8-10 Beta lactams (Cell wall synthesis) Flashcards
1
Q
Which are the beta lactams?
A
- Penicillins
-
Monobactams
- beta-lactamase resistant
- Cephalosporins
-
Carbapenems
- High resistance to beta-lactamases
-
beta-lactamase inhibitors
- Inhibit a lot of b-lactamases
2
Q
Which are the common characteristics of beta-lactams?
A
- May induce hypersensitivity (Penicillin allergy is the most common)
- May induce seizures (dose has to adjust to renal function!)
- Lack of activity against:
- Intracellular bacteria
- MRSA (except Ceftaroline)
3
Q
What are the mechanisms of action of beta-lactam resistance?
A
- The resistance of penicillin may arise due to mutations in the active site of transpeptidase enzyme.
- Production of b-lactamase that destroys the b-lactam ring
- BL – with narrow spectrum - hydrolysis penicillins (Staph. Haemophillus, E. coli)
- ESBL – extended spectrum beta-lactamase hydrolyses penicillins and cephalosporins (E. coli, Kleibsiella)
- AmpCBL – Pseudomonas aeruginosa
- metalloBL – hydrolysis carbapenems
- Altered PBP that prevents the binding of penicillin
- Production of b-lactamase that destroys the b-lactam ring
- Decreased penetration that prevent the entry of penicillin in the bacterium cell
- Some gram (-) bacteria may produce efflux pump
- Multidrug efflux pumps traverse both the inner and outer membranes of gram negative bacteria.
4
Q
What are the advantages and disadvantages of beta lactams?
A
Advantages of b__-lactams:
- Bactericidal agents with broad spectrum (bacteriostatic against enterococci)
- Good penetration
- Synergistic effect with aminoglycosides
- Non-toxic drugs
- Provides a wide scale of derivatives with diverse antimicrobial activity and kinetic properties
Disadvantages of b__-lactams:
- Gaps in antimicrobial spectrum: MRSA, intracellular pathogens
- Increasing bacterial resistance
- Hypersensitive reactions
- Some of them are expensive
5
Q
Whar are the penicillins? Mechanism of action?
A
- b-lactam antibiotics that are produced by fungal specimens originally
- All cell-wall synthesis inhibitors are bactericidal!!!!!!!!
Mechanisms of action:
- Bacterial cell wall is a cross-linked polymer of polysaccharides and pentapeptides
- Penicillins bind cytoplasmic penicillin-binding proteins (PBPs) ==> inhibit transpeptidation reactions involved in cross-linking, the final steps in cell-wall synthesis ==> ø cell wall synthesis
- Bacteria produce degradative enzymes, autolysins, that participate in the normal remodeling of the cells wall. When penicillin is present, the degradative action of autolysins is not stopped ==> cell lysis (bactericidal effect)
6
Q
Which are the mechanisms of resistance of penicillins? What are the general considerations of penicillins?
A
Mechanisms of resistance:
- b-lactamases break lactam ring structure (e.g. staphylococci)
- Structural change in PBPs (e.g. methicillin-resistant Staphylococcus aureus [MRSA], penicillin-resistant pneumococci)
- Change in porin structure (e.g. Pseudomonas)
General considerations:
- Activity increases if used in combination with b-lactamase inhibitors (clavulanic acid, sulbactam)
- They are suicide inhibitors: Metabolism of a substrate by an enzyme to form a compound that irreversibly inhibits that enzyme.
- Synergy with aminoglycosides against pseudomonal and enterococcal species
7
Q
What are the pharmacokinetics of penicillins?
What inhibits tubular secretion?
A
Pharmacokinetics:
- GI absorption of the acid-stable derivatives is rapid (except amoxicillin, it is impaired by food)
- The extent of binding to serum albumin vary from 20 to 97 %
- They are largely confined to the extracellular compartment
-
Tissue distribution:
- In many tissues, near to serum level
- Poor penetration into the eye, prostate (ampicillins are the only ones that can go to the biliary system)
- In CSF, less than 3 % of serum concentration, inflammation enhances penetration
- Intracellular concentration is insignificant
-
Elimination:
- Kidney (tubular secretion)
- Tubular secretion may be blocked by probenecid
- Elimination half-lives are very short (30-80min)
- All are given 3-4 times a day except penicillin G, 6x/day.
