8-10 Beta lactams (Cell wall synthesis)

Question 1

Which are the beta lactams?

Answer 1

• Penicillins
• Monobactams
  
  • beta-lactamase resistant
• Cephalosporins
• Carbapenems
  
  • High resistance to beta-lactamases
• beta-lactamase inhibitors
  
  • Inhibit a lot of b-lactamases

Question 2

Which are the common characteristics of beta-lactams?

Answer 2

• 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)

Question 3

What are the mechanisms of action of beta-lactam resistance?

Answer 3

• 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
• 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.

Question 4

What are the advantages and disadvantages of beta lactams?

Answer 4

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

Question 5

Whar are the penicillins? Mechanism of action?

Answer 5

• 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)

Question 6

Which are the mechanisms of resistance of penicillins? What are the general considerations of penicillins?

Answer 6

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

Question 7

What are the pharmacokinetics of penicillins?

What inhibits tubular secretion?

Answer 7

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.
• They are the safest compounds in pregnancy

Question 8

What are the adverse effects of penicillins?

Answer 8

• 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
• Nephritis
• Neurotoxicity:
  
  • In very high dose ==> seizures
• Neutropenia

Question 9

Which are the basic penicillins and their spectrum?

Answer 9

• 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

Question 10

Which are the antistaphylococcal penicillins and their spectrum?

Answer 10

• Methicillin
  
  • Not used anymore. MRSA
• Nafcillin
• Oxacillin
• Cloxacillin
• Dicloxacillin
• Flucloxacillin

Very narrow spectrum,* *b**-lactamase resistant:

• b-lactamase producing staphylococci

Question 11

Which are the aminopenicillins?

Spectrum?

Pharmacokinetics?

Indications?

Adverse effects?

Answer 11

• 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

Question 12

Whcih are the anti-pseudomonal penicillins and their indications?

Answer 12

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)

Question 13

What is the classification scheme of cephalosporins? Common characteristics? Mechanisms of action and resistance?

Answer 13

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

Question 14

What are the pharmacokinetics and adverse effects of cephalosporins?

Answer 14

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, …

Question 15

Which are the 1st generation cephalosporins?

Spectrum?

Pharmacokinetics?

Clinical uses?

Answer 15

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

Question 16

Which are the 2nd generation cephalosporins?

Spectrum?

Pharmacokinetics?

Clinical use?

Answer 16

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

Question 17

Which are the 3rd generation cephalosporins?

Spectrum?

Indication?

Pharmacokinetics?

Subtypes?

Answer 17

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 %)

1^st 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

2^nd 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

Question 18

Which are the 4th generation cephalosporins?

Answer 18

• Parenteral, infusion

Cefepime:

• Antibacterial spectrum: broad spectrum
• Enhanced b-lactamase stability
• Good activity against staphylococci

Ceftolozon (+ tazobactam):

• Antibacterial spectrum: broad spectrum, but not active against MRSA/E and Enterococci
• Indication:
  
  • Complicated intraabdominal and urinary infections

Question 19

Which are the 5th generation cephalosporins?

Answer 19

Ceftaroline fosamil:

• Spectrum: MRSA/E, broad gram (-) activity
• Indication:
  
  • Complicated skin and soft tissue infection, nosocomial pneumonia

Question 20

Which are the carbapenem drugs?

(According to generations)

Answer 20

Question 21

About Carbapenems…

Spectrum?

Mechanism of resistance?

Pharmacokinetics?

Adverse effects?

Answer 21

Overview:

• They are synthetic b-lactam antibiotics that differ in structure from the penicillins

Spectrum:

• Very good spectrum
• Gram (+) and (-) bacteria, including Pseudomonas Aeruginosa
• Penicillin resistant pneumococci
• Enterococcus faecalis (only imipenem), B. fragilis, anaerobes
• No activity against MRSA/MRSE, Clostridium difficile, Enterococcus faecium

Mechanism of resistance – changes in permeability, efflux:

• Resistance develops more frequently towards the non-fermentating gram (-) bacteria (e.g. Pseudomonas aeruginosa, Acinetobacter), than towards other bacteria

Pharmacokinetics:

• Long post-antibiotic effect (PAE)
• Excellent tissue penetration, including CNS (except biliary tract)
• Elimination via kidney
• Administration
  
  • Only parenteral
    
    • Ertapenem – long half-life, 1x/day
    • Imipenem is given with cilastatin (a dihydropeptidase inhibitor) to prevent inactivation as half-life is very short (3-4 times/day)

Adverse effects:

• Pseudomembranous colitis
• Allergy, seizures when imipenem is in high dose (imipenem not recommended in meningitis)
  
  • Lower incidence of seizures with doripenem

Question 22

Which are the monobactams?

Answer 22

Drugs:

• Aztreonam
  
  • Enters CNS
  • Parenteral

Spectrum:

• Only gram (-) spectrum (may act against resistant Pseudomonas Aeruginosa)
• Stable to many BLs, except AmpCBL and ESBL

Clinical usage:

• Nosocomial infections (pneumonia, sepsis, meningitis)

Allergy:

• It can be given to penicillin allergic patient skin rash, GI symptoms only

Question 23

Which are the beta-lactamse inhibitors?

Answer 23

• Clavulanic acid, sulbactam, tazobactam
  
  • Fixed combination of beta-lactam and beta-lactam inhibitor that prevent the splitting of beta-lactam ring assuring good activity against the beta-lactamase producer bacteria.
• Fixed combinations:
  
  • Amoxicillin – clavulanic acid
  • Ampicillin – Sulbactam
  • Piperacillin – Tazobactam
  • (Sultamicillin: ampicillin/sulbactam)