Antibacterials Pt. 2 Flashcards
General Mechanisms of Action Aminoglycosides: Tetracycline and Chloramphenicol: Chloramphenicol: Erythromycin and Clindamycin:
Aminoglycosides: Premature release of ribosome from mRNA - misreading of mRNA
Tetracycline and Chloramphenicol: Prevent tRNA from binding
Chloramphenicol: Blocks peptide bond formation
Erythromycin and Clindamycin: Block translocation step
Aminoglycosides
Gentamicin
Tobramycin
Amikacin
Tetracyclines
Doxycycline
Minocycline
Tigecycline (Glycycline)
Macrolides
Erythromycin
Clarithromycin
Azithromycin
Oxazilidinones
Linezolid
Aminoglycosides - General Properties
Bactericidal or Static?
Administration:
Mechanism:
Bactericidal
Administration: IV, IM, topical
Mechanism: Transported into bacteria by energy requiring aerobic process
- Binds to several ribosomal sites (30S/50S interface)
- Stops initiation and causes premature release of ribosome
- Causes mRNA misreading
Uses of Aminoglycosides
Primarily for gram-neg. ‘aerobic’ bacilli (Often in combination with cell wall inhibitors or quinolones) - synergism
Poor activity against anaerobes
Gram positive activity requires drug combinations
- Cell wall inhibitors enhance permeability of aminoglycosides
Use restricted to serious infections (due to side effects)
Why don’t you mix aminoglycosides with β-lactams in vitro?
Chemical reaction inactivates the aminoglycosides
Post antibiotic effect of aminoglycosides
Sustained activity for several hours after aminoglycoside concentration has dropped below effective levels
- Concentration dependent killing
Less frequent dosing
Problem: Toxicity is dose-related
When do you use amikacin?
Choice agent for gentamicin and tobramycin -resistant strains
Aminoglycosides side effects
Narrow therapeutic window
Nephrotoxicity (usually reversible)
Ototoxicity (mostly irreversible)
Nueromuscular blockade
Tetracyclines: Mechanism
Bacteriostatic
Transported into the cells by protein carrier system
Prevent attachment of aminoacyl-tRNA bind to 30S ribosomal subunits
Tetracycline Resistance
Drug efflux pump
- Resistance to one tetracycline often implies resistance to them all
Uses of Tetracyclines (no longer broad spectrum)
Preferred agents for “unusual” bugs
- Rickettsia
- Lyme Disease
- Chlamydia, Mycoplasma, Ureaplasma
Doxycycline
Uses:
Half Life:
Uses: For patients with impaired renal function; alternative for PenG-sensitive syphilis and uncomplicated N. gonorrhoeae
Half Life: 24 hours
Minocycline
Uses:
Half Life:
Uses: Alternative for PenG-sensitive syphilis and uncomplicated gonorrhea
Half Life: 11-26 hours
Tetracyclines Administration:
What slows absorption?
Oral, Parenteral
Binds calcium which inhibits absorption
- Tetracycline > minocycline > doxycycline
- Do not take with high-calcium foods
Side effects of Tetracyclines
Gastrointestinal disturbances including enterocolitis Candida superinfection in coon Photosensitization with rash Teeth discoloration - Avoid use in children <8 years old - Contraindicated in pregnancy
Tigecycline (New drug class - Glycylcyclines)
Mechanism:
Resistance:
Mechanism: Bacteriostatic; like tetracyclines but also binds additional sites in the ribosomes
Resistance: No cross resistance with other antibacterials including tetracyclines
Tigecycline Uses:
Gram negatives:
Gram Positives:
Anaerobes:
- Skin/Skin structure infections
- Complicated intra-abdominal infections
- CAP (community-acquired pneumonia)
Gram negatives: E. Coli, Citrobacter, Klebsiella, Enterobacter (NOT pseudomonas)
Gram Positives: Staphylococcus (MSSA and MRSA), Streptococcus
Anaerobes: Bacteroides, Clostridium Perfringens
Tigecycline
Administration:
Adverse reactions:
Administration: IV only (does not inhibit P450s)
Adverse reactions: Nausea, vomiting (35%), enterocolitis
- Other side effects similar to tetracylines including calcium binding
- FDA alert: increased risk of DEATH
Chloramphenicol
Mechanism:
Resistance:
Mechanism: Interferes with binding of aminoacyl-tRNA to 50S ribosomal subunit and inhibits peptide bond formation
Resistance: Acetylation by CAT (chloramphenicol transacetylase)
Chloramphenicol
Spectrum of activity:
Broad
- Aerobes and anaerobes
- Gram-pos. and gram-neg.
