazobactam)
Uses is limited by penicillinases
Never used alone

Spectrum:
GP, but not MRSA
Some GN – Pseudomonas

Beta Lactamase Inhibitors:

what do they do?
Common agents
Spectrum

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Extend the activity of penicillins and overcome much of resistance
Ampicillin – sulbactam
· Adds S. aureus (not MRSA), B-lactamase-producing GN and anaerobes
Amoxicillin – clavulanic acid (augmentin)
· Similar, but PO

Piperacillin-tazobactam
· Adds S. aureus (not MRSA), B-lactamase producing GN and anaerobes (including Pseudomonas)
· Becomes broad spectrum antibiotic

Beta Lactam: Cephalosporins

Common Adverse Effects
General Spectrum

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Common Adverse Effects:
Well tolerated; Some cross re-activity with PCN allergy

Spectrum:
Most have some GP coverage
Gram Negative coverage increases with generations 1 through 4

First Generation Cephalosporins

Common agents
Spectrum
Clinical uses

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Cefazolin (IV)
Cephalexin (PO)

Good Gram + activity

Surgical prophylaxis – prevent infections caused by pathogens at site surgery (i.e. common Strep/Staph get in through skin)
Skin/soft tissue infections (limited/resistance)

S. Pyogens - - Impetigo

Second Generation Cephalosporins - Common Agents: Spectrum Clinical uses

Cefoxitin (IV) Some GP coverage Increased Gram-negative activity Excellent anaerobe activity (rare to see with cephalosporins) Prophylaxis for intra-abdominal surgery · GI tract: want to include Gram – and anaerobes

Third Generation Cephalosporins - Common agents Spectrum which one covers pseudomonas ?

Ceftriaxone, IV (will see a lot) Ceftazidime, IV Excellent GN activity -- but NOT pseudomonas Ceftriaxone: · Community-acquired pneumonia, N. meningitis -- can penetrate the CSF · Many uses, serious infections Ceftazidime · Has activity against pseudomonas

4th Generation Cephalosporins - Common Agents - Resistances - Spectrum

Cefepime, IV only Highly resistant b-lactamases Broad spectrum · Gram-negative (excellent) – including pseudomonas · Gram-positive Serious or resistant infections

5th Generation Cephalosporins - Common agent - what is unique about its coverage ? - Clinical uses

Ceftaroline, IV Overcomes MRSA resistance, binds PBP2a Broad spectrum · Gram positive – only cephalosporin with MRSA activity · Gram negative – some, NOT pseudomonas

Beta Lactam: Carbapenem - Common Agents - Spectrum - what resistances are avoided

Imipenem Meropenem Ertapenem - Resistant to Beta Lactamases ``` VERY BROAD SPECTRUM · Gram negative, including pseudomonas · Gram-positive · Anaerobes Ertapenem – NO activity against Pseudomonas/Acinetobacter ``` Empiric treatment for serious infections Resistant infections

Beta Lactam: MonoBactams - Common Agents; - Spectrum - When is it used?

Aztreonam (IV) Spectrum: GN ONLY (including pseudomonas, but really a last resort) Clinical Uses: Only when there is allergy to other beta lactams

Glycopeptides: Common Agent Mechanism of Action - Mechanism of Resistance Bactericidal or Static ?

Vancomycin ``` Binds to terminal D-ala-D-ala (intermediate in cell wall synthesis) Inhibits transglycosylase (new chains) Inhibits transpeptidase (cross-links) ``` Alteration of binding site · VanA gene (D-ala D-lac can’t bind vancomycin) Bactericidal

Glycopeptide Common Adverse Events? Spectrum? Clinical Uses

Red Man Syndrome - Infusion reaction; Not Hypersensitivity Nephrotoxicity Spectrum: GP ONLY - Staph (including MRSA) - Sterp, Entero, C. diff GNs are intrinsically resistant Empiric therapy for severe infections C. Diff Infection

Cyclin Lipopeptides Common Agent Mechanism Bactericidal or Static

Daptomycin: IV Only Lipophilic tail inserts into cell membrane Membrane depolarization/K+ efflux Cessation of vital processes (i.e. ATP production) Cell death (without lysis) Bactericidal

Cyclin Lipopeptides: - Adverse Events - Spectrum - Clinical Uses

``` GI Distress: Headaches Elevated CPK/rhabodmyolysis · Associated with BID dosing · Clinical/lab monitoring Avoid statins ``` ``` Spectrum: - Gram-positive ONLY · Staphylococci (including MRSA) · Enterococci (including VRE) · GP anaerobes No gram-negative! ``` Clinical uses: Complicated Gram + infections · Skin/soft tissue · Bacteremia/endocarditis

Polymixins: | Common Agents:

Polymyxin B and Colistin Common Adverse Events: Nephrotoxicity; Neurotoxicity; Bronchospams Spectum: GN ONLY used for Pseudomonas Clinical Uses: Serious Resistant GN Infections Inhaled - resistant GN PNA

Bacitracin Fosfomycin

Bacitracin: Topical; GP only Fosfomycin: Oral, UTI only

What drugs are Anti-Pseudomonal?

Piperacillin+tazobactam 3rd generation Cephalosporins 4th Generation cephalosporins Ciprofloxacin Amonoglycosides: Gentimycin, Amikacin Polymixins -- monobactam: aztreonam

For what condition should you never use daptomycin? | why?

Never use daptomycin for PNA Daptomycin is inhibited by pulmonary surfactant

what are the best drugs for MSSA? po iv

po -Dicloxacillin, cephalexin iv - Nafcillin, Cefazolin

What are the best drugs for MRSA? iv po

iv - Linezolid, ceftaroline Vancomycin, Daptomycin -- high grade bacteremia, endovascular infections of bone/joint. ``` po - Clindamycin TMP/SMX Doxycyclin Linezolid ```

Lecture 38 & 41 - Intro to Anti-Microbials + Cell Envelope Anti-Microbials Flashcards

(40 cards)