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Questions and Answers
What is the mechanism of action of vancomycin?
binds to the terminal end of the growing peptidoglycan to prevent further elongation and cross-linking
Which bacteria are carbapenems powerful against?
Aztreonam is resistant to Beta-lactamases.
True
What is the main purpose of empiric therapy when selecting anti-microbial agents?
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Which factor affects the penetration of drugs to the Central Nervous System through the Blood-Brain Barrier?
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Penicillins inhibit bacterial growth by preventing the cross-linking of peptidoglycan polymers.
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The _____________ of beta-lactam ring is required for the antibacterial activity of penicillins.
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What type of bacteria are synthetic penicillins useful for treating?
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What is the major cause of resistance to penicillins?
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Which component irreversibly inhibits beta-lactamase and is used in combination products with penicillins?
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Cephalosporins have the same mechanism of action as penicillins.
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Synthitc pencilin are inactivated by ________.
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Match the following cephalosporin generations with their typical uses:
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Study Notes
Selection of Antimicrobial Agents
- Defining the organism: Culture, Detection of antigens, PCR, Detection of microbial DNA or RNA, Detection of immune response
Empiric Therapy
- In critically ill patients: Use broad-spectrum antimicrobial agents
- In settings where it is hard to get a sensitivity test: Use antimicrobial agents that are usually effective in such situations
Prophylaxis Therapy
- Prevent rather than treat an infection
- Directed against the most likely organism
- Examples of situations:
- Pharingitis: Rheumatic heart disease
- Endocarditis: GABHS
- Before dental extraction: GABHS
- Tuberculosis in contact
- Pre-surgery (GI, urinary sys): Infection afterward gram -ve rods
- Anti-HIV: Prevents transmission
About the Anti-Microbial Agent
- Bacteriostatic vs. Bactericidal: Division is important
- Penetration to the site of infection: Lipid solubility, Molecular weight, Binding to plasma proteins
- Efficacy: Dose, Route of administration, Duration of treatment
- Safety: Less side effects
About the Patient
- Immune status: HIV, DM, Immunosuppressants, Alcohol, etc.
- Antagonistic effect: Bacterecidal + Bacteriostatic
Resistance to Antimicrobial Agents
- Inherited Resistance
- Acquired Resistance: Genetic alterations, Decreased accumulation, Enzymatic inactivation
Complications of Antimicrobial Agents
- Hypersensitivity: Simple hives to anaphylaxis
- Direct toxicity
- Superinfection
Classification of Antimicrobial Agents
- Inhibitors of bacterial cell wall biosynthesis
- Inhibitors of bacterial protein synthesis
- Inhibitors of bacterial metabolism
- Inhibitors of bacterial nucleic acid synthesis
- Inhibit cell membrane function
Inhibitors of Bacterial Cell Wall Biosynthesis
- Penicillins
- Natural penicillins (G, V)
- Synthetic penicillins:
- Antistaphylococcal (penicillinase resistant)
- Extended spectrum
- Antipseudomonal
- Cephalosporins
- Carbapenemes
- Monobactams
- Others: Vancomycin
Beta-Lactam Ring
- Unstable: Degraded by beta-lactamase
- Inactivation: Penicillin-binding proteins (PBPs) involved in cell wall synthesis
Inhibitors of Bacterial Cell Wall Biosynthesis (Continued)
- Mechanism of action: Bind to, and inactivate, penicillin-binding proteins (PBPs) involved in cell wall synthesis
- Spectrum: Gram-positive bacteria with thick external cell walls are particularly susceptible
- Absorption: Rapidly absorbed after enteral administration
- Penetrate the cerebrospinal fluid (CSF) and ocular fluid to a significant extent during inflammation
Natural Penicillins
- Penicillin G: Mainly used to treat infections with the following organisms:
- Gram-positive cocci: Pneumococci (Streptococcus pneumoniae), streptococci
- Gram-positive rods: Bacillus species (B. anthracis)
- Gram-negative cocci: Gonococci and meningococci
- Anaerobes: Most, except Bacteroides fragilis
- Other: Treponema pallidum (syphilis) and Leptospira spp
Synthetic Penicillins
- Penicillinase-resistant penicillins:
- Oxacillin
- Dicloxacillin
- Methicillin
- Nafcillin
- Extended-spectrum penicillins:
- Ampicillin
- Amoxicillin
- Anti-pseudomonas agents:
- Piperacillin
- Ticarcillin
Beta-Lactamase Inhibitors
- Clavulanic acid
- Sulbactam
- Tazobactam
- Used in combination products: Amoxicillin/clavulanic acid (Augmentin), Ticarcillin/clavulanic acid (Timentin)
Cephalosporins