- Kidney (tubular secretion)
- They are the safest compounds in pregnancy
8
Q
What are the adverse effects of penicillins?
A
-
Hypersensitivity reactions:
- In ~5% of patients and ranges from rashes to angioedema and anaphylaxis
- Cross-allergic reactions occur among the b-lactam antibiotics
-
Diarrhea:
- Dysbacteriosis: disruption of the intestinal flora causes this (only gram (-) bacteria)
- Usually occurs with ampicillin per os
- Dysbacteriosis: disruption of the intestinal flora causes this (only gram (-) bacteria)
- Nephritis
-
Neurotoxicity:
- In very high dose ==> seizures
- Neutropenia
9
Q
Which are the basic penicillins and their spectrum?
A
- Penicillin G (parenteral)
- Penicillin V
- Penamecillin
Narrow spectrum,* *b**-lactamase sensitive:
- S. Pyogenes (tonsillitis, erysipelas, toxic shock syndrome, endocarditis, etc.)
- Spirochete infections
- Syphilis (treponema pallidum), lyme disease (Borrelia burgdorferi), leptospira
- Anaerobic gram (+): Actinomyces
- Obligate aerobe gram (+) rods (Anthrax, Clostridia)
- Fusobacterium
- N. Gonorrhea
- Pasteurella multocida
10
Q
Which are the antistaphylococcal penicillins and their spectrum?
A
-
Methicillin
- Not used anymore. MRSA
- Nafcillin
- Oxacillin
- Cloxacillin
- Dicloxacillin
- Flucloxacillin
Very narrow spectrum,* *b**-lactamase resistant:
- b-lactamase producing staphylococci
11
Q
Which are the aminopenicillins?
Spectrum?
Pharmacokinetics?
Indications?
Adverse effects?
A
- Ampicillin
- Amoxicillin
Broad spectrum* *b**-lactamase sensitive: same as for the basic penicillins +
- Enterobacteriacea (against shigella only ampicillin)
- H. influenza
- Listeria monocytogenes
- S. Agalactiae
- Pneumococcus (resistance)
- Enterococcus (high resistance)
- H. pylori (in combination)
- DON’T ACT AGAINST PSEUDOMONAS
Pharmacokinetics:
- Weak/medium bioavailability for aminopenicillin
- Good bioavailability for amoxicillin
Indications:
- Upper respiratory, ENT infections:
- Tonsillitis, pharyngitis, laryngitis, rhinitis, sinusitis, otitis media (first drug of choice in acute otitis)
- Lower respiratory infections:
- Acute and chronic bronchitis; pneumonia (except intracellular)
- Urinary infections:
- Cystitis, urethritis, pyelonephritis
- Biliary infections (ampicillin)
- Pregnancy bacteriuria
- Dental practice
Adverse effects:
- Dysbacteriosis
- Ampicillin rash
12
Q
Whcih are the anti-pseudomonal penicillins and their indications?
A
Only parenteral
-
Carboxypenicillins
- Ticarcillin (spectrum includes P. Aeruginosa)
-
Ureidopenicillins:
- Piperacillin (broad spectrum including P. Aeruginosa, Klebsiella pneumoniae)
Indication:
- Severe pneumonia
- Complicated urinary infections
- Complicated intra-abdominal infections
- Complicated skin and soft tissue infections (including diabetic food)
13
Q
What is the classification scheme of cephalosporins? Common characteristics? Mechanisms of action and resistance?
A
Classification scheme: According to “generations”
- Gram (+) activity is decreased while gram (-) activity is increased as one progresses from first to third generation cephalosporins.
- Tissue penetration improves from first to third generation cephalosporins.
