Lecture 38 & 41 - Intro to Anti-Microbials + Cell Envelope Anti-Microbials Flashcards
Name the 2 Folate Anti-Metabolites
Sulfonamides
Trimethoprim
Sulfonamide:
Common Agent
Mechanism
Common Agent: Sulfamethoxazol
Mechanism: Analogous structure to PABA.
Inhibition of Dihydropteroate Synthetase
Trimethoprim:
Mechanism
Inhibition of DIhydrofolate Reductase
Bacteriostatic when used alone
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
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
Name the Classes of abx that are “DNA inhibitors”
- Quinolones, Fluoroquinolones
- Nitrofurantoin
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
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
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
What abx are considered RNA inhbitors?
Rifamycins: Rifampin, Rifabutin, Rifaximin
Fidaxomicin
Rifamycins -
Mechanism
Bacteriostatic or Cidal?
Adverse Effects?
Mechanism: Inhibition of RNA Polymerase
Bacteriostatic
GI: N, V, D, abd pain
Heme: Thrombocytopenia, anemia, hepatitis
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
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
What Abx Classes Attack the Cell-Envelope?
Beta Lactams: PCN and derivatives, Cephalosporins, Carbapenams, Monobactams
Glyocopeptides
Cyclic Lipopeptides
Other (Polymyxins, bacitracin, fosfomycin)
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
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
PCN (General)
- Bactericidal or static?
- Common Adverse Effects:
- Bactericidal
- Adverse Effects:
hypersensitivity: Rash, hives, anaphylaxis, serum sickness, cytopenias, nephritis - Seizures are high doses
PCN (G)
- Spectrum
- Clinical uses
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
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
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:
- 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
- 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
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
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