- Structure and mechanism of action: Similar to penicillins
- Pharmacokinetic properties: Widely distributed in body fluids, some penetrate the CSF
- Categorized by antibacterial spectrum: First-generation, Second-generation, Third-generation, Fourth-generation
- First-generation cephalosporins:
- Cephalexin
- Cefazolin
- Cefadroxil
- Uses: Urinary tract infections, Prophylactic in various surgical procedures### Cephalosporins
- Second-generation cephalosporins:
- Include: Cefoxitin, Cefuroxime, Cefotetan, and Cefaclor
- Have a broader spectrum of activity than first-generation drugs
- Used to treat streptococcal infections, H. influenzae, Enterobacter aerogens, Nisseria, Proteus, E. coli, and Klebsiella (HENPECK)
- Decreased activity against gram-positive bacteria (S. epidermidis not covered)
- Uses of second-generation cephalosporins:
- Urinary tract infections (E. coli)
- Respiratory tract infections
- Bone and soft-tissue infections
- Prophylactically in various surgical procedures
- Have been largely replaced by third-generation agents
- Except for cefuroxime, these agents do not penetrate the CSF
Third-generation cephalosporins
- Include:
- Cefdinir (oral)
- Cefixime (oral)
- Cefotaxime (Claforan IV)
- Ceftizoxime (IV)
- Cefoperazone (IV)
- Ceftazidime (Fortum IV)
- Ceftriaxone (Rocephin IV)
- Characteristics:
- Enhanced activity against gram-negative organisms
- Active against H. influenzae, N. gonorrhoeae, N. meningitides, Enterobacter, Salmonella, indole-positive Proteus, and E. coli
- Moderate activity against anaerobes
- Sensitive to cephalosporinase (a β-lactamase)
- Uses of third-generation cephalosporins:
- Empiric therapy for community-acquired meningitis
- Sexually transmitted infections caused by N. gonorrhoeae
- Serious hospital-acquired gram-negative infections, alone or in combination with an aminoglycoside
Fourth-generation cephalosporins
- Cefepime:
- Given IV
- Has powerful coverage against Pseudomonas spp, gram-negative bacteria, and gram-positive staph and strep
Fifth-generation cephalosporins
- Ceftaroline:
- Given IV
- Used to treat community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI)
Adverse effects and drug interactions
- Cephalosporins:
- May cause hypersensitivity reactions (2-5%)
- 5-10% of penicillin-sensitive individuals are also hypersensitive to cephalosporins
- Ceftriaxone:
- May cause bleeding disorders, which can be prevented by vitamin K administration
- Nephrotoxic when administered with diuretics
- All cephalosporins are eliminated by the kidney (except ceftriaxone), and dose adjustment should be considered in patients with renal insufficiency
- May cause superinfection with gram-positive organisms or fungi
- Carbapenems:
- Relatively resistant to β-lactamases
- Demonstrate no cross-resistance with other antibiotics
- Useful for infections caused by penicillinase-producing S. aureus, E. coli, Klebsiella spp., Enterobacter spp., and H. influenzae
- Can cause nausea, vomiting, diarrhea, and skin rashes, and at higher doses, seizures (particularly for imipenem)
Monobactam
- Aztreonam:
- Lacks the thiazolidine ring, making it highly resistant to β-lactamases
- Has good activity against gram-negative organisms
- Lacks activity against anaerobes and gram-positive organisms
- Useful for various infections caused by E. coli, P. aeruginosa, and Enterobacter spp.
- Has no cross-reactivity with penicillins or cephalosporins for hypersensitivity reactions
Other inhibitors of bacterial cell wall biosynthesis
- Vancomycin:
- Mechanism of action: binds to the terminal end of the growing peptidoglycan to prevent further elongation and cross-linking
- Active against gram-positive organisms
- Resistant strains have been reported
- Used to prevent infection with MRSA in patients undergoing prosthetic implantation, and for patients allergic to penicillins and cephalosporins
- Penetrates CSF only during inflammation
- Side effects: fever, chills, flushing, and phlebitis
- Daptomycin:
- Binds to and depolarizes the cell membrane, resulting in loss of membrane potential and rapid cell death
- Has antibacterial actions similar to those of vancomycin
- Active against MRSA and vancomycin-resistant enterococci (VRE)
- Used for complicated skin infections and endocarditis
- Inactivated by lung surfactant; never used in pneumonia
- Telavancin:
- Derivative of vancomycin
- Mechanism of action: similar to vancomycin (cell wall) + disruption of cell membrane (similar to daptomycin)
- Used to treat complicated skin infections caused by resistant gram-positive organisms
- Not active against vancomycin-resistant enterococci (VRE)
- Side effects: metallic taste, N/V, insomnia, headache, and foamy urine
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Description
This quiz covers the selection of anti-microbial agents, including defining the organism through culture and detection of antigens. It is part of the pharmacology course at the Faculty of Medicine & Health Sciences, An-Najah National University.