Common characteristics:
- Closely related to penicillins structurally and functionally
- Higher b-lactamase resistance (however ESBL inactivates)
- Lower risk of allergy
- No effect against enterococci, weak effect against anaerobes
Mechanisms of action and resistance:
- Identical to penicillins
14
Q
What are the pharmacokinetics and adverse effects of cephalosporins?
A
Pharmacokinetics:
- Renal clearance similar to penicillins, with active tubular secretion blocked by probenecid
- Dose modification in renal dysfunction
- Ceftriaxone is largely eliminated in the bile
Adverse effects:
- Hypersensitivity reactions
- Neutropenia, anemia
- Dysbacteriosis, pseudomembranous colitis
- Pseudocholelithiasis (ceftriaxon)
- Cephalosporins (cefamandol, cefotetan, cefoperazon)
- May cause hypoprothrombinemia and bleeding disorders (K vitamin may prevent it)
- Ethanol intolerance: Some compounds inhibit acetaldehyde dehydrogenase ==> acetaldehyde intoxication in the body ==> dyspnea, vomiting, tachycardia, cardiac problems, …
15
Q
Which are the 1st generation cephalosporins?
Spectrum?
Pharmacokinetics?
Clinical uses?
A
Spectrum:
- Same as the basic penicillins
- Staphylococci, non-enterococcal streptococci, E. coli
- Week gram (-), b-lactamase stability
Pharmacokinetics:
- Cefazolin: elimination half-life 2h
- Don’t enter CNS
Clinical use:
- Mild community acquired RTI (respiratory tract infection), uncomplicated UTI
- Surgical prophylaxis (non-abdominal) staph infections (endocarditis, bacteremia)
- The least toxic drugs against b-lactamase producing E. Coli or K. pneumoniae
16
Q
Which are the 2nd generation cephalosporins?
Spectrum?
Pharmacokinetics?
Clinical use?
A
Spectrum:
- Same as amino + lactamase inhibitors (less active against anaerobes and Listeria!!)
- gram (-) rods, including some anaerobes
-
Cefoxitin:
- Activity against anaerobes (B. fragilis), but not so active against H. influenza
-
Cefuroxime:
- H. Influenza, pneumococci
Pharmacokinetics:
- Cefamandol penetrates into the bile
- Don’t enter CNS except Cefuroxime
Clinical use:
- Mild and moderately severe community acquired and nosocomial infections
17
Q
Which are the 3rd generation cephalosporins?
Spectrum?
Indication?
Pharmacokinetics?
Subtypes?
A
Spectrum:
- Gram (-) cocci and rods, but less active against gram (+) cocci
- Cefoperazone, ceftazidime: pseudomonas aeruginosa
- Ceftriaxone, cefotaxime: streptococcus pneumonia
- Ceftriaxone: Neisseria Gonorrhea
Indication:
- Upper and low RTI
- UTI
- Cefixime also in biliary infections
- Frequently used in pediatric practice
Pharmacokinetics:
- Excellent penetration, enters CNS
- Generally short half-life (1-2 hours)
- Ceftriaxone: metabolized in the liver
- Long elimination half-life (7-8 hours);
- Cefoperazone: excreted in the bile (60-80 %)
1st subtype:
- Good gram (-) spectrum, good CNS penetration, no activity against Pseudomonas
- Cefotaxime - short half-life
- Ceftriaxone – 40-60 % elimination via bile, long
-
Indication:
- Meningitis (not Listeria)
- Severe urinary infection
- Biliary infection
- Abdominal infections (together with metronidazole)
- Gonorrhea
2nd subtype:
- Good against Pseudomonas aeruginosa
- They might be effective in nosocomial gram (-) infection
- Ceftazidime: weak gram (+) spectrum
- Cefoperazone: more effective against gram (+), does not penetrate into the brain
-
Indication:
- Nosocomial infections (respiratory, biliary, abdominal, meningitis, urinary, skin and soft tissue)
- Prophylactic treatment before abdominal surgery
20
Q
Which are the carbapenem drugs?
(According to generations)
A