- Including Bacteroides fragilis
Chloramphenicol - Current Indications
Meningitis - alternative for those with serious cephalosporin allergy (N. Meningitidis, S. Pneumoniae)
Brain abscesses (often anaerobes)
H. Influenzae
Salmonella Typhi/Invasive salmonella infections
* Generally bacteriostatic
Chloramphenicol - Side Effects
Bone Marrow Depression - Fatal aplastic anemia (1 in 30,000)
Grey baby syndrome
Optic Neuritis and Blindness
GI effects including enterocolitis
Macrolides
Drugs:
Mechanism:
Drugs: Erythromycin; Clarithromycin; Azithromycin
Mechanism: Bacteriostatic - binds to 50S subunit, blocks translocation along ribosomes
Erythromycin - Uses
Primarily against gram positive
- Streptococcus - Recommended for Strep. throat in penicillin-allergic patients
- Some Staph
Also effective against “unusual” or “atypical” bugs:
- Chlamydia, Mycoplasma
- Legionella (azithromycin now preferred)
- Bordetella
Erythromycin - Side Effects
Nausea, vomiting (20-40%) - from enhance GI motility
Inhibits CYP3A4 metabolism/excretion of many drugs
Increases risk of arrythmias and cardiac arrest (doubles the risk on its own)
Clarithromycin
Mechanism:
Differences from Erythromycin:
Mechanism: Similar to erythromycin Differences from Erythromycin: - Better kinetics: less frequent dosing - Less GI motility effects (50% less) - Somewhat wider antibacterial spectrum * Also some CV risk
Clarithromycin Uses:
3 drug combo:
Same as erythromycin plus: - Haemophilus influenzae, Moraxella - Penicillin-resistant Strep. pneumoniae - Atypical mycobacteria - Lycensed for Helicobacter pylori 3 drug combo: 2 antibacterials: clarithromycin + amoxicillin + acid blocker
FDA-approved treatments for Helicobacter eradication
1) Clarithromycin + amoxicillin + omeprazole
2) Metronidazole + tetracyline + bismuth subsalicylate + PPI
- combinations are more effective than single antibiotic
Azithromycin - Uses
- Very common for outpatient respiratory tract infections
- Genital infections (chlamydia)
- Gonorrhea (CDC recommends ceftriaxone + azithromycin or doxycycline)
Macrolides Adverse Reactions:
Erythromycin > Clarithromycin > Azithromycin
Azithromycin has few effects on CYP3A4
- QT prolongation
Clindamycin
Mechanism:
Binds to 50S ribosomal subunit, locks translocation along ribosomes
- Significant cause of enterocolitis
Clindamycin Uses
Gram Pos. cocci (Strep and MSSA)
- NOT for enterococcus or hospital acquired MRSA
- Suppresses bacterial toxin production (Strep. and Staph.)
Many anaerobes including Bacteroides fragilis
- NOT FOR C. DIFFICILE!!
Clindamycin side effects
GI irritation, Diarrhea (about 20%)
Antibiotic-associated enterocolitis (3-5%)
Hepatotoxicity
Linezolid
Mechanism:
Bacteriostatic
- Inhibits protein synthesis
- Binds to 50S ribosomal subunit, interfering with formation of 70S initiation complex
Linezolid Uses
Skin infections:
Nosocomial pneumonia:
Gram positive spectrum Skin infections - VRE: vancomycin resistant Enterococcus faecium - Staph Aureus - Streptococcus, group. A and B Nosocomial pneumonia - Strep. Pneumoniae - Staphylococcus
Linezolid Side effects
Non selective inhibitor of MAO - Avoid foods with tyramin - Possible drug interactions Diarrhea, superinfection including enterocolitis Headache, nausea/vomiting Bone marrow suppression
Anti-folates
Drugs:
Sulfonamides: Sulfamethoxazole, Sulfadiazine
Trimethoprim
Sulfonamides
Mechanism of Action:
Bacteriostatic
Competitive analogs of p-aminobenzoic acid, a precursor in folate synthesis
Sulfonamide - Uses
Today, most commonly used sulfonamides are combined with other antibacterials
Which sulfonamide is used with trimethoprim and why?
Sulfamethoxazole (synergistic combination)
Best pharmacokinetic match to trimethoprim (proper ratio)
Silver sulfadiazine use
Used topically for infection in burn patients
Sulfonamides - Side Effects
Hypersensitivity - Rashes, serum sickness (sunlight UV makes rash worse) GI disturbances Renal damage (crystalluria) Potentiate action of other drugs - Inhibit CYP2C9
Trimethoprim
Mechanism:
Inhibits folate synthesis in bacteria by competitively inhibiting dihydrofolate reductase
- Dihydrofolate analog
Trimethoprim Uses:
TMP/SMX combination:
Usually in combination with sulfamethoxazole:
- Synergistic effect
- 2 static drugs = 1 cidal combination
TMP/SMX combination:
- First choice therapy for uncomplicated UTIs
- Upper respiratory tract ear infections (H. influenzae, Moraxella, Strep. pneumoniae)
- GI infections (Salmonella, Shigella)
- Pneumocystis jiroveci - 1st choice treatment and prophylaxis
TMP/SMX side effects
All of the other sulfonamide side effects
Trimethoprim adds:
- Nausea, vomiting, diarrhea, rashes
- Bone marrow suppression
* side effects especially pronounced with long-term use (AIDS)
Drug selection Prophylactic: Empiric: Pathogen-directed: Susceptibility-guided:
Prophylactic: Based on predominant flora at site of interest
Empiric: Which drugs have good activity against most common pathogens
Pathogen-directed: Which drugs likely target this pathogen
Susceptibility-guided: susceptibility results
Empiric Diagnosis: Diagnostic Steps
1) Obtain culture/diagnostic tests
2) Empiric therapy
3) Diagnostic results - sensitivity profile
4) Modify therapy as needed
5) Cure
Once common use of empiric therapy
Uncomplicated cystitis in nonpregnant women
- 1st choice: TMP-SMX
Reasons for Antibacterial Failures
Drug Choice - Susceptibility of pathogen - Site of infection Host Factors - Do abscesses need draining - Immune response OK - Are there foreign bodies, implants, mechanical devices, indwelling lines
Widespread overuse of antibacterials has led to…
- Large numbers of antibiotic resistant strains
- Ever-increasing need for new drugs
- > 50% of us carry multiply-resistant strains
CDC 2013 - Urgent threats
C. Difficile
- Rapid increase in hypertoxigenic strains assoc. with antibacterial use
N. gonorrhoeae
- Ceftriaxone is the only agent left (use with either doxycycline or azithromycin)
Carbapenem-resistant Enterbacteriaceae
- Resistant to most drugs including carbapenems
CDC 2013 - Serious threats
Multi-drug resistant Acinetobacter Multi-drug resistant Pseudomonas Aeruginosa Drug-resistant Campylobacter ESBL gram negs (extended-spectrum β-lactamases) Salmonella/Salmonella Typhi Strep Pneumoniae VRE (Vancomycin-resistant Enterococcus) MRSA
Drugs for MRSA
Hospital-acquired:
Community-acquired:
Hospital-acquired: - Vancomycin - Linezolid - Daptomycin - Tigecycline Community-acquired: - Linezolid - Doxycycline, minocycline - Clindamycin - TMP-SMX
